State of the art treatment of hypertension: established and new drugs Prof. M. Burnier Service of Nephrology and Hypertension Lausanne, Switzerland
First line therapies in hypertension ACE inhibitors AT 1 -receptor blockers Calcium antagonists ß-blockers Diuretics First-line therapies Adapted from the 2009 Reappraisal of ESH/ESC Hypertension Guidelines
Changes in SBP, mmhg Placebo-corrected changes in SBP 0-5 -10-15 -blockers ACE inhibitors Thiazides Half standard dose Standard dose Calcium antagonists AT 1 -receptor blockers Law et al, BMJ 2003 Twice standard dose
Percentage of patients with AE 20 15 10 N of trials : 59 96 62 5 0 96 44-5 Half standard dose Standard dose Twice standard dose -blockers ACE inhibitors Thiazides Calcium antagonists AT 1 -receptor blockers Law et al, BMJ 2003
Isolated systolic hypertension Hypertension in blacks Angina pectoris Post-myocardial infarction Left ventricular hypertrophy Atrial fibrillation Heart failure Carotid/coronary atherosclerosis Metabolic syndrome Non diabetic nephropathy Diabetic nephropathy Proteinuria/microalbuminuria Blockers of the RAS Dihydropyridines Thiazides Adapted from ESH/ESC Hypertension Guidelines
Control rate (%) ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 90 80 78.5 81.7 70 60 50 40 30 20 37.2 37.9 Baseline Control Rates 10 ACEI / HCTZ N=5733 P<0.001 at 30 months follow-up Control defined as <140/90 mmhg CCB / ACEI N=5713
One topic of debate: ACEI or ARB? Arguments regarding: Impact on morbidity and mortality Tolerability profile and risk of SAE
Cumulative Hazard Rates ONTARGET Ramipril vs Telmisartan Time to Primary Outcome 0.0 0.05 0.10 0.15 0.20 0.25 # at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5 T 8542 8177 7778 7420 7051 4575 R 8576 8214 7832 7472 7093 4562 Telmisartan Ramipril 0 1 2 3 4 Years of Follow-up N Engl JMed 2008;358:1547-59
N Engl JMed 2008;358:1547-59 ONTARGET Non-Inferiority ONTARGET Comparison CV Death MI Stroke CHF Hosp All Death Telmisartan better Ramipril better 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 RR (95% CI) Note that the outcomes are presented as point estimates with confidence intervals. The solid line is the 95% CI representing 1.96 SD for each outcome
Angiotensin receptor blockers and all cause mortality, stratified by comparison group (placebo v active treatment). Bangalore S et al. BMJ 2011;342:bmj.d2234
Angiotensin receptor blockers and myocardial infarction, stratified by comparison group (placebo v active treatment). Bangalore S et al. BMJ 2011;342:bmj.d2234
Angiotensin receptor blockers and stroke, stratified by comparison group (placebo v active treatment). Bangalore S et al. BMJ 2011;342:bmj.d2234
ONTARGET Reasons for Permanently Stopping Study Medications Ram Tel Tel vs. Ram N=8576 N=8542 RR P Hypotension 149 224 1.51 0.0001 Syncope 15 18 1.20 0.593 Cough 359 93 0.26 <0.0001 Diarrhea 12 19 1.59 0.20 Angioedema 25 10 0.40 0.0115 Renal Impairment Any Discontinuation 59 68 1.16 0.41 2098 1962 0.94 0.02 N Engl JMed 2008;358:1547-59
Risk of angioedema : ARBs vs ACEIs Incidence of angioedema is higher in patients with heart failure Makani et al, Am J Cardiol 2012; 110:383
The importance of tolerability is reflected by withinclass differences in discontinuation rates ACEIs ARBs Captopril Moexipril Spirapril Fosinopril Quinapril Benazepril Trandolapril Delapril Cilazapril Lisinopril Enalapril Perindopril Zofenopril Ramipril 0 10 20 30 40 Standardised discontinuation rate (100 patients/month) Losartan Eprosartan Telmisartan Irbesartan Candesartan Valsartan Olmesartan 0 2 4 6 8 10 12 Standardised discontinuation rate (100 patients/month) Mancia et al. J Hypertens 2011;29:1012-1018.
Another question: which calcium antagonist?
Patients with primary events (%) ACCOMPLISH: RAS-blocker/CCB combined therapy offers benefits in higher-risk patients 16 The primary cardiovascular composite end point was significantly lower with an ACEI/CCB than an ACEI/diuretic combination 14 12 Benazepril plus hydrocholorthiazide 10 8 6 4 Benazepril plus amlodipine 20% lower 2 0 No. at risk: Benazepril / AML Benazepril / HCTZ 0 6 12 18 24 30 36 42 Months 5512 5317 5141 4959 4739 2826 1447 5483 5274 5082 4892 4655 2749 1390 Jamerson et al. N Engl J Med 2008;359:2417-28
Incidence of adverse responses to different classes of drugs as reported by physicians 25 20 ** % 15 10 5 0 Diur ß-block CCB ACEi Alphablock other E.Ambrosioni et al, J Hypertens ;18, 2000
Adherence to cardiovascular drugs in primary prevention Naderi et al, The American Journal of Medicine (2012) 125, 882-887
Peripheral edema:
Adverse events in the VALUE trial Valsartan Amlodipine (n=7622) (n=7576) P Pre-specified adverse events Peripheral edema 1135 (14.9%) 2492 (32.9%) <0.0001 Dizziness 1257 (16.5%) 1083 (14.3%) <0.0001 Headache 1120 (14.7%) 947 (12.5%) <0.0001 Fatigue 739 (9.7%) 674 (8.9%) 0.0750 Additional common adverse events Diarrhea* 670 (8.8%) 515 (6.8%) <0.0001 Edema other* 243 (3.2%) 462 (6.1%) <0.0001 Hypokaliemia* 266 (3.5%) 469 (6.2%) <0.0001 *With an incidence >3% and a difference between treatment groups >1% Julius et al. Lancet. 2004;363:2022-2031.
Adverse events in the ASCOT trial Adverse event* Amlodipine perindopril n (%) Atenolol thiazide n (%) p-value Bradycardia 34 (0.4) 536 (6) <0.0001 Chest pain 740 (8) 849 (9) 0.0040 Cough 1859 (19) 782 (8) <0.0001 Diarrhoea 377 (4) 548 (6) <0.0001 Dizziness 1183 (12) 1555 (16) <0.0001 Dyspnoea 599 (6) 987 (10) <0.0001 Eczema 493 (5) 383 (4) 0.0002 Erectile dysfunction 37 556 %(6) of edema 707 (7) <0.0001 Fatigue 782 (8) 1556 (16) <0.0001 Joint swelling 1371 (14) 308 (3) <0.0001 Lethargy 202 (2) 525 (6) <0.0001 Oedema peripheral 2188 (23) 588 (6) <0.0001 Peripheral coldness 81 (1) 579 (6) <0.0001 Vertigo 642 (7) 745 (8) 0.0039
% patients with S.E.s PREVALENCE OF DRUG-SPECIFIC AE s IN THE LERCANIDIPINE CHALLENGE STUDY. Ankle edema 100 96 P<0.001 87 80 60 P<0.001 52 yes no 40 20 0 CCB Lercanidipine CCB Borghi C et al, Blood Pressure, 2003
% of patients % OF PTS WITH ANKLE EDEMA OVER TIME 20 18 16 14 12 10 8 6 4 2 0 Lercanidipine Amlodipine Lacidipine P<0.001 Baseline 1 month 2 months 3 months 6 months End of COHORT Study, Am J Hypertens, 2002 study
Impact of lercanidipine on peripheral edema in 2199 patients followed by GPs in Switzerland Premature treatment interruption due to adverse events Initiation Add-on Substitution (n=683) (n=844) (n=672) 4.4 7.8 8.8 Ankle edema Headache Flush Others 0.6 0.6 0.4 2.8 1.9 1.1 1.3 3.8 3.0 1.1 0.6 4.3 Burnier and Gasser, 2007
Last question: which diuretic? Hydrochlorothiazide Chlorthalidone Indapamide
Dose-response relationships for thiazides vs BP (A and B) (C) serum potassium; and (D) serum urate. Peterzan M A et al. Hypertension 2012;59:1104-1109
Risk of cardiovascular events in patients receiving HCTZ or chlorthalidone according to the changes in systolic BP Roush G C et al. Hypertension 2012;59:1110-1117
Antihypertensive Efficacy of Hydrochlorothiazide vs Chlorthalidone Combined with Azilsartan Medoxomil Bakris et al, The American Journal of Medicine 2012, 125; p1229.e1-e10
Azilsartan + CLD vs olmesartan + HCTZ Cushman W C et al. Hypertension 2012;60:310-318
Change in systolic blood pressure by ABPM at week 12. Cushman W C et al. Hypertension 2012;60:310-318
Percentage of patients Over one year, compliance and persistence with anti-hypertensive therapy typically falls to <50% Study of hypertensive patients in clinical studies 4783 patients in 21 Phase IV trials Evaluated by medication event monitoring system 100 90 80 70 60 50 0 Fall in adherence because of poor execution of dosing regimen Persistence Adherence/compliance Perfect adherence Fall in persistence because of discontinuation of treatment 0 50 100 150 200 250 300 350 Time (days) No of patients remaining in study 3108 980 828 618 474 400 331 Vrijens et al. BMJ 2008;336:1114-7.
Adherence to cardiovascular drugs Naderi et al, The American Journal of Medicine (2012) 125, 882-887