Drugs acting on the reninangiotensin-aldosterone

Drugs acting on the reninangiotensin-aldosterone system John McMurray Eugene Braunwald Scholar in Cardiovascular Diseases, Brigham and Women s Hospital, Boston & Visiting Professor, Harvard Medical School

Inhibiting the renin-angiotensin-system Liver Angiotensinogen Renin DRI ACTH Corticosteroids Adrenal gland MR MRA K + Aldosterone Kidney β-blocker Chymase Angiotensin I Angiotensin II AT 1 R ACE BK Breakdown products ACE inhibitor ARB DRI, direct renin inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; K + potassium ion; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); BK, bradykinin; AT 1 R, angiotensin II type 1 receptor; MR, mineralcorticoid receptor

Mortality (%) Mortality (%) Trials comparing an ACE inhibitor to placebo in patients with systolic heart failure. CONSENSUS 253 NYHA class IV patients 3% β-blocker/53% MRA SOLVD-T 2569 mainly NYHA class II/III patients 7% β-blocker 80 80 60 Placebo 60 40 20 RRR 27% P=0.003 Enalapril 40 20 Placebo Enalapril RRR 16 (5-26)% P=0.0036 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 6 12 18 24 30 36 42 48 Months Months The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435. The SOLVD Investigators. N Engl J Med. 1991;325:293-302.

Trials comparing an ACE inhibitor or ARB to placebo in systolic heart failure SOLVD-T 2569 mainly NYHA class II/III patients 7% β-blocker CHARM-Alternative 2028 mainly NYHA class II/III patients 55% β-blocker/24% MRA Death or HF hosp (%) 60 Placebo 50 Death or HF hosp (%) 60 50 Placebo 40 Enalapril 40 30 30 Candesartan 20 20 10 RRR 26% P<0.0001 10 RRR 20% p=0.001 0 0 1 2 3 3.5 Years 0 0 1 2 3 3.5 Years The SOLVD Investigators. N Engl J Med. 1991;325:293-302. Granger CB, et al. Lancet. 2003;362:772-776.

Combination RAAS blockade ARB? Aldosterone/MR antagonist?

Why add an ARB to an ACE inhibitor? Angiotensin I Angiotensin I ACE ACE chymase angiotensin II angiotensin II blood adrenals blood adrenals vessels heart kidney vessels heart kidney

Why add an ARB to an ACE inhibitor? Angiotensin I ACE Kininase II BK Angiotensin I ACE chymase angiotensin II Breakdown products angiotensin II blood adrenals vessels heart kidney blood adrenals vessels heart kidney

CHARM-Added and Val-HeFT CV death or HF hospitalisation 50 40 Placebo ARB % 30 20 10 42.3% 37.9% 29.5% 25.9% 0 CHARM HR 0.85 95% CI 0.75-0.96 P=0.011 Val-HeFT HR 0.86 95% CI 0.77-0.95 P=0.004

Probability of survival Trials comparing an aldosterone/mr antagonist to placebo (added to an ACE inhibitor) in systolic HF Probability of survival 1.00 RALES 1663 NYHA class III/IV patients 95% ACE-I/10% β-blocker 1.00 EMPHASIS-HF 2737 NYHA class II patients 93% ACE-I or ARB/87% β-blocker 0.90 0.90 Eplerenone 0.80 0.80 Placebo 0.70 Spironolactone 0.70 0.60 Placebo 0.60 0.50 0.00 RRR (95% CI) 30 (18-40)% P < 0.001 0 1 2 3 Years from randomization 0.50 0.00 RRR (95% CI) 22 (5-36)% P = 0.0139 0 1 2 3 Years from randomization Pitt B, et al. N Engl J Med. 1999;341:709-717. Zannad F, et al. N Engl J Med. 2010;364:11-21.

Which drug should be added to an ACE inhibitor and beta blocker? ARB? Aldosterone/MR antagonist?

CV death or hospitalisation (%) CV death or hospitalisation (%) Trials comparing either an ARB or a MRA to placebo (added to an ACE inhibitor) in systolic HF CHARM-Added 2548 mainly NYHA class III patients 100% ACE-I/55% β-blocker/17% MRA EMPHASIS-HF 2737 NYHA class II patients 93% ACE-I or ARB/87% β-blocker 50 50 40 40 30 Placebo 30 Placebo 20 Candesartan 20 Eplerenone 10 RRR 15 (4-25)% P=0.011 10 RRR 37 (26-46)% P<0.001 0 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0 0.5 1.0 1.5 2.0 2.5 3.0 Time since randomization (years) Time since randomization (years) McMurray, et al. Lancet. 2003;362:767-71. Zannad F, et al. N Engl J Med. 2010;364:11-21.

New approaches to RAAS blockade Renin inhibitor? ARNi?

ACE inhibitor vs. renin inhibitor ACE inhibitor angiotensinogen renin angiotensin I X ACE chymase angiotensin II Renin inhibitor angiotensinogen renin X angiotensin I ACE chymase angiotensin II AT 1 R - - AT 2 R AT? R - - - - AT 1 R - - AT 2 R AT? R - - - -

RAS blockers ACE inhibitor ARB Renin inhibitor

ALOFT: Study design 18 years, NYHA class II IV, prior/current diagnosis of HT, ACE inhibitor (or ARB) and beta-blocker, BNP > 100 pg/ml Placebo Placebo Aliskiren 150 mg + Standard therapy for heart failure continued throughout study in all patients 2 week placebo run-in 12 weeks double-blind treatment Primary assessment: tolerability of aliskiren added to standard HF therapy Other outcomes: NT-pro BNP; BNP; aldosterone; hs-crp; hsil-6; TNF ; MMP-9; PIIINP; renin; IGF; PRA; 24-hour urine for aldosterone, sodium, creatinine and protein; cardiac ultrasound; 24-hour Holter for HRV; glucose metabolism markers (FPG, insulin, HbA 1c and HOMA IR) and QoL (KCCQ)

Change in BNP (pg/ml) ALOFT BNP reduction in perspective 10 0 10 20 30 40 50 60 70 Baseline BNP concentration (pg/ml) ALOFT 3 months Val-HeFT 4 months RALES 3 months A-HeFT 6 months n=137 n=148 n=1850 n=51 n=50 n=340 n=343 12 p=0.016 61 Placebo +2 n=1890 p<0.0001 34 Aliskiren Valsartan 6 p=0.02 15 8 p=0.05 291 181 ~70 ~300 39 Spironolactone Hydralazine-isosorbide dinit

Can we beat an ACE inhibitor? ATMOSPHERE: design overview Primary outcome: CV death or heart failure hospitalization (event driven: 2162 patients) Randomization Open-label run-in Enalapril 10 mg twice daily (n=2,200) Enalapril Enalapril + aliskiren Aliskiren 300 mg once daily (n=2,200) 4-8 weeks Aliskiren 300mg/enalapril 20 mg Daily (n=2,200) Double-blind ~48 weeks (event driven)

Acute heart failure

design overview Randomization Primary outcome: CV death or HF hospitalization at 6 months (381 events) Acute HF LVEF<40% BNP >400pg/mL SBP 110mmHg ~1,800 patients Aliskiren 150 mg Aliskiren 300 mg Placebo Conventional therapy In-hospital entry 2 weeks ~15 months (event-driven)* and initiation Except concomitant use of an ACEI and ARB * Follow-up at Week 2, Month 1, 2 and 3, with on-going assessments every 3 months thereafter

A new approach? ARNi Angiotensin Receptor Neprilysin inhibitor

LCZ 696: an Angiotensin Receptor Neprilysin inhibitor (ARNi) Molecular complex of: An ARB - valsartan A NEP/neprilysin inhibitor AHU 377 NEP inhibition blocks breakdown of natriuretic peptides and augments plasma concentrations

Potentially beneficial effects of natriuretic peptides

LCZ696 in hypertension

mm Hg LCZ 696: Mean Sitting Systolic BP Reduction Mean Sitting Systolic BP Reduction: 0 PLAC AHU 200 Vals 80 LCZ 100 Vals 160 LCZ 200 Vals 320 LCZ 400-5 -7.72-10 -15-4.2 0.0057-11.93-12.44-13.75-13.4-14.2-20 - 1.3 p=0.4036-18.7-20.2-25 -5.3 p=0.0006-6.0 p=<0.0001 Valsartan LCZ 696 Placebo AHU 200

PARADIGM-HF A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction Single-blind period Double-blind period LCZ696 200 mg BID (n~4000) Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid 1-2 weeks 1-2 weeks 2 weeks Prior ACEi/ARB use discontinued Enalapril 10 mg BID (n~4000) N = 7980 (1:1 randomization) Outcomes driven (estimated mean f/u = 30-32 months) Primary objectives Secondary objectives Patient population Evaluate if LCZ696 is superior in delaying time to first occurrence of either CV mortality or HF hospitalization in CHF pts (NYHA Class II IV) with reduced ejection fraction All cause mortality Renal progression (egfr change) Clinical summary score (assessed by KCCQ) 7980 patients with CHF NYHA class II IV and reduced ejection fraction (LVEF < 40%) BNP>150 pg/ml (NTproBNP > 600 pg/ml) or BNP > 100 pg/ml (NTproBNP > 400 pg/ml) and hospitalization within the last 12 months

HF with preserved EF We still do not have evidence-based treatment

ARBs in HF-PEF CHARM-Preserved CV death or HF hosp. I-PRESERVE Death or CV hosp. HR 0.89 (0.77-1.03), P=0.12 HR 0.95 (0.86-1.05), P=0.35

Treatment Of Preserved Cardiac function heart failure with an Aldosterone antagonist

TOPCAT Hypothesis: Spironolactone will reduce morbidity and mortality in mild HF and preserved LV function Population: 4500 patients >50 yrs with NYHA II HF (and admission or elevated BNP), EF 45% Intervention: Spironolactone (15-45 mg) vs placebo Primary endpoint: CV death, RCA, HF hospitalisation Status: Recruitment started 2008; slow; expected completion uncertain

RAAS blockade in HF: Summary and conclusions ACE inhibitors improve symptoms, reduce hospitalisation and increase survival in patients with systolic HF, irrespective of NYHA class (if not tolerated, an ARB is an alternative) MRAs improve symptoms, reduce hospitalisation and increase survival in patients with systolic HF, irrespective of NYHA class (if not tolerated, an ARB is an alternative) Renin inhibitors and ARNis are alterative/ additional therapies currently being tested in RCTs in systolic HF ARBs not beneficial in HF-PEF; ongoing RCT with a MRA in this type of HF