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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