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

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1 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

2 DISCLOSURE INFORMATION Stefano Taddei negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Servier Pfizer Boheringer Ingelheim MSD Menarini Sanofi Aventis

3 Resistant hypertension Resistant hypertension is a misleading concept. Guidelines do not define resistant hypertension as an incurable disease, but as a pathological condition which needs a more accurate investigation!

4 Resistant hypertension/definitions 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

5 True resistant hypertension/current thinking 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 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.

6 Patients with resistant hypertension have a greater CV Risk! Adjusted Multivariate Hazard Ratio of Events in RH (n = 6790) vs Non-RH (n = 46740) HR (95% CI) Risk CV death / MI / Stroke CV death / MI / Stroke / CV rehosp. All-cause mortality CV mortality NF-Stroke F-Stroke NF MI Hospitalization for CHF Greater in non-rh Greater in RH Kumbhani DJ et al., Eur Heart J 2013

7 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

8 Resistant hypertension: an incurable disease or just a challenge for our medical skill? First, exclude pseudo-resistant hypertension

9 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

10 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

11 Dose-response curves of antihypertensive drugs A B 5 mg 5 mg 10 mg 20 mg 10 mg 20 mg Duration of action (hrs) Duration of action (hrs) Drugs with a linear dose-response curve: diuretics b-blockers a 1 -blockers b/a 1 -blockers calcium-antagonists Drugs with a flat dose-response curve: ACE-inhibitors AT 1 -antagonists Taddei S Am J Cardiovasc Drugs 2015

12 ACE-inhibitors BP Enalapril 5 mg 10 mg 15 mg 20 mg Duration of action (hrs) BP Ramipril 2.5 mg 5 mg 7.5 mg 10 mg Duration of action (hrs) Taddei S Am J Cardiovasc Drugs 2015

13 Angiotensin Receptor Blockers Irbesartan 75 mg 150 mg 300 mg Duration of action (h) Taddei S et al Am Cardiovasc Drugs 2015

14 Il diuretico, farmaco utilizzato poco e male!!!

15 BP reduction and side effects* of thiazide diuretics *hypokalemia, increase in total cholesterol and glycaemia BP reduction Hydrochlorothiazide adverse metabolic effect Questa dose corrisponde a: Igroton ½ cpr 12, Dose (mg/day) adapted from Carter BL et al. Hypertension 2004

16 BP reduction and side effects* of thiazide diuretics *hypokalemia, increase in total cholesterol and glycaemia BP reduction Hydrochlorothiazide adverse metabolic effect Moduretic: Amiloride 5 mg/htcz 50 mg Questa dose corrisponde a: Igroton ½ cpr 12, Dose (mg/day) adapted from Carter BL et al. Hypertension 2004

17 Homeopathic combinations Ramipril 2.5 mg / HTCZ 12.5 mg Valsartan 80 mg /HTCZ 12.5 mg

18 Diuretics have remained the cornerstone of antihypertensive treatment since at least the first Joint National Committee (JNC) report in 1977 [412] and the first WHO report in 1978 [413], and still, in 2003, they were classified as the only first-choice drug by which to start treatment, in both the JNC-7 [264] and the WHO/International Society of Hypertension Guidelines [55,264]. It has also been argued that diuretics such as chlorthalidone or indapamide should be used 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 ( 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.

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20 Meta-analysis comparing hydrochlorothiazide (HCTZ) and indapamide (INDAP) in patients with HTN Roush G. et al. Hypertension. 2015

21 Effects on serum potassium in meq/l, in studies comparing hydrochlorothiazide (HCTZ) and indapamide (INDAP) Roush G. et al. Hypertension. 2015

22 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

23 Modificazioni medie rispetto al basale della potassiemia meq/dl Effetto dell associazione di un AT-1 antagonista e di un diuretico sulle concentrazioni plasmatiche di potassio 0,2 0,1 0-0,1-0,2-0,3-0,4-0,5 0 6,25 12,5 25 Dose HCTZ mg/die ,5 Dose Irbesartan mg/die Kochar M et al, Am J Hypertens 1999

24 Possible combinations strategies according to event based controlled clinical trials ESH ESC Guidelines Committee. J Hypertens 2013

25 Le associazioni razionali sono realizzate tenendo conto del meccanismo d azione dei farmaci antipertensivi Diuretici Calcio antagonisti Alfa-antagonisti SRA ACE-inibitori AT-1 antagonisti Beta-bloccanti Vasodilatatori SNS ACE-inibitori AT-1 antagonisti Beta-bloccanti Simpatomodulatori

26 ALLHAT Study Farmaco Associazione Clortalidone Atenololo Razionale Amlodipina Atenololo Razionale Lisinopril Atenololo Non razionale

27 ALLHAT Study Mean Systolic Blood Pressure Mean Diastolic Blood Pressure mmhg mmhg Chlorthalidone Amlodipine Lisinopril Follow-up, y Follow-up, y JAMA 2002

28 Associazioni non razionali dei farmaci antipertensivi

29 Non rational combinations of antihypertensive drugs! Combination of drugs without additive blood pressure lowering effect - Diuretic + Ca-antagonist - b-blocker + ACE-inhibitor (or AT 1 -antagonist) - ACE-inhibitor + AT 1 -antagonist Combination of drugs with negative interaction on blood pressure lowering effect - a 1 -antagonist + clonidine

30 Associazioni di 3 o più farmaci antiipertensivi 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 Diuretico, perché ha un interazione positiva con l ACEinibitore (o AT-1 antagonista) b-bloccante, perché ha un interazione positiva con il Caantagonista

31 Benefici clinici di associazioni di farmaci antiipertensivi che non hanno effetto additivo sulla pressione arteriosa ACE-inibitore (o AT-1 antagonista) + b-bloccante INDICAZIONE Pazienti con infarto del miocardio Pazienti con scompenso cardiaco ACE-inibitore + AT-1 antagonista POSSIBILE INDICAZIONE Pazienti con proteinuria

32 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

33 Non-adherence to treatment: the most prevalent cause of resistant hypertension? Undetectable levels of ALL anti- HT drugs: 32% 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 Brinker S et al., JACC 2014

34 Methods to improve adherence to physicians recommendations 2013 ESH/ESC Guidelines for the management of arterial hypertension

35 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 ( ) SPC 1.53 ( ) Egan et al. Hypertension 2012

36 2 out of 3 hypertensive patients are already treated by combination therapy Bramlage P et al. J Clin Hypertens 2010

37 % patients with adherence to treatment 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 n=17465, 12-month follow-up. 1 Adherence 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 P< 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. Xie L et al. CMRO. 2015;30(12):

38 Conclusioni La terapia di associazione è indispensabile per ottenere la normalizzazione dei valori pressori nella maggioranza dei pazienti con ipertensione arteriosa e ancor di più nei pazienti con ipertensione resistente. I farmaci antiipertensivi possono essere associati se hanno caratteristiche farmacocinetiche simili, ma caratteristiche farmacodinamiche complementari Nelle associazioni i farmaci devono essere utilizzati ai dosaggi adeguati. Se disponibile, è sempre preferibile usare una combinazione fissa. Tuttavia, nella maggior parte delle combinazioni fisse con HTCZ, la dose di diuretico è poco efficace. In ogni caso la scelta della terapia da utilizzare nella pratica clinica deve essere determinata, quando possibile, dai risultati degli studi clinici controllati basati su eventi e da una attenta conoscenza della letteratura scientifica.