Post on 14-Feb-2019
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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
nce
to
tre
atm
en
t
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.