MIMS Doctor October 2017 MY

YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA MALAYSIA OCTOBER 2017
Highlights Managing hyper-

from ESC 2017 and hypothyroidism
& ERS 2017 in primary care
Rivaroxaban + aspirin
reduces atherothrombotic events
in stable CVD MEDICAL PROFESSIONAL COPY
NOT FOR SALE
CONTENTS
MIMS DOCTOR - YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA CEO
Yasunobu Sakai
Vice-President of Marketing Platform

Aundrey Yeoh
Senior Editor
Saras Ramiya
OCTOBER ISSUE
Associate Editor
Pank Jit Sin
Malaysia Focus
6 Bringing integrity, heart into the healthcare equation Contributing Editors
Christina Lau, Jackey Suen, Dr Joseph
Delano Fule Robles, (Hong Kong),
8 Local misconceptions of dengue management a concern Rachel Soon, Dr Joslyn Ngu, (Malaysia),
Elvira Manzano, Audrey Abella, Roshini
Claire Anthony, Pearl Toh, Stephen Padilla
10 New patient handbook on cholesterol aims to debunk myths (Singapore), Jairia Dela Cruz, Elaine
Soliven, Dr Katrina Florcruz (Philippines)
11 Companion animals may be source of disease Designers

Razli Rahman, Tina Ng, Peggy Tio,
Sam Shum
12 NKF offers financial aid for peritoneal dialysis
Production
Raymond Choo, Nurul Farzana
14 Words with the President of Malaysian Society of Hypertension
Circulation Executive
Pauline Hoe
16 Watch out for the raspy breath of IPF
Accounting Manager
Minty Kwan
Advertising Coordinator
Raymond Choo
Published by
MIMS Medica Sdn Bhd
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Quattro West,
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06 12 Advertising Enquiries:
China
Cover Story Yang Xuan
Tel: (8621) 6157 3888
18 Rivaroxaban + aspirin reduces atherothrombotic events in stable CVD Email: enquiry.cn@mims.com
Hong Kong
Conference Coverage Jacqueline Cheung, Polly Lam,
European Society of Cardiology (ESC) Congress 2017, Cecilia Wong, Sigourney Liu
Tel: (852) 2559 5888
August 26-30, Barcelona, Spain Email: enquiry.hk@mims.com
20 Anacetrapib reduces major coronary events in high-risk CVD patients
Indonesia
Ruth Theresia
21 Anti-inflammatory canakinumab reduces CV risk independent of lipid lowering Tel: (62 21) 729 2662
Email: enquiry.id@mims.com
22 Rivaroxaban plus aspirin a potential new treatment option in PAD
23 Routine use of supplemental oxygen does not improve survival in MI patients
AUSTRALIA • MALAYSIA • HONG KONG

INDIA • INDONESIA • CHINA • MYANMAR
NEW ZEALAND • PHILIPPINES • VIETNAM
SINGAPORE • SOUTH KOREA • THAILAND
21 23
1
DOCTOR | OCTOBER ISSUE
CONTENTS
MIMS DOCTOR - YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA India
Monica Bhatia
Tel: (9180) 2349 4644
Email: enquiry.in@mims.com
Korea
Choe Eun Young
Tel: (822) 3019 9350
Email: inquiry@kimsonline.co.kr
OCTOBER ISSUE
Malaysia
24 Blocking PCSK9 synthesis with siRNA shows promise in LDL-C lowering Tiffany Collar, Sumitra Pakry,
Tel: (603) 7623 8000
Email: enquiry.my@mims.com
25 Avoid sildenafil in residual pulmonary hypertension after corrected
valvular heart disease Philippines
Gracia Cruz, Rowena Belgica,
Cyrish Ong, Roan Tandingan, Mike
28 Renal denervation effective for uncontrolled HTN in patients not taking medications Malicsi, Richard Rivera
Tel: (632) 886 0333
Email: enquiry.ph@mims.com
29 Drug-specific effects of NSAIDs on BP may impact CV risk
Singapore
Josephine Cheong, Ronald Ho,
30 Upstream rhythm control superior to conventional therapy for AF Kelvin Sor, Elaine Teo, Brandon Wong,
Shelby Sekar
Tel: (65) 6290 7400
31 Ultra-low LDL-C cuts CV risk with no safety concerns Email: enquiry.sg@mims.com
Thailand
32 Dual antithrombotic therapy an option for AF patients undergoing PCI Nawiya Witayarithipakorn, Auranat A.
Tel: (662) 741 5354
Email: enquiry.th@mims.com
Vietnam
Nguyen Thi Lan Huong,
Nguyen Thi My Dung
Tel: (848) 3829 7923
Email: enquiry.vn@mims.com
28 32
27th International Congress of the European Respiratory Society (ERS 2017),

September 9-13, Milan, Italy
34 Benralizumab impact greater with higher eosinophil count,
frequent exacerbation history
35 Macitentan a promising therapy in inoperable CTEPH
36 BiPAP to CPAP: Is switching safe?
38 Mepolizumab may help reduce exacerbations in eosinophilic COPD

HOW TO CONTACT US
40 Tezepelumab promising for persistent, uncontrolled asthma
To subscribe:
enquiry.my@mims.com
43 Fluticasone furoate + vilanterol superior to usual care in asthma control
To contact the editor:
jitsin.pank@mims.com
To submit an article:
jitsin.pank@mims.com
2nd Floor, West Wing,

Quattro West,
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Selangor, Malaysia
36 38
3
CONTENTS
MIMS DOCTOR - YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA MIMS Doctor is published 12 times a year
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50 61
4
MALAYSIA FOCUS
Bringing integrity, heart into the

healthcare equation
At the heart of every establishment is the core value which drives and dictates the direction
of its business. MIMS Doctor spoke to Michelle Erwee, general manager of Takeda Vietnam.
Malaysia and Singapore; and Gordon Cameron, vice president of Asia Pacific to find out how
‘Integrity’ has helped shape role and image of the company in the region.
PANK JIT SIN
P
erhaps the most outstand-
ing feature of both Erwee and
Cameron is the passion both
exhibit for their jobs and the company
they work for. This is most telling from
the number of years both have spent
at Takeda building their careers—20
for Cameron and 10 for Erwee. Cam-
eron said: “Takeda spends a lot of ef-
fort on (getting the right people hired)
on an effective devolved model.” He
noted that the emphasis placed by
Takeda on human capital develop-
ment has helped the company to
grow in a wholesome manner.
“People are at the centre of ev-

erything we do,” said Cameron. This
is because the staff is important as across different countries and func- such as leadership development,
they are the ones that will look af- tions, have long-term development performance management, organi-
ter the reputation of the company. programmes and systems in place zational culture, compensation and
Being medium-sized (Takeda has a to help aid an individual succeed. benefits. Currently, women account
worldwide headcount of about 1,600 Furthermore, by identifying gaps, for more than 50 percent of Takeda’s
people) also contributes to the com- they hope to constantly improve and employees, 42 percent of the leader-
pany’s ability to focus on its workers’ equip themselves for the new gener- ship roles and 50 percent of the com-
wellbeing. Cameron said the compa- ation of employees. pany’s board of directors.
ny has a structured programme for
employees which involves two-way This focus on employees is re- Beyond the Mulher certification,
discussions as opposed to the usual flected in several awards bestowed Takeda has also been awarded with
one way management style. upon Takeda, seven of which were Top Employer certification awards
top employer awards. Some of the across 20 countries in their emerg-
The structured programme in- awards Takeda have won include the ing markets category, seven of which
cludes individual development plans ‘Great Place to Work’ Mulher certifi- were in the APAC (Asia-Pacific) re-
Takeda has for employees. These cation which is a recognition of the gion. When asked about her proud-
individual development plans were company’s excellence in promot- est moment in the company, Erwee
developed by Takeda in response to ing women’s access and inclusion said: ”Every day is a proud moment.
meet the needs of employees across in different sectors and providing [It is] how we go about our daily lives.”
a large global organization. In fact, great employee (working) conditions.
the company strives to ensure that Takeda was awarded for putting dif- Being in the APAC brings with
all employees, at different levels and ferential practices into place in areas it many challenges, some of which
6
MALAYSIA FOCUS
”
include the diversity of the region. Er- The company has also set in mo-
wee said they work to constantly find tion changes in its research structure. “... the staff is important
ways for improving access of medi- While research and development
cines to the population in the region used to be centred in Japan and
as they are the ones
while at the same time maintaining Boston, they are increasingly ex- that will look after
the integrity of the company as well panding to other sites by partnership the reputation of the
as the affordability of the medicines. and through the development of new company”
Beyond accessibility, one of the main products. Erwee noted the company
concerns Takeda has is the prop- is now a leader in the gastroenterol-
er usage of its medicines—an issue ogy field, specifically in Crohn’s dis-
which requires proper education and ease and is due to launch an oncolo- Having an independent party
monitoring to address. gy product in 2018. handle the programme ensures ab-
solute transparency and integrity in
A shift in the works Patient access the dispensing of medicines for qual-
In recent times, Takeda has shifted programme ified patients and it also maximizes
and refined their focus. Gordon said During the interview, Gordon and Er- the impact of the programme for the
the company has cleaned up and wee alluded to Takeda’s patient ac- benefit of patients. The independent
fine-tuned their direction, sticking to cess programme (PAP), which is run party determines a patient’s suitabil-
four main specialties: oncology, spe- by a third-party, independent body. ity, and economical standing then
cialty gastrointestinal, central nervous The PAP helps patients by providing decides the amount of help or sub-
system and vaccines. support in terms of medicines and is sidy, in terms of medicines, to offer
handled on a case-by-case basis. the patient.
LATEST FA 01_Tramada_Mims Doctor Oct 2017.pdf 1 9/14/2017 4:08:17 PM
7
MALAYSIA FOCUS
Local misconceptions of dengue

management a concern
RACHEL SOON
D
espite the prevalence of den-
gue fever in Malaysia, a large
proportion of the local popu-
lation may still lack basic knowledge
regarding management of the dis-
ease, says a recent survey.
According to the South-East Asia

(SEA) Dengue survey, commissioned
by GlaxoSmithKline (GSK) Consumer
Healthcare, up to 70 percent of Ma-
laysians believe that antibiotics are [L–R:] Dr Ravindran Naidu (president, Malaysian Medical Association), Heather Pelier (Southeast
effective against dengue fever, while a Asia Area marketing director, GSK Consumer Healthcare), Bharati Suresh Chand (vice president,
Malaysian Pharmaceutical Society), Associate Professor Dr Yeong Siew Wei (deputy vice chan-
similar proportion believe that a cure cellor, UCSI University) and Christina Low (marketing director, Guardian Health and Beauty Sdn
exists for the disease. Sixty-eight per- Bhd).
cent were unaware that paracetamol
was the only WHO-recommended marily drawn from cities, with 80 president, speaking at the event. “For
medication for symptomatic treat- percent of participants hailing from example, it is of great importance to
ment of fever associated with den- urban areas (100 percent in the case be aware that a diagnosis of dengue
gue, while only 49 percent of Malay- of Singapore). fever can be made on the first day of
sians surveyed felt confident in their infection with a simple needle prick.”
knowledge of dengue symptoms. New public and private
allies in anti-dengue Known as the fastest-spread-
“The majority of Malaysians coalition ing vector-borne viral disease in
surveyed report taking proactive In conjunction with the release of the world, almost 40 percent of the
measures to help prevent dengue, the survey results, it was announced world’s population is estimated to be
but when the fever strikes, we feel that Allied Against Dengue (AAD), a at risk of dengue; South East Asia
uncertain about how to recognize joint initiative to address education- carries the largest regional burden
the symptoms, the steps to take to al needs of dengue management from the disease, with over 2.9 million
manage the disease, and most im- in South-east Asia, had added new people affected annually.
portantly, how to find out this crucial partners to the existing coalition;
information,” said Heather Pelier, UCSI University Malaysia, Caring “When considering the signifi-
South East Asia marketing director at Pharmacy Group Berhad, Apex cance of disease understanding and
GSK Consumer Healthcare. “This un- Pharmacy Marketing, and MIMS perceptions, empowerment is the
certainty illustrates that the need for Health Today. Initial partners include best tool to combat dengue,” said
education has become greater than the Malaysian Medical Association, Bharati Suresh Chand, vice presi-
ever, to ensure that Malaysians are Malaysian Pharmaceutical Society, dent of the Malaysian Pharmaceu-
equipped with both the confidence Guardian Health & Beauty Sdn Bhd tical Society. “Through successful
and knowledge to tackle dengue.” and GSK Consumer Healthcare. collaboration with our new partners,
and the ever-growing support from
The survey involved 3,000 partici- “The Malaysian Medical Asso- healthcare providers, industry lead-
pants aged 18 years and above, with ciation (MMA) is continually seeking ers, NGOs and members of the pub-
500 drawn from each of six ASEAN ways in which patients and health- lic, AAD will continue to intensify our
countries—Indonesia, Malaysia, the care professionals can be empow- public advocacy programme to help
Philippines, Singapore, Thailand and ered with knowledge on [dengue] it- mitigate the impact of dengue on our
Vietnam. Country samples were pri- self,” said Dr Ravindran Naidu, MMA communities.”
8
MALAYSIA FOCUS
New patient handbook on cholesterol aims

to debunk myths
DR JOSLYN NGU line over a qualified medical special- smoking cessation, healthy diet and
A
ist’s advice,” said consultant cardiol- physical activity. Having said that,
novel patient handbook on ogist, Dr Emily Tan. reliance on incorrect information on
cholesterol was launched behavioural changes, which is wide-
by the National Heart Insti- According to the National Health ly available on the Internet, can be
tute and Pfizer Malaysia to improve and Morbidity Survey 2015, nearly 1 harmful, said Dr Vicknesh Welluppil-
awareness and knowledge on cho- in 2 Malaysian adults have hypercho- lai, stakeholder medical lead, Pfizer
lesterol. lesterolemia and the prevalence in- Asia Pacific.
creases with age. [Available at: www.
The handbook aims to encourage iku.gov.my/images/IKU/Document/ The handbook was developed
more discussions between patients REPORT/nhmsreport2015vol2.pdf] via a joint effort between experts in
and doctors on cholesterol manage- The prevalence is higher among the medical field and Pfizer Malay-
ment, said Dato’ Seri Dr Mohd Azhari women compared to men (52.2 vs sia. Both parties hope this collab-
Yakub, Chief Executive Officer of the 43.5 percent). Race may also be a oration will help patients achieve a
National Heart Institute. Additionally, factor to consider as hypercholes- basic-level understanding of choles-
it will help patients distinguish credi- terolemia is more common in Malays terol and its on-going management,
ble information from fake news about and Indians (50.1 percent) compared said Vicknesh. With the launch of
cholesterol, and provide them with with Chinese (47.5 percent). this handbook, the right information
facts on cholesterol and its manage- will be easily available. Hopefully, this
ment. Hypercholesterolemia is a risk will contribute to better discussion
factor for non-communicable diseas- between patients and their doctors,
With health information easily ac- es (NCDs); an increased prevalence improve patient adherence and aid
cessible to patients via internet and of hypercholesterolemia indicates an the general population in discerning
social media, it is crucial to ensure increase in NCDs. As such, it is timely the right and wrong information on
patients have at least a basic under- to have a concerted effort centred to cholesterol.
standing and knowledge about cho- improve awareness and understand-
lesterol so they can discern the facts ing about cholesterol and its man- Azhari, Tan and Vicknesh were
from myths. “I have nothing against agement, said Azhari. speaking at the launch of the pa-
searching online for information, but tient handbook titled All You Need
it is a bother when patients prefer to Most NCDs can be prevented to Know About Cholesterol, held in
trust the information they obtain on- via behavioural changes such as Kuala Lumpur recently.
10
MALAYSIA FOCUS
Companion animals may be source of

disease
PANK JIT SIN
A
nimals such as cats and dogs
are increasingly being brought
into homes and bedrooms as
companion animals, thereby increas-
ing the risk of animal-human cross
infection, say a panel of experts.
Speaking at a media roundtable

in conjunction with the World Associ-
ation for the Advancement of Veteri-
nary Parasitology 2017 Conference,
founding members of the Tropical
Council for Companion Animal Par-
asites (TroCCAP) called for improved
protection of pets from parasites. [L–R:] Dr Robert Mencke, Associate Professor Rebecca Traub, Dr Felipe Dantas-Torres and Dr
These parasites include the likes of Tawin Inpankeaw
fleas, ticks and worms and proper

prophylaxis against these organisms Dr Tawin Inpankeaw, council er has long been engaging with the
are key to mitigating the risk of zoo- member of TroCCAP, said the trop- scientific and veterinary community
noses. ics, with its warmer climate and en- around the world to advance knowl-
hanced parasite life cycle, require edge and research in parasitology,
According to Associate Professor specifically developed parasite pre- zoonotic and vector-borne diseas-
Rebecca Traub, director and execu- vention protocols in order to effec- es.“ He also noted that keeping our-
tive secretary of TroCCAP, cats and tively mitigate the infection risk to all selves healthy requires us to ensure
dogs are increasingly considered animals, including those that serve as our companion animals are healthy
to be part of the family and in close companions. “Dogs and cats in the as well.
proximity with people. Many mental tropics need to be protected from
and physical benefits can be gained ticks, fleas and heartworm all year Zoonoses is a two-way
from keeping companion animals but round, unlike temperate countries road
by bringing these animals into our where the risk of infection is season- While we like to think that animals
homes, new precautions need to be al,” said Inpankeaw. can spread diseases to humans, the
taken to protect the health of both reverse is just as likely to happen.
parties. TroCCAP’s director, Dr Filipe When asked about the risk of blas-
Dantas-Torres, said the guidelines tocystis infection from companion
She said: “This means that ef- for canines is already available on animals, Traub said that according
fectively protecting our pets from the council’s website. Guidelines for to a study conducted on animals in
parasites not only helps keep them felines are also in the works and is a farm, the blastocystis samples in
healthy, but ultimately, it also benefits due to be out in 2018. Malaysia is the the animals were human strains, sug-
our own health.” Traub called for pet first country to launch the TroCCAP gesting they were infected by their
owners to proactively protect their guidelines and it will be rolled out to human companions.
pets by keeping up with their annual other countries in the region soon.
checkups with the veterinarian and Similarly, hookworm infestations
staying up-to-date with vaccinations. The media roundtable was can infect pets and humans in both
Additionally, pets should also be pro- helmed by Dr Norbert Mencke, head directions, thus necessitating proper
vided protection from fleas, ticks and of policy and stakeholder affairs, Bay- hygiene and deworming for owner
worms. er Animal Health. Mencke said: “Bay- and their pets.
11
MALAYSIA FOCUS
NKF offers financial aid for peritoneal

dialysis
DR JOSLYN NGU
I
n conjunction with the 1st Asia Pa-
cific Conference on Acute Kidney
Injury (AKI) and Continuous Renal
Replacement Therapy (CRRT) held
concurrently with the 33rd Annual
Congress of the Malaysian Society
of Nephrology (MSN), the National
Kidney Foundation (NKF) is launching
a new funding program for peritone-
al dialysis (PD) that aims to provide
financial assistance to poor patients
with end stage renal failure (ESRF)
who opt for PD over other therapeu-
tic modalities.
According to 2013 statistics,

around 80 percent of patients under-
going PD were on continuous ambu-
latory peritoneal dialysis (CAPD) and
15 percent on automated peritoneal
dialysis (APD), said board member of
NKF Malaysia, Dr Lee Wan Tin. The
bulk of patients on PD obtain treat- for financially poor patients who opt Additionally, there are criteria for
ment from MOH and university hospi- for CAPD. As for APD, the maximum the referring PD centre for the appli-
tals. However, budgetary constraints monthly subsidy is RM4,000 for cant to be eligible for consideration.
limit the number of patients for that hardcore poor patients and RM3,000 Among them are: the centre has been
treatment option. for financially poor ones. in operation for more than 2 years, is
providing PD therapy to more than 10
Third party payers such as the The subsidy will be provided for a patients and has a designated lead
Public Services Department, PERKE- year, and patients will need to man- clinician in PD who is a qualified ne-
SO, insurance agencies and Pusat ually apply for renewal as there is no phrologist leading a multidisciplinary
Zakat assist with the payment of PD auto-renewal policy, explained Lee. team.
expenses for patients undergoing The application process is similar to
treatment in university hospitals and the application for haemodialysis. At the moment, the NKF has
private medical centres. The NKF Assessment for eligibility will take identified 11 PD centres that are eli-
aids patients who are unable to get around 1 to 2 weeks. gible, namely University Malaya Med-
financial assistance from any other ical Centre, UKM Medical Centre,
sources, he noted. There are various criteria for a pa- Selayang Hospital, Serdang Hospi-
tient to be eligible for consideration, tal, Tunku Ja’afar Hospital, Sarawak
On average, the monthly cost such as being a Malaysian citizen or General Hospital, Miri Hospital, Pen-
of CAPD is RM2,400 to RM2,600, permanent resident, has ESRF and ang General Hospital, Hospital Raja
and RM3,300 to RM4,000 for APD, has been assessed by a qualified ne- Permaisuri Bainun, Queen Elizabeth
said Lee. The NKF’s PD financial aid phrologist as suitable for PD therapy, Hospital and Hospital Tengku Am-
programme will provide a maximum and will receive treatment from a PD puan Afzan. The NKF is continuously
monthly subsidy of up to RM2,600 for centre which meets NKF’s criteria. assessing more centres to determine
hardcore poor patients and RM1,600 their eligibility.
12
MALAYSIA FOCUS
Words with the President of Malaysian

Society of Hypertension
The Malaysian Society of Hypertension was officially formed in 1993 with the Registrar of
Societies with the aim of promoting public education about hypertension. It further aims
to help patients achieve optimum control of hypertension and encourage research and
publication to contribute better care in the management of hypertension in the country.
MIMS Doctor reached out to Datin Dr Chia Yook Chin, president of the Malaysian Society
of Hypertension (MSH), to find out more about the society she helms and the society’s aims
and activities.
inception. As part of its ongoing ef-

fort to educate doctors, Chia said the
society is proactive in bringing edu-
cation to primary care physicians.
She said: “We know it is hard to hold
CME events in small towns so when
we can get 30 to 40 participants, we
will go to them and provide training.
The main thing is to get the mes-
sage out there.” The society tries to
run education programmes at least
twice in a year. These include public
forums—but there is the problem of
the same familiar faces popping up
at every event. Chia said: ”The mes-
sage isn’t getting out to more peo-
ple, as it’s usually the same people
showing up at every public forum.”
O
fficially, the society’s specific choosing generics that work over The MSH partakes in most inter-
objectives are many folds. costlier originators. national health days associated with
The first is to promote ba- hypertension and cardiovascular
sic and clinical studies and to edu- MSH’s fourth objective is to liaise disease. This year, MSH participated
cate doctors and paramedical staff with international bodies which are in the World Salt Awareness Week
regarding hypertension as well as related to hypertension and to or- from 20 to 26 March and also in the
to propagate correct knowledge on ganize educational meetings and to World Hypertension Day 2017 on 17
hypertension. Secondly, the society provide services at local and region- May. Additionally, the International
aims to educate the public and to al levels. MSH’s annual meeting will Society of Hypertension launched
be of service to all persons with hy- be coming soon, in January, 2018 in an initiative called the May Measure-
pertension in Malaysia and to those Kuala Lumpur. Lastly, MSH strives to ment Month (MMM) 2017 which ran
interested in hypertension—this can compile, print, publish and distribute across the month of May. The initia-
come in the form of advising patients brochures or journals by experts on tive sought to increase awareness
to remain active and to lead a nor- hypertension (as an extension to their of blood pressure worldwide and to
mal, productive life. Thirdly, MSH education drive). screen the blood pressure of as many
strives to promote cost-effective people as possible who had not had
management and control of hyper- Activities, activities and their blood pressure checked in the
tension. Chia said it is important to more activities past year. The aim for MMM 2018 is
stretch the fund available as much The society has been actively push- to screen a total of 3 million persons
as possible and this usually meant ing the hypertension agenda since its among member countries.
14
MALAYSIA FOCUS
It was revealed that almost two- years ago. The WHO advocates a their doctors.
thirds of people tested did not know daily intake of salt which is less than
they had elevated blood pressure five grams a day. The average person It was also important to let pa-
and those falling in the 30 to 40 year consumes about nine to 12 grams tients know that their doctor can be
age group were the most likely to of salt a day; thus it takes concerted contacted at any time they encoun-
have undiagnosed high blood pres- effort from governments, consumers ter a problem. Chia said: “Earn their
sure. Diagnosis of high blood pres- and food manufacturers to tackle the trust, and they will be your obedient
sure (≥140/90 in two checks within excessive consumption of salt. patients.”
a month or 2 weeks) is sometimes
missed because blood pressure Another easy to perform task is to
checks are not mandatory and very initiate blood pressure checks at ev-
few people follow up on their blood ery opportunity. With blood pressure
pressure readings after the first one. monitoring machines being so com-
mon, everybody can just step into a
The MSH is working on the fifth pharmacy or health foods store to get
edition of guidelines for treatment their blood pressure taken.
of hypertension and the publication
is scheduled to be launched during ‛Doctor Google’ rears its
the conference in January. Chia said ugly head
there is also an upcoming consensus Chia noted that patients tend to be
guideline on home blood pressure more challenging nowadays. “They
monitoring, which is due out by next come to you already knowing what
World Hypertension day. The guide- condition afflicts them,” said Chia.
lines will be targeted at pharmacists These patients would have searched
and the lay public. online for possible diagnoses and
treatment options. Closing words
Message for doctors Chia reiterated the importance
and the public However, she said if the doc- of salt reduction in our daily diet.
Chia said one of the most effective tor knows his or her field sufficiently “Reducing salt is the cheapest
and cheapest ways of controlling well, there is no reason to be afraid of option in hypertension treat-
hypertension is through dietary salt these patients. A good doctor should ment.” The onus is now on the
reduction. The method was original- be able to debunk all the myths fly- entire medical fraternity to help
ly championed by Professor Graham ing around in cyberspace and also to push this endeavour.
McGregor, of London, UK, some 25 allay the suspicions patients have of
15
MALAYSIA FOCUS
Watch out for the raspy breath of IPF

PANK JIT SIN
O
ne of the earliest signs of
idiopathic pulmonary fibro-
sis (IPF) is the raspy, Vel-
cro®-ripping sound audible through
the lungs via the stethoscope.
However, due to the rarity of the

disease, many GPs and even spe-
cialists may miss the symptoms as
they don’t recognize it for what it is—
the progressive, debilitating disease
known as IPF. “Diagnosing IPF is dif-
ficult as the symptoms are similar to
other respiratory diseases like chron-
ic obstructive pulmonary disease,
asthma or congestive heart failure. It
also requires specific tests, such as
a pulmonary function test and lung
imaging using a high-resolution CT-
scan [to conclusively diagnose],”
said Dato’ Dr Hj Abdul Razak Abdul available for IPF in the country. Ra- should be ordered to get to the root
Muttalif, senior consultant chest phy- jakanth Raman, executive director of of the problem.
sician, Institute of Respiratory Medi- Rainbow Across Borders, said the
cine. diagnosis of a life-threatening dis- As with chronic obstructive pul-
ease (such as IPF and lung cancer) monary disease and lung cancer,
Speaking at the launch of a cam- often causes distress and anxiety in there is currently no available cure
paign for improved awareness of IPF patients. “Apart from medical care, for IPF. However, early diagnosis and
called ‘Breathe for Life: Fight Lung patients need emotional support treatment will afford patients with
Scarring,’ Abdul Razak noted that from the earliest stage possible to better quality of life and less com-
globally, 50 percent of people with help them manage their journey with plications. Very often, the disease is
IPF are misdiagnosed and diagnosis the disease.” diagnosed at very late stages and by
in Malaysia is often low and late. The then the patient would have suffered
late diagnosis is attributable to poor Malaysia is the key kick-off point greatly, with poor quality of life.
disease knowledge among doctors for the campaign and it is hoped
and patients. The campaign is sup- that the movement will catch on and Conversely, early diagnosis will
ported by a patient support group spread to the rest of Southeast Asia. afford the patient with many options
alliance called Rainbow Across Bor- for IPF treatment. Syazatul said:
ders and Boehringer Ingelheim. Cough, cough, cough “They can receive pharmacological
Dr Syazatul Syakirin Sirol Afiah, treatment, supplemental oxygen
The campaign aims to reach out respiratory physician, Institute of treatment, cough management, pul-
to the public, patients and health- Respiratory Medicine, said one of monary rehabilitation as well as lung
care professionals through online the most obvious signs that some- transplantation as a last resort.”
and offline channels as well as on- thing is wrong is prolonged cough.
ground engagements. The initiatives She said all diseases that affect the Abdul Razak, Rajakanth and
are focused on driving awareness lung irritate the organ and result in Syazatul were speaking at the launch
on IPF—highlighting the importance coughing. Hence, persistent cough of the Breathe for Life: Fight Lung
of early diagnosis and helping pa- lasting more than 2 weeks should Scarring’ campaign launch, held in
tients realize the treatment options sound alarm bells and further checks Kuala Lumpur recently.
16
COVER STORY
Rivaroxaban + aspirin
reduces atherothrombotic events
in stable CVD
CHRISTINA LAU
R
ivaroxaban in combination
with aspirin significantly re-
duces cardiovascular (CV)
death, stroke or MI vs aspirin alone
in patients with stable cardiovas-
cular disease (CVD), according to
late-breaking results of the COM-
PASS trial presented at the Euro-
pean Society of Cardiology (ESC)
Congress 2017 in Barcelona,
Spain.
The COMPASS trial includ-

ed 27,395 patients with stable
coronary artery disease (CAD) or
peripheral artery disease (PAD)
recruited from 33 countries in
North America, South America,
Asia, Western Europe, Eastern Eu-
rope, South Africa, and Australia.
In patients randomized to receive
rivaroxaban 2.5 mg twice daily in
combination with aspirin 100 mg
once daily (n=9,152), the primary
composite endpoint of CV death,
MI or stroke (ie, major adverse
cardiovascular event [MACE]) was
reduced by 24 percent compared
with those who received aspirin
100 mg once daily (n=9,126) (4.1
vs 5.4 percent; p<0.0001). [N Engl
J Med 2017, doi: 10.1056/NEJ-
Moa1709118]
“The Kaplan-Meier curves for

MACE separated very early and
continued to diverge during fol-
low-up,” reported co-principal in-
vestigator Dr John Eikelboom of
McMaster University, Hamilton,
Canada. “However, no significant
difference in MACE was observed
18
COVER STORY
between patients receiving monothera- bleeding vs aspirin alone [hazard ratio

py with rivaroxaban 50 mg twice daily (HR), 1.70; p<0.0001], but no signif-
[n=9,117] and those receiving aspirin icant increase in fatal bleeding [HR,
alone [4.9 vs 5.4 percent; hazard ratio 1.49; p=0.32], intracranial haemor-
(HR), 0.90; p=0.12].” rhage [HR, 1.10; p=0.77] or bleeding in
other critical organs [HR, 1.43; p=0.14]
“Looking at individual components was observed,” said Eikelboom.
of the primary composite endpoint,
rivaroxaban plus aspirin reduced the
risk of CV death by 22 percent [1.7 vs
2.2 percent; p=0.02], the risk of stroke
by 42 percent [0.9 vs 1.6 percent;
p<0.0001], and the risk of MI by 14
percent [1.9 vs 2.2 percent; p=0.14] vs
aspirin alone,” he continued.
In view of the clear superiority of the

combination of rivaroxaban and aspirin
over aspirin alone, the data and safety Dr John Eikelboom
monitoring board recommended on 6
February 2017 – after a mean follow-up “The results clearly show a net clini-
of 23 months – that the rivaroxaban cal benefit with the combination of rivar-
and aspirin arms be discontinued. At oxaban and aspirin over aspirin alone
that point, 99.8 percent of follow-up [HR, 0.80; p=0.0005],” he concluded.
was completed ahead of the planned “For every 1,000 patients treated for an
”
follow-up duration of 3–4 years. average of 23 months, rivaroxaban plus
aspirin could prevent 13 CV deaths,
MIs or strokes, and seven all-cause
“Rivaroxaban plus aspirin deaths, at a cost of 12 major bleeds,
reduced the risk of CV most of which were readily treatable.”
death by 22 percent, the “The results of COMPASS repre-

risk of stroke by sent an important step in thrombocar-
42 percent, and the risk diology. They should lead to changes
of MI by 14 percent vs in guidelines on the management of
stable CAD,” commented discussant
aspirin alone” Dr Eugene Brauwald of Brigham and
Women’s Hospital, Boston, Massachu-
setts, US.
In terms of secondary endpoints,
the combination of rivaroxaban and “In the ATLAS ACS 2 – TIMI 51
aspirin reduced the risk of CAD mor- trial, rivaroxaban in combination with
tality, ischaemic stroke, MI or acute dual antiplatelet therapy [DAPT] re-
limb ischaemia by 28 percent vs as- duced the risk of MACE by 26 percent
pirin alone (p<0.0001). The risk of CV [p=0.02] and the risk of CV mortality by
death, ischaemic stroke, MI or acute 34 percent [p=0.002] compared with
limb ischaemia was reduced by 26 DAPT alone,” said Brauwald. [N Engl
percent (p<0.0001), while the risk of J Med 2012;366:9-19] “The next step
all-cause mortality was reduced by 18 of research would be to compare ri-
percent (p=0.01 [prespecified threshold varoxaban plus aspirin with DAPT and
p=0.0025]). with rivaroxaban plus a P2Y12 inhibitor.
It would also be logical to compare ri-
“The addition of rivaroxaban to as- varoxaban plus a P2Y12 inhibitor with
pirin resulted in an increase in major DAPT.”
19
CONFERENCE COVERAGE
European Society of Cardiology (ESC) Congress 2017 • August 26-30 • Barcelona, Spain
Anacetrapib reduces major coronary events

in high-risk CVD patients
ELAINE TAN The double-blind, placebo-con- HDL-C levels produced by anacetrapib
L
trolled trial included 30,449 men and does not have much impact on risk,”
ate-breaking results from a multi- women aged 50 years or older with he remarked.
national trial show for the first time established atherosclerotic vascular
that adding anacetrapib, a cho- disease recruited from more than 400 “Nevertheless, the possible contri-
lesteryl ester transfer protein (CETP) hospitals in the UK, US, Canada, Chi- bution of HDL-C–raising to CV benefit
inhibitor, to intensive statin therapy na, Germany, Italy, and Scandinavia. is not excluded if anacetrapib-induced
reduces cardiovascular (CV) events in The patients were effectively stabilized lowering of LDL particle species engen-
high-risk patients, with the possibility on atorvastatin (20 or 80 mg; 10 or ders elevation in the atherogenicity and
of providing greater benefit with longer 20 mg daily in China; mean baseline concentrations of specific LDL particle
duration of treatment. HDL-cholesterol [HDL-C], LDL-choles- subfractions, as shown in earlier stud-
terol [LDL-C] and non–HDL-C were 1.0, ies,” commented discussant Profes-
Results of the REVEAL (Random- 1.6, and 2.4 mmol/L, respectively). sor John Chapman of the University of
ized Evaluation of the Effects of Anac- Pierre and Marie Curie, France.
etrapib through Lipid-modification) trial,
presented at ESC 2017, showed that At trial midpoint, HDL-C and non–
adding anacetrapib (100 mg daily) to ef- HDL-C levels were 104 percent higher
fective doses of atorvastatin produced (+1.1 mmol/L) and 18 percent lower,
a 9 percent proportional reduction in respectively, in the anacetrapib vs the
the incidence of the primary outcome control group. The mean LDL-C level
of major coronary event (a composite was 41 percent lower in the anacetrapib
of coronary death, MI, or coronary re- vs the control group as measured us-
vascularization) vs placebo (10.8 per- ing direct assay (which underestimated
cent vs 11.8 percent; p=0.004) at the the LDL-C level among patients treat-
end of 4 years. [N Engl J Med 2017; ed with anacetrapib), and 17 percent
doi:10.1056/NEJMoa1706444] lower as measured by beta quantifica-
tion in a randomly selected subgroup
Coronary death or MI was reduced Prof Martin Landray of 2,000 patients. Adding anacetrapib
by 11 percent with anacetrapib vs to statin therapy also slightly reduced
placebo (6.1 percent vs 6.9 percent; “The findings of REVEAL are in the risk of new-onset diabetes mellitus
p=0.008), while coronary revascular- marked contrast to the disappointing (5.3 percent vs 6 percent with placebo;
ization was reduced by 10 percent (7.1 results of previous trials of other CETP p=0.05).
”
percent vs 7.9 percent; p=0.01). inhibitors, which were stopped after
about 2 years due to unexpected haz- “Anacetrapib was well tolerated.
ards or an apparent lack of efficacy,” There was no evidence of major clini-
“The findings of REVEAL said REVEAL’s co-principal investigator cal safety issues, no increase in death,
are in marked contrast to Professor Martin Landray, of the Univer- cancer or other serious medical events,
sity of Oxford, UK. and no effect on the liver, macular de-
the disappointing results
generation or cognitive function. The
of previous trials of other “The full effects of anacetrapib were small increase in blood pressure ob-
CETP inhibitors, which not seen until after the first year, like served did not translate to hypertensive
were stopped after about in statin trials. Furthermore, the pro- serious adverse events, and the small
portional reduction in coronary death reduction in kidney function also did not
2 years due to unexpected
or MI relative to the absolute reduc- result in renal failure adverse events,”
hazards or an apparent tion in non-HDL-C was similar to that reiterated Landray.
lack of efficacy” shown in other LDL-C–lowering trials, * COMPASS: Cardiovascular Outcomes for People
suggesting that the large increase in using Anticoagulation Strategies
20
CONFERENCE COVERAGE
Anti-inflammatory canakinumab reduces

CV risk independent of lipid lowering
JACKEY SUEN dian reduction in hsCRP at 3 months
T
[HR, 0.73; p=0.0001]. In contrast, the
he anti-inflammatory agent CV risk in patients with below medi-
canakinumab is found to reduce an hsCRP reduction at 3 months was
the risk of cardiovascular (CV) comparable to that in the placebo
events in high-risk patients, providing group [HR, 0.95; p=0.47],” he contin-
proof of concept that inhibiting inflam- ued. “This finding may help identify pa-
mation can improve CV outcomes in- tients who may benefit from treatment
dependent of cholesterol levels. with canakinumab.”
The findings came from the CAN- “Leukopenia and fatal infection
TOS study (Canakinumab Anti-Inflam- were more commonly reported in pa-
matory Thrombosis Outcomes Study), Prof Paul Ridker tients receiving canakinumab vs place-
which compared CV outcomes of three bo, suggesting that patients receiving
doses of canakinumab (50 mg, 150 levels (81.2–83.5 mg/dL) and high me- canakinumab should be monitored for
mg, and 300 mg) with placebo in pa- dian hsCRP levels (4.1–4.2 mg/dL) at early signs of infection,” reported Rid-
tients with previous myocardial infarc- baseline. ker.
tion (MI) and elevated levels (≥2 mg/L)
of the inflammatory marker high-sensi- At 48 months, hsCRP levels were “Our study suggests that sta-
tivity C-reactive protein (hsCRP) but low reduced by a median of 26 percent, 37 tin-treated patients with residual inflam-
LDL-cholesterol levels. [N Engl J Med percent, and 41 percent with canaki- matory risk, as opposed to those with
2017; doi:10.1056/NEJMoa1707914] numab 50 mg, 150 mg, and 300 mg, residual cholesterol risk, may be man-
respectively, compared with placebo. aged differently,” he advised.
“For the first time, we definitively
showed that lowering inflammation in- “The primary endpoint was reduced Interestingly, the study also showed
dependent of cholesterol levels reduc- by 15 percent with canakinumab 150 significant reductions in cancer mor-
es CV risk,” said principal investigator mg [incidence rate, 4.5 vs 3.9 per 100 tality (HR, 0.49; p=0.0009), lung can-
Professor Paul Ridker of Harvard Med- person-years; hazard ratio [HR], 0.85; cer incidence (HR, 0.33; p=0.00008),
ical School, Boston, Massachusetts, p=0.021] and 14 percent with canaki- and lung cancer mortality (HR, 0.23;
US. “Our findings may represent the numab 300 mg [incidence rate, 4.5 vs p=0.0002) with canakinumab 300 mg
endgame of more than 2 decades of 3.9 per 100 person-years; HR, 0.86; vs placebo. [Lancet 2017; doi:10.1016/
research, stemming from the observa- p=0.031] vs placebo. The secondary S0140-7; doi 6736(17)32247-X]
tion that half of heart attacks occur in endpoint was reduced by
people who do not have high choles- 17 percent with canaki-
terol levels.” numab 150 mg and 300
mg,” reported Ridker. “Due
The CANTOS investigators ran- to multiplicity testing, only
domized 10,061 patients to receive pla- the 150 mg dose of canak-
cebo or canakinumab 50 mg, 150 mg, inumab formally met statis-
or 300 mg every 3 months. The primary tical significance for both
endpoint was major adverse CV event primary and secondary
(MACE) comprising nonfatal MI, non- endpoints.”
fatal stroke, and CV death, while the
secondary endpoint was MACE or hos- “Notably, the second-
pitalization for unstable angina requiring ary endpoint was reduced
urgent revascularization. Patients in all by 27 percent among
arms had low median LDL-cholesterol patients with above me-
21
CONFERENCE COVERAGE
Rivaroxaban plus aspirin a potential new

treatment option in PAD
CHRISTINA LAU daily and those who received aspirin
R
alone (6 vs 6.9 percent; hazard ratio
ivaroxaban in combination with [HR], 0.86; p=0.19).
aspirin has emerged as a po-
tential new treatment option for “These results, from 7,470 patients
patients with peripheral artery disease with stable PAD of the lower extremities
(PAD) as late-breaking results from the or carotid artery disease, are consistent
PAD cohort of the COMPASS trial show with overall results of the COMPASS
significantly reduced rates of major ad- trial,” said Professor Sonia Anand of
verse cardiovascular events (MACE) McMaster University, Hamilton, Can-
and major adverse limb events (MALE) ada, who led the PAD component of
compared with aspirin alone. COMPASS.
Prof Sonia Anand
The results, presented at the ESC “In patients with PAD, the combina-
Congress 2017, showed a significant tion of rivaroxaban and aspirin reduced rivaroxaban monotherapy given at the
28 percent reduction in the risk of the risk of MI by 24 percent, stroke by higher dose (3.2 percent; HR, 1.68 vs
cardiovascular (CV) death, myocardi- 46 percent, and CV mortality by 28 per- aspirin alone; p=0.004). “However, no
al infarction (MI) or stroke in patients cent compared with aspirin alone,” she increase in fatal bleeding, intracranial
randomized to receive rivaroxaban 2.5 reported. haemorrhage or bleeding in other crit-
mg twice daily plus aspirin 100 mg dai- ical organs was observed,” said Anand.
ly compared with those who received MALE, defined as severe limb isch-
aspirin alone (5.1 vs 6.9 percent; aemia leading to an intervention and “The net clinical benefit of rivarox-
p=0.005), after a mean follow-up dura- major amputation above the forefoot aban plus aspirin over aspirin alone is
tion of 21 months. due to vascular causes, was reduced significant [HR, 0.72; p=0.0008] in the
by 46 percent with rivaroxaban plus as- PAD cohort of COMPASS. The benefit
No significant difference in MACE pirin vs aspirin alone (1.2 vs 2.2 percent; is consistent in patients with symptom-
was found, however, between patients p=0.005), while major amputation was atic PAD, PAD of lower extremities, or
who received rivaroxaban 5 mg twice reduced by 70 percent (0.2 vs 0.7 per- carotid artery disease,” she noted.
cent; p=0.01). With rivaroxaban mono-
therapy, the risks of these endpoints “The results of COMPASS PAD
were reduced by 37 percent (p=0.03) suggest that rivaroxaban plus aspirin is
and 44 percent (p=0.07), respectively. a new treatment alternative in patients
with PAD. Until now, we have only had
“The risk of the key composite out- aspirin, which is modestly effective,”
come of MACE, MALE or major ampu- commented discussant Professor Lars
tation was significantly reduced by 31 Wallentin of Uppsala Clinical Research
percent [p=0.0003] with rivaroxaban Centre, Uppsala University, Sweden.
plus aspirin vs aspirin alone,” report-
ed Anand. “The risk reduction was not “However, the optimal timing of
significant for rivaroxaban monotherapy starting patients on this combination
[HR, 0.84; p=0.08].” therapy remains unknown, because
transition from post-acute coronary
In the PAD cohort, rivaroxaban plus syndrome treatment was avoided in the
aspirin was associated with increased trial,” he continued. “It is also uncertain
major bleeding vs aspirin alone (3.1 vs whether rivaroxaban or aspirin should
1.9 percent; HR, 1.61; p=0.009). Ma- be discontinued in the event of bleed-
jor bleeding was also increased with ing.”
22
CONFERENCE COVERAGE
Routine use of supplemental oxygen does

not improve survival in MI patients
DR JOSEPH DELANO FULE ROBLES
T
he practice of giving oxygen to
patients with myocardial infarc-
tion (MI) is challenged by a re-
cent registry-based randomized clinical
trial showing that this widely accepted
practice does not improve survival,
according to results presented at ESC
2017.
The DETO2X-AMI study showed

that in patients with suspected MI with-
out hypoxaemia, giving supplemental
oxygen at 6 litres per minute for a me-
dian of 11.6 hours (range 6–12 hours)
through an open face mask did not
reduce mortality rate within 1 year vs Stockholm, Sweden. DEHEART, the country’s online cardiac
ambient air (5.0 vs 5.1 percent; hazard registry.
ratio [HR], 0.97; p=0.8). [N Engl J Med There was also no significant differ-
2017;doi:10.1056/NEJMoa1706222] ence between the two groups in terms “The population recruited for the
of cumulative troponin T concentration study is at least six times larger than
“The absence of an effect of sup- (oxygen group 946.5 ng/L vs ambient populations of similar studies done in
plemental oxygen on mortality was air group 983 ng/mL; p=0.97). previous years,” Hoffman pointed out.
consistent in all subgroups, such as
in patients who were smokers or non- “ESC guidelines have gradually “This form of clinical trial is cost-ef-
smokers, and patients with or without shifted towards more restrictive use of fective and efficient, representative of
diabetes, chronic kidney disease, pre- oxygen. While the current recommen- real-world practice, able to recruit pa-
vious MI or previous percutaneous cor- dations were based on expert opinion tients with ease, and ideal for testing
onary intervention procedures, regard- only, we can now add substantial data ‘established’ treatments… The major
less of baseline characteristics or final from this clinical trial,” said investigator implication is that registry-based ran-
diagnosis,” said investigator Dr Robin Professor Stefan James ,of the Uppsa- domized clinical trials may become the
Hoffman of the Karolinska Institutet, la University, Uppsala, Sweden. new gold standard for routine clinical
implementation,” discussant Dr David
The registry-based nationwide ran- Newby, of the University of Edinburgh,
domized clinical trial, with 69 participat- Scotland, commented.
ing Swedish centres, included 6,229
predominantly male patients (70 per- Oxygen therapy has been used
cent) with classical acute MI symptoms for more than a century and is widely
for less than 6 hours. The patients had recommended by guidelines including
a median age of 68 years (range, 59-76 those of the ESC, the rationale being
years), oxygen saturation of ≥90 per- that increased oxygen delivery to the
cent, and presence of ischaemic ECG ischaemic myocardium reduces infarct
changes and troponin elevation. size and subsequent complications
such as heart failure or arrhythmias.
Data analysis was done through the [Eur Heart J 2016; 37:267-315; Eur
Dr Robin Hoffman Swedish population registry and SWE- Heart J 2012; 33: 2569-2619]
23
CONFERENCE COVERAGE
Blocking PCSK9 synthesis with siRNA shows

promise in LDL-C lowering
JACKEY SUEN to receive a single injection of inclisiran
B
200 mg, 300 mg, or 500 mg, two in-
locking the synthesis of propro- jections (given on day 1 and day 90) of
tein convertase subtilisin/kexin inclisiran 100 mg, 200 mg, or 300 mg,
type 9 (PCSK9) with one to two or placebo.
injections of small interfering RNA (siR-
NA) provides sustained LDL-cholesterol The 6-month outcomes, report-
(LDL-C) lowering for up to 1 year in pa- ed previously, showed that the pri-
tients with high cardiovascular (CV) risk mary endpoint of LDL-C reduction
and elevated LDL-C levels, the phase II was greatest in patients who received
ORION-1 study has shown. two injections of inclisiran 300 mg. [N
Engl J Med 2017;doi:10.1056/NEJ-
“In contrast to PCSK9 monoclonal Moa1615758]
antibody treatments which require 12 Prof Kausik Ray
to 26 injections per year, the investigat- “At 1-year extended follow-up, the
ed siRNA approach requires only one overall safety profile remained numer- mained steady throughout 90 and 270
to two injections per year,” explained ically similar between the treatment days, with a time-averaged LDL-C re-
principal investigator Professor Kausik groups and placebo groups. No new duction of 51 percent accompanied by
Ray of the Imperial College London, safety concerns were identified,” re- a tight interquartile range,” said Ray.
UK. ported Ray. “This suggests that inclisiran may be
given at a dose of 300 mg on day 1 and
Inclisiran, the drug studied in ORI- The time-averaged LDL-C reduc- day 90, and every 180 days thereafter.”
ON-1, is a PCSK9 messenger RNA-tar- tions at 1 year were 30 percent, 37
geted siRNA. It is conjugated to N-ac- percent, and 39 percent with one dose “With these exciting findings, incli-
tylgalactosamine for targeted delivery to of inclisiran 200 mg, 300 mg, and 500 siran is now being investigated in mul-
hepatocytes, the major site for PCSK9 mg, respectively, and 30 percent, 40 tiple phase III trials. These include ORI-
production. percent, and 46 percent with two dos- ON-10 and ORION-11 [3,000 patients
es of inclisiran 100 mg, 200 mg, and with ASCVD or high CV risk], ORION-9
The study included 501 patients 300 mg, respectively. [400 patients with heterozygous familial
who had either atherosclerotic CV dis- hypercholesterolaemia (FH)], and ORI-
ease (ASCVD) and LDL-C levels >70 “In patients receiving two doses ON-5 [60 patients with homozygous
mg/dL despite maximum tolerated sta- of inclisiran 300 mg, the mean LDL-C FH],” he noted. “We are also designing
tin therapy or LDL-C levels >100 mg/dL levels on day 270 were similar to that a CV safety outcome trial, which will in-
without ASCVD. They were randomized on day 90. The LDL-C levels also re- clude 15,000 patients with high ASCVD
risk.”
“In contrast to PCSK9 monoclonal

antibodies, inclisiran inhibits all func-
tions of PCSK9 as it blocks the synthe-
sis of PCSK9,” commented Professor
Philip Barter of the University of New
South Wales, Sydney, Australia. “A
longer and larger study is needed to
confirm the safety of inclisiran, as the
impact of PCSK9 synthesis blockade
beyond LDL-C lowering remains uncer-
tain.”
24
CONFERENCE COVERAGE
Avoid sildenafil in residual pulmonary

hypertension after corrected
valvular heart disease
JENNY NG
S
ildenafil should not be used to
treat residual pulmonary hyper-
tension in patients with correct-
ed left valvular heart disease, according
to the results of a late-breaking trial pre-
sented at ESC 2017.
“We saw that a greater proportion

of patients taking sildenafil experienced
worse clinical outcomes than those re-
ceiving placebo,” said Dr Javier Berme-
jo of the Hospital General Universitario “Pulmonary hypertension is a high- vs 15 percent; odds ratio [OR] for im-
Gregorio Marañon in Madrid, Spain, risk complication for valvular heart dis- provement, 0.39; p<0.001).
lead investigator of the SIOVAC (Silde- ease even after the regional valvular
nafil for Improving Outcomes after Val- lesion has been corrected,” Bermejo Patients receiving sildenafil also
vular Correction) trial. “Patients receiv- explained. “This type of pulmonary had a significantly higher risk of major
ing sildenafil also had twice the number hypertension is a well-established risk clinical events (death or hospitalizations
of hospital admissions due to heart fail- factor for disability and increased mor- due to heart failure) vs placebo (haz-
ure compared with placebo recipients.” tality in the long-term. However, there ard ratio, 2.0; p=0.044). In particular,
is currently no treatment for these pa- sildenafil led to a significant increase in
The phosphodiesterase (PDE)-5 in- tients.” hospital admissions due to heart fail-
hibitor sildenafil, indicated for treatment ure vs placebo (OR, 0.43; p=0.035).
of erectile dysfunction, is also com- Bermejo and colleagues conducted There was no difference in the risk of
monly used to treat pulmonary arterial the SIOVAC trial to specifically assess death between the two treatment arms
hypertension. However, use of silde- whether sildenafil could improve out- (deaths, 3 patients receiving silde-
nafil in patients with pulmonary hyper- comes in patients with residual pul- nafil vs 2 patients receiving placebo;
tension due to left heart disease is not monary hypertension after successful p=0.63).
well established, with previous studies correction of a valvular lesion. The dou-
addressing this showing discordant re- ble-blind, placebo-controlled clinical “Based on these results, off-label
sults. trial included 200 patients from 18 ter- use of sildenafil in this specific popu-
tiary-care hospitals in Spain, who were lation of patients should be discour-
randomized to receive sildenafil 40 mg aged,” Bermejo advised.
three times daily or placebo.
“The message from the SIOVAC trial
After 6 months of follow-up, a sig- is very clear. Patients receiving sildenafil
nificantly higher proportion of patients 40 mg three times daily did worse,” said
receiving sildenafil experienced wors- Dr Irene Lang of the Medical University
ening of clinical outcomes vs those of Vienna, Vienna, Austria, who dis-
receiving placebo, as measured by a cussed the results. “Although SIOVAC
composite clinical score of all-cause is a negative study, it is very important
death, hospital admission for heart fail- because it shows what we should not
ure, worsening exercise tolerance, and do – treat pulmonary hypertension due
Dr Javier Bermejo self-assessed worsening (33 percent to left heart disease with sildenafil.”
25
Your choice of
treatment could mean
your asthma patients
don’t have to miss out.
Product
ProductName
Name&&ActiveActiveIngredient:
Ingredient: Dosage
Dosageand
andAdministration:
Administration:
Relvar
RelvarEllipta
Ellipta100/25
100/25micrograms
microgramsinhalation
inhalationpowder,
powder,pre-dispensed
pre-dispensed
(delivered Asthma
Asthma Adults
Adultsand
andadolescents
adolescentsaged
aged1212years
yearsand
andover
over
(delivered dose of 92
dose of 92 micrograms
micrograms of of fluticasone
fluticasone furoate
furoate and
and 22
22
micrograms One
Oneinhalation
inhalationof
ofRelvar
RelvarEllipta
Ellipta100/25
100/25micrograms
microgramsor or200/25
200/25micrograms
microgramsonce
oncedaily.
daily.IfIfsymptoms
symptomsarise
ariseinin
microgramsof ofvilanterol
vilanterol(as
(astrifenatate)).
trifenatate)).
Relvar Ellipta 200/25 micrograms inhalation powder, pre-dispensed the
theperiod
periodbetween
betweendoses,
doses,ananinhaled,
inhaled,short-acting
short-actingbeta2-agonist
beta2-agonistshould
shouldbe
betaken
takenfor
forimmediate
immediaterelief.
relief.
Relvar Ellipta 200/25 micrograms inhalation powder, pre-dispensed
(184 IfIfpatients are inadequately controlled on Relvar Ellipta 100/25 micrograms, the dose can be
patients are inadequately controlled on Relvar Ellipta 100/25 micrograms, the dose can be increased increased
(184 micrograms
micrograms of of fluticasone
fluticasone furoate
furoate and
and 22
22 micrograms
micrograms ofof
vilanterol toto200/25
200/25micrograms,
micrograms,which
whichmaymayprovide
provideadditional
additionalimprovement
improvementininasthma
asthmacontrol.
control.The Themaximum
maximum
vilanterol(as
(astrifenatate)).
trifenatate)).
recommended
recommendeddose doseisisRelvar
RelvarEllipta
Ellipta200/25
200/25micrograms
microgramsonce oncedaily.
daily.
Indications:
Indications:
Asthma: COPD
COPD Adults
Adultsaged
aged18 18years
yearsand
andover
over
Asthma: Relvar
Relvar Ellipta
Ellipta isis indicated
indicated for
for the
the regular
regular treatment
treatment of
of
asthma One
Oneinhalation
inhalationof ofRelvar
RelvarEllipta
Ellipta100/25
100/25micrograms
microgramsonce
oncedaily.
daily.
asthmaininadults
adultsand
andadolescents
adolescentsagedaged12 12years
yearsand
andolder
olderwhere
whereuse
use
of Relvar
Relvar Ellipta 200/25 microgramsisisnot
Ellipta 200/25 micrograms notindicated
indicatedfor
forpatients
patientswith
withCOPD.
COPD.
ofaacombination
combinationmedicinal
medicinalproduct
product(long-acting
(long-actingbeta2-agonist
beta2-agonistand
and
inhaled
inhaledcorticosteroid)
corticosteroid)isisappropriate:
appropriate:
•• patients Elderly
Elderlypatients
patients(>65
(>65 No
Nodose
doseadjustment
adjustmentisisrequired
requiredininthis
thispopulation
patientsnot
notadequately
adequatelycontrolled
controlledwith
withinhaled
inhaledcorticosteroids
corticosteroids population
and years)
years)and
andRenal
Renal
and ‘asneeded’
‘as needed’inhaled
inhaledshort
shortacting
actingbeta2-agonists.
beta2-agonists.
impairment:
impairment:
COPD
COPD (Chronic
(Chronic Obstructive
Obstructive Pulmonary
Pulmonary Disease):
Disease): Relvar
Relvar Ellipta
Ellipta isis
indicated
indicated for
for the
the symptomatic
symptomatic treatment
treatment of
of adults
adults with
with COPD
COPD Hepatic
Hepaticimpairment
impairment Caution
Cautionshould
shouldbe
beexercised
exercisedwhen
whendosing
dosingpatients
patientswith
withhepatic
hepaticimpairment
impairmentwho
whomay
maybebemore
moreatatrisk
riskof
of
with
with a FEV1<70% predicted normal (post-bronchodilator)with
a FEV1<70% predicted normal (post-bronchodilator) withanan systemic
systemicadverse
adversereactions
reactionsassociated
associatedwith
withcorticosteroids.
corticosteroids.For
Forpatients
patientswith
withmoderate
moderateor
orsevere
severehepatic
hepatic
exacerbation
exacerbationhistory
historydespite
despiteregular
regularbronchodilator
bronchodilatortherapy.
therapy. impairment
impairmentthe
themaximum
maximumdose doseisis100/25
100/25micrograms.
micrograms.
Method
Methodof ofadministration
administration
Relvar
RelvarEllipta
Elliptaisisfor
forinhalation
inhalationuse
useonly.
only.ItItshould
shouldbe
beadministered
administeredat
atthe
thesame
sametime
timeof
ofthe
theday,
day,each
eachday.
day.After
Afterinhalation,
inhalation,patients
patientsshould
shouldrinse
rinsetheir
theirmouth
mouthwith
withwater
waterwithout
withoutswallowing.
swallowing.
Contraindications:
Contraindications:
Hypersensitivity
Hypersensitivityto
tothe
theactive
activesubstances
substancesor
orto
toany
anyof
ofthe
theexcipients
excipientslike
likelactose
lactosemonohydrate
monohydrateand
andmagnesium
magnesiumstearate.
stearate.Patients
Patientswith
withrare
rarehereditary
hereditaryproblems
problemsof
ofgalactose
galactoseintolerance,
intolerance,the
theLapp
Lapplactase
lactasedeficiency
deficiency
or
orglucose-galactose
glucose-galactosemalabsorption
malabsorptionshould
shouldnot
nottake
takethis
thismedicinal
medicinalproduct.
product.
Warnings
Warnings&&Precautions:
Precautions:
Deterioration
Deteriorationof
of Fluticasone
Fluticasonefuroate/vilanterol
furoate/vilanterolshould
shouldnot
notbebeused
usedto
totreat
treatacute
acuteasthma
asthmasymptoms
symptomsor oran
anacute
acuteexacerbation
exacerbationininCOPD,
COPD,for
forwhich
whichaashort-acting
short-actingbronchodilator
bronchodilatorisisrequired.
required.Increasing
Increasing
disease
disease use
useofofshort-acting
short-actingbronchodilators
bronchodilatorsto torelieve
relievesymptoms
symptomsindicates
indicatesdeterioration
deteriorationof
ofcontrol
controland
andpatients
patientsshould
shouldbebereviewed
reviewedbybyaaphysician.
physician.Patients
Patientsshould
shouldnot
notstop
stoptherapy
therapywith
with
fluticasone
fluticasonefuroate/vilanterol
furoate/vilanterolininasthma
asthmaororCOPD,
COPD,without
withoutphysician
physiciansupervision
supervisionsince
sincesymptoms
symptomsmaymayrecur
recurafter
afterdiscontinuation.
discontinuation.
Paradoxical
Paradoxical Paradoxical
Paradoxicalbronchospasm
bronchospasmmaymayoccur
occurwith
withananimmediate
immediateincrease
increaseininwheezing
wheezingafter
afterdosing.
dosing.This
Thisshould
shouldbe betreated
treatedimmediately
immediatelywith
withaashort-acting
short-actinginhaled
inhaledbronchodilator.
bronchodilator.Relvar
Relvar
bronchospasm
bronchospasm Ellipta
Elliptashould
shouldbe
bediscontinued
discontinuedimmediately,
immediately,the
thepatient
patientassessed
assessedand
andalternative
alternativetherapy
therapyinstituted
institutedififnecessary.
necessary.
Cardiovascular
Cardiovascular Cardiovascular
Cardiovasculareffects,
effects,such
suchas
ascardiac
cardiacarrhythmias
arrhythmiase.g.
e.g.supraventricular
supraventriculartachycardia
tachycardiaand
andextrasystoles
extrasystolesmay
maybe beseen
seenwith
withsympathomimetic
sympathomimeticmedicinal
medicinalproducts
productsincluding
includingRelvar
Relvar
effects:
effects: Ellipta.
Ellipta.In
Inaaplacebo-controlled
placebo-controlledstudy
studyininsubjects
subjectswith
withaahistory
historyof,
of,or
oran
anincreased
increasedrisk
riskof,
of,cardiovascular
cardiovasculardisease,
disease,there
therewas
wasno
noincrease
increaseininthe
therisk
riskof,
of,cardiovascular
cardiovascularevents,
events,serious
serious
cardiovascular events, or adjudicated cardiovascular deaths in patients receiving fluticasone furoate/vilanterol compared with placebo. However, fluticasone
cardiovascular events, or adjudicated cardiovascular deaths in patients receiving fluticasone furoate/vilanterol compared with placebo. However, fluticasone furoate/vilanterol furoate/vilanterol
should
shouldbe beused
usedwith
withcaution
cautionininpatients
patientswith
withsevere
severecardiovascular
cardiovasculardisease
diseaseororheart
heartrhythm
rhythmabnormalities,
abnormalities,thyrotoxicosis,
thyrotoxicosis,uncorrected
uncorrectedhypokalaemia
hypokalaemiaor orpatients
patientspredisposed
predisposedto tolow
low
levels
levelsofofserum
serumpotassium.
potassium.
Systemic
Systemic Systemic
Systemiceffects
effectsmay
mayoccur
occurwith
withany
anyinhaled
inhaledcorticosteroid,
corticosteroid,particularly
particularlyat
athigh
highdoses
dosesprescribed
prescribedfor
forlong
longperiods.
periods.These
Theseeffects
effectsare
aremuch
muchless
lesslikely
likelyto
tooccur
occurthan
thanwith
withoral
oral
corticosteroid
corticosteroid corticosteroids.
corticosteroids.Possible
Possiblesystemic
systemiceffects
effectsinclude
includeCushing’s
Cushing’ssyndrome,
syndrome,Cushingoid
Cushingoidfeatures,
features,adrenal
adrenalsuppression,
suppression,decrease
decreaseininbone
bonemineral
mineraldensity,
density,growth
growthretardation
retardationininchildren
children
effects
effects and
andadolescents,
adolescents,cataract
cataractand
andglaucoma
glaucomaand andmore
morerarely,
rarely,aarange
rangeofofpsychological
psychologicalororbehavioural
behaviouraleffects
effectsincluding
includingpsychomotor
psychomotorhyperactivity,
hyperactivity,sleep
sleepdisorders,
disorders,anxiety,
anxiety,depression
depression
or
oraggression
aggression(particularly
(particularlyininchildren).
children).Fluticasone
Fluticasonefuroate/vilanterol
furoate/vilanterolshould
shouldbebeadministered
administeredwith
withcaution
cautionininpatients
patientswith
withpulmonary
pulmonarytuberculosis
tuberculosisor orininpatients
patientswith
withchronic
chronicoror
untreated
untreatedinfections.
infections.
Hyperglycaemia
Hyperglycaemia There
Therehave
havebeen
beenreports
reportsof
ofincreases
increasesininblood
bloodglucose
glucoselevels
levelsinindiabetic
diabeticpatients
patientsand
andthis
thisshould
shouldbe
beconsidered
consideredwhen
whenprescribing
prescribingto
topatients
patientswith
withaahistory
historyof
ofdiabetes
diabetesmellitus.
mellitus.
Pneumonia
Pneumoniain in An
Anincrease
increaseininthe
theincidence
incidenceof ofpneumonia,
pneumonia,including
includingpneumonia
pneumoniarequiring
requiringhospitalisation,
hospitalisation,has
hasbeen
beenobserved
observedininpatients
patientswith
withCOPD
COPDreceiving
receivinginhaled
inhaledcorticosteroids.
corticosteroids.There
Thereisis
patients
patientswith
withCOPD
COPD some
someevidence
evidenceof ofan
anincreased
increasedrisk
riskof
ofpneumonia
pneumoniawith withincreasing
increasingsteroid
steroiddose
dosebut
butthis
thishas
hasnot
notbeen
beendemonstrated
demonstratedconclusively
conclusivelyacross
acrossall
allstudies.There
studies.Thereisisno
noconclusive
conclusiveclinical
clinical
evidence
evidenceforforintra-class
intra-classdifferences
differencesininthe
themagnitude
magnitudeof ofthe
thepneumonia
pneumoniarisk
riskamong
amonginhaled
inhaledcorticosteroid
corticosteroidproducts.
products.Physicians
Physiciansshould
shouldremain
remainvigilant
vigilantfor
forthe
thepossible
possibledevelopment
development
of
ofpneumonia
pneumoniaininpatients
patientswith
withCOPD
COPDas asthe
theclinical
clinicalfeatures
featuresof
ofsuch
suchinfections
infectionsoverlap
overlapwith
withthe
thesymptoms
symptomsof ofCOPD
COPDexacerbations.
exacerbations.Risk
Riskfactors
factorsfor
forpneumonia
patientswith
withCOPD
COPD
include
includecurrent
currentsmoking,
smoking,older
olderage,
age,low
lowbody
bodymass
massindex
index(BMI)
(BMI)and
andsevere
severeCOPD.
COPD.Relvar
RelvarEllipta
Ellipta200/25
200/25micrograms
microgramsisisnot
notindicated
indicatedfor
forpatients
patientswith
withCOPD
COPD
Pneumonia
Pneumoniain in The
Theincidence
incidenceof
ofpneumonia
patientswith
withasthma
asthmawas
wascommon
commonat atthe
thehigher
higherdose.
dose.The
Theincidence
incidenceof
ofpneumonia
patientswith
withasthma
asthmataking
takingfluticasone
furoate/vilanterol
patients
patientswith
with 200/25
200/25micrograms
microgramswas
wasnumerically
numericallyhigher
highercompared
comparedwith
withthose
thosereceiving
receivingfluticasone
furoate/vilanterol100/25
100/25micrograms
microgramsor orplacebo.
placebo.No
Norisk
riskfactors
factorswere
wereidentified.
identified.
asthma
asthma
Caution
Cautionmust
mustbebetaken
takenwhen
whenadministering
administeringwith
withbeta-blockers,
beta-blockers,CYP3A4
CYP3A4inhibitors
inhibitors(e.g.
(e.g.ketoconazole,
ketoconazole,ritonavir),
ritonavir),P-glycoprotein
P-glycoproteininhibitors
inhibitorsand
andsympathomimetic
sympathomimeticmedicinal
medicinalproducts,
products,or
orininpregnancy
pregnancyand
andwomen
women
who
whoare
arebreast
breastfeeding.
feeding.(Refer
(Referto
tofull
fullprescribing
prescribinginformation
informationBEFORE
BEFOREprescribing
prescribingto
topatient)
patient)
Adverse
AdverseEvents:
Events:
The
Thefollowing
followinghas
hasbeen
beenused
usedfor
forthe
theclassification
classificationof
offrequencies:
frequencies:very
verycommon
common(≥1/10);
(≥1/10);common
common(≥1/100
(≥1/100to
to<1/10);
<1/10);uncommon
uncommon(≥1/1,000
(≥1/1,000to
to<1/100).
<1/100).
System
Systemorgan
organclass
class Adverse
Adversereaction(s)
reaction(s) Frequency
Frequency
Infections
Infectionsand
andinfestations
infestations Pneumonia,
Pneumonia,Upper
Upperrespiratory
respiratorytract
tractinfection,
infection,Bronchitis,
Bronchitis,Influenza,
Influenza,Candidiasis
Candidiasisof
ofmouth
mouthand
andthroat
throat Common
Common
Nervous
Nervoussystem
systemdisorders
disorders Headache
Headache Very
Verycommon
common
Cardiac
Cardiacdisorders
disorders Extrasystoles
Extrasystoles Uncommon
Uncommon
Respiratory,
Respiratory,thoracic
thoracicand
andmediastinal
mediastinal •• Nasopharyngitis
Nasopharyngitis Very
Verycommon
common
disorders
disorders •• Oropharyngeal
Oropharyngealpain,
pain,Sinusitis,
Sinusitis,Pharyngitis,
Pharyngitis,Rhinitis,
Rhinitis,Cough,
Cough,Dysphonia
Dysphonia Common
Common
Gastrointestinal
Gastrointestinaldisorders
disorders Abdominal
Abdominalpain
pain Common
Common
Musculoskeletal
Musculoskeletaland
andconnective
connective Arthralgia,
Arthralgia,Back
Backpain,
pain,Fractures
Fractures Common
Common
tissue
tissuedisorders
disorders
General
Generaldisorders
disordersand
andadministration
administration Pyrexia
Pyrexia Common
Common
site
siteconditions
conditions
Please
Pleaseread
readthe
thefull
fullprescribing
prescribinginformation
informationprior
priorto
toadministration,
administration,available
availablefrom:
from:
GlaxoSmithKline
GlaxoSmithKlinePharmaceutical
PharmaceuticalSdn SdnBhd
Bhd(3277-U),
(3277-U),Level
Level6,
6,Quill
Quill9,
9,112
112Jalan
JalanSemangat,
Semangat,46300
46300Petaling
PetalingJaya,
Jaya,Selangor
SelangorDarul
DarulEhsan,
Ehsan,Malaysia
Malaysia
Abbreviated
AbbreviatedPrescribing
PrescribingInformation
InformationVersion
Version02
02based
basedon
onEUSPC
EUSPC13
13October
October2016
2016and
andGDS08/IPI09.
GDS08/IPI09.Date
Dateof
ofcreation:
creation:30
30August
August2017
2017
which is available upon request.
MY/FFT/0050/17
MY/FFT/0050/17 10/17
10/17
CONFERENCE COVERAGE
Renal denervation effective for uncontrolled

HTN in patients not taking medications
DR JOSEPH DELANO FULE ROBLES
R
“SYMPLICITY HTN-3, a predeces-
enal denervation is efficacious in sor trial, failed to demonstrate signifi-
reducing blood pressure in adult cant blood pressure lowering with renal
patients with uncontrolled hyper- denervation. The novelty of the SPYRAL
tension (HTN) not taking any medica- HTN-OFF MED trial is we went into the
tions, according to late-breaking results [main renal artery] branches and treat-
from the SPYRAL HTN-OFF MED study ed an average of 5.2 branches per pa-
presented at ESC 2017. tient. We also did an average of 17.9
main artery ablations and 25.9 branch
The international, multicentre, ablations per patient,” commented in-
prospective, randomized, sham-con- vestigator Professor Michael Boehm,
trolled study included 80 patients who of the University of Saarland in Hom-
were drug-naive or had discontinued burg/Saar, Germany. [J Am Coll Cardiol Prof Michael Boehm
antihypertensive maintenance thera- 2015;65:1314-1321]
py. Results showed more significant contrast to the mono-electrode, se-
reductions in systolic blood pressure “Other differences from the SYM- quential ablation system used in the
(SBP) and diastolic blood pressure PLICITY HTN-3 trial include the ab- SYMPLICITY HTN-3 trial,” he contin-
(DBP) at 3 months, as measured by sence of antihypertensive drugs at ued.
24-hour ambulatory blood pressure the time of randomization, and imple-
monitoring (ABPM), in the renal de- mentation of drug adherence testing in “In SPYRAL HTN-OFF MED, the
nervation vs sham control group (SBP, serum and urine to avoid interference procedure was performed by more
-5.5 vs -0.5 mm Hg [p=0.04]; DBP, of drug effects on the procedure. Fur- highly experienced operators who did
-4.8 vs -0.4 [p=0.002]). [Lancet 2017, thermore, patients with isolated systolic an average of 43.8 ablations per pa-
doi: http://dx.doi.org/10.1016/S0140- hypertension [ISH] were excluded from tient, as compared with an average of
6736(17)32281-X] the trial as they could be hyporespon- 11.2 ablations per patient in the SYM-
sive to renal denervation procedures,” PLICITY HTN-3 trial,” he pointed out.
The renal denervation group also added Boehm.
showed more significant reductions in “The study provided biologic proof
office SBP and DBP at 3 months vs “The procedure in the SPYRAL of principle for the efficacy of renal
the sham control group (SBP, -10.0 vs HTN-OFF MED trial involved the use of denervation, demonstrating clinically
-2.3 mm Hg [p=0.02]; DBP, -5.3 vs -0.3 a four-electrode, simultaneous ablation meaningful blood pressure reductions
[p=0.008]). system to assure circumferentiality, in and no major safety events, which may
pave the way for designing larger pivot-
al trials,” Boehm concluded.
“The main caveat in the study is

predicting which patients will respond
because of the variations observed in
mean blood pressure response despite
a standardized treatment delivery with
multi-electrodes … The study population
excluded patients with ISH, the most
common and the most difficult to treat
hypertension phenotype,” commented
discussant Professor Bryan Williams of
the University College London, UK.
28
CONFERENCE COVERAGE
Drug-specific effects of NSAIDs on BP

may impact CV risk
NAOMI RODRIG nary artery disease received celecoxib
L
(100–200 mg BID), ibuprofen (600–800
ate-breaking data presented at the mg TID) or naproxen (375–500 mg BID)
ESC Congress 2017 have shown with matching placebos in a 1:1:1 al-
that ibuprofen is associated with location. The primary endpoint was
greater increase in blood pressure (BP) change from baseline in 24-hour ambu-
than celecoxib or naproxen in patients latory BP at 4 months. Baseline patient
with arthritis, potentially increasing their characteristics in terms of age, gender,
risk of cardiovascular (CV) events. [Eur BP, laboratory tests, and co-medica-
Heart J 2017;doi: 10.1093/eurheartj/ tion were well matched between the
ehx508] groups.
“Both selective and nonselective The change in mean 24-hour sys-

NSAIDs are amongst the most wide- tolic BP at 4 months was -0.3 mm Hg
ly prescribed drugs worldwide but for celecoxib, +3.7 mm Hg for ibupro-
are linked with increased BP and CV fen, and +1.6 mm Hg for naproxen, and
events,” said lead investigator Dr Frank these differences manifested regard-
Ruschitzka from the University Heart less of comorbidities such as baseline
Centre in Zurich, Switzerland. “PRE- hypertension or chronic kidney disease.
CISION-ABPM [Prospective Random- Similar differences between the drugs
ized Evaluation of Celecoxib Integrated were observed for diastolic and arterial
Safety vs Ibuprofen Or Naproxen - Am- BP.
bulatory Blood Pressure Measurement]
was designed to determine the effects “The changes in systolic BP result- lecoxib vs naproxen. [N Engl J Med
of the selective COX-2 inhibitor cele- ed in a significant difference of -3.9 mm 2016;375:2519-2529]
coxib on BP, as compared with the Hg between celecoxib and ibuprofen
nonselective NSAIDs naproxen and [p=0.0009]. The -1.8 mm Hg differ- “The PRECISION trial, which includ-
ibuprofen.” ence between celecoxib and naproxen ed over 24,000 patients, also indicated
and -2.1 mm Hg difference between a trend towards lower CV and all-cause
In the randomized, multicentre tri- naproxen and ibuprofen were not sta- mortality with celecoxib as compared
al, 444 patients with osteoarthritis or tistically significant,” noted Ruschitzka. with ibuprofen or naproxen,” said Rus-
rheumatoid arthritis who had evidence chitzka.
of or were at increased risk of coro- In addition, patients receiving ibu-
profen had a 61 percent higher inci- The finding that ibuprofen is asso-
dence of new-onset hypertension. “The ciated with a significant increase in BP,
percentage of patients with normal a higher incidence of new-onset hyper-
baseline BP who developed hyperten- tension, and a higher CV risk suggests
sion at 4 months was 10.3 percent for that the elevated CV risk with NSAIDs
celecoxib, 23.2 percent for ibuprofen, may be partly due to drug-specific in-
and 19.0 percent for naproxen,” he re- creases in BP.
ported.
“Increases in systolic BP with dif-
These results support and extend ferent NSAIDs as observed in PRE-
the findings of the original PRECISION CISION-ABPM should be considered
trial, which showed a 40 percent lower clinically significant, especially for the
rate of hospitalization for hypertension elderly population with a high preva-
with celecoxib vs ibuprofen (p=0.04) lence of arthritis and hypertension,” he
Dr Frank Ruschitzka but not significantly lower with ce- concluded.
29
CONFERENCE COVERAGE
Upstream rhythm control superior

to conventional therapy for AF
DR JOSEPH DELANO FULE ROBLES protein cholesterol levels in the risk fac-
R
tor-driven upstream therapy group vs
isk factor-driven upstream ther- conventional treatment group at 1-year
apy, including treatment of risk follow-up (p<0.05).
factors and lifestyle modifica-
tion, is effective and feasible to improve “Risk factor-driven upstream ther-
maintenance of sinus rhythm in patients apy refers to interventions that aim
with early persistent atrial fibrillation to modify the atrial substrate with fa-
(AF), according to late-breaking results vourable effects on risk factors and
from the RACE 3* trial presented at diseases underlying AF. In the study,
ESC 2017. the upstream therapy group received
cardiac rehabilitation including phys-
In this international, prospective, ical activity, dietary restrictions, and
randomized, open-label trial where regular counselling, mineralocorticoid this group was not treated,” discus-
250 patients with symptomatic, early receptor antagonists, statins and an- sant Professor Joseph Brugada of the
persistent AF and early mild-to-mod- giotensin-converting enzyme inhibitors Hospital Clinic, University of Barcelona,
erate heart failure were included, sinus and/or angiotensin receptor blockers,” Spain, commented.
rhythm was attained at 1 year in a sig- said investigator Professor Isabelle Van
nificantly higher proportion of patients Gelder of the University of Groningen, “Weight and body mass index [BMI],
”
who received risk factor driven up- The Netherlands. the presence of alcohol abuse, and the
stream therapy vs conventional treat- intensity of exercise are some of the
ment (75 percent vs 63 percent; odds other factors that may affect the inci-
ratio [OR], 1.765; p=0.021). “Risk factor-driven dence of AF. If we address all of these
upstream therapy refers factors and include them in further
The multicentre study (n=245), studies, we would be able to admin-
conducted between 2009 and 2015,
to interventions that ister more effective preventive therapy
included predominantly male patients aim to modify the atrial and reduce the number of AF patients
(80 percent, mean age 65 years). The substrate with favourable and the overall burden of this disease in
results also showed greater decreases effects on risk factors and our society,” Brugada added.
in systolic and diastolic blood pressure,
N-terminal pro b-type natriuretic pep-
diseases underlying AF” “The effect [of upstream therapy]
tide (NT-proBNP) and low density lipo- instead of atrial remodelling was fa-
vourable and may contribute to the
The primary endpoint (ie, the pres- shift of focus on risk factor modification
ence of sinus rhythm after 1 year of fol- to improve AF outcomes,” Van Gelder
low-up) was assessed with continuous concluded.
7-day Holter monitoring during the last
week of the study. Sinus rhythm maintenance is cum-
bersome due to atrial remodelling,
“Note that in the conventional treat- caused by risk factors and diseases
ment group, 63 percent of patients underlying AF and AF itself. [Circ Ar-
achieved sinus rhythm at 1 year. In this rhythm Electrophysiol 2008;1:62-73]
group, 43 percent of patients received
anti-arrhythmic drugs and 2 percent *RACE 3: Routine versus Aggressive
underwent atrial ablation. The benefit Upstream Rhythm Control for Preven-
[of risk factor-driven upstream thera- tion of Early Atril Fibrillation in Heart
Prof Isabelle Van Gelder py] would probably be even greater if Failure
30
CONFERENCE COVERAGE
Ultra-low LDL-C cuts CV risk with

no safety concerns
NAOMI RODRIG achieved with evolocumab were sub-
V
stantially lower than those in previous
ery aggressive reduction of low trials with lipid-lowering therapies,”
density lipoprotein cholesterol said lead author Dr Robert Giugliano,
(LDL-C) with the proprotein con- of Harvard Medical School, Boston,
vertase subtilisin-kexin type 9 (PCSK9) Massachusetts, US, who presented
inhibitor evolocumab was associated the data. “Our analysis explored the re-
with progressively fewer cardiovas- lationship between progressively lower
cular (CV) events without compromis- LDL-C concentrations achieved at 4
ing safety in patients with established weeks of treatment and clinical efficacy
atherosclerotic disease, according to and safety, and assessed whether there
a secondary analysis of the FOURIER is a threshold below which there is no
trial (Further Cadiovascular Outcomes added clinical benefit or an increase in Dr Robert Giugliano
Research with PCSK9 Inhibition in Sub- adverse events.”
jects with Elevated Risk) presented re- was observed for the secondary com-
cently at ESC 2017. [Lancet 2017; doi: The 25,982 patients included in posite endpoint of CV death, MI and
10.1016/S0140-6736(17)32290-0] the analysis were stratified into five stroke, with risk reductions between 10
groups based on their LDL-C levels at and 31 percent.”
Previously, FOURIER showed that 4 weeks: (1) <0.5 mmol/L (10 percent);
evolocumab, when added to back- (2) 0.5–1.3 mmol/L (31 percent); (3) No safety issues appeared with
ground statin therapy with or without 1.3–1.8 mmol/L (13 percent); (4) 1.8– lower LDL-C levels with regard to 10
ezetimibe, lowered LDL-C concentra- <2.6 mmol/L (29 percent); and (5) ≥2.6 prespecified safety endpoints, such as
tions to a median of 0.8 mmol/L and mmol/L (17 percent, referent group). serious adverse events, adverse events
significantly reduced the risk of CV leading to evolocumab discontinuation,
events vs placebo at 2.2 years. No sig- “We found that the risk of the pri- elevation in liver enzymes, new or recur-
nificant differences were found in major mary efficacy endpoint – a composite rent cancer, new-onset diabetes, and
safety events or prospective cognitive of CV death, MI, stroke, coronary re- cataract-related events. Among 1,154
function tests between the evolocum- vascularization or unstable angina – patients who underwent formal cogni-
ab and placebo groups. [N Engl J Med declined progressively as LDL-C levels tive testing, there were no adverse ef-
2017;376:1713-1722; N Engl J Med decreased, with risk reductions ranging fects on memory or executive function
2017;377:633-643] from 3 percent for group 4 to 24 per- associated with lower LDL-C levels.
cent for group 1 vs the referent group,”
“The LDL-C concentrations said Giugliano. “A similar association “Importantly, the CV benefit extend-
ed down to the bottom first percentile of
LDL-C concentration, as an exploratory
analysis in a subgroup of 504 patients
with LDL-C <0.26 mmol/L showed
even further reduction in CV events,
with no increase in adverse events,”
he emphasized. “Although longer fol-
low-up will be important, our findings
are unique, representing the first anal-
ysis of a large patient cohort to achieve
extremely low LDL-C levels. These data
support further LDL-C lowering to be-
low currently recommended levels in
patients with atherosclerotic disease.”
31
CONFERENCE COVERAGE
Dual antithrombotic therapy an option

for AF patients undergoing PCI
CHRISTINA LAU
I
n patients with atrial fibrillation (AF)
undergoing percutaneous coronary
intervention (PCI), dual antithrombot-
ic therapy with dabigatran and a P2Y12
inhibitor significantly reduces bleeding
vs triple therapy with warfarin, a P2Y12
inhibitor, and aspirin, with comparable
rates of thromboembolic events, re-
sults of the RE-DUAL PCI trial show.
“Based on these results, dual an- lor) and aspirin (for 1–3 months). Elder- syndrome or stable coronary artery
tithrombotic therapy regimens using ly patients ≥80 years of age outside the disease, and patients who underwent
doses of dabigatran approved for US and those ≥70 years of age in Ja- PCI with drug-eluting or bare metal
stroke prevention offer clinicians ad- pan were randomized to receive dabig- stents.”
ditional options for managing patients atran 110 mg BID plus a P2Y12 inhibitor
with AF after PCI,” said lead investiga- or triple therapy. The risk of ISTH major bleeding was
tor Professor Christopher Paul Cannon reduced by 48 percent and 36 percent
of Harvard Medical School, Boston, After a mean follow-up of 14 in patients who received dual therapy
Massachusetts, US, who presented months, the primary endpoint of first with dabigatran 110 mg [p=0.0003]
the study’s results at ESC 2017. [N major or clinically relevant nonmajor and 150 mg [p=0.022], respectively,
Engl J Med 2017; doi:10.1056/NEJ- bleeding event, as defined by the In- compared with triple therapy.
Moa1708454] ternational Society on Thrombosis and
Haemostasis (ISTH) criteria, was re- “Intracranial haemorrhage was re-
In the multicentre study, 2,725 pa- duced by 48 percent with dabigatran duced by 70 percent in the dabigatran
tients with AF were randomized within 100 mg dual therapy vs warfarin triple 110 mg arm [0.3 percent vs 1 percent
120 hours of PCI to receive dual an- therapy (15.4 percent vs 26.9 percent; vs triple therapy; p=0.064], and by 88
tithrombotic therapy with dabigatran p<0.001 for noninferiority and supe- percent in the dabigatran 150 mg arm
150 mg BID or 110 mg BID plus a riority). With dabigatran 150 mg dual [0.1 percent vs 1 percent; p=0.047],”
P2Y12 inhibitor (clopidogrel or ticagre- therapy, the risk of first ISTH major or said Cannon.
lor), or triple therapy with warfarin, a clinically relevant nonmajor bleeding
P2Y12 inhibitor (clopidogrel or ticagre- event was reduced by 28 percent vs The efficacy endpoint – a com-
triple therapy (20.2 percent vs 25.7 posite of thromboembolic events (MI,
percent; p<0.001 for noninferiority). stroke, or systemic embolism), death
or unplanned revascularization – oc-
“The differences between dual curred in 13.7 percent of patients who
therapy and triple therapy emerged received dual therapy vs 13.4 percent
early, and widened throughout the du- of patients who received triple therapy
ration of the trial,” Cannon reported. (hazard ratio [HR], 1.04; p=0.0047 for
“Subgroup analyses showed consis- noninferiority).
tent reductions in ISTH major or clin-
ically relevant nonmajor bleeding with “Dual therapy with dabigatran and
dual therapy in elderly vs nonelderly a P2Y12 inhibitor was noninferior to
patients, patients who received clopi- warfarin triple therapy in terms of the
dogrel or ticagrelor as P2Y12 inhibitor risk of overall thromboembolic events,”
Prof Christopher Paul Cannon therapy, patients with acute coronary said Cannon.
32
CONFERENCE COVERAGE
27th International Congress of the European Respiratory Society (ERS 2017) • September 9-13 • Milan, Italy
Benralizumab impact greater

with higher eosinophil count,
frequent exacerbation history
ROSHINI CLAIRE ANTHONY Q8W, respectively, vs 1.16 for place-
T
bo; rate ratio [RR], 0.63, 95 percent
he anti-eosinophilic monoclonal confidence interval [CI], 0.54–0.74 and
antibody benralizumab improves RR, 0.64, 95 percent CI, 0.55–0.75 for
annual exacerbation rates (AER) benralizumab Q4W and Q8W, respec-
in patients with severe, uncontrolled tively; p<0.0001 for each comparison).
asthma, with the improvement more [Lancet Respir Med 2017;doi:10.1016/ Previous studies have indicated
pronounced with increasing baseline S2213-2600(17)30344-2; ERS 2017, that blood eosinophil count alone is not
blood eosinophil levels and a history of abstract OA2902] a sufficient biomarker to detect eosin-
more frequent exacerbations, pooled ophilic airway inflammation. [J Allergy
analysis of the phase III SIROCCO* and The effects of benralizumab on AER Clin Immunol 2013;132:72-80; Allergy
CALIMA** trials show. improvement were more evident with 2013;68:402-406]
increasing blood eosinophil counts in
“Patients with a combination of patients on benralizumab Q4W and “Our findings illustrate the lim-
greater baseline blood eosinophil Q8W (RR, 0.61 and 0.63 [≥150 cells/ itations of clinicians’ and regulatory
counts and a history of more frequent µL], RR, 0.59 and 0.57 [≥300 cells/µL], agencies’ use of only blood eosinophil
exacerbations achieved the greatest and RR, 0.59 and 0.50 [≥450 cells/µL]; counts [≥300 cells/µL] to identify pa-
benefit,” said the researchers. p<0.0001 for all comparisons vs place- tients with eosinophilic inflammation,”
bo). said the researchers. “In the consider-
“[E]xacerbation history could be ation of treatment options, other fac-
used to identify patients who would po- In patients with blood eosinophil tors, including clinical characteristics
tentially be responsive to benralizumab, counts of ≥300 cells/µL, patients with such as exacerbation history, should be
with patients with a history of more fre- ≥3 exacerbations in the year prior had factored in alongside blood eosinophil
quent exacerbations achieving greater better AER improvements than those counts,” they said.
benefit,” they said. with two exacerbations, regardless of
benralizumab dosing schedule (≥3 ex- “[I]dentification of treatable traits
Patients with severe, uncontrolled acerbations; RR, 0.55 [benralizumab would be the basis for future develop-
asthma with a history of exacerbations Q4W] and 0.45 [benralizumab Q8W]; ment of precision medicine for airways
and receiving high-dose inhaled cor- p<0.0001 for each comparison vs pla- diseases,” said Professor Marc Hum-
ticosteroids and long-acting β2 ago- cebo; two exacerbations; RR, 0.65; bert from Université Paris-Sud, Paris,
nists (LABA) for ≥12 months prior were p=0.0016 [benralizumab Q4W] and RR, France, in a commentary. [Lancet Re-
randomized to receive subcutaneous 0.73; p=0.0194 [benralizumab Q8W]). spir Med 2017;doi:10.1016/S2213-
benralizumab (30 mg, Q4W [n=756] or 2600(17)30343-0]
Q8W with the first three doses given Patients on benralizumab with
Q4W [n=762]) or placebo Q4W (n=777) blood eosinophil counts of ≥0 cells/ “Well-defined predictors of im-
for 48 (SIROCCO, mean age 48.8 µL also had improved prebronchodila- proved response to benralizumab will
years, 66 percent female) or 56 weeks tor forced expiratory volume in the first be of great interest to support precision
(CALIMA, mean age 50.2 years, 62 per- second (FEV1) compared with those on medicine in severe asthma,” he said.
cent female). placebo at treatment end (difference in
least squares mean change from base- * SIROCCO: Efficacy and safety study of
benralizumab added to high-dose inhaled
Patients who had baseline blood line, 0.072 L; p=0.0038 and 0.099 L; corticosteroid plus LABA in patients with
eosinophil counts of ≥0 cells/µL and p<0.0001 for benralizumab Q4W and uncontrolled asthma
received benralizumab had lower AER Q8W, respectively), with improvement ** CALIMA: Efficacy and safety study of
benralizumab in adults and adolescents
than those who received placebo (0.73 increasing with baseline blood eosino- inadequately controlled on inhaled corticosteroid
and 0.75 for benralizumab Q4W and phil count. plus LABA
34
CONFERENCE COVERAGE
Macitentan a promising therapy in inoperable

CTEPH
ROSHINI CLAIRE ANTHONY
T
he dual endothelin-receptor
antagonist macitentan shows
promise in improving haemody-
namics and exercise capacity in pa-
tients with inoperable chronic throm-
boembolic pulmonary hypertension
(CTEPH), according to results of the
phase II MERIT-1* trial presented at
ERS 2017.
tan did not appear to confer any effect (8 percent), and upper respiratory tract
In this multicentre (36 hospitals in on Borg dyspnoea score compared infection (8 percent). One patient in
16 countries), double-blind trial, 80 pa- with placebo (least-squares mean dif- each group experienced haemoptysis
tients (mean age 57.5 years, 64 percent ference -0.39; p=0.35). None of the and three patients on placebo experi-
female, 38 percent Asian) with inopera- patients on macitentan experienced enced hypotension.
ble CTEPH, WHO functional class II-IV worsening of WHO functional class
with resting pulmonary vascular resis- compared with three in the placebo “Surgical removal of the throm-
tance (PVR) ≥400 dyn.s/cm5, 6-minute group (odds ratio, 0.21; p=0.096). boembolic obstructions [in CTEPH]
walk distance (6MWD) of 150–450 m, with pulmonary endarterectomy is the
and mean pulmonary arterial pressure The findings were consistent re- recommended treatment of choice for
and pulmonary arterial wedge pressure gardless of the use of PAH therapies most patients and is potentially curative
of ≥25 mm Hg and ≤15 mm Hg, re- at baseline among the patients, point- in some patients,” said the researchers.
spectively, were randomized 1:1 to re- ing to a potential benefit of combining However, many patients are not eligible
ceive once-daily oral doses of maciten- macitentan with other PAH therapies, or choose not to undergo the surgery,
tan (10 mg) or placebo for 24 weeks. the researchers said. they said.
Sixty-one percent of patients were on
pulmonary arterial hypertension (PAH) “[T]he consistency of results found “The similarities between histologi-
medications at baseline. in patients with and without background cal changes in the microvasculature of
treatment encourages future trials on patients with CTEPH and in those with
Resting (geometric mean) PVR combination therapy with CTEPH,” PAH provide a rationale for the use of
was significantly improved at week said Dr Adam Torbicki from the Center therapies for PAH in patients with inop-
16 in patients assigned to macitentan for Postgraduate Medical Education, erable CTEPH,” the researchers said.
compared with those on placebo (73.0 Otwock, Poland, in a commentary.
percent vs 87.2 percent of baseline, [Lancet Respir Med 2017;doi:10.1016/ “[A]though MERIT provided two im-
a reduction of 206 and 86 dyn.s/cm5 S2213-2600(17)30342-9] portant messages – namely that a drug
from baseline, respectively; geometric that acts on the endothelin pathophys-
means ratio 0.84, 95 percent confi- Serious adverse event (AE) inci- iological pathway can be successfully
dence interval, 0.70–0.99; p=0.041). dence was lower among patients on applied in nonoperable CTEPH, and
[Lancet Respir Med 2017;doi:10.1016/ macitentan compared with placebo (8 that combination therapy is likely to be
S2213-2600(17)30305-3; ERS 2017, percent vs 18 percent). The most com- useful also in CTEPH, and therefore re-
abstract OA1984] mon AE in both groups was peripheral quires further research – we are still far
oedema (23 percent vs 10 percent of from finding the optimal way through
At week 24, 6MWD increased by patients on macitentan and placebo, the vascular labyrinth of CTEPH,” con-
35.0 m and 1.0 m from baseline in the respectively), while other AEs in the cluded Torbicki.
macitentan and placebo groups, re- macitentan group were decreased hae- * MERIT-1: Macitentan in the treatment of
spectively (p=0.033), though maciten- moglobin (15 percent), pain in extremity inoperable CTEPH
35
CONFERENCE COVERAGE
BiPAP to CPAP: Is switching safe?

ELVIRA MANZANO
S
witching from bilevel positive
airway pressure (BiPAP) to con-
tinuous positive airway pressure
(CPAP) ventilation therapy may be
safe and cost-effective in patients with
obesity hypoventilation syndrome and
sleep apnoea, a small study presented
at ERS 2017 has shown.
“We all felt pretty neutral on this

when we started, but our results were
very positive,” said primary investigator
Dr María Paola Arellano-Maric from the
Pontifical Catholic University of Chile in
”
Santiago, Chile.
“Our patients did not

experience respiratory Arellano-Maric and colleagues stabilized, they were sent home with a
sought to determine if switching to CPAP device.
insufficiency with CPAP”
CPAP after >3 months of BiPAP is safe
- Dr Arellano-Maric in patients with obesity hypoventilation “The pressure was set at 14 cm
syndrome and sleep apnoea. [ERS of water. It was high … we’re worried
”
207, abstract OA4427] they couldn’t sleep at all,” said Arel-
It was thought that patients with lano-Maric. Three weeks after CPAP
a pressure gradient for inhalation and therapy, patients were subjected to
exhalation, which is the key feature of “Switching to CPAP polysomnography and reported that
the BiPAP devices, would have easier they were sleeping better. Fifty-seven
may not only be safe
time to get air in and out of the lungs. percent of patients expressed prefer-
On the contrary, CPAP devices can only and effective, it has also ence for CPAP therapy, despite high
be set to a single pressure and exhaling far-ranging implications levels of pressure (mean, 13.8 mbar).
against the constant, singular, continu- in terms of cost and
ous stream of pressurized air may be Of note, levels of partial pressure of
compliance”
difficult for most patients. carbon dioxide in arterial blood (PaCO2)
stabilized at 45 mm Hg (normal value:
“However, our patients did not ex- 35-45 mm Hg) in 71 percent of patients
perience respiratory insufficiency with Patients (n=42) had been receiving after 6 weeks of CPAP therapy.
CPAP,” said Arellano-Maric. “This was noninvasive BiPAP ventilation at home
after they were stabilized on BiPAP for for an average of 3-4 months. All had Switching to CPAP may not only be
at least 3 months.” apnoea and more than half had chronic safe and effective, it has also far-rang-
obstructive pulmonary disease (COPD) ing implications in terms of cost and
Current guidelines do not recom- of either GOLD stage I or II. Average compliance, Arellano-Maric said. As
mend automatic titrating of CPAP ma- BMI was 45.1 kg/mg². Eight out of 10 the BiPAP device is more expensive,
chines for COPD and apnoea patients. were either current or former smokers. “patients could rent the device for a
To add to that, there is a dearth of stud- They spent a night in the hospital and short period and then purchase a CPAP
ies on BiPAP being switched to CPAP were hooked to an automatic positive device for home use” to improve treat-
therapy. airway pressure (APAP) device. Once ment adherence.
36
EMPOWERING
HEALTHCARE
COMMUNITIES
CONFERENCE COVERAGE
Mepolizumab may help

reduce exacerbations
in eosinophilic COPD
ROSHINI CLAIRE ANTHONY at screening and no evidence of ≥300/
T
mm3 in the past year), while METREO
he addition of the monoclonal participants were restricted to patients
”
antibody interleukin-5 inhibitor with eosinophilic phenotype COPD.
mepolizumab to maintenance
therapy appears to reduce the rate of
exacerbations in patients with eosin- “These findings suggest
ophilic phenotype chronic obstructive that eosinophilic airway
pulmonary disease (COPD), according
inflammation contributes
to results of the phase III METREX*
and METREO** trials presented at ERS to COPD exacerbations
2017. and that the use of
mepolizumab directed
Patients aged ≥40 years with COPD
by blood eosinophil
and a history of moderate or severe ex-
acerbations in the previous 12 months counts might represent
were, in addition to inhaled glucocorti- a precision-medicine
coid-based triple maintenance therapy, approach to the
randomized to receive mepolizumab
management of COPD in
(100 mg in the METREX [n=417] and
100 [n=223] or 300 mg [n=225] in the selected patients”
METREO trials) or placebo (n=419 and
226 in the METREX and METREO tri-
als, respectively) subcutaneously every Fewer exacerbations with
”
4 weeks for 52 weeks. mepolizumab
In the METREX trial, patients with eo-
sinophilic phenotype COPD (n=462)
“In the METREX trial, assigned to mepolizumab had a lower
patients with eosinophilic mean annual rate of moderate (requir-
phenotype COPD ing treatment with systemic glucocor- significant (1.19, 1.27, and 1.49 per
ticoids, antibiotics, or both) or severe year, corresponding to rate ratios of
assigned to mepolizumab (requiring hospitalization or resulting in 0.80; p=0.07 and 0.86; p=0.14 in the
had a lower mean death) exacerbations compared with 100 mg and 300 mg groups vs place-
annual rate of moderate those on placebo (1.40 vs 1.71 per bo, respectively).
or severe exacerbations year, rate ratio, 0.82, 95 percent con-
fidence interval, 0.68–0.98; p=0.04). Median time to first exacerbation
compared with those [N Engl J Med 2017;doi:10.1056/NEJ- was longer among patients with eo-
on placebo” Moa1708208; ERS 2017, abstract OA sinophilic phenotype COPD on mepo-
3194] lizumab compared with placebo only
in the METREX trial (192 vs 141 days,
Patients in the METREX trial were In the METREO trial, the mean an- hazard ratio, 0.75; p=0.04).
stratified according to blood eosino- nual rate of exacerbations was lowest
philic count (eosinophilic: ≥150/mm3 in patients on mepolizumab 100 mg, A meta-analysis of both trials found
at screening or ≥300/mm3 in the pre- followed by mepolizumab 300 mg, and that the impact of mepolizumab on
vious year; noneosinophilic: <150/mm3 placebo, though the findings were not exacerbation rate was more evident in
38
CONFERENCE COVERAGE
”
“[T]hese trials should
promote further
prospective studies aimed
at clarifying the role of
eosinophils in COPD
… [and] encourage the
development of new
strategies for further
stratifying patients”
The researchers acknowledged

that the small number of events posed
a limitation as did a lack of information
on exacerbation triggers.
Future investigations
“The results of the current trials indicate
that a subgroup of patients with COPD
may benefit from biologic therapies, but
I think that blood eosinophil count is
an imperfect biomarker and that other
disease factors confound the eosin-
ophil signal, even in carefully selected
subgroups,” said Professor Christine
McDonald from the Department of Re-
spiratory and Sleep Medicine, Austin
Health, Victoria, Australia, in a commen-
tary. [N Engl J Med 2017;doi:10.1056/
NEJMe1710326]
“[T]hese trials should promote fur-

patients with higher eosinophil counts. Comparable safety profile ther prospective studies aimed at clar-
Adverse event (AE) and serious AE ifying the role of eosinophils in COPD
“[T]hese trials show the importance incidence was comparable between … [and] encourage the development
of blood eosinophils in COPD exacer- patients on mepolizumab and placebo of new strategies for further stratifying
bations,” said the researchers. “These in both trials, with the most common patients, as an alternative to focusing
findings suggest that eosinophilic air- AEs being exacerbation or worsening solely on eosinophils,” said McDonald.
way inflammation contributes to COPD COPD, nasopharyngitis, headache,
exacerbations and that the use of and pneumonia. Antidrug antibodies
mepolizumab directed by blood eo- were present in 4 and <1 percent of
sinophil counts might represent a pre- patients on mepolizumab and placebo,
cision-medicine approach to the man- respectively in METREX, while in ME- * METREX: Mepolizumab vs placebo as add-on
agement of COPD in selected patients TREO, antidrug antibodies were pres- treatment for frequently exacerbating COPD
who continue to have exacerbations ent in 6, 2, and 1 percent of patients patients
** METREO: Mepolizumab vs placebo as add-on
despite inhaled glucocorticoid-based on mepolizumab 100 mg, 300 mg, and treatment for frequently exacerbating COPD
triple maintenance therapy,” they said. placebo, respectively. patients characterized by eosinophilic level
39
CONFERENCE COVERAGE
Tezepelumab promising
for persistent,
uncontrolled asthma
ELVIRA MANZANO for the treatment of persistent, uncon-
T
trolled asthma to date,” said Dr Elisa-
he human IgG2 monoclonal an- beth Bel from the Department of Re-
tibody tezepelumab reduces spiratory Medicine, Academic Medical
asthma exacerbations in patients Center, University of Amsterdam, the
whose disease remained uncontrolled Netherlands, who is unaffiliated with the
despite treatment with long-acting study, in an editorial. However, she cau-
beta-agonists and inhaled glucocorti- tioned that the potential negative effects
”
coids, a phase II trial showns. of targeting upstream cytokines must
be considered, adding that the possi-
bility of infections arising as a result of
“Tezepelumab appears to thymic stromal lymphopoietin (TSLP)
inhibition should not be dismissed. [N
be the broadest and most
Engl J Med 2017;377:989-991]
promising biologic for the
treatment of persistent, Subcutaneous
uncontrolled asthma tezepelumab vs placebo
Corren and his team sought to evaluate
to date. However, the
the efficacy and safety of three differ-
potential negative effects ent doses of tezepelumab vs placebo
of targeting upstream over a 52-week treatment period in 584
cytokines must be patients (age 18–75 years) with mod-
erate-to-severe uncontrolled asthma.
considered”
Patients were randomly assigned to
subcutaneous injections of tezepelum-
ab 70 mg every 4 weeks (n=145), 210
At week 52, significant and clinically mg every 4 weeks (n=145), 280 mg
meaningful reductions in exacerbation every 2 weeks (n=146), or placebo ev-
rates were observed with the teze- ery 2 weeks (n=148). Patients receiving
pelumab groups relevant to placebo 4-week dosing regimens received pla- percentage of patients with at least one
(p<0.001 for all comparisons). “The cebo at the intermediate visits. severe asthma exacerbation.
[primary endpoint of] annual asthma
exacerbation rate was also lower in the Secondary endpoints included Longer time to first
tezepelumab vs the placebo group, in- changes from baseline in the prebron- asthma exacerbation
dependent of baseline blood eosinophil chodilator and postbronchodilator with tezepelumab
count or other indicators of Th2 [type 2 forced expiratory volume in 1 second At the end of the study period, teze-
helper T cytokine] status,” said princi- (FEV1), symptom and quality-of-life pelumab was associated with a longer
pal investigator of the trial, Dr Jonathan questionnaire scores, forced vital ca- time to first asthma exacerbation at all
Corren from the David Geffen School pacity, annual rate of severe asthma doses studied. The risk for any exac-
of Medicine at the University of Califor- exacerbations (leading to hospital ad- erbation was lower with tezepelumab
nia, Los Angeles, US. [N Engl J Med missions of 24 hours or longer) at week vs placebo by 34 percent (hazard ratio
2017;377:936-946] 52, time to first asthma exacerbation, [HR], 0.66; p=0.08), 54 percent (HR,
time to first severe asthma exacerba- 0.46; p=0.003), and 45 percent (HR,
“Tezepelumab appears to be the tion, the percentage of patients with at 0.55; p=0.02) in the low-, medium-,
broadest and most promising biologic least one asthma exacerbation, and the and high-dose groups, respectively.
40
FRIDAY – SATURDAY NOVOTEL SINGAPORE
20 – 21 OCTOBER 2017 CLARKE QUAY
S YM P O SIUM OB JEC TIV E Featuring

The goal of SPCRS 2017 is to provide the most up-to-date information on Keynote Speaker
prevention and rehabilitation in cardiovascular health to multi-disciplinary Professor Hugo Saner
MD, FESC
teams under this year’s theme, Advances in Cardiac Rehabilitation for
Professor of Medicine, University of Bern
Improved Health: Special Focus on E-Health. Our international and local Director of Cardiovascular Prevention and
expert speakers will help lead engaging discussions and provide useful Rehabilitation Swiss Cardiovascular Centre
Bern University Hospital
insights during a series of interactive workshops and our main symposium. Switzerland
Topic highlights for SPCRS 2017 include:

• Impact of E-Health on Cardiac Rehabilitation
Other International Speakers
Professor David Thompson
• Importance of Psychosocial Management in Cardiac Rehabilitation
Director of the Centre for the
• Barriers to Cardiac Rehabilitation and How to Overcome Them Heart and Mind
• Standing or Sitting at Work – A Revolution in the Office Mary Mackillop Institute for Health
Research
• How Current and New Pharmacotherapy Affect Cardiac Australia
Rehabilitation
Professor Nizal Sarrafzadegan
Director of Isfahan Cardiovascular
ON LINE RE GIS TR ATION Research Institute, Isfahan University
of Medical Sciences
Iran
Online registration closes on Sunday 30th September. Register soon at
www.spcrs.sg to secure your place at this year’s meeting! Slots for the
Professor John Buckley
pre-symposium workshops are limited. The topics are: Hands-on Healthy Professor of Applied Exercise Science
Cooking | E-Health | Policy and Strategy | Nursing and Allied Health | in Health, University Centre
Shrewsbury
Exercise Prescription. United Kingdom
C A LL FO R A B S TR AC TS
Abstract submission is open! For the opportunity to have your work included in our scientific programme, you can submit your
abstracts on the following: Telehealth/IT in Cardiac Rehabilitation | Policy and Strategy | Nursing and Allied Health |
Exercise Prescription. The SPCRS 2017 Scientific Committee will select the best abstracts to be shortlisted for oral presentation
during the conference.
The submission deadline has been extended to Friday 22nd September 2017. To submit your abstracts, or for more information
on submission criteria, please visit www.spcrs.sg.
Supported By:
For further information, please contact:

Congress Secretariat
MIMS Pte Ltd
Phone: +65 6290 7532
Organised By: Email: enquiry@spcrs.sg
Website: www.spcrs.sg
CONFERENCE COVERAGE
”
“Due to its activity early
in the inflammatory
cascade, tezepelumab
may be suitable for
patients with both T2
[type 2] and non-T2
driven asthma, including
those ineligible
for current biologic
therapies which only
target the T2 pathway”
kine, an upstream driver of inflamma-

tion in asthma. As TSLP acts upstream
of the main allergic immune cascade,
tezepelumab may be effective in a
broader population of patients com-
pared with therapies that inhibit a single
downstream pathway, said Corren.
“Due to its activity early in the in-

flammatory cascade, tezepelumab
may be suitable for patients with both
T2 [type 2] and non-T2 driven asthma,
including those ineligible for current bi-
ologic therapies which only target the
T2 pathway.”
The significant reductions in blood

eosinophil counts, IgE, and FeNO lev-
To add to that, the change from exhaled nitric oxide (FeNO) levels. There els shown in the study indicate that
baseline in the prebronchodilator FEV1 were also progressive decreases in to- tezepelumab may impact interleukin-4,
at 52 weeks was higher in all teze- tal serum immunoglobulin E (IgE) in all -5, and -13 pathways, and may have
pelumab groups than in the placebo tezepelumab groups, the researchers broader physiological impact than just
group (difference of 0.12 L with the low noted. The overall incidence of adverse targeting individual Th2 cytokines, said
dose [p= 0.01], 0.11 L with the medi- events was comparable between the the researchers.
um dose [p=0.02], and 0.15 L with the tezepelumab and the placebo groups
high dose [p=0.002]). “The differences and so was the discontinuation rate. Confirming tezepelumab’s safety,
were comparable when the prebron- The most common adverse events in as well as the mode of delivery, in future
chodilator FEV1 was measured as the the tezepelumab-treated patients were trials is warranted, said Dr Christopher
percent of the predicted value,” the re- asthma, nasopharyngitis, headache, Caroll, of the Connecticut Children’s
searchers said. and bronchitis. Medical Center, Hartford, Connecticut,
US. While the results are promising,
As early as week 4, there were sub- First-in-class treatment “the fact that tezepelumab is given sub-
stantial and persistent decreases in that blocks TSLP cutaneously once every 4 weeks could
blood eosinophil counts and fractional Tezepelumab targets the TSLP cyto- limit its use in clinical practice.”
42
CONFERENCE COVERAGE
Fluticasone furoate + vilanterol superior

to usual care in asthma control
I
nitiating therapy with fluticasone furo-
ate plus vilanterol resulted in improved
asthma control over usual care in in-
dividuals with symptomatic asthma,
according to results of the Salford Lung
Study presented at ERS 2017.
“[T]his is the first time the [flutica-

sone furoate plus vilanterol] combina-
tion has shown additional benefits, in vilanterol and usual care, respectively, “[O]ur data suggest that there are
terms of asthma control, when com- changed medications. other important factors underlying
pared with optimized usual care in a asthma exacerbations in the everyday
broad patient population,” said the re- In the primary effectiveness analysis care setting, which are independent
searchers. population, at 24 weeks, patients as- of asthma control and not present in a
signed to fluticasone furoate plus vilan- tightly controlled efficacy trial,” said the
Patients aged ≥18 years (n=4,233, terol had a higher likelihood of being researchers.
mean age 50 years, 59 percent female) responders (asthma control test [ACT]
from 74 GP clinics in Salford and South score ≥20 or increase by ≥3 points When accounting for treatment
Manchester, UK, with GP-diagnosed from baseline) compared with patients modification, incidence of pneumo-
symptomatic asthma and on mainte- on usual care (71 percent vs 56 per- nia was low and comparable between
nance therapy (inhaled corticosteroids cent; odds ratio [OR], 2.00, 95 percent groups; however, according to ran-
with or without a long-acting β-agonist) confidence interval [CI], 1.70–2.34; domized group, pneumonia incidence
were randomized to receive once-dai- p<0.0001). These findings were sus- was higher among patients assigned to
ly inhaled doses of fluticasone furo- tained throughout the follow-up period fluticasone furoate plus vilanterol com-
ate (100 or 200 µg) plus vilanterol (25 (OR, 2.04, 1.77, and 1.83 at weeks 12, pared with usual care (n=23 vs 16).
µg, n=2,114) or optimized usual care 40, and 52, respectively; p<0.0001 for
(n=2,119) and were followed up for 12 all). [Lancet 2017;doi:10.1016/S0140- The researchers acknowledged
months. 6736(17)32397-8; ERS 2017, abstract that the open-label design may have
OA 3193] affected the results and highlighted
The primary effectiveness analysis the role of effectiveness trials in routine
population consisted of patients with The findings were similar in the care in influencing clinical guidelines for
ACT score <20 at baseline; 1,207 pa- analysis of the total population at week chronic diseases.
tients with scores ≥20 (602 and 605 in 24 (74 percent vs 60 percent; OR, 1.97,
the fluticasone furoate plus vilanterol 95 percent CI, 1.71–2.26; p<0.0001). “Embedded within a primary care
and usual care groups, respectively) setting, [this trial] assesses important
were thus excluded from the primary Mean ACT score in the primary patient outcomes by use of the ex-
analysis. Patients who had been ran- analysis population at 24 weeks was isting electronic health record … [it]
domized to fluticasone furoate plus also more elevated in patients on flu- gives estimates of what might be ex-
vilanterol could add on or replace this ticasone furoate plus vilanterol com- pected to happen when you treat the
treatment with other asthma medica- pared with those on usual care (mean next patient with asthma in your clin-
tions while those randomized to usual increase from baseline, 4.4 vs 2.8; dif- ic,” said Professor Peter Gibson, of
care could change to other medica- ference, 1.6, 95 percent CI, 1.3–2.0; the John Hunter Hospital, New South
tions except for fluticasone furoate plus p<0.0001), while adjusted annual exac- Wales, Australia, in a commentary.
vilanterol. Twenty-two and 18 percent erbation rate did not significantly differ [Lancet 2017;doi:10.1016/S0140-
of patients on fluticasone furoate plus between groups (p=0.6969). 6736(17)32398-X]
43
CONFERENCE COVERAGE
HRT may preserve lung function in

middle-aged women
ELVIRA MANZANO
H
ormone replacement thera-
py (HRT) may help delay lung
function decline in middle-aged
women, according to results of a lon-
gitudinal analysis presented at the ERS
Congress 2017, demonstrating a pos-
sible role for female sex hormones in
the preservation of lung function.
“Lung function peaks during the

mid-20s, and from then on it will go
down,” said lead investigator Dr Kai
Triebner, a postdoctoral fellow at the
University of Bergen in Bergen, Norway.
“However, it is possible to identify which
factors influence the decline – either by
slowing it down, or accelerating it. One
accelerating factor, for example, is the
menopause. Therefore, a key question
is whether HRT could, at least partly,
counteract it.” with nonusers. Long-term use of HRT There have been safety concerns
was associated with less lung function on the use of HRT. Debates are still on-
Triebner and his team sought to decline (-56.7 mL for FEV1 and -65.6 going hence, it may be too early to rec-
analyse spirometry data of 3,713 Eu- mL for FVC) compared with nonuse. ommend this therapy in the lung-health
ropean women participating in the Eu- setting. Trieber clarified that he is not
ropean Community Respiratory Health The results may not be clinically sig- advocating for HRT though and that
Survey who were followed for an aver- nificant in healthy women, said Triebner. their findings merely offer more infor-
age of 20 years (1990 to 2010). Women “However, in women who are suffering mation that can help women and their
who took oral HRT for 2 years or lon- from airway diseases, the decline in physicians in making the right treatment
ger (n=236) were matched with women lung function may influence quality of decisions.
who never took HRT (n=236) for age, life, as it could lead to an increase in
height, age at menopause, smoking shortness of breath, reduced work ca-
history, and baseline lung function. The pacity, and fatigue.”
women were nonmenopausal at base- Scan the
line and postmenopausal at study end. “To put these findings in context, if QR code for full
Mean age in 2010 was 59 years. Lung a woman smoked a pack of cigarettes coverage of
function was assessed at baseline and a day for 3 years, the loss of FVC would ERS 2017
20 years later. [ERS 2017, abstract correspond roughly in size to 46 mL,”
OA4420] he further elucidated.
Women who had oral HRT for 2 Of note, physical activity and sur-
years or longer performed better in lung gical menopause were not significantly
function tests as assessed by forced vi- associated with lung function decline.
tal capacity (FVC) and forced expiratory “However, in my personal opinion,
volume in one second (FEV1) compared physical exercise is still desirable.”
44
NEWSBITES
Leflunomide or low-dose rituximab have similar

benefit when added to methotrexate in RA
AUDREY ABELLA 85 percent for ACR20#, 64 percent vs protection against pneumococcal in-
A
60 percent for ACR50#, and 32 percent fections, the researchers said.
leflunomide-methotrexate com- vs 35 percent for ACR70#). Leflunomide is a more cost-ef-
bination was as effective as, fective measure where a 20 mg/day
and more cost effective than, a “[Our results suggest that] both le- dose costs an estimated US$ 192 for
low-dose rituximab-methotrexate com- flunomide and [two infusions of] low- a one-year treatment vs US$ 2,850 for
bination for patients with rheumatoid dose rituximab were [successful] in two infusions of low-dose rituximab.
arthritis (RA) refractory to conventional, controlling disease activity when added Although the findings favour lefluno-
first-line nonbiologic DMARDS*, ac- to methotrexate,” said the researchers. mide over low-dose rituximab in terms
cording to a new study. of cost, both are still relatively cheaper
There was also a significant reduc- compared with standard high-dose rit-
In this double-blind trial, researchers tion in disease activity at 24 weeks vs uximab (1,000 mg, US$ 5,700 for two
evaluated 40 patients who responded baseline (DAS <3.2 vs DAS 28 >5.1) infusions), said the researchers.
poorly to methotrexate (at least 10 mg/ in both leflunomide (42 percent vs 100
week) for more than 6 months (Disease percent) and rituximab arms (40 per- “[Overall, the] lower costs of both
Activity Score [DAS] >3.2). Participants cent vs 95 percent). European League treatment options should enable more
were randomized to receive lefluno- Against Rheumatism (EULAR) good re- patients with refractory RA to be
mide (n=20, 10–20 mg/day) or low- sponse rates were also similar to DAS treated successfully in resource-lim-
dose rituximab (n=20, 500 mg on days (42 and 40 percent in the leflunomide ited settings,” they said, though they
1 and 15) in addition to methotrexate and rituximab arms, respectively). recommended use of the lefluno-
(10–20 mg/week). [BMC Musculoskelet mide-methotrexate combination first,
Disord 2017;doi:10.1186/s12891-017- There was a significant reduction in given previous evidence showing the
1673-3] memory B cells in both leflunomide and safety of leflunomide-methotrexate. [J
rituximab arms (p<0.01 and p<0.001, Rheumatol 2013;40:228-235]
At week 24, American College of respectively) as well as pneumococ-
Rheumatology (ACR) responses reflect- cal antibody levels (p<0.05 for both) at * DMARDs: Disease-modifying antirheumatic drugs
# ACR20, ACR50, and ACR70: Varying degrees of
ed a comparable efficacy between le- week 24, the latter being a concern, as improvement in RA symptoms corresponding to
flunomide and rituximab (84 percent vs it increases the likelihood of reduced 20, 50, and 70 percent on a scale of 28 intervals
45
NEWSBITES
Antibiotic resistance in H. pylori should influence

treatment strategy in Asia-Pacific
T
he increasing resistance to cer-
tain antibiotics in Helicobacter
pylori (H. pylori) eradication ther-
apies is associated with a reduction in
treatment efficacy in Asia-Pacific coun-
tries, and treatments should be adapt-
ed accordingly, according to a system-
atic review and meta-analysis.
“The rise in clarithromycin and levo-

floxacin resistance in the past 25 years
in most countries in the Asia-Pacific
region is concerning, and this should Primary H. pylori resistance prev- reduced efficacy of clarithromycin-con-
prompt the development of effective alence was most evident for metroni- taining H. pylori treatment regimens
strategies to control antibiotic resis- dazole (mean prevalence, 44 percent), (<80 percent). Conversely, countries
tance,” said the researchers led by Dr followed by levofloxacin, clarithromy- with low clarithromycin resistance (<15
Kuo Yu-Ting from the National Taiwan cin, tetracycline, and amoxicillin (mean percent) demonstrated higher efficacy
University Hospital Bei-Hu Branch in prevalence, 18, 17, 4, and 3 percent, of clarithromycin triple therapy (>80
Taipei, Taiwan. respectively). [Lancet Gastroenterol percent).
Hepatol 2017;doi:10.1016/S2468-125
“First-line treatment strategies 3(17)30219-4] “These findings collectively suggest
should be adapted to resistance pat- that, although clarithromycin-based
terns on a country-by-country basis … There was a marked increase in triple therapy can still be used as the
[and] prospective studies are warranted resistance to clarithromycin, metroni- standard first-line treatment in countries
to continuously monitor the prevalence dazole, and levofloxacin between the where clarithromycin resistance is low-
of antibiotic resistance in H. pylori in years prior to 2000 and 2011–2015 (7 er than 15 percent, alternative first-line
the Asia-Pacific region,” said Kuo and percent to 21 percent for clarithromy- regimens, such as bismuth quadru-
co-authors. cin, 36 percent to 45 percent for met- ple therapy or nonbismuth quadruple
ronidazole, and 2 percent to 27 per- therapies, should be considered in
The systematic review and me- cent for levofloxacin), while resistance countries with high clarithromycin resis-
ta-analysis involved two analyses of to amoxicillin and tetracycline did not tance,” said Kuo and co-authors.
studies published between January change drastically over time.
1990 and September 2016 – analysis The researchers acknowledged the
of primary antibiotic resistance (obser- According to the researchers, the significant heterogeneity between stud-
vational studies and RCTs; 176 articles increase in clarithromycin resistance ies, which was influenced by the study
from 24 countries) and analysis of ef- could be attributed to the rise in con- regions, periods, resistance-measuring
ficacy of first-line H. pylori eradication sumption of macrolides, while metro- methods, and region-specific infec-
therapy (RCTs only; 170 articles from nidazole resistance, which was higher tions.
16 countries). in developing countries and lower in
countries with higher socioeconomic “Our findings provide policy makers
Study participants were adults status, may be linked to the use of this with the necessary evidence to decide
(aged ≥18 years) diagnosed with H. antibiotic for conditions such as para- optimal first-line eradication regimens
pylori using a standard diagnostic site infestations or dental infections in according to local prevalence of pri-
method, with no history of receiving developing countries. mary antibiotic resistance and develop
eradication therapy for H. pylori, and effective strategies to control the rising
no antibiotic use in the 2 weeks prior to Countries with high clarithromycin antibiotic resistance in their countries,”
recruitment. resistance rates (>20 percent) had a they said.
46
NEWSBITES
Breastfeeding may lower risk of asthma

exacerbations in children
PEARL TOH
B
reastfeeding in children with
asthma was associated with a
reduced risk of asthma exac-
erbations, especially in children with a
family history of asthma, according to
the PACMAN* study.
Compared with asthmatic children

who were never breastfed, those who
had been breastfed were 45 percent
less likely to experience asthma exac-
erbations at age 4–12 years (adjusted
odds ratio [OR], 0.55; p=0.01), after
adjusting for age and eczema. The pro-
portion of children with asthma exacer-
bations were also significantly lower in
those who were ever-breastfed vs nev- tions in children (OR, 0.48; p=0.01) the previous year and asthma control
er-breastfed (9 percent vs 15 percent; while the association was no longer based on ACQ-6 within the last week
p=0.007). [Pediatr Allergy Immunol significant for a breastfeeding duration of visit were also documented.
”
2017;doi:10.1111/pai.12760] of ≥6 months (OR, 0.71; p=0.20).
“Although in our study, breastfeed-
When the analysis was stratified ing was shown to be a protective factor
by family asthma history, the associ- “[T]he relation might be for asthma exacerbations, it is still un-
ation between asthma exacerbations explained by the influence clear whether there is a causal relation
and breastfeeding was only significant between breastfeeding and asthma
of breastfeeding on the
in children with a positive history (OR, exacerbations,” said Maitland-van der
0.34; p=0.001), but not in those with- immune system” Zee.
out (OR, 1.08; p=0.82).
“[An] important limitation is the
“[T]he relation might be explained However, no association was found cross-sectional nature of our study.
by the influence of breastfeeding on the between breastfeeding and the like- When exposure and outcome are mea-
immune system. Changes in the com- lihood for poor asthma control as as- sured at one moment [or period] in
position and activity of the gut microbi- sessed by Asthma Control Question- time, the risk of reverse causality would
ome in early life can influence the im- naire (ACQ)-6 after controlling for family be a major problem … The optimal de-
mune system and these changes might asthma history (OR, 1.04; p=0.83). The sign for this study is a prospective lon-
indirectly lead to changes in asthma results remained even after stratifying gitudinal design,” said Maitland-van der
later in life,” said principal investigator the analysis by duration of breastfeed- Zee and co-authors.
Professor Anke-Hilse Maitland-van der ing.
Zee from the Department of Respirato- They also added that question-
ry Medicine at the University of Amster- The study involved 960 children naire-based data are subjected to recall
dam in the Netherlands. (mean age 8.4 years, 62 percent boys, bias and suggested further studies be
74 percent breastfed) who were using conducted to confirm the association
Stratifying the analysis by the du- regular asthma medication for the past and understand the underlying mech-
ration of breastfeeding, the research- 2 years in the Netherlands. Breast- anisms.
ers found that breastfeeding for up to feeding exposure and duration were
* PACMAN: Pharmacogenetics of Asthma
6 months was significantly associated self-reported by the parents based on medication in Children ─ Medication with ANti-
with a lower risk of asthma exacerba- questionnaire. Asthma exacerbations in inflammatory effects
47
NEWSBITES
Ridinilazole potentially effective for C. difficile

infection
AUDREY ABELLA
T
he novel, targeted-spectrum an-
timicrobial ridinilazole showed
potential in the treatment of initial
Clostridium difficile (C. difficile) infection
compared with vancomycin, a new
study finds.
In a phase 2, double-blind trial,

100 C. difficile-positive patients were
randomized to receive ridinilazole 200
mg/12 hours (n=50) or vancomycin
125 mg/6 hours for 10 days (n=50).
A total of 69 patients (n=36 and 33 in
the ridinilazole and vancomycin arms,
respectively) were included in the mod-
ified intention-to-treat (ITT) population. “The superiority of ridinilazole [over] “[Furthermore, recurrence] places a
”
[Lancet Infect Dis 2017;17:735-744] vancomycin with regard to sustained substantial burden on patient welfare,
clinical response was driven by a is associated with increased morbidity
marked reduction in recurrent C. difficile and mortality, and is difficult to treat.”
“[S]afe and effective infection, which is likely due to the high-
alternatives that do not ly selective activity of ridinilazole against Given the high recurrence rates as-
C. difficile and the absence of collateral sociated with other antibiotics recom-
negatively affect the
damage to the microbiota during thera- mended for C. difficile, such as metro-
normal gut microbiota py,” said the researchers. nidazole and vancomycin, and the lack
[may facilitate the] of improvement against other C. difficile
prevention of recurrent On subgroup analysis, ridinilazole strains (ie, BI/NAP1/027) with fidaxo-
remained associated with more sus- micin, it is imperative to evaluate other
C. difficile infection …
tained clinical responses than vanco- drugs that could mitigate these out-
Ridinilazole has potential mycin in patients >75 years (ETD, 42.7 comes, noted the researchers.
as a new treatment for C. percent), those with severe disease
difficile infection, owing to (ETD, 15.9 percent), and those with “[S]afe and effective alternatives
previous episodes of C. difficile infec- that do not negatively affect the nor-
its good sustained clinical
tion (ETD, 19.9 percent). mal gut microbiota [may facilitate the]
response rates” prevention of recurrent C. difficile infec-
“[These subgroups were evaluated tion … Ridinilazole has potential as a
as] all are at increased risk of infec- new treatment for C. difficile infection,
Clinical response at test of cure in tion and of disease recurrence follow- owing to its good sustained clinical re-
the ridinilazole and vancomycin arms ing treatment,” said the researchers, sponse rates … probably as a result of
had an estimated treatment difference adding that having faecal-toxin-posi- decreased disturbance of the normally
(ETD) of 8.3 percent (90 percent confi- tive subjects adds significance to their protective intestinal microbiota,” they
dence interval [CI], −9.3 to 25.8), trans- evaluation given the worse clinical out- said.
lating to noninferiority of ridinilazole to comes associated with the presence of
vancomycin. In addition, sustained faecal toxins. Although the results are encour-
clinical response established superior- aging, the researchers called for larger
ity of ridinilazole over vancomycin (ETD, It is important to treat C. difficile studies with longer follow-up periods to
21.1 percent, 90 percent CI 3.1–39.1; infection as it entails a significant eco- further confirm the findings.
p=0.0004). nomic burden, noted the researchers.
48
NEWSBITES
Nonavalent HPV vaccine effective for more than

5 years
the nonavalent HPV vaccine had 97.4
percent efficacy in the prevention of
high-grade cervical, vulvar and vaginal
disease associated with the addition-
al five HPV genotypes. Both vaccines
were equally effective for HPV 6, 11, 16
”
and 18, and had similar safety profiles.
“The participants were

given three intramuscular
injections over a
duration of 6 months of
either the nonavalent
or quadrivalent HPV
vaccine”
The primary outcomes measured

in the study were the incidence of
high-grade cervical disease, vulvar dis-
DR JOSLYN NGU a senior scientist at the UAB Compre- ease and vaginal disease associated
A
hensive Cancer Center, US. with HPV 31, 33, 45, 52 and 58; and
ccording to a study, the nona- non-inferiority of anti-HPV 6, 11, 16
valent Gardasil® 9 vaccine is The study is a follow-up of a pre- and 18 geometric mean titres.
effective in preventing infections vious efficacy and safety study of the
caused by all nine human papilloma vi- nine-valent HPV vaccine published in Human papilloma virus can cause
rus (HPV) genotypes for longer than 5 The New England Journal of Medicine. cervical, vulvar, vaginal and anal can-
years. [Lancet 2017;doi:http://dx.doi. A total of 14,215 women between the cers. Globally, cervical cancer is the
org/10.1016/S0140-6736(17)31821- ages of 16 and 26 who were healthy, fourth most common cancer in women
4] with no history of abnormal cervical cy- and in low-income countries, HPV is
tology, no previous abnormal cervical the cause of nearly all cervical cancers.
“Seventy-five years ago, cervical biopsy results, and ≤4 lifetime sexual [Arch Pharm Res 2017;doi:10.1007/
cancer was a very common cause of partners, participated in the study. The s12272-017-0952-8. Epub ahead of
mortality in the US. Looking forward, participants were given three intra- print]
with widespread vaccination, it is high- muscular injections over a duration of
ly likely that cervical cancer will evolve 6 months of either the nonavalent or There are three HPV vaccines avail-
into historical interest only, and screen- quadrivalent HPV vaccine. able in the market, namely Cervarix
ing, like Pap smears, might go away (bivalent), Gardasil and Gardasil 9. De-
altogether. HPV vaccines are one of The older quadrivalent HPV vaccine spite the availability of vaccines, vacci-
the most scrutinized vaccines ever, but called Gardasil is effective against four nation rates are suboptimal. According
multiple studies have demonstrated HPV genotypes: HPV 6, 11, 16 and to studies, the reasons include a lack
the vaccine to be safe and well-toler- 18. The newer nonavalent HPV vac- of knowledge on the disease and vac-
ated,” said primary author Dr Warner cine—Gardasil 9—is effective against cine, and not receiving a recommenda-
Huh, professor and director of the the same four genotypes and also an tion from healthcare practitioner. [Glob
University of Alabama, Birmingham Di- additional five: HPV 31, 33, 45, 52 and Health Action 2016;9(1):29336, J Ado-
vision of Gynaecologic Oncology and 58. According to the study findings, lesc Health 2017;61(3):288–293]
49
CLINICAL INSIGHTS | DEVICE
Cuff BP readings differ from

invasive measures
PEARL TOH derestimation, but significant overes-
N
timation of DBP and underestimation
oninvasive cuff-measured blood of pulse pressure was still observed,”
pressure (BP) is significantly dif- noted the researchers.
ferent from invasive method of
measuring intra-arterial BP, particularly The third meta-analysis showed
for individuals with pre- or stage 1 hy- that although the difference between
pertension (HTN) in whom intra-arterial intra-arterial aortic SBP and cuff read-
brachial systolic BP (SBP) is underesti- ing was small (0.3 mm Hg; p=0.77), the
mated and diastolic BP (DBP) is over- agreement remained poor at the indi-
estimated by cuff measurement, reveal vidual level.
recent meta-analyses, suggesting a
need for improved noninvasive meth- Based on the JNC 7 categories for
ods of measuring BP. BP classification, cuff BP only agreed
with intra-arterial brachial BP at 60, 50,
The study comprised three me- 53, and 80 percent of the time in clas-
ta-analyses using individual participant sifying patients into normal, pre-HTN,
data involving 3,073 participants from HTN stage 1 or stage 2, respectively,
74 studies, which compared the accu- which according to the researchers, in-
racy of cuff BP with intra-arterial BP as dicates that “the observed variability in
reference standards. [J Am Coll Cardiol cuff BP accuracy adversely influenced
2017;70:572-586] correct classification of BP … with par-
ticular discordance in the range from
The first meta-analysis examined pre-HTN to stage 1 HTN.” “The mean
the level of agreement between true in- difference in the magnitude of the un-
tra-arterial brachial and aortic BP, mea- derestimation often exceeded 10 mm
sured using invasive methods. The re- Hg. Translating these error margins
searchers found that intra-arterial SBP to the traditional classification of BP
was higher by 8 mm Hg when mea- based on intra-arterial SBP readings,
sured at the brachial site than at the cuff BP correctly identified pre-HTN
aortic site (p<0.0001), while intra-arte- and stage 1 HTN in only about one-half
rial brachial DBP was lower than aortic of the participants, whether based on
readings by 1.0 mm Hg (p=0.038). intra-arterial brachial or aortic SBP,” ob-
served the researchers.
”
Comparing cuff and intra-arterial
BP in the second meta-analysis, in- “Improvement of BP device accura-
tra-arterial brachial SBP was underesti- cy standards is desirable … Intra-arteri-
“The observed mated by 5.7 mm Hg (p<0.0001) while al BP measured under rigorous criteria
variability in cuff BP intra-arterial brachial DBP was over- has the strongest level of BP accura-
accuracy adversely estimated by 5.5 mm Hg (p<0.0001) cy and may be a better choice as the
in cuff readings, regardless of whether comparator for BP device validation.
influenced correct oscillometric or auscultatory methods But, it is less practical, and it is not eth-
classification of BP (with a mercury sphygmomanometer) ical to use among some populations,”
… with particular were used. they added, noting that mercury sphyg-
discordance in the momanometer is often used as a refer-
“Compared with intra-arterial bra- ence in BP validation protocols. “These
range from pre-HTN chial BP, the mercury method per- findings indicate that stronger accuracy
to stage 1 HTN” formed better than oscillometric BP standards for BP devices may improve
with respect to the level of SBP un- cardiovascular risk management.”
50
CLINICAL INSIGHTS | IN PRACTICE
Managing hyper- and

hypothyroidism in primary
care
H
yperthyroidism and hypothy- presents with symptoms that could be
roidism can lead to various related to thyroid conditions, or if the
complications if left untreated. GP notices anything about the patient
Dr Adoree Lim Long-standing hyperthyroidism can which could be caused by a thyroid
lead to, among others, atrial fibrillation, condition.
cardiac failure, and osteoporosis, and
severe untreated hyperthyroidism (and Some symptoms and physical
noncompliance to treatment) puts a signs associated with hyperthyroidism
patient at risk of thyroid storm. include anxiety and nervousness, trem-
bling hands, weight loss, constantly
Untreated hypothyroidism can feeling warm, frequent bowel move-
lead to generalized slowing of the me- ments, and a fast heart rate. In women,
tabolism and multiple cardiovascular menstrual periods may become irreg-
complications. In extreme situations, ular. In patients with Graves’ disease,
hypothyroidism can result in myxoede- eyes may become more prominent.
ma coma, the hallmarks of which are
decreased mental status and hypo- Symptoms and physical signs as-
thermia, as well as hypotension, bra- sociated with hypothyroidism include
dycardia, hyponatraemia, hypoglycae- constant tiredness, dry skin, hair loss,
mia, and hypoventilation, and patients constipation, leg cramps, and weight
will exhibit clinical features of severe gain. In women, menstrual periods may
hypothyroidism such as puffiness of become heavier. However, many of
the hands and face, a thickened nose, these symptoms are not very specific
swollen lips, enlarged tongue, and typ- and may be experienced by otherwise
ical “hung-up” reflexes. normal individuals.
Causes of hyper- and If there are relevant symptoms and

hypothyroidism signs, a blood test for the patient’s thy-
Common causes of hyperthyroidism in- roid function should be obtained. Hy-
clude Graves’ disease, toxic adenoma, perthyroidism is confirmed by perform-
or toxic multinodular goitre. More un- ing a blood test which measures both
commonly, subacute thyroiditis might T4 and TSH levels, where T4 levels
Roshini Claire Anthony be a cause of transient hyperthyroid- would be high and TSH levels very low.
ism. The most common cause of hy-
speaks to Dr Adoree
pothyroidism is Hashimoto’s thyroiditis. The best way to diagnose hypothy-
Lim, a consultant Some patients may be hypothyroid due roidism is also with a blood test, where
at the Department to previous treatment with radioactive patients would have low T4 and high
of Endocrinology, iodine or surgical thyroidectomy. Occa- TSH levels.
Singapore General sionally, patients on certain drugs (eg,
Hospital, on how GPs amiodarone or lithium) may also have The TSH-receptor antibody levels
hypothyroidism. may be tested to diagnose Graves’ dis-
can help tackle hyper-
ease in patients with hyperthyroidism,
and hypothyroidism Diagnosis while the thyroid peroxidase antibody
in the primary care The GP should take a thorough histo- (TPOAb) will help diagnose Hashimo-
setting. ry of possible symptoms and perform to’s thyroiditis in patients with hypothy-
a physical examination if the patient roidism.
51
CLINICAL INSIGHTS | IN PRACTICE
Patients who have a constellation of

autoimmune conditions should also be
sent to the specialist.
Conclusion
While we do not have data on the
prevalence of all thyroid conditions in
Singapore, it is fair to say that thyroid
problems are relatively common and
we expect their prevalence in Singa-
pore to be fairly similar to that of oth-
er developed countries. As such, it is
Some symptoms of thyroid condi- whereas others may relapse and may helpful to have a good knowledge of
tions are nonspecific and may there- need referral for definitive treatment in how to manage the more straightfor-
fore overlap with other diagnoses. As specialist care. Patients with hypothy- ward cases in the primary care setting.
such, it is important to take a detailed roidism will usually require lifelong thy-
history and perform a thorough phys- roxine replacement.
ical examination to look for evidence Practice Guidelines
that supports the diagnosis of a thyroid Surgery may be necessary in a
condition. patient with Graves’ disease who has
American Thyroid Association
previously relapsed but does not want
www.thyroid.org/professionals/ata-
Routine screening is probably un- radioactive iodine as a treatment op-
professional-guidelines/
necessary. However, there are certain tion. Thyroid surgery involves removing
patients who might be at a higher risk most of the thyroid gland. This is an
British Thyroid Association
for thyroid conditions (ie, patients with effective treatment for hyperthyroidism,
www.british-thyroid-association.org/
a history of other autoimmune condi- and is particularly recommended if the
current-bta-guidelines-
tions such as type 1 diabetes or pa- goitre is very big and cosmetically un-
tients with a very strong family history attractive. Surgery is also carried out if
American Family Physician
of thyroid diseases). there is a concern about thyroid can-
www.aafp.org/afp/
cer.
topicModules/viewTopicModule.
Treatment
htm?topicModuleId=67
Hyperthyroidism may be treated with Specialist referral
either carbimazole or propylthiouracil. GPs should refer the patient to a spe-
National Comprehensive
The dose given is usually dependent on cialist whenever they feel that they
Cancer Network
the initial level of thyroid hormones. As are not comfortable with the patient’s
www.tri-kobe.org/nccn/guideline/
the condition improves (and depending progress. In particular, some cases of
gynecological/english/cervical_
on the underlying cause of hyperthy- Graves’ disease, especially the ones
screening.pdf
roidism), the dose of the medications who have previously relapsed or have
should be decreased according the high antibody levels, may be more dif-
patient’s symptoms and thyroid func- ficult to treat and may need specialist
tion tests. input or further treatment, such as ra-
dioactive iodine, which is only available
Scan the
Hypothyroidism should be treated at tertiary hospitals.
QR code to
with levothyroxine replacement. The
view more of
dose of levothyroxine will vary from pa- There are specific conditions that
MIMS clinical
tient to patient and should be adjusted should definitely be managed by a spe-
news
according to the patient’s symptoms cialist. Patients whose thyroid function
and thyroid function tests. tests do not fall into the typical pattern
of either primary hyperthyroidism or hy-
Patients with Graves’ disease may pothyroidism should be sent to a spe-
be treated with antithyroidal medica- cialist for further evaluation. Patients
tions for 12–18 months and reassessed diagnosed with thyroid conditions and
after that. Some of these patients who later become pregnant should
may no longer need further treatment also be sent for further specialist care.
52
Sponsored Meeting Highlights
GPs in co-management of IBD:

The follow-up phase
Last August, the article 'Role of General Practitioners in Early Detection of
Inflammatory Bowel Disease' highlighted proper screening and early specialist
referral by the general practitioner (GP) as vital components in reducing the
burden of inflammatory bowel disease (IBD). This year, the focus is on the role
of GPs in co-managing a patient with IBD at the follow-up phase.
Professor Dr Ida Normiha Hilmi Associate Professor Dr Alex Leow

Consultant Gastroenterologist Consultant Gastroenterologist & Hepatologist
Professor of Medicine Associate Professor of Medicine
University Malaya Medical Centre University Malaya Medical Centre
GP
s aa GP
AAs
 What can you do to co-manage patients with IBD?
 What are the warning signs and symptoms indicative of IBD flares to look out for?
 How often should you refer a co-managed patient back to a specialist?
A multidisciplinary team, which includes symptoms and underlying disease activity.4 A workup with
GPs, improves the quality of patient care proper screening tests may be better predictors of IBD
flares.3,4
in IBD
IBD is a complex condition that requires co-management
involving a multidisciplinary team to effectively treat patients
with this disease. A multidisciplinary team is important
because it helps to address the various facets of IBD
“ Patients are usually aware of
their own IBD flare warning signs
”
Professor Ida Normiha Hilmi
management and also to improve the quality of patient That being said, it is still beneficial to brief the patient
care. In a hospital setting, a multidisciplinary team for IBD on warning signs or symptoms to look out for as this
should consist of gastroenterologists, surgeons, dieticians knowledge may help patients seek medical care in a
and nurses.1 timely manner. Fever, diarrhoea, bleeding, loss of appetite
and bowel discomfort are signs and symptoms that may
The inclusion of GPs to support the multidisciplinary team
suggest of an impending IBD flare.2
is an area worthy of further consideration.1 Local GPs with
special interest in IBD may assist the gastroenterologist in
co-managing an IBD patient by providing ongoing support Co-managing IBD at the GP’s clinic:
and monitoring of patients with IBD.1 Co-management Things to watch out for
of IBD with a GP also gives a patient the advantage of
receiving routine management from a physician with Proper disease workup and objective assessment of
whom the patient usually has a closer relationship and a patients’ symptoms and laboratory markers are important
greater rapport. Another advantage of involving GPs in IBD in controlling the frequency of IBD flares.5
co-management is convenience. Convenience and travel
distance play key roles in patient follow-up and adherence. When a patient is referred to a GP by the gastroenterologist,
This is particularly relevant in areas with limited access to the GP should obtain the patient’s IBD-relevant
tertiary care hospitals.2 measurements from the referring institution. If reports
of laboratory findings are not available, the GP may
Knowledge of warning signs and symptoms consider conducting a series of tests presented in
of IBD flares may lead patients to timely Table 1 to construct a patient’s baseline measurement.
The tests should be repeated frequently (every 3 to 6
medical care
months) during routine follow-ups even for asymptomatic
It is important to note that for patients with IBD, symptoms patients. Markers showing a noticeable increasing trend,
alone are a poor indicator of disease flare.3 Patient-reported particularly faecal calprotectin and C-reactive protein
symptoms tend to be subjective in nature, and research that are indicative of inflammation, may facilitate early
shows that there is poor correlation between patient detection of an impending flare. 5–9
Approximately one-third of patients with IBD have Table 2: Lifestyle modification advices for patients
extraintestinal manifestations (EIMs), which may be present with IBD
even when the disease is inactive.10 Common EIMs to look
out for include arthralgia, jaundice, rashes and uveitis, Eat a balanced diet15,16  A balanced diet is important for IBD
and GPs can play a role in detecting these during routine patients because many may have
some form of nutrient deficiency as
follow-ups.11,12
a result of intestinal inflammation
that impairs nutrient absorption.
Table 1: Suggested routine IBD tests in primary care  There is often a perception
that excluding certain foods is
Test Monitoring considerations important in avoiding flares in IBD
but the ESPEN guidelines for IBD
FBC6–8  Haemoglobin levels should be do not recommend exclusion diets
monitored. for the majority of patients.
 Anaemia is common among IBD  Advocate a balanced diet consisting
patients. Causes include iron- of a variety of food from major food
deficiency anaemia as a result of groups – such as meat, fish, dairy
impaired iron absorption due to products and vegetables – while
intestinal inflammation, anaemia keeping in mind to ensure an adequate
of chronic disease and anaemia intake of calories and nutrients.
secondary to medications such as
azathioprine. Compliance to  Advise patients not to stop taking
 In patients with small bowel Crohn’s medications17–25 their medications. Adherence to
disease, vitamin B12 should also be treatment is crucial in preventing
monitored. flares and ensuring patients stay in
remission.
LFTs6  Monitoring of liver function may be  Educate patients on the possible
required as certain medications, side effects associated with IBD
such as, azathioprine may cause liver medications.
toxicity.
÷ Azathioprine is used in IBD for its
 LFTs are also used to diagnose rare immunosuppressive properties
liver complications associated with IBD and is an effective therapy to
such as primary sclerosing cholangitis. maintain remission in IBD. Side
effects of azathioprine include
CRP6,8  CRP, an inflammation marker, bone marrow depression,
is not IBD-specific but can be nausea, liver damage and GI
used to monitor disease activity disturbances.
since increased disease activity
is associated with increased ÷ Mesalazine, an anti-inflammatory
inflammation. It is useful for detecting under the drug class of
trends in inflammation. 5-aminosalicylates, is commonly
used to suppress inflammation
Faecal calprotectin  Faecal calprotectin is a non-invasive and prevent IBD flare-ups. Side
test6,8,9,13,14 surrogate marker of intestinal effects include GI disturbances,
inflammation that can be used to headaches, dizziness and rashes.
monitor disease activity. Interstitial nephritis is a very rare
but serious potential side effect.
 Regular faecal calprotectin tests may
reduce the frequency of colonoscopy.  Educate the patients on the use of
other medications or alternative
Stool culture 6,7  A stool culture should be carried out in treatments. For example, cautious
IBD flares to rule out infections which use of NSAIDs (ideally avoided
can both mimic and precipitate flares. but not contraindicated) and
discourage the use of alternative
CRP: C-reactive protein; FBC: full blood count; IBD: inflammatory treatments with poor evidence,
bowel disease; LFTs: liver function tests such as, traditional Chinese
medication.
Address unhealthy  Advise patients to stop smoking.

Patient education is another area for the habits24,26,27
 Studies show that smokers are
role of GPs in co-managing IBD more likely to develop Crohn’s
disease compared with non-
Patient education is crucial to setting patients’ expectations smokers; smoking also increases
and reinforcing their role in managing IBD flares. In this the severity of the disease.
aspect, GPs, key figures in Malaysian primary care setting,
 Educate patients on the importance
can assist in educating patients on lifestyle modifications of managing stress properly as
and dispelling myths and misbeliefs associated with the stressful situations have been linked
disease (Table 2). Through education, patients can be to increased risk of IBD flares.
empowered to play an active role in managing IBD by
ESPEN: European Society for Clinical Nutrition and Metabolism;
seeking proper medical care and advice when the situation GI: gastrointestinal; IBD: inflammatory bowel disease; NSAIDs:
calls for it. nonsteroidal anti-inflammatory drugs
The internet is a treasure trove of patient education References: 1. Crohns’s & Colitis UK. Multidisciplinary approach is key
to best treatment of IBD. Available at: https://www.crohnsandcolitis.org.
materials on IBD. www.guts4life.com.my is an example of uk /news/a-multidisciplinary-approach-is-key-to-best-treatment-of-
an online resource on IBD available in Bahasa Malaysia ibd. Accessed 3 July 2017. 2. Kelly C, et al. BMJ Open 2016;6:e013059.
that is tailored to Malaysian patients. 3 . Me d s c a p e. Inf la mmato r y B owe l D i s e a s e. Ava ila ble at: ht tp: //
emedicine.medscape.com/article/179037-overview. Accessed 3 July
2017. 4. European Crohn’s and Colitis Organisation. Correlation of clinical
English Bahasa Malaysia symptoms to current biomarkers of intestinal inflammation in patients
with Crohn’s disease. Available at: https://www.ecco-ibd.eu/index.
php/publications/congress-abstract-s/abstracts-2013/item/p266 -
correlation-of-clinical-symptoms-to-current-biomarkers-of-intestinal-
inflammation-in-patients-with-crohn-s-disease.html. Accessed 12 July
2017. 5. Vermeire S, et al. Gut 2006;55:426–431. 6. Crohn’s & Colitis
UK. Tests and Investigations for IBD. Available at: http://s3-eu-west-1.
amazonaws.com/files.crohnsandcolitis.org.uk/Publications/tests-and-
Scan to access Scan to access investigations.pdf. Accessed 3 July 2017. 7. Alves RA, et al. Sao Paulo
www.guts4life.com www.guts4life.com.my Med J 2014;132:140–146. 8. Medscape. Inflammatory Bowel Disease
Workup. Available at: http://emedicine.medscape.com/article/179037-
workup#. Accessed 3 July 2017. 9. United Healthcare Oxford. Fecal
Calprotectin Testing. Available at: https://www.oxhp.com/secure/
When to refer back to a specialist policy/fecal_calprotectin_testing.pdf. Accessed 3 July 2017. 10. Adams
SM, Bornemann PH. Am Fam Physician 2013;87:699 –705. 11. Agrawal
D, et al. Minerva Gastroenterol Dietol 2007;53:233–248. 12. Levine
Timely referral to a specialist centre for advanced JS, et al. Gastroenterol Hepatol (NY) 2011;7:235–241. 13. Oxfordshire
procedures such as colonoscopy helps to improve the Clinical Commissioning Group. Integrating faecal calprotectin testing
management of IBD flares, leading to better patient into the diagnostic pathway for IBD and IBS. Available at: http://www.
oxfordshireccg.nhs.uk /professional-resources/documents/clinical-
outcomes. A patient assessed to be at risk of an IBD flare guidelines/gastroenterology/faecal-calprotectin-CCG-aug-2014.pdf.
or one in whom an IBD complication is suspected that Accessed 25 July 2017. 14. European Crohn’s and Colitis Organisation.
The use of faecal calprotectin in IBD and reducing unnecessary
requires specialized intervention should be referred back colonoscopy. Available at: https://www.ecco-ibd.eu/publications/
to the gastroenterologist. Patients’ risk of IBD flares can be congress-abstract-s/abstracts-2014/category/poster-presentations-
detected through routine monitoring of patients’ symptoms clinical-diagnosis-outcome.html. Accesed 25 July 2017. 15. Crohn’s
& Colitis Foundation. Diet and Nutrition. Available at: http://www.
as well as evaluation of IBD-relevant laboratory markers.5 c r o h n s c o l i t i s fo u n d a t i o n .o r g /r e s o u r c e s /d i e t- a n d - n u t r i t i o n.h t m l.
Patients with IBD are at increased risk of developing Accessed 5 July 2017. 16. Forbes A, et al. Clin Nutr 2017;36:321–347.
17. Trivedi I, et al. Inflamm Bowel Dis 2016;22. 18. Feagins LA, et al.
colorectal cancer; regular surveillance may aid in early World J Gasteroenterol 2014;20:4329 –4334. 19. Association for Patient
detection of cancer. Multiple gastroenterology societies Experience. Improving Medication Compliance. Available at: http://
recommend a colonoscopy every 1 to 3 years depending www.patient-experience.org/Resources/Best-Practices/Case-Studies/
Improving-Medication-Communication.aspx. Accessed 12 July 2017.
on the patient’s assessed risk, with higher risk patients 20. Crohn’s & Colitis Foundation. Maintenance Therapy. Available
requiring yearly screening.28–30 at:ht tp://www.crohnscolitisfoundation.org/resources/maintenance-
therapy.html. Accessed 3 July 2017. 21. Drug Bank. Azathioprine.
Available at: https://www.drugbank.ca/drugs/DB00993. Accessed 5 July
Summary 2017. 22. MIMS Malaysia. Azathioprine. Available at: http://www.mims.
com/malaysia/drug/info/azathioprine. Accessed 5 July 2017. 23. MIMS
Malaysia. Mesalazine. Available at: http://www.mims.com/malaysia/
IBD is a chronic inflammatory disease that requires lifelong drug/info/mesalazine. Accessed 5 July 2017. 24. BMJ Best Practice.
treatment and management. A multidisciplinary team Crohn’s Disease. Available at: http://bestpractice.bmj.com/best-
that includes GPs helps to improve the quality of patient practice/monograph/42/follow-up/recommendations.html. Accessed 5
July 2017. 25. Mowat C, et al. Gut 2011;60:571–607. 26. Crohn’s & Colitis
care in IBD. The role of GPs in co-managing IBD include UK. Smoking and IBD. Available at: http://s3-eu-west-1.amazonaws.
routine monitoring and evaluation of clinical symptoms com/files.crohnsandcolitis.org.uk/Publications/smoking-and-IBD.pdf.
Accessed 10 July 2017. 27. Bernstein CN, et al. Am J Gasteroenterol
and laboratory markers; as well as patient education in 2010;105:19 9 4 –2002. 28. American Society for Gastrointestinal
recognizing the warning signs of disease flare-ups, the Endoscopy Standards of Practice Committee. The role of endoscopy in
importance of treatment adherence to ensure remission, inflammatory bowel disease. Available at: https://www.asge.org/docs/
default-source/education/practice_guidelines/doc-endoscopy_in_ibd.
possible medication side effects to look out for and pdf. Accessed 10 July 2017. 29. Cairns SR, et al. Gut 2010;59:666–689.
maintaining a healthy lifestyle. In a properly implemented 30. Crohn’s & Colitis Foundation. Consensus Conference: Colorectal
Cancer Screening and Surveillance in Inflammatory Bowel Disease.
co-management setting, GPs can be invaluable partners Available at: http://www.crohnscolitisfoundation.org/assets/pdfs/
in ensuring timely referral of IBD patients to specialist care. consensus-conference.pdf. Accessed 12 July 2017.
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Sponsored Symposium Highlights
Evolution of influenza vaccines

– broader protection for patients with
chronic respiratory diseases and lung cancer
At the Malaysian Thoracic Society Annual Scientific Congress 2017 held recently in Kuala Lumpur,
Associate Professor Pang spoke on the importance of influenza vaccination in patients with chronic
respiratory diseases and lung cancer, highlighting the benefit of quadrivalent influenza vaccines (QIVs) in
providing a wider spectrum of protection against influenza types A and B.
Influenza disease burden in chronic

respiratory patients and the role Associate Professor Yong-Kek Pang
Consultant Respiratory Physician
University of Malaya Medical Centre
of influenza vaccination
Influenza is a major public health concern worldwide – about and 2.4% to 37.6% among children aged 6–7 years.6
3–5 million cases of severe illness and 300,000–500,000 deaths Children with asthma are at high risk of severe disease
are reported every year.1 Seasonal influenza viruses circulate and complications from influenza infection. In a study
mainly during winter in countries with temperate climates. In to investigate the association between upper and lower
contrast, tropical countries like Malaysia have irregular, seasonal respiratory viral infections and acute exacerbations of asthma
influenza outbreaks which may occur all year round.1 The exact in schoolchildren, investigators found that viral infections of
incidence of influenza in this country is unknown. In a recent the upper respiratory tract, including influenza, are the main
report on the evolution and epidemiology of influenza viruses in cause of asthma exacerbations.7 In addition, the average
Malaysia from 2012 to 2014, the influenza A and B were noted to hospitalization rates as a consequence of influenza were
circulate simultaneously (Figure).2 significantly higher among children with asthma than healthy
children (2.8 vs 0.6 cases per 1,000 children).8 Therefore,
in line with the recommendation from the US Centers for
Figure. Monthly distribution of
Disease Control and Prevention (CDC), influenza vaccination
influenza A and B infections in Malaysia2 is suggested for people with asthma aged 6 months and older.8
40
Influenza vaccination in patients with chronic obstructive
No. of influenza positive case
35
Influenza A
30 Influenza B pulmonary disease (COPD) is associated with fewer hospitalizations
and outpatient visits
25
20
Patients with COPD are at an increased risk of respiratory
15
illness-related hospitalization during influenza outbreaks,
10 regardless of age and degree of morbidity.9 According to the
5 Global initiative for chronic Obstructive Lung Disease (GOLD)
0 2017 guidelines, influenza vaccination has level B evidence in
reducing serious illnesses and deaths in patients with COPD.10 In
Feb-12
May-12
Aug-12
Nov-12
Feb-13
May-13
Aug-13
Nov-13
Feb-14
May-14
the Malaysian clinical practice guidelines, influenza vaccination

is listed as a strategy in managing COPD.11 The effectiveness of
influenza vaccination in patients with COPD was investigated
Persons with underlying medical conditions, including those with by Menon et al, who found that the total number of outpatient
asthma and chronic lung disease, are at higher risk of influenza- visits and hospitalizations in the 87 patients studied were
associated hospitalization.3,4 The World Health Organization significantly lower (4 outpatient visits and hospitalizations,
(WHO) states that, for high-risk patients, annual immunization respectively) in the 1 year post-vaccination compared with
with influenza vaccine is the best way to prevent influenza and the 1-year pre-vaccination period (8 outpatient visits and
its complications.5 14 hospitalizations) (p=0.02).12 In COPD patients with acute
respiratory illness (ARI), influenza vaccination was shown
to be highly effective in preventing influenza-related ARI,
Influenza vaccination in persons irrespective of the severity of COPD.12
with chronic respiratory diseases
demonstrates substantial health benefits Influenza vaccination in elderly persons with chronic lung
disease is associated with fewer hospitalizations and outpatient
Influenza vaccination in children with asthma reduces respiratory visits for pneumonia
illnesses and asthma-related events
In a retrospective, multiseason cohort study, elderly
Asthma is one of the most common non-communicable persons with chronic lung disease who were unvaccinated
diseases among children, with a global prevalence ranging for influenza during influenza seasons had twice as high
from 0.8% to 32.6% among children aged 13–14 years, hospitalization rates for pneumonia and influenza as
Sponsored Symposium Highlights
vaccinated patients. 13 A lower risk of death (adjusted odds

ratio, 0.30; 95% confidence interval [CI], 0.21–0.43) and fewer Table. Seasonal influenza vaccines were found
hospitalizations (adjusted risk ratio, 0.48; 95% CI, 0.28–0.82) to be cost-effective and cost saving17
due to pneumonia and influenza were reported in elderly
persons who were vaccinated than in those unvaccinated. 13 Review Target group Studies Conclusion
Newall, 2012 Children ≤18 years old 20 Cost saving or
cost-effective
Immunized patients with lung cancer
Coleman, 2006 Children 7 Not discussed
showed acceptable immune responses to
influenza vaccine Nichol, 2011 Children ≤18 years old 20 Cost saving or
Patients with lung cancer are priority candidates for influenza cost-effective
vaccination as they are at high risk of complications due Savidan, 2008 Children <18 years old 15 Cost saving or
to influenza, including hospitalization and death.15 In a cost-effective
prospective study to evaluate the immunogenicity of Burls, 2006 Healthy adults, 14 Mostly cost
influenza vaccine in patients with lung cancer who were healthcare workers saving
undergoing chemotherapy, the patients showed acceptable Gatwood, 2012 Healthy adults 18–64 7 Generally not
immune responses to influenza vaccination, suggesting that years old cost saving
annual influenza vaccination has protective effects in patients Hogan, 2012 Healthy adults 10 Mostly favoured
with cancer.16 vaccination
Newall, 2009 Healthy adults 18–64 6 Cost-effective
years old
QIVs provide wider protection against de Waure, 2012 Adults >50 years old, 20 Cost saving or
influenza B viruses high-risk cost-effective
Annual influenza vaccination is the primary measure for Postman, 2006 Elderly 18 Most cost saving
preventing influenza and its complications. In fact, influenza or cost-effective
vaccination is a highly cost-effective healthcare intervention –
more than a hundred studies concluded that targeted seasonal Summary
vaccination were cost-effective or cost-saving in particular target Annual influenza vaccination is recommended for high-risk
groups (Table).17 patients, including patients with chronic respiratory disease and
lung cancer. Influenza vaccination has been shown to provide
The conventional trivalent influenza vaccines (TIVs) provide beneficial effects in children with asthma, COPD patients at high
protection against three different types of viruses: the risk of exacerbations, elderly persons with chronic lung disease
influenza strains A/H1N1 and A/H3N2, and one strain of and lung cancer patients. With the inclusion of a second influenza
influenza type B.18 However, the split of influenza B virus into B virus to the vaccine formulation, individuals who are receiving
two antigenically distinct lineages (B/Yamagata and B/Victoria) QIVs will be more optimally protected against influenza infection.
that now co-circulate among the human population supports
the need to broaden the spectrum of protection against the References: 1. World Health Organization. Influenza Factsheet 211. Available at: http://www.
evolving strains of influenza.19 who.int/mediacentre/factsheets/fs211/en/. Accessed 14 August 2017. 2. Oong XY, et al. PLOS One
2015;10:e0136254. 3. Centers for Disease Control and Prevention. Flu and people with asthma.
Available at: https://www.cdc.gov/flu/asthma/index.htm. Accessed 16 August 2017. 4. World
Patients who receive QIVs will benefit from the extra Health Organization. Vaccines against influenza. WHO position paper. Available at: http://www.
protection against the circulating influenza B virus lineages who.int/immunization/position_papers/PP_influenza_november2012_summary.pdf. Accessed
14 August 2017. 5. World Health Organization. Wkly Epidemiol Rec. 2012;87:461–476. 6. Lai
because the additional influenza B virus lineage is included in CKW, et al. Thorax 2009:64:476–483. 7. Johnston SL, et al. BMJ 1995;310:1225–1229. 8. Miller EK,
the QIVs.20 Moreover, during the seasons in which influenza B et al. Paediatrics 2008;121:1–8. 9. Monto AS. Am J Med 1987;82:20–25. 10. Global initiative for
chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and
virus circulation is minimal, individual who are vaccinated with prevention of chronic obstructive pulmonary disease, 2017 report. Available at: http://goldcopd.
QIVs will be equipped with a strong immunity against both org/wp-content/uploads/2016/12/wms-GOLD-2017-Pocket-Guide.pdf. Accessed 16 August
influenza B lineages in the subsequent seasons.20 Therefore, 2017. 11. Clinical Practice Guidelines. Management of chronic obstructive pulmonary disease,
2nd Edition. Available at: http://www.moh.gov.my/penerbitan/CPG2017/4749.pdf. Accessed
QIVs provide wider protection against influenza B viruses and 16 August 2017. 12. Menon B, et al. Int J Clin Pract 2008;62:593–598. 13. Wongsurakiat P, et al.
are preferred over TIVs, according to Professor Pang. Data Chest 2004;125:2011–2020. 14. Nichol KL, et al. Ann Intern Med 1999;130:397–403. 15. Centers
for Disease Control and Prevention. Cancer, the flu, and you. Available at: https://www.cdc.gov/
from an analysis by the CDC suggests that, in the USA, the use cancer/flu/index.htm. Accessed 16 August 2017. 16. Nakashima K, et al. Hum Vaccin Immunother
of QIVs during the influenza seasons between 2001 and 2008 2017;13:543–550. 17. Mark J, et al. Hum Vaccin Immunother 2013;9:834–840. 18. Centers for
Disease Control and Prevention. Quadrivalent influenza vaccine. Available at: https://www.cdc.
would have resulted in about 2.1 million fewer influenza cases, gov/flu/protect/vaccine/quadrivalent.htm. Accessed 16 August 2017. 19. Belshe RB. Vaccine
20,000 fewer hospitalizations and 1,200 fewer deaths.20 2010;D45–D53. 20. Ambrose CS, Myron JL. Hum Vaccin Immunother 2012;8:81–88.

Sponsored as a service to the medical profession by:
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publisher or sponsor. Any liability or obligation for loss or damage
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RESEARCH REVIEW
High levels of di-

etary manganese up
fatal heart infection
FWHR predicts
sex drive, infidelity
T
he size and shape of a person’s face may predict sex
drive and intended infidelity, research has shown.
E
Researchers examined the role of men and women’s facial xcessive intake of the mineral manganese can be
width-to-height ratio (FWHR) in sexual relationships, infidelity, toxic to the heart, according to a new study.
and partner selection using two separate studies.
Manganese can be found in leafy vegetables such as
The first study examined 145 undergraduate students of spinach and kale as well as in pineapple, nuts, and tea.
Caucasian descent, 48 percent of whom were male, who are
in romantic heterosexual relationships. They filled in question- A study in mice conducted by Dr Eric Skaar, the Ernest
naires that polled their sexual behaviour and sex drive, and W. Goodpasture Professor of Pathology, Microbiology, and
provided a photograph of their face. Immunology at the Vanderbilt University Medical Center in
Nashville, Tennessee, US showed that high levels of the
Measurements of the students’ faces were taken; the dietary manganese increase lethality and heart colonization
width of the face was divided by the height of the upper face. by Staphylococcus aureus (S. aureus). The bacterium is
Multiple regression analyses showed a strong positive correla- also the leading cause of skin infections (eg, boils and fu-
tion between FWHR and sex drive in both men and women. runcles), fatal bloodstream infections, pneumonia, as well
as infective or bacterial endocarditis.
A second study was conducted to see if the findings could
be replicated in a wider sample, this time involving 314 sub- The researchers fed a group of mice with thrice the
jects. Sociosexuality and intended fidelity were added as vari- normal amount of manganese and compared with another
ables to assess if both correlate with facial size and shape. group of mice fed with a normal diet. Most of the mice
that received excessive manganese died from S. aureus
FWHR predicted libido in both men and women. Those infection.
with a higher FWHR (faces that are shorter, wider, and more
squarish) reported a higher sex drive. The researchers put forth an explanatory mechanism
for their findings, which involves the immune system’s ox-
A correlation between high FWHR and infidelity and socio- idative oxygen burst. During oxidative burst, oxygen-con-
sexuality was also found in men. The findings suggest that fa- taining molecules are rapidly released by the immune cells
cial characteristics might convey important information about into the site of infection. However, excessive manganese
human sexual motivations, said the researchers. However, the appears to counteract this process, rendering the calpro-
study is observational and cannot establish causality. tectin ineffective at protecting the heart.
Arnocky S, et al, the Facial Width-to-Height Ratio Predicts Sex Drive, Juttukonda L et al, Dietary Manganese Promotes Staphylococcal Infection
Sociosexuality, and Intended Infidelity, Arch Sex Behav 2017;doi.org/10.1007/ of the Heart, Cell Host & Microbe 2017;doi:http://dx.doi.org/10.1016/j.
s10508-017-1070-x chom.2017.08.009
61
Sponsored Interview
The gentle approach towards

effective management of
constipation
Constipation is a common disorder which adversely affects the wellbeing and quality of life of
patients.1 Recently, MIMS Doctor spoke to Associate Prof Dr Raja Affendi Raja Ali on the landscape
of constipation in Malaysia, emphasizing on effective and early management of the condition.
Assoc Prof Dr Raja Affendi Raja Ali
MB BCh, MSc, MD, FRCP
Certain medications, particularly, opioid-containing analgesics
Consultant Physician & Gastroenterologist; are known to cause constipation.5,6 Constipation is also
Head of Gastroenterology Unit a hallmark symptom in patients with depression.9 More
Hospital Canselor Tuanku Muhriz recently, dysbiosis (imbalance between good and bad
Department of Medicine bacteria in the intestine) of the gut microbiota has been
UKM Medical Centre, Kuala Lumpur
Malaysia identified as an emerging risk factor of constipation.10 Other
risk factors include intake of food high in sugar and fat
Constipation is one of the most common content and lack of physical activities.11
gastrointestinal (GI) problems worldwide.
What do we know about the epidemiology of How is constipation diagnosed?
this condition here in Malaysia? Constipation is diagnosed when a patient has fewer than
Constipation is not a disease entity, but rather a general three defecations per week.2 Since constipation is a symptom
term used by patients to describe difficulties in bowel rather than a disease entity, a thorough medical history and
movement.2 As such, data on the incidence and prevalence physical examination of the patient will enable the doctor
of constipation in Malaysia is limited. If we look beyond to identify the root cause of constipation, ie, an isolated
Malaysia, ie, in Asia, constipation affects 15% to 23% of incident or a symptom of an undiagnosed medical condition.4
women and 11% of men.3 Constipation is also a symptom The Bristol stool scale is a useful tool to assist patients in
commonly associated with irritable bowel syndrome (IBS).4 describing their stool consistency, which helps the doctor in
identifying if the patient has constipation (Figure).4
Are there specific populations that are more
commonly affected? Figure. The Bristol stool scale is a useful tool to
Populations most commonly affected by constipation are diagnose constipation
those with gastrointestinal (GI) or non-GI diseases such as, IBS
(particularly in young women), the elderly, children, individuals Type 1 Separate hard lumps, like nuts (difficult to pass)
on certain medications (especially opioid-containing
analgesics), pregnant women on iron therapy, individuals Type 2 Sausage-shaped, but lumpy
who lack high fibre and water intake, and individuals who lack
exercise.5,6 Others include patients with long standing and Type 3 Like a sausage but with cracks on its surface
poorly controlled diabetes, neurodegenerative diseases such
as Parkinson’s disease, hypothyroidism, too much calcium Type 4 Like a sausage or snake, smooth and soft
in the blood, diverticular disease, spinal or pelvic nerve injury
and any ano-rectal disorders. Type 5 Soft blobs with clear cut edges (passed easily)
What are some of the risk factors for Type 6 Fluffy pieces with ragged edges, a mushy stool
constipation among Malaysians?
The main risk factor of constipation is the lack of dietary Type 7 Watery, no solid pieces. Entirely liquid
fibre. Statistics show that an estimated 50% of Malaysians
do not achieve the recommended daily dietary fibre intake.7
Furthermore, the average adult in Kuala Lumpur consumes
only 13.2 g of dietary fibre per day, which is about half When should a general practitioner
the recommended intake.8 According to the World Health refer a patient with constipation to a
Organization (WHO), the average adult should consume gastroenterologist?
more than 25 g of dietary fibre per day7 – in layman terms, Constipation with alarming symptoms such as, bleeding
this is equivalent to 16 slices of wholemeal bread or 10 from the rectum, intermittent change in bowel habit with
apples per day. Such habits may not be practical in daily life, bloody or non-bloody diarrhoea, significant unexplained
which is why dietary fibre supplements like SURBEX® Nutri- weight loss, unexplained iron deficiency anaemia, strong
Fibre provide a simplified and convenient way of achieving family history of colon cancer, and chronic abdominal
the recommended dietary allowance for fibre. pain should be referred to a gastroenterologist as soon
as possible for further investigation, in particular a
Another common risk factor for constipation is the lack of colonoscopic examination.4 As for constipation alone with
water intake.5,6 The average adult is encouraged to drink no alarming symptoms, a referral is advised if the patient
around 7 to 10 glasses of water per day; in reality, many has chronic constipation, ie, constipation lasting more than
Malaysians consume less than that. 6 weeks and does not resolve with laxative therapy and ife
Sponsored Interview
style and diet modifications. We have to remember that longer intestinal transit time means longer contact time
chronic constipation is a symptom of colon cancer. between the stool and the intestines and this translates
to harder stools, thus worsening constipation. Osmotic
A range of treatment modalities are available laxatives stimulate the intestine to absorb excessive
for constipation. What is the first approach amounts of water from the body. The process is slow,
when managing a patient with constipation? sometimes taking days to affect stool consistency. Osmotic
The first approach when managing a patient with laxatives basically softens the stool for easy passage.
constipation is ‘to do no harm’. “I always recommend dietary Osmotic laxatives are the alternative therapy for patients
modification as the first step whereby assessment of the who do not respond well to dietary modifications or fibre
patient’s diet is done and necessary dietary modifications supplementation. 13 Osmotic laxatives exert a more
will be suggested accordingly”, said Dr Raja Affendi. For ‘gentle’ approach in managing constipation.
constipation that is due to a lack in dietary fibre, the patient
will be advised to increase intake of dietary fibre and protein,
and reduce the intake of fatty foods and sugar.12 For some patients, although their rectum is distended with
stool content, there is no signal from the brain to inform the
When advising a patient with constipation to go on a ‘high patient that it is time for defecation; in such cases, stimulant
fibre diet’, it is important for doctors to define the meaning laxatives are then prescribed to ensure that stools are
of ‘high fibre diet’ to their patients. “In my practice, I found propelled out regularly.12
that using the food pyramid (show to patient the type of
food which contain high fibre and inform them to reduce the Are laxatives associated with dependency?
intake of red meat) helps patients understand better with Overuse of laxatives is not recommended as they can actually
regards to the amount of fibre that they need to add to their
worsen the symptoms of constipation. Chronic laxative use
accordingly”, said Dr Raja Affendi. In addition to dietary
modifications, doctors should also advice patients with results in discoloration of the lining of the large intestines
constipation to exercise regularly (for example 150 minutes and rectum, resulting in a condition known as melanosis coli,
per week or at least three times per week for one hour each which is easily identified during a colonoscopy.12 Melanosis
session) and increase their intake of water.12 coli got its name because it was thought that the colour
change was the result of the pigment melanin. Laxatives
However, for patients with chronic constipation, who present must be used sparingly and not as a routine medication.
with at least one of the alarm symptoms, the first immediate Upon relieve of constipation with the use of laxatives, the
approach is to perform a colonoscopy examination as soon patient should practice a high fibre diet and not depend on
as possible. laxatives. Patients should understand that laxatives are only
temporary and short term measures to relieve constipation.
When should fibre supplementation be
considered and what are the important
References: 1. Serra J et al. Gastroenterol Hepatol 2017;40:303−316.
criteria to take note of when choosing the 2. McCrea GL et al. World J Gastroenterol 2008;14:2631−2638. 3. Lim
appropriate fibre supplements? YJ et al. PLoS ONE 2016;11:e0167243. 4. World Gastroenterology
Fibre supplements will be initiated for patients with persistent Organization Global Guidelines. Constipation: A global perspective.
constipation despite fibre modifications. Furthermore, Available at: http://www.worldgastroenterology.org/UserFiles/file/guidelines/
patients will also be referred to a dietitian, to obtain advice constipation-english-2010.pdf. Accessed 10 July 2017. 5. Sanchez MIP et
on the appropriate fibre supplements to take. al. Can J Gastroenterol 2011;25:11B−15B. 6. Vallerand AH. J Nurse Pract
2017;13:170−174. 7. Ng TKW et al. Mal J Nutr 2010;16:271−280. 8. Shahar
S et al. Mal J Nutr 2004;10:173−182. 9. Hosseinzadeh ST et al. Gastroenterol
What is the difference between osmotic and Hepatol Bed Bench 2011;4:159−163. 10. Zhao et al. Springerplus
stimulant laxatives? 2016;5:1130. 11. Talley et al. Am J Gastroenterol 2003;98:1107−1111.
The main function of the large intestines is to absorb water 12. Portalatin M et al. Clin Colon Rectal Surg 2012;25:12−19. 13. Johanson.
from the stool, but this makes the stool hard. Furthermore, MedGenMed 2007;9:1−10.
damage howsoever arising is hereby disclaimed. ©2017 MIMS Medica. All rights reserved.
No part of this publication may be reproduced by any process in any language without
the written permission of the publisher. Enquiries: MIMS Medica Sdn Bhd (891450-U), Abbott Laboratories (M) Sdn Bhd (163560-X)
2nd Floor, West Wing, Quattro West, No. 4, Lorong Persiaran Barat, 46200 Petaling Jaya,
Selangor, Malaysia. Tel: (603) 7623 8000 Fax: (603) 7623 8188 Email: enquiry.my@mims.com No. 22, Jalan Pemaju U1/15, Seksyen U1, HICOM-Glenmarie Industrial Park,
Website: www.mims.com MY-ABB-200 40150 Shah Alam, Selangor D E, Malaysia. Tel: 03-5566 3388 Fax: 03-5569 3240
Sponsored Interview
An update on nonalcoholic fatty

liver disease and nonalcoholic
steatohepatitis
N
onalcoholic fatty liver disease (NAFLD), Dr Wah Kheong Chan
including simple steatosis and nonalcoholic Associate Professor of Medicine
steatohepatitis (NASH), is widely considered University of Malaya;
as the liver manifestation of the metabolic syndrome.1 Consultant Physician and Gastroenterologist
University of Malaya Medical Centre and
It is a major cause of liver disease worldwide and its University of Malaya Specialist Centre
prevalence is expected to rise in tandem with the Kuala Lumpur, Malaysia
rising prevalence of obesity and diabetes mellitus.1
Recently, MIMS Doctor spoke to Associate Professor
Dr Wah Kheong Chan, a Consultant Physician and
Gastroenterologist at the University of Malaya Medical
Centre and University of Malaya Specialist Centre,
3 Please share with us the common
clinical challenges in managing
to provide an update on NAFLD, with a particular patients with NAFLD.
emphasis on the use of silymarin for the treatment of
Firstly, patient education and counselling is limited
NASH. Here are the highlights from the interview. in many settings in Malaysia. It is important for the
1 What is NAFLD and its prevalence in clinician to empower their patients to play an active
role in managing NAFLD by educating them on the
Malaysia?
disease and motivating them to make lifestyle changes.
NAFLD is characterized by the accumulation of fat Furthermore, NASH could progress to cirrhosis and its
in the liver in persons who do not consume alcohol complications (ie, hepatocellular carcinoma and end-
or who consume alcohol in an amount considered stage liver disease), leading to an increasing number
insufficient to cause liver damage. 2 NASH, a more of patients requiring liver transplantation.7 NASH has
severe form of NAFLD, is characterized by steatosis, emerged as the second leading cause of chronic liver
lobular inflammation and hepatocellular ballooning, and disease and hepatocellular carcinoma needing liver
can lead to fibrosis and cirrhosis.2 NAFLD is closely transplantation in the United States.7 Many people still
associated with obesity, insulin resistance, type 2 consider NAFLD a completely benign condition!
diabetes, dyslipidaemia and hypertension, which are all
risk factors for cardiovascular disease.1–3 The reported
global prevalence of NAFLD is 25% whereas NASH
4 Can you tell us the treatment goals for
is estimated to affect about 3% to 5% of the general
patients with this condition?
population.3,4 In Malaysia, the prevalence of NAFLD was The management of patients with NAFLD consists
found to be 23%.5 of treating the liver disease as well as the associated
2 The progression of NAFLD can take

metabolic comorbidities. Current management of
NAFLD focuses on diet and lifestyle modifications. For
years, even decades. Is the condition patients who are overweight or obese, it is important
reversible? for clinicians to encourage their patients to embark on
a proper weight loss programme by reducing caloric
The pathophysiological mechanism underlying
intake and increasing physical activity. The practice
the development of NAFLD in most patients is
guideline developed by the American Association for
overnutrition and inappropriate diets. The imbalance the Study of Liver Disease (AASLD) states that reduction
between dietary intake and energy expenditure could of at least 3% to 5% of body weight may effectively
lead to chronic elevation of glucose, insulin and free improve steatosis while weight loss up to 10% may be
fatty acid levels in the blood. So, if the imbalance needed to improve lobular inflammation.2
is corrected through lifestyle interventions (ie,
reducing calories intake and increasing physical Pharmacotherapeutic options with long-term effectiveness
activity) to produce stable weight loss, this could lead that would affect the course of fibrosis in patients
to the resolution of NASH and fibrosis improvement. with NASH is very limited. The AASLD guideline
In a study of patients with biopsy-proven NASH who recommends high-dose vitamin E (800 IU/day) as first-
received lifestyle intervention (using a combination line pharmacotherapy for nondiabetic patients with
of diet, exercise and behaviour modification) for a biopsy-proven NASH.2 Pioglitazone can be used to treat
duration of 52 weeks, all patients who lost at least patients with biopsy-proven NASH.2 Both vitamin E and
10% of their weight had reductions in their NAFLD pioglitazone have been shown to be associated with
activity score (NAS), 90% had resolution of NASH and significant reductions in steatosis (p=0.005 for vitamin E
45% had regression of fibrosis.6 vs placebo; p<0.001 for pioglitazone vs placebo)
Sponsored Interview
and lobular inflammation (p=0.02 for vitamin E vs There was no significant difference in adverse events in
placebo; p=0.004 for pioglitazone vs placebo). 8 the silymarin and placebo groups, and all adverse events
However, long-term administration of vitamin E has been were deemed unrelated to silymarin. We concluded that
associated with increased risk of all-cause mortality and silymarin may have a role as an antifibrotic treatment in
of developing prostate cancer.2 Similarly, the use of NASH patients, and that silymarin in the treatment of
pioglitazone has been associated with weight gain and NASH is safe and well tolerated, and deserves further
cardiovascular events.2,8 study, especially with respect to appropriate dose and
5 Could you share with us any latest duration of treatment.
clinical trials for NAFLD? 7 Do you think there is a role for

Currently, there are several drugs in phase III clinical trials silymarin in the treatment of NASH?
for NAFLD. In a multicentre, randomized, double-blind, What are the advantages of using
placebo-controlled trial of patients with non-cirrhotic silymarin and how would you
NASH, 45% of patients who received obeticholic acid position silymarin in the treatment
25 mg daily for 72 weeks had a significant improvement armamentarium of NASH?
in liver biopsy findings versus baseline, compared with There is certainly a role for silymarin in the treatment of
21% of patients in the placebo group (relative risk [RR], NASH. In our study, the use of silymarin was associated
1.9; 95% confidence interval [CI], 1.3–2.8; p=0.0002).9 with significantly greater fibrosis improvement compared
In another multicentre, randomized, double-blind, with placebo.11 While larger trials to confirm our
placebo-controlled trial of patients with biopsy-proven observation and to determine the optimum dosage are
NASH without cirrhosis, 19% of patients who received desirable, silymarin is currently the only commercially
elafibranor 120 mg daily for 52 weeks had resolution of available compound that has been shown to result in
NASH without fibrosis worsening, compared with 12% fibrosis improvement in patients with NASH.11 Moreover,
of patients in the placebo group (odds ratio [OR], 2.31; silymarin is safe and well tolerated,11–13 and has been
95% CI, 1.02–5.24; p=0.045).10 used as a liver supplement for a long time.14
6 Your group recently published a study 8 In the study, silymarin was given at
titled A Randomized Trial of Silymarin a high dose,11 what would be your
for the Treatment of Nonalcoholic recommended dose of silymarin for
Steatohepatitis.11 Can you share with patients with NAFLD?
us important findings from the study? Due to the high pill burden and higher cost of high-
We conducted a single-centre, randomized, double-blind, dose silymarin, I would recommend giving the standard
placebo-controlled trial of patients with biopsy-proven dose of silymarin until a higher dose per unit formulation
NASH and a NAS of at least 4 to evaluate the efficacy and more evidence becomes available. As silymarin
of silymarin in these patients. Patients were randomly undergoes enterohepatic circulation, a standard dose
assigned to receive silymarin 700 mg three times daily may be adequate to achieve desired therapeutic effect,13
or placebo for 48 weeks. A repeat liver biopsy was although this requires another study to confirm.
performed at the end of 48 weeks. In the intention-to-
References: 1. Weiß J, et al. Dtsch Arzteb Int 2014;111:447–452. 2. Chalasani
treat analysis, we found that, compared with placebo, N, et al. Hepatology 2012;55:2005–2023. 3. Younossi ZM, et al. Hepatology
silymarin did not significantly reduce the NAS by 30% 2016;64:73–84. 4. Vernon G, et al. Aliment Pharmacol Ther 2011;34:274–
or more (32.7% vs 26.0%; p=0.467). Based on the liver 285. 5. Goh SC, et al. Hepatol Int 2013;7:548–554. 6. Vilar-Gomez E, et al.
Gastroenterology 2015;149:367–378. 7. Wong RJ, et al. Gastroenterology
biopsy findings, a significant percentage of patients in 2015;148:547–555. 8. Sanyal AJ, et al. N Eng J Med 2010;362:1675–1685.
the silymarin group had reductions in fibrosis compared 9. Neuschwander-Tetri BA, et al. Lancet 2015;385:956–965. 10. Ratziu
with placebo (22.4% vs 6.0%; p=0.023). A significant V, et al. Gastroenterology 2016;150:1147–1159. 11. Chan WK, et al. Clin
proportion of patients in the silymarin group had at Gastroenterol Hepatol 2017 pii: S1542-3565(17)30459-7. doi: 10.1016/j.
cgh.2017.04.016. 12. Loguercio C, et al. Free Radic Biol Med 2012;52:1658–
least 30% improvement in liver stiffness measurement 1665. 13. Hawke RL, et al. J Clin Pharmacol 2010;50:434–449. 14. Flora K, et
compared with placebo (24.2% vs 2.3%; p=0.002). al. Am J Gastroenterol 1998;93:139–143.

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MIMS CAREER
MIMS Career is the

latest healthcare
recruitment platform in Asia.
Infection Control Manager | MIMS Career Choice – KL
Location Kuala Lumpur

Employment type Full time
Salary Range Confidential
Working day Not fixed
Specialty Infectious Diseases
Job Description Job Requirement

Takes a leadership role for the organization when faced with Bachelor’s Degree/Post Graduate Diploma/Professional
infectious outbreaks. Monitors implementation of staff health Degree with updated APC. Preferably candidate with
policies. Infection Control experience.
Medical Officer | MIMS Career Choice – Shah Alam
Location Shah Alam, Selangor

Specialty Others

This position is for medical officer already holding either full Posses good communication skills, Chinese-speaking would
or conditional medical registration with the Malaysia Medical be an added advantage. Able to multi-task. Medical officer
Council and having current APC. that keen to work in corporate environment are welcome to
apply
Cardiology Consultant / Associate Consultant | Melorita – Saudi Arabia
Location Saudi Arabia

Specialty Cardiology

Responsible for caring patients with diseases or deformities Min 6 years’ experience after Master or Min 2-3 years’
in heart or vascular system. Vacancies are for cardiologist experience post board/fellowship (US Board, FRCS-Irish, UK,
and interventional cardiologist. Canadian, New Zealand, Australia, French board is a plus).
70
MIMS CAREER
To explore job openings, please visit MIMS Career

www.doctor-job.com/malaysia
portal at doctor-job.mims.com/malaysia
Employers interested in posting healthcare jobs,
please visit MIMS Career portal for more information.
Locum Doctor | Job4Locum
Location Kuala Lumpur & Selangor

Employment type Locum
Specialty General Practice

Locum slots available in October, November and December Possess valid MMC registration number and updated APC
2017. with good communication skills. Preferably locum that able to
take many slots.
Nephrologist | Putra Medical Centre
Location Alor Setar, Kedah

Employment type Full Time
Specialty Nephrology

Roles involve mainly establishing a plan of care for kidney Possess full registration with Annual Practicing Certificate
patients. (APC). Registered with National Specialist Register (NSR).
Hospital Operation Manager | MIMS Career Choice – KL
Location Kuala Lumpur

Specialty Others (Managerial & Administrative)

To assist the General Manager of the hospital in day to day MBA is added advantage. Minimum 5 years managerial
operations and strategic directions. experience preferable in hospital/healthcare industry. Mobility
is preferred.
71
CALENDAR
NOVEMBER NOVEMBER NOVEMBER
09-12
THURSDAY - SUNDAY
17-19
FRIDAY - SATURDAY
23-26
THURSDAY - SUNDAY
College of Physicians Academy 1M-World Congress in Sports Kuala Lumpur International

of Medicine of Malaysia and Exercise Medicine Neonatology Conference
(CPAMM) Annual Scientific (1M-WCSEM) 2017 (KLINC) 2017
Meeting 2017 Location: Kuala Lumpur Location: Kuala Lumpur
Location: Sungai Buloh, Selangor Info: Society of Sports and Exercise Info: Academy of Medicine of Malaysia
Secretariat: Ms. Bazilah, CPAMM Medicine Malaysia / WCSEM 2017 Tel: (03) 4023-4700, 03 4025-4700/3700
Tel: (03) 8996-0700/1700/2700 Secretariat Fax: (03) 4023-8100
Fax : (03) 8966-4700 Tel: (012) 280-3243 Fax: (03) 4251-3790 Email: klincsecretariat@gmail.com
Email: admin@cpamm.asc.org.my Email: info@wcsem2017.org Website: klinc.org.my
Website: cpamm.asc.org.my Website: www.wcsem2017.org
NOVEMBER JANUARY 2018 FEBRUARY 2018
24-26
FRIDAY - SUNDAY
19-21
FRIDAY - SUNDAY
11-12
SUNDAY - MONDAY
26th Malaysian Urological 15th Annual Scientific Meeting Inaugural International

Conference of the Malaysian Society of Integrative Medicine Conference
Location: Kuching, Sarawak Hypertension – MSH 2018 Location: Kuala Lumpur
Info: Ms. Najatushima Abdul Wahab, Location: Kuala Lumpur Email: info@integrativemedicinemalaysia.org
Malaysian Urological Association Info: Fay Cheah Website: integrativemedicinemalaysia.org
Tel: (03) 4025-1251 Tel: (012) 212 1328
Fax: (03) 4025-1252 Email: msh.asm.secretariat@gmail.com
Email: muc2017.kuching@gmail.com /
malaysianurologicalassociation@gmail.com
Website: www.muc2017.com
MARCH 2018 MAY 2018 APRIL 2018
14-17
WEDNESDAY - SATURDAY
11-13
FRIDAY - SUNDAY
6-8
FRIDAY - SUNDAY
9th Global Basic to Intermediate Annual General Meeting / Endoscopy 2018

Hands-on Musculoskeletal MRI Annual Scientific Congress Location: Kuala Lumpur
& Ultrasound Conference and of the College of Surgeons, Info: Secretariat
Workshop for Radiologists Academy of Medicine Malaysia Email: secretariat@msgh.org.my
Location: Ampang, Selangor Location: Ipoh, Perak Website: www.msgh.org.my
Info: Global Futuristic Management Services Info: College of Surgeons of Malaysia
Email: globalfuturistic@gmail.com Email: secretaroiat@csamm.asm.org.my
Website: www.penangmskrad.com
72
E
CPD arn Your
Cred
its H
ere
INTRODUCING NEW MODULES

on childhood vaccinations
Childhood immunizations:
Catch-up and diphtheria
Immunization protects children from
serious, life-threatening infectious diseases.
Certain reasons, for eg, missing one or more
appointments or illness during the time a child
should receive a shot, explain why children may
not be fully immunized. The goal of this activity
is to refresh doctors’ knowledge on catch-up
immunization and also diphtheria, an acute,
toxin-mediated bacterial infection that often
strikes unimmunized children.
Impact of PCVs on
pneumococcal disease
Pneumococcal disease poses a substantial
health burden particularly in children.
In this video, Professor Ron Dagan talks

about the impact of pneumococcal
conjugate vaccines (PCVs) on the overall
landscape of pneumococcal disease.
Log in to register now

www.mims-cpd.com.my
Start earning CPD credits at www.mims-cpd.com.my
For your convenience, you can monitor your CPD credits earned at the website anytime.
MY-CPD-029
Scan to
Your personal My CPD Log can be printed or emailed.
register
Enquiries:
MIMS Medica Sdn Bhd (891450-U)
2nd Floor, West Wing, Quattro West, No.4, Lorong Persiaran Barat, 46200 Petaling Jaya, Selangor, Malaysia
Tel: +603 7623 8000 Fax: +603 7623 8188 Email: enquiry.my@mims.com Website: www.mims.com

MIMS Doctor October 2017 MY

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YOUR TRUSTED SOURCE OF HEALTHCARE INFORMATION IN ASIA MALAYSIA OCTOBER 2017

Highlights Managing hyper-

Vice-President of Marketing Platform

11 Companion animals may be source of disease Designers

22 Rivaroxaban plus aspirin a potential new treatment option in PAD

23 Routine use of supplemental oxygen does not improve survival in MI patients

AUSTRALIA • MALAYSIA • HONG KONG

27th International Congress of the European Respiratory Society (ERS 2017),

35 Macitentan a promising therapy in inoperable CTEPH

36 BiPAP to CPAP: Is switching safe?

38 Mepolizumab may help reduce exacerbations in eosinophilic COPD

2nd Floor, West Wing,

PP17111/12/2012 (031349) ISSN 1608-5086

Bringing integrity, heart into the

PANK JIT SIN

“People are at the centre of ev-

LATEST FA 01_Tramada_Mims Doctor Oct 2017.pdf 1 9/14/2017 4:08:17 PM

Local misconceptions of dengue

According to the South-East Asia

New patient handbook on cholesterol aims

Companion animals may be source of

Speaking at a media roundtable

fleas, ticks and worms and proper

NKF offers financial aid for peritoneal

According to 2013 statistics,

Words with the President of Malaysian

inception. As part of its ongoing ef-

Watch out for the raspy breath of IPF

However, due to the rarity of the

The COMPASS trial includ-

“The Kaplan-Meier curves for

between patients receiving monothera- bleeding vs aspirin alone [hazard ratio

In view of the clear superiority of the

death by 22 percent, the “The results of COMPASS repre-

Anacetrapib reduces major coronary events

Anti-inflammatory canakinumab reduces

Rivaroxaban plus aspirin a potential new

Routine use of supplemental oxygen does

The DETO2X-AMI study showed

Blocking PCSK9 synthesis with siRNA shows

“In contrast to PCSK9 monoclonal

Avoid sildenafil in residual pulmonary

“We saw that a greater proportion

which is available upon request.

Renal denervation effective for uncontrolled

“The main caveat in the study is

Drug-specific effects of NSAIDs on BP

“Both selective and nonselective The change in mean 24-hour sys-

Upstream rhythm control superior

Ultra-low LDL-C cuts CV risk with

Dual antithrombotic therapy an option

Benralizumab impact greater

Macitentan a promising therapy in inoperable

BiPAP to CPAP: Is switching safe?

“We all felt pretty neutral on this

“Our patients did not

Mepolizumab may help

The researchers acknowledged

“[T]hese trials should promote fur-

S YM P O SIUM OB JEC TIV E Featuring

Topic highlights for SPCRS 2017 include:

For further information, please contact:

kine, an upstream driver of inflamma-

“Due to its activity early in the in-