L’ IMPORTANZA DELL’ADERENZA

TERAPEUTICA IN RELAZIONE ALLA

TIPOLOGIA CARATTERIALE DEL MALATO

Dr. Franco Veglio

IPERTENSIONE E MALATTIE CORRELATE:
L’IMPORTANZA DI UN TRATTAMENTO
FARMACOLOGICO MIRATO E PRECOCE

Dr. Franco Veglio

Hypertension silent killer, global public health crisis
 Premessa
• L’ipertensione arteriosa è la seconda causa di visita
ambulatoriale, nel mondo occidentale, con circa 30
milioni di visite annue negli Stati Uniti
(mod. National Ambulatory Medical Care Survey: 1997 Summary. Atlanta, GA: CDC
1999. Advance data N.° 305)
• Circa 12 milioni di accessi ambulatoriali per anno, in
Italia
(mod. Zaninelli A at al, Am J Hypertens, 2001; 14: 138A)
In 2015, an estimated 3.5 billion adults had SBP of at least 110 to
115 mm Hg and 874 million adults had SBP of 140 mmHg or higher.
Behavioral and dietary risk factors

mod. Ezzati, NEJM 2013

Definizione e classificazione della
Normotensione e dell’Ipertensione Arteriosa
Prevalenza di Ipertensione Arteriosa nel mondo
OMS 2014 Soggetti maschi di età > 18 anni

In tutto il mondo > 1 miliardo di ipertesi

Prevalenza ipertensione italia

mod.AIFA 2014
Documentation and treatment of hypertension:
in a family medicine resident clinic

• In the USA, uncontrolled hypertension

contributes to 1000 deaths a day

• US$ 131 billion a year in healthcare costs

Mod. da WHO, 2015
Mod. da WHO, 2015
Mod. da WHO, 2015
Mod. da WHO, 2015
Prevalenza di Ipertensione Arteriosa nel mondo
OMS 2014 Soggetti maschi di età > 18 anni

In tutto il mondo > 1 miliardo di ipertesi

Global Disparities of hypertension Prevalence

Mod. da Mills, Circulation 2016

Global Disparities of hypertension Prevalence

Mod. da Mills, Circulation 2016

Epidemiologia Ipertensione in Italia
Why in 2016 are patients with hypertension not
100% controlled? A call to action

Mod. da Redon, J Hypertension 2016

Worldwide achievement of BP treatment targets
Prevalence of BP control in Italy

Mod. da Tocci, J Human Hypert 2016

Prevalence of BP control in Italy

Mod. da Tocci, J Human Hypert 2016

 Heart Disease and Stroke
Statistics—2015 Update
National Health and Nutrition
Examination Survey: 2007–2012

Mod. Dariush Mozaffarian et al. Mod. Tocci et al.J Clin

Circulation, 2015 Hypertens, 2015
A call to action and a lifecourse strategy to address the global
burden of raised blood pressure on current and future generations:
the Lancet Commission on hypertension

Mod. da Holsen, Lancet 2016

The lifecourse approach to management of
elevated blood pressure

Mod. da Holsen, Lancet 2016

Key actions within diagnosis and evaluation

Mod. da Holsen, Lancet 2016

Shared responsibility concept for improving
blood pressure control

Mod. da Redon, J Hypertension 2016

2013 ESH/ESC Guidelines
Aspetti Terapeutici Generali

• Perche’ trattare

• Quando trattare

• Obiettivi pressori

• Come trattare
Incidenza di eventi cardiovascolari
in soggetti con Ipertensione Arteriosa

Mod. Lim S et al, Lancet 2013

Reduction in the rate of CHD and Stroke for a BP
reduction of 10 mm Hg SBP or 5 mm Hg DBP

Mod. da Law,BMJ 2009

Rischio di vita per 12 malattie cardiovasculari
in soggetti normotesi ed ipertesi

Lancet 2014; 383: 1899–911

Mod. da N Engl J Med, 2015
Fattori usati per stratificare il rischio CV
nell’ipertensione secondo le linee guida ESH-ESC 2013

2013 ESH-ESC Guidelines, J Hypertens 2013

Stratificazione del rischio CV totale nella
popolazione degli ipertesi

2013 ESH-ESC Guidelines, J Hypertens 2013

Valutazione del danno d’organo asintomatico,
e delle malattie cardiovascolari e renali

2013 ESH-ESC Guidelines, J Hypertens 2013

Obiettivi pressori nei pazienti ipertesi

2013 ESH/ESC Hypertension Guidelines

Obiettivi pressori secondo le diverse
Linee Guida Internazionali (mmHg)
Indicazioni su cambiamento stili di vita
ed inizio terapia farmacologica

2013 ESH/ESC Hypertension Guidelines

Riduzione degli outcomes correlati alla riduzione dei
valori pressori (47 trials, pt =153.825 )

Thomopoulos C, Parati G, Zanchetti A. J Hypertens 2014,

MONOTERAPIA VS TERAPIA DI
COMBINAZIONE
Inizio

Limiti

Beneficio atteso e
scelte preferite

Combinazioni fisse
vs. estemporanee

Mod. ESH-ESC- 2013, J Hypertens 2013

Monoterapia vs Strategie di combinazione

2013 ESH/ESC Hypertension Guidelines

Terapia di combinazione negli ipertesi

Petrák, J Human Hypert 2015

 1 paziente su 3 è in trattamento
con 3 antipertensivi

Southern Europe (CR 19.6%)

Northern Europe (CR 13.4%)

Bramlage, J Clin Hypertens, 2010

Spese annuali per il trattamento dell’ipertensione e le sue complicazioni
in base ai livelli di aderenza alla terapia (miliardi €, 2003)

Livello di aderenza: Alto >80%, Intermedio 40-79%, Basso <40%

Mod. Ambrosioni E et al, ESH Manual of HBP

Costo-efficacia della terapia antipertensiva
secondo Linee Guida JNC 2014

Moran, NEJM 2015

SPRINT
Outcomes favor target systolic blood pressure
below 120 mmHg

SPRINT 2015, NEJM

SPRINT
Outcomes favor target systolic blood pressure
below 120 mmHg

SPRINT 2015, NEJM

 SPRINT 2015

Antihypertensive Drug Management to Achieve Systolic Blood Pressure <120 mmHg in SPRINT
Recommended two-drug combinations
of antihypertensive drugs

Mod. Poulter, Lancet 2015

2013 ESH-ESC Recommendations
for Combining BP-lowering Drugs

Mod. J Hypertens 2013

ACE-inibitori/sartani e calcio-antagonisti rappresentano la
combinazione preferita secondo le linee guida NICE-BHS più
recenti
Randomized Controlled Trials of Blood
Pressure Lowering in Hypertension

Zanchetti, Circ Res 2015

Randomized Controlled Trials of
Blood Pressure Lowering in Hypertension

Zanchetti, Circ Res 2015

Terapia antipertensiva

Nelle popolazioni speciali ed in presenza

di comorbilita’
Ipertensione e Comorbidita’:
Complessità nella Complessità

Valori pressori piu’ controllati

nel pz iperteso con polimorbidita’
Multimorbidity and Blood Pressure Control in 37 651
Hypertensive Patients From Danish General Practice

Paulsen, J Am Heart Assoc. 2012

Hypertension: a cross-sectional study of the role
of multimorbidity in blood pressure control

Sarkar, BMC Family Practice, 2015

How does the health care professional choose among
10 classes (66+ compound) cardiovascular drugs?
Farmaci antipertensivi e patologie specifiche

2013 ESH/ESC Hypertension Guidelines

 Titolazione temporale dei farmaci antipertensivi

18 trials/4168 pts
ACEI

DD
Clon.
BB

DHP
ARB

Lasserson,Heart 2011
Quarter-dose quadruple combination therapy for initial
treatment of hypertension: placebo-controlled,
crossover, randomised trial and systematic review

Mod. da Chow, Lancet 2017

Antihypertensive treatment strategies in
the elderly

2013 ESH/ESC Hypertension Guidelines

Antihypertensive treatment strategies in
the elderly

2013 ESH/ESC Hypertension Guidelines

Therapeutic Approaches in Special
Conditions

Diabetes Type 1 and Type 2

1) Antagonists of the RAAS

2) Calcium antagonists
3) Diuretics
4) Beta-blockers
5) Alpha-blockers
6) Sympatholytic agents
Types of hypertensive crisis
among diabetics and non-diabetics.

Al Bannay, International Journal of Cardiology, 2011

Proportion of diabetic complications
attributable to hypertension

Campbell, Can Fam Physician 2011

Treatment strategies in patients with
diabetes

2013 ESH/ESC Hypertension Guidelines

Treatment strategies in patients with
diabetes

2013 ESH/ESC Hypertension Guidelines

Treatment of the diabetic-hypertensive

Grossman, Am J Hyperten 2011

Standards of Medical Care in
Diabetes 2014 (ADA)

Diabetes, 2014
Standards of Medical Care in
Diabetes 2014 (ADA)

Diabetes, 2014
Therapeutic strategies in hypertensive
patients with nephropathy

2013 ESH/ESC Hypertension Guidelines

Therapeutic strategies in hypertensive
patients with nephropathy

2013 ESH/ESC Hypertension Guidelines

A physiology-based algorithm for hypertension
in CKD, from identification to treatment

Nephrol Dial Transplant (2014)

Pharmacological Treatment of Hypertension in
patient with Heart comorbidities

AHA, JACC, ASH, Hypertension 2015

Therapeutic strategies in hypertensive
patients with heart disease

2013 ESH/ESC Hypertension Guidelines

Therapeutic strategies in hypertensive
patients with heart disease

2013 ESH/ESC Hypertension Guidelines

Therapeutic strategies in hypertensive
patients with cerebrovascular disease

2013 ESH/ESC Hypertension Guidelines

 Treatment with angiotensin receptor
blocker before stroke

P< 0.002)
CNS: Canadian Neurological Scale

Fuentes, J Hypertens 2010

Trattamento non farmacologico per la riduzione della
pressione arteriosa
Modifiche dello stile di vita

Mod. Poulter N , Lancet 2014

Documentation and treatment of hypertension:
in a family medicine resident clinic

• In the USA, uncontrolled hypertension

contributes to 1000 deaths a day.

• US$ 131 billion a year in healthcare costs.

So, Postgrad Med J 2015

 aTRH

• Apparent treatment-resistant hypertension

aTRH is defined as uncontrolled hypertension

despite the use of ≥3 antihypertensive
medication classes.

or controlled hypertension while treated with

≥4 antihypertensive medication classes.
Prevalence of aTRH

Achelrod, Am J Hypert 2014

Definition of Resistant Hypertension
by Blood Pressure Monitoring

Muxfeldt, Am J Hypert 2014

Hypertension Therapy classification

Mod. da Dudenbostel , Hypertension 2016

“Device refractory hypertension”
Prognosi aTRH

Muntner, Hypertension 2014

Prevalence of pseudoresistant
hypertension phenotypes

Florczak, J Human Hyperten 2013

Forme di non aderenza

Modificato da Colivicchi F, Abrignani MG, G. Ital Cardiol 2010

 Possibili rimedi alla non aderenza

• Medico ruolo primario nella educazione e motivazione continua del

paziente

• Fondamentale rapporto con paziente (più tempo) per migliorare

aderenza

• Controllare alcuni parametri indiretti (ad es FC se betabloccante o CA

non diidropiridinico) piuttosto che concentrazione farmaco

• Misuratori PA per automisurazione nell’attesa della visita da MMG

• Applicazioni tecnologiche per “remind” e/o informazioni

• Utilizzare farmaci in associazione

• Ruolo farmacista: collaborazione vs barriera

Risk factors and pathogenic mechanisms associated
with treatment-resistant hypertension

Rimoldi Eur Heart J 2015

Clinical strategies in resistant
hypertension
Indizi clinici per la scelta del trattamento
dell’ipertensione arteriosa resistente

Mann,The Journal of Clinical Hypertension, 201

Indizi clinici per la scelta del trattamento
dell’ipertensione arteriosa resistente

Mann,The Journal of Clinical Hypertension, 2012

Combination therapy for high-risk
hypertension

TRIALS

ACCOMPLISH
ACCORD
ASCOT
GUARD
HIJ-CREATE
J-CORE
SHEP

Kario, J Am Soc Hyperten 2010

Mechanism-based algorithm for treating
Resistant hypertension

Mann, J Clin Hypertens 2011

Selezione dei farmaci antipertensivi in relazione
allo stato emodinamico del paziente

Aoka, Clinical and Experimental Hypertension, 201

Effetti dei farmaci antipertensivi sui meccanismi
fisiopatologici dell’ipertensione arteriosa

Hallow, Am J Physiol Regul Integr Comp Physiol 2014

Guideline Development Group, BMJ, 201
Antihypertensive drug therapy in
patients with resistant hypertension

Rimoldi Eur Heart J 2015

 Molecular structure of ARAs
(Facultative Diuretics)

α-spironolactone

Canrenone

Kolkhof, Molecular and Cellular Endocrinology, 2012

PATHWAY-2

Williams, BMJ 2015

PATHWAY-2

Williams, Lancet 2015

Finerenone

Liu, Exper Opin Invest Drugs 2015

TERAPIE DI COMBINAZIONI
NON USUALI
JNC-7 Algorithm for the treatment of
resistant hypertension

Trewet, Southern Medical Journal, 2008

Additional Options for the Treatment of
Resistant Hypertension

Combined α- and β-blocker (carvedilol, labetalol)

or β-blocker (non–α-blocking) +α-blocker

Aldosterone antagonist

Non-DHP CCB + DHP CCB

Vasodilator –Minoxidil (with a β-blocker + loop diuretic)

Centrally acting agent

Adams, Postgraduate Medicine, 2012

JNC-7 Algorithm for the treatment of
resistant hypertension

Trewet, Southern Medical Journal, 200

JNC-7 Algorithm for the treatment of
resistant hypertension

2 CCBs
(different types)

Trewet, Southern Medical Journal, 200

 Effects of L-type and combined L-/T-type Ca2
channel blockers in large and microvessels.

DHP-CCB Non-DHP-CCB

Ge,Hypertension 2009
Comparison of Nifedipine Alone and With
Diltiazem or Verapamil in Hypertension

Saseen, Hypertension,1996
Nifedipine (NIF) Cp versus time after
steady-state oral dosing of stud medication

CYP3A4

Saseen, Hypertension, 1996

 Long-Term Effectiveness of Extended-Release Nitrate for
the Treatment of Resistant Systolic Hypertension

Subjects (n=16)

Stokes, Curr Opinion Hypertension, 2010

 Combination of Organic Nitrate and Phosphodiesterase
Type 5 Inhibitor in Treatment-Resistant Hypertension

Subjects (n=6)

Placebo ■
Sildenafil ▲
ISMN ○
Combined sildenafil and ISMN ◊
Oliver, Hypertension, 2010
Screening for device-based interventions

Rimoldi Eur Heart J 2015

Invasive approach to resistant
hypertension

BAROREFLEX ACTIVATION THERAPY (BAT)

(Scheffers, J Am Coll Cardiol 2010), available since 2009

RENAL DENERVATION (RDN)

(Krum, Lancet 2010)

Central arteriovenous coupler (ROX)

(Lobo, Lancet 2015)
Principali indici di spesa, di consumo e di
esposizione apparato cardiovascolare

AIFA 2014
Similarita’ fra farmaci antipertensivi
generici e brand

Corrao, J Hypertens 2014

 1. Diagnosi clinica ipertensione arteriosa

PA clinica ≤ 140/90 mmHg PA clinica ≥ 140/90 mmHg

e Consigliabile confermare con
PA domiciliare ≤ 130/85 mmHg ABPM ≥ 125/80 mmHg
oppure
facoltativo PA domiciliare ≥ 130/85 mmHg
ABPM ≤ 125/80 mmHg

2. DIAGNOSI DIFFERENZIALE &

VALUTAZIONE DANNO D’ORGANO
ESCLUSIONE
IPERTENSIONE ARTERIOSA
CONTROLLO ANNUALE
3. IMPOSTAZIONE TERAPIA FARMACOLOGICA
2. Valutazione diagnostica ipertensione
arteriosa
NUOVI FARMACI ANTIIPERTENSIVI
Eirin, Trends Cardiovasc Med, 2016
Eirin, Trends Cardiovasc Med, 2016
Drugs in development for hypertension

Lobo, Eur Heart Journal 2016

Impact of Neprilysin inhibitors on mortality and
major cardiovascular endpoints in hypertension

Bavishi, Eur Heart J 2015

Impact of Neprilysin inhibitors on mortality and
major cardiovascular endpoints in hypertension

Bavishi, Eur Heart J 2015

Site of action of the sodium–glucose cotransporter type 2
(SGLT2) inhibitors compared with sites of action of the
classic diuretics

Diabetes & Metabolism 42 (2016)

The Future

Lobo, Eur Heart Journal 2016