Are all Antihypertensives the same?

Transcription

1 Are all Antihypertensives the same? Athanasios J. Manolis MD, FACC, FESC, FAHA Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece. Adj. Ass. Professor, Hypertension Section, Boston University, MA, USA Adj. Professor of Medicine, Emory University, Atlanta, USA

2 Disclosures Research Grants, Honoraria, Advisory Boards SERVIER MENARINI NOVARTIS PFIZER GSK BAYER ASTRA ZENECA WIN ABBOTT RECORDATI FERRER AMGEN BOERINGHER INGHELHEIM ALGORITHM ELPEN SANOFI

3 From Hypertension to Target Organ Damage Inflammation Thrombosis Diabetes Mellitus Mets HTN Endothelial dysfunction LVH Microalbuminuria CHD Subclinical Organ Damage TOD CHF HF HF-PEF Stroke Dyslipidemia Vasoconstriction Vascular Remodeling IMT CKD AF Manolis AJ

4 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Although meta-analyses occasionally claim superiority of one class for some outcomes this largely depends on selection bias of trials. The largest meta-analyses do not show clinically relevant between-class differences Current Guidelines reconfirm that the following drugs classes are all suitable for initiation and maintenance of antihypertensive treatment either as monotherapy or in some combinations with each other (IA) Diuretics (thiazides / chlorthalidone / indapamide) Calcium channel blockers Beta-blockers ACE-inhibitors Angiotensin receptor blockers

5 Goals Of Antihypertensive Treatment BP reduction Risk Factors HT Prevention NOD Prevention TOD regression/ prevention AF Prevention ESRD CHD CHF Stroke Cognitive Dysfunction Dementia LVH IMT Microalbuminaria Arterial stiffness Endotheliadysfunction Cardiacfibrosis

6 2013 ESH/ESC Hypertension Guidelines Drugs To Be Preferred In Specific Conditions

7 Are all Antihypertensives of each class the same?

8 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Diuretics (thiazides / chlorthalidone / indapamide) Calcium Channel blockers Beta-blockers ACE-inhibitors Angiotensin receptor blockers

9 2013 ESH/ESC Hypertension Guidelines Diuretics Meta-analyses claiming that HCTZ has lesser ability to reduce ABP (vs other agents) and outcome (vs chlorthalidone) is based on limited number of trials / no head-to-head comparisons In MRFIT no random assignment to HCTZ or chlorthalidone and chlorthalidone used at higher doses RCT evidence of protection by thiazides / thiazide-like / indapamide

10 From: Efficacy of Low-Dose Chlorthalidone and Hydrochlorothiazide as Assessed by 24-h Ambulatory Blood Pressure Monitoring J Am Coll Cardiol. 2016;67(4): doi: /j.jacc Figure Legend: Low-Dose Thiazides in Hypertension: 24-h and Nighttime Ambulatory BP After 12 Weeks of Therapy A significant decrease of both 24-h and nighttime ambulatory BP with chlorthalidone, 6.25 mg/day, was observed. There was no significant decrease with HCTZ, 12.5 mg/day. p < 0.001; p < 0.01; Wilcoxon signed rank tests were used for comparison. CTD = chlorthalidone; HCTZ = hydrochlorothiazide; SBP = systolic blood pressure. Date of download: 1/29/2016 Copyright The American College of Cardiology. All rights reserved.

11 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Diuretics (thiazides / chlorthalidone / indapamide) Calcium Channel blockers Beta-blockers ACE-inhibitors Angiotensin receptor blockers

12 Classification of Calcium Channel Blockers Phenilalkylamines Verapamil Benzothiazepines Diltiazem Calcium channel blockers 1 st generation Nifedipine Dihydropyridines 2 st generation Isradipine Nicardipine Felodipine 3 st generation Amlodipine Manidipine Lercanidipine

13 Calcium Channel Blockers: Differences Peripheral and coronary vasodilation Depression of cardiac contractility Depression of SA node Depression of AV node Dihydropyridines Benzodiazepines Phenylalkylamines

14 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Diuretics (thiazides / chlorthalidone / indapamide) Calcium Channel blockers Beta-blockers ACE-inhibitors Angiotensin receptor blockers

15 Pharmacologic Properties of Various β-blockers Bradycardia Negative inotropy BP ß 1 - SELECTIVE Less bronchospasm Fewer peripheral effects Metabolic effects Circulatory NONSELECTIVE (ß 1 ß 2 ) Similar cardiac and antihypertensive effects More marked pulmonary and peripheral effects

16 Main Factors Contributing to Heterogeneity Within the β-blocker Class β 1 /β 2 Selectivity Vasodilation Properties β-blocker class Side effects Metabolic profile Efficacy

17 Mechanisms of Action of Nebivolol in CV System

18 Traditional Beta-blockers vs Nebivolol Advantages (+) / Disadvantages (-) BP reduction CV event reduction CHD prevention CHF prevention CHF treatment CHD treatment Subclinical OD PAD COPD (moderate/severe) Dysmetabolic effects New onset diabetes Central BP NO release Side effects profile/adherence Sexual dysfunction Pulmonary hypertension Contrast induced nephropathy Β-blockers Nebivolol ? /? +/? Manolis AJ et al. Future in Cardiology 29014:10;

19 2009 ESH Reappraisal and 2014 ESH/ESC Guidelines on Hypertension Management when discussing β-blockers, however, it should not be ignored that they are no homogeneous class, and that vasodilating β-blockers such as carvedilol and nebivolol appear not to share some of the negative properties described for other compounds

20 2013 ESH/ESC Hypertension Guidelines Choice Of Antihypertensive Drugs - Conclusions From 2013 (And 2003 And 2007) Guidelines The main benefits of antihypertensive treatment are due to lowering BP per se and are largely independent of the drug employed Diuretics (thiazides / chlorthalidone / indapamide) Beta-blockers Calcium antagonists ACE-inhibitors Angiotensin receptor blockers

21 Renin-Angiotensin Aldosterone System Angiotensinogen Renin Non-ACE pathways (eg, chymase) Angiotensin I ACE Angiotensin II Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation AT 1 Aldosterone AT 2 Cough, angioedema Benefits? Bradykinin Inactive fragments Vasodilation Antiproliferation (kinins)

22 RAS Blockers: ACE-I s or ARB s?

23 2013 ESH/ESC Guidelines Combinations Between Some Classes of Antihypertensive Drugs Thiazide diuretics Thiazide diuretics ß-blockers AT 1 -receptor antagonists ACCOMPLISH ADVANCE HYVET ASCOT ONTARGET AT 1 -receptor antagonists α-blockers Calcium antagonists Calcium antagonists ACE inhibitors ACE inhibitors Pronounced antihypertensive effect CV protection Optimal tolerability

24 2013 ESH/ESC Guidelines Combinations Between Some Classes of Antihypertensive Drugs Thiazide diuretics Thiazide diuretics ß-blockers AT 1 -receptor antagonists ACCOMPLISH ADVANCE HYVET ASCOT ONTARGET AT 1 -receptor antagonists α-blockers Calcium antagonists Calcium antagonists ACCOMPLISH: ADVANCE: HYVET: ASCOT: ACE inhibitors ACE-I ACE-I ACE-I ACE-i ACE inhibitors Pronounced antihypertensive effect CV protection Optimal tolerability

25 Clinical Trials With ACEI Chronic HF Post-MI CONSENSUS I 40% RRR in mortality at 6 mo (1 endpoint) 50% RRR mortality from worsening heart failure AIRE SAVE 27% RRR overall mortality (1 endpoint) 19% RRR combined death, AMI, worsening heart failure, stroke 19% RRR overall mortality (1 endpoint) 25% RR recurrent MI SOLVD Treatment 16% RR mortality (1 endpoint) 26% combined reduction mortality / hospitalisation from progressive heart failure TRACE 21% RRR CV mortality 22% RRR all-cause mortality (1 endpoint) 29% reduction in progression of heart failure SOLVD Prevention Non-significant reduction in all-cause mortality (1 endpoint) 20% reduction in combined incidence of death or heart failure hospitalisation GISSI-3 ISIS-4 12% decrease in mortality at 6 weeks (1 endpoint) 7% reduction in mortality at 5 weeks (1 endpoint) ATLAS 8% non-significant RRR mortality (1 endpoint) 12% RRR mortality + hospitalisation in higher dose group. 24% RRR heart failure hospitalisation CONSENSUS II SMILE No improvement in survival 6 months post - MI (1 endpoint) 34% RRR in combined death or progression to severe heart failure at 6 weeks (1 endpoint) 29% RRR mortality at 1 year

26 Use of ACE inhibitors in CV Continuum Heart failure LV dysfunction Post-myocardial infarction Diabetic nephropathy Non-diabetic nephropathy LV hypertrophy Carotid atherosclerosis Proteinuria/Microalbuminuria Atrial fibrillation Metabolic syndrome

27 Makami H. et al. Eur Heart Journal 2013 Antihypertensive Efficacy of ARB s as Monotherapy as Evaluated By ABPM: A Meta-analysis 62 studies, patients Conclusions: In this comprehensive analysis of the antihypertensive efficacy of ARBs by 24 h ABP, we observed a shallow dose response curve, and uptitration marginally enhanced the antihypertensive efficacy.

28 ACE-I s or ARB s? Because ARB s might offer less protection against MI than ACE-I s, ACE-I s should remain the preferred renin system inhibitor for CV prevention in ACE-I tolerant patient Staessen JA et al. Hypertension 2010;55:819 Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Wu HY et al. BMJ 10/2013 Savarese G et al J Am Coll Cardiol 2013;61:131

29 OR OR Effect of ACE-I or ARBs on Cardiovascular Outcomes % * * % % * % * * Composite outcome Cardiovascular death Myocardial infarction Stroke % * % * % * * ACE-Is ARBs All-cause death New heart failure onset New diabetes onset Outcome significantly reduced as compared to placebo (p<0.005) Saverese G at al. JACC 2013

30 ACEI s but not ARB s Confer Myocardial Infarction Protection when Blood Pressure Reduction is Modest Conclusion: Our study confirmed a relationship of the rate of MI to the extent of SBP reduction. However, there is an apparent excess of MI below a 10 mm Hg reduction of BP with ARBs while ACE inhibitors have a beyond BP benefit Manolis AJ, Taddei S ESH Abs

31 Effect of ACE-I and ARBs on Total Mortality in Hypertensive Patients Both of them? ACE-I s? ARB s? Van Vark LC et al. Eur Heart J 2012

32 Effect of ACE-I and ARBs on Total Mortality in Hypertensive Patients Van Vark LC et al. Eur Heart J 2012

33 Efficacy and Safety of ARB s in Older Patients: A Meta-analysis of Randomized Trials 16 trials, patients Conclusions: ARB s should be used with caution in older patients Elgendy I et al Am J Hypertens 2014, November 14 on line

34 Cheng J et al. JAMA 2014;348: Effect of ACE-I s and ARB s on All-Cause Mortality, CV Deaths, and CV Events in Patients With DM:A Meta-analysis CONCLUSIONS: AND RELEVANCE : ACE-I s reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

35 Differences in the Clinical Effects of ACE-I s and ARB s: A Critical Review of the Evidence Total mortality -1% NS CV mortality -3% NS Heart failure Stroke -9% NS Myocardial infarction -7% NS 15-15% NS 20 ARB Dezsi C et al. Am J Cardiovasc Drugs 2014

36 Differences in the Clinical Effects of ACE-I s and ARB s: A Critical Review of the Evidence Total mortality -1% NS Myocardial infarction 10-10% P=0.056 NS* -18% Vs. placebo P<0.001 CV mortality -3% NS Cardiac Heart failure -11% P=0.056 NS* -21% Vs. placebo P<0.001 Heart failure -15% NS New onset diabetes -14% Vs placebo P<0.001 Stroke -9% NS Stroke -10% Vs placebo P< % Vs placebo P<0.004 Myocardial infarction -7% NS CV mortality +3% P=0.748 NS* -10% Vs placebo P<0.132 Total mortality +1% P=0.006 NS* -8% Vs placebo P<0.006 ARB ACE-inhibitors Dezsi C et al. Am J Cardiovasc Drugs 2014

37 Cardioprotective Properties of Bradykinin Actions of Bradykinin Vasodialtion Antiadhesion of monocytes Antiremodeling effect Antioxidant effect Preserved endothelial function t-pa and fibrinolysis enos expression Manolis AJ, Gavras I, Gavras H. Hypertens Res 2010

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40 ACE-Inhibitors Pharmacological Effects: Just a Matter of mm Hg? Are all ACE-I s the same?

41 EUROPA: Primary endpoint % CV death, MI or cardiac arrest % Risk reduction Placebo Perindopril 4 2 p = Placebo annual event rate: 2.4% Years Lancet 2003;362:782-7

42 PEACE Vs EUROPA Primary CV End Point PEACE EUROPA N Engl J Med 2004;351: , Lancet 2003;362:782-7

43 Editorial: Comments On The PEACE Results «The possibility that not all ACE inhibitors are equally effective for all indications should also be considered I will continue to use ACE inhibitors that have been shown to be effective for this indication in several groups of patients» Pitt B. N Engl J Med 2004;351:

44 Final Primary Outcome - Ramipril vs Placebo Kaplan-Meier Rates Ramipril Placebo Days of Follow-up RR=0.78 ( ) P=

45 Comparison of Patients in the HOPE, EUROPA, and PEACE Trials Characteristic HOPE EUROPA PEACE % (unless otherwise specified) n=9297 n=12218 n=8290 Mean age Prior MI Diabetes mellitus Prior CABG or PCI Mean LV EF NA NA 58 Mean SBP/DBP 139/79 137/82 133/78 Aspirin/antiplatelet Lipid lowering Beta blocker

46 SMILE-4 Study Design AMI < 24 hours + Clinical CHF and/or EF<45% Systolic B.P. > 100 mmhg Zofenopril mg bid Zofenopril 15 mg b.id. Ramipril 2.5 mg b.i.d. Zofenopril mg b.i.d. Ramipril mg b.i.d ASA 100 mg/day 4 days 1 week 1 year C.Borghi et al, Clinical Cardiology 2012

47 SMILE-4 Primary End-point : One Year CV Mortality And Hospitalization For CV Causes C.Borghi et al, Clinical Cardiology 2012

48 SMILE-4 Primary End-point : One Year CV Mortality and Hospitalization for CV Causes RR (95% CI)= 0.70 ( ) Adjusted P=0.028 C.Borghi et al, Clinical Cardiology 2012

49 Zofenopril and Ramipril and Acetylsalicylic Acid in Postmyocardial Infarction Patients with Left Ventricular Systolic Dysfunction: A Retrospective Analysis in Hypertensive Patients of the SMILE-4 Study Death+Hospitalization (primary end-point) Zofenopril Ramipril C. Borghi et al. J Hypertens, 2013

50 Editorial: Comments on The SMILE Results «The possibility that not all ACE inhibitors are equally effective for all indications should also be considered I will continue to use ACE inhibitors that have been shown to be effective for this indication in several groups of patients» I will continue to use ACE-inhibitors that have been shown to be effective for this indication vs the other ACE-I in several group of patients

51 Angiotensin Converting Enzyme Inhibitors Pharmacology Prodrug SH SH Group High Lipophilicity Captopril Lysinopril Zofenopril Captopril Zofenopril Quinapril Ramipril Zofenopril

52 ACE-I s Effects Prodrug SH Group High Lipophilicity Long duration of action Effective in patients with renal and hepatic impairment Free radical scavenging Reduce oxidative stress Prevention of ED Anti-ischemic effects Anti-inflammatory effects Anti-atherogemic effects Reverse of apoptosis Increase of NO High myocardial and vescular uptake High tissue ACE blockade Increased of coronary flow Reduced cellular hypertrophy

53 Are All Antihypertensives the Same?