Terapia dell’ipertensione arteriosa resistente con multipli fattori di rischio: guida alla scelta razionale delle

associazioni farmacologiche

Stefano Taddei

Dipartimento di Medicina Clinica e Sperimentale

DISCLOSURE INFORMATIONStefano Taddei

negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in

campo sanitario:ServierPfizerBoheringer IngelheimMSDMenariniSanofi Aventis

Resistant hypertension

Resistant hypertension is a misleading concept.Guidelines do not define resistant hypertension as anincurable disease, but as a pathological condition whichneeds a more accurate investigation!

• No BP control despite 3 antihypertensive drugs (including a diuretic), all at adequate doses

• No BP control despite 3 antihypertensive drugs at adequate doses, regardless whether a diuretic is included

• Use of 4 or more antihypertensive drugs, irrespective of the BP status

Resistant hypertension/Definitions

• Overall prevalence around 5% (even less in some studies)• Prevalence highly variable according to environmental/

clinical setting• 2-3% General population• 4-5% General Practitioners• 20-30% Hypertension Centers• 40-50% Nephrology Units

True resistant hypertension/Current thinking

However, even if the incidence is low (around 5%), the absolute number of patients is very large, expecially considering the high CV risk associated to resistant hypertension.

Adjusted Multivariate Hazard Ratio of Eventsin RH (n = 6790) vs Non-RH (n = 46740)

CV death / MI / Stroke

CV death / MI / Stroke / CV rehosp.

All-cause mortality

CV mortality

NF-Stroke

F-Stroke

NF MI

Hospitalization for CHF

Risk

+11

+18

- 3

+ 1

+26

+14

+ 4

+36

HR (95% CI)

0.5 1 2

Greater in RHGreater in non-RH

Kumbhani DJ et al., Eur Heart J 2013

Patients with resistant hypertension have a greater CV Risk!

Causes of resistant hypertension

• Secondary hypertension

• Low therapeutic compliance

• Drug induced hypertension

• Lifestyle

-Body weight increase

-Alcohol assumption

• Plasma hypervolemia

-Insufficient diuretic dosing

-Chronic renal failure

-High salt intake

ESH-ESC Guidelines, J Hypertens 2013 JNC-7 Report, JAMA 2014

Resistant hypertension: an incurable disease or just a challenge for our medical skill?

First, exclude pseudo-resistant hypertension

Pseudoresistant hypertension

• Poor blood pressure measurement technique / Failure to use

large cuff on large arm

• White coat hypertension

• Inadequate drug therapy

– Inadequate drug dosage

– Inadequate drug combination

Calhoun 2008, Hypertension. 2008

• Poor blood pressure measurement technique / Failure to use

large cuff on large arm

• White coat hypertension

• Inadequate drug therapy

– Inadequate drug dosage

– Inadequate drug combination

Pseudoresistant hypertension

Calhoun 2008, Hypertension. 2008

Dose-response curves of antihypertensive drugs

Duration of action (hrs)

0 6 12 18 24

B

5 mg

Duration of action (hrs)

A

0 6 12 18 24

10 mg

20 mg

5 mg

10 mg

20 mg

Drugs with a linear dose-response curve:

• diuretics• b-blockers• a1-blockers• b/a1-blockers• calcium-antagonists

Drugs with a flat dose-response curve:

• ACE-inhibitors• AT1-antagonists

Taddei S Am J Cardiovasc Drugs 2015

ACE-inhibitors

5 mg

Duration of action (hrs)

BP

0 6 12 18 24

15 mg10 mg 20 mg

Enalapril

2.5 mg

Duration of action (hrs)

BP

0 6 12 18 24

7.5 mg5 mg 10 mg

Ramipril

Taddei S Am J Cardiovasc Drugs 2015

75 mg

Duration of action (h)0 6 12 18 24

150 mg

300 mg

Angiotensin Receptor Blockers

Irbesartan

Taddei S et al Am Cardiovasc Drugs 2015

Il diuretico,

farmaco utilizzato poco e male!!!

BP reduction and side effects* of thiazide diuretics*hypokalemia, increase in total cholesterol and glycaemia

12,5 25 50 100

Dose (mg/day)

Hydrochlorothiazide

BP reduction

adverse metabolic effect

adapted from Carter BL et al. Hypertension 2004

Questa dose corrisponde a: Igroton ½ cpr

BP reduction and side effects* of thiazide diuretics*hypokalemia, increase in total cholesterol and glycaemia

12,5 25 50 100

Dose (mg/day)

Hydrochlorothiazide

BP reduction

adverse metabolic effect

adapted from Carter BL et al. Hypertension 2004

Questa dose corrisponde a: Igroton ½ cpr

Moduretic:Amiloride 5 mg/HTCZ 50 mg

Ramipril 2.5 mg / HTCZ 12.5 mg

Valsartan 80 mg /HTCZ 12.5 mg

“Homeopathic” combinations

…Diuretics have remained the cornerstoneof antihypertensive treatment since at least

the first Joint National Committee (JNC) report in1977 [412] and the first WHO report in 1978 [413],and still, in 2003, they were classified as the onlyfirst-choice drug by which to start treatment, inboth the JNC-7 [264] and the WHO/InternationalSociety of Hypertension Guidelines [55,264].

…It has also been argued that diuretics such aschlorthalidone or indapamide should beused in preference to conventional thiazide

diuretics, such as hydrochlorothiazide [271].

…D: If diuretic treatment is to be initiated or

changed, offer a Thiazide-like Diuretics like Chlortalidone (12.5-25 mg once daily) or

Indapamide (1.5 modified-release or 2.5 once

daily) in preference to a conventional thiazide diuretic such as Bendroflumethiazide or Hydrocholorothiazide.

Roush G. et al. Hypertension. 2015

Meta-analysis comparing hydrochlorothiazide (HCTZ) and indapamide (INDAP) in patients with HTN

Effects on serum potassium in mEq/L, in studies comparing hydrochlorothiazide (HCTZ) and indapamide (INDAP)

Roush G. et al. Hypertension. 2015

Long-term (9 months) metabolic profile of Indapamide SR in patients with hypertension. Pooled results of 3 RCT

Weidmann P et al, Drug Safety 2001

-0,5

-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

0 6,25 12,5 25

037,5

100300

Dose HCTZ mg/die

Mo

dif

icaz

ion

i med

ie r

isp

etto

al b

asal

e d

ella

p

ota

ssie

mia

m

Eq/d

l

Dose Irbesartanmg/die

Kochar M et al, Am J Hypertens 1999

Effetto dell’associazione di un AT-1 antagonista e di un diuretico sulle concentrazioni plasmatiche di potassio

Possible combinations strategies according to event based controlled clinical trials

ESH – ESC Guidelines Committee. J Hypertens 2013

Le associazioni razionali sono realizzate tenendo conto del meccanismo d’ azione dei farmaci antipertensivi

DiureticiCalcio antagonistiAlfa-antagonisti

SRAACE-inibitoriAT-1 antagonistiBeta-bloccanti

Vasodilatatori SNSACE-inibitoriAT-1 antagonistiBeta-bloccantiSimpatomodulatori

ALLHAT Study

Farmaco

Clortalidone

Amlodipina

Lisinopril

Associazione

Atenololo

Atenololo

Atenololo

Razionale

Razionale

Non razionale

ALLHAT Study

150

145

140

135

1300 1 2 3 4 5 6

Chlorthalidone

Amlodipine

Lisinopril

90

85

80

75

70 0 1 2 3 4 5 6

Follow-up, y Follow-up, y

Mean Systolic Blood Pressure Mean Diastolic Blood Pressure

mmHg

JAMA 2002

mmHg

Associazioni non razionali dei

farmaci antipertensivi

Combination of drugs without additive blood pressure lowering effect

- Diuretic + Ca-antagonist

- b-blocker + ACE-inhibitor (or AT1-antagonist)

- ACE-inhibitor + AT1-antagonist

- a1-antagonist + clonidine

Combination of drugs with negative interaction on blood pressure lowering effect

Non rational combinations of antihypertensive drugs!

Quando si associano più farmaci antiipertensivi, l’ importante è che almeno 2 di essi abbiamo un meccanismo d’ azione complementare:

ACE-inibitore (o AT-1 antagonista) + Ca-antagonista

Associazioni di 3 o più farmaci antiipertensivi

Diuretico, perché ha un’ interazione positiva con l’ ACE-inibitore (o AT-1 antagonista)

b-bloccante, perché ha un’ interazione positiva con il Ca-

antagonista

ACE-inibitore (o AT-1 antagonista) + b-bloccante

Benefici clinici di associazioni di farmaci antiipertensivi che non hanno effetto additivo sulla pressione arteriosa

INDICAZIONE

•Pazienti con infarto del miocardio

•Pazienti con scompenso cardiaco

ACE-inibitore + AT-1 antagonista

POSSIBILE INDICAZIONE

•Pazienti con proteinuria

Causes of resistant hypertension

• Secondary hypertension

• Low therapeutic compliance

• Drug induced hypertension

• Lifestyle

-Body weight increase

-Alcohol assumption

• Plasma hypervolemia

-Insufficient diuretic dosing

-Chronic renal failure

-High salt intake

ESH-ESC Guidelines, J Hypertens 2013 JNC-7 Report, JAMA 2014

Non-adherence to treatment: the most prevalent cause of resistant hypertension?

Brinker S et al., JACC 2014

Non-adherence ratio = ratio of numbers of undetectable antihypertensive drugs to the total number of antihypertensive drugs tested among RH patients undergoing therapeutic drug monitoring

Undetectable

levels of ALL anti-

HT drugs: 32%

Methods to improve adherence to physicians’ recommendations

2013 ESH/ESC Guidelines for the management of arterial hypertension

BP Control at 1 year: Impact of Initiating Therapy with 1, 2 or SPC Formulations

Strategy HR (95%CI)

Monotherapy Ref (1.0)

Two drugs 1.34 (1.31-1.37)

SPC 1.53 (1.47-1.58)

Egan et al. Hypertension 2012

2 out of 3 hypertensive patients are already treated by combination therapy

Bramlage P et al. J Clin Hypertens 2010

Effect of a triple combination of RAAS-I, Amlo, and Diur given as 3 pills, 2 pills, and single pill on the rate of adherence to treatment

Xie L et al. CMRO. 2015;30(12):2412-2422.

n=17465, 12-month follow-up. 1Adherence defined as proportion of days covered (≥80%)

*3 pills: RAAS + Aml + DIU

**2 pills: RAAS/Aml + DIU or RAAS/DIU + Aml

***SPC: single-pill combination RAAS/Aml/DIU

“…those in the triple-pill cohort were 74% less likely to be adherent to their antihypertensive drugs compared to patients prescribed the single-pill combination over 12 months of follow-up.”

P<0.0001

% p

atie

nts

wit

h a

dh

ere

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atm

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Conclusioni

• La terapia di associazione è indispensabile per ottenere lanormalizzazione dei valori pressori nella maggioranza dei pazienti conipertensione arteriosa e ancor di più nei pazienti con ipertensioneresistente.

• I farmaci antiipertensivi possono essere associati se hanno caratteristichefarmacocinetiche simili, ma caratteristiche farmacodinamichecomplementari

• Nelle associazioni i farmaci devono essere utilizzati ai dosaggi adeguati.

• In ogni caso la scelta della terapia da utilizzare nella pratica clinica deveessere determinata, quando possibile, dai risultati degli studi clinicicontrollati basati su eventi e da una attenta conoscenza della letteraturascientifica.

• Se disponibile, è sempre preferibile usare una combinazione fissa.Tuttavia, nella maggior parte delle combinazioni fisse con HTCZ, la dose didiuretico è poco efficace.