The Therapeutic Potential of Novel Approaches to RAAS. Professor of Medicine University of California, San Diego

Transcription

1 The Therapeutic Potential of Novel Approaches to RAAS Inhibition in Heart Failure Barry Greenberg, M.D. Professor of Medicine University of California, San Diego

2 Chain of Events Leading to End-Stage Heart Failure Coronary thrombosis MyocardiaI infarction Arrhythmia and loss of muscle Sudden death Myocardial ischemia i Silent angina Hibernation Remodeling CAD Ventricular dilatation Atherosclerosis LVH CHF Risk factors (lipids, BP, DM) insulin resistance platelets, fibrinogen, etc. End-stage heart disease Dzau and Braunwald. Am Heart J. 1991;121(4 part 1):1244..

3 Ang II and Cardiovascular Risk

4 The RAAS Cascade: Formation of Angiotensin II

5 The RAAS Cascade: Formation of Angiotensin II

6 The RAAS Cascade: Formation of Angiotensin II

7 Angiotensin Receptors The AT 1 receptor is responsible for most effects of Ang II. AT 1 stimulation results in salt/water retention, arterial vasoconstriction, release of secondary growth factors (e.g. TGF- ET-1), myocyte hypertrophy y and fibroblast activation. AT 1 receptor density is increased in the post-mi and failing heart.

8 Structural Remodeling g Post-MI Days Weeks MI due to coronary Scarring and reshaping occlusion of the heart (remodeling) Months - Years Heart enlarges and leads to congestive heart failure F. Netter CIBA

9 SAVE Radionuclide EF 40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiographic EF 35% All-Cause Mortality Pro obability of Even nt Placebo ACE-I Placebo: 866/2971 (29.1%) ACE-I: 702/2995 (23.4%) 0.05 OR: 0.74 ( ) 0.83) Years ACE-I Placebo Flather MD, et al. Lancet. 2000;355:

10 VALIANT Objective VALIANT was designed as a mortality trial in high-risk MI patients (SAVE, AIRE, TRACE) who derived particular benefits from an ACE inhibitor. To determine whether: Diovan was superior to captopril in improving survival and with equal statistical power the addition of the Diovan to captopril was superior to the proven dose of captopril in improving survival If Diovan was not superior to captopril, a non-inferiority analysis was prespecified to determine whether Diovan could be considered as effective as captopril

11 VALIANT Study Drug Dose Titration Step I Step II Step III Step IV CAPTOPRIL (tid) Cap 6.25 mg Cap 12.5 mg Cap 25 mg Cap 50 mg (tid) VALSARTAN (bid) Val 20 mg Val 40 mg Val 80 mg Val 160 mg (bid) COMBINATION Cap 6.25 mg Val 20 mg Cap 12.5 mg Val 20 mg Cap 25 mg Val 40 mg Cap 50 mg (tid) Val 80 mg (bid) GOAL by 3 months Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

12 Probabili ity of Ev vent VALIANT Mortality by Treatment Captopril Valsartan Valsartan + Captopril Valsartan vs. Captopril: HR = 1.00; P = Months Valsartan + Captopril vs. Captopril: HR = 0.98; P = Captopril Valsartan Valsartan + Cap Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

13 VALIANT All Cause Mortality Non-inferiority Analysis Hazard Ratio noninferiority P-value (97.5% CI) (noninferiority) i it margin Intention-to-Treat Patient Population (n = 14,703) Per Protocol Patient Population (n = 14,285) Noninferiority Noninferiority not Demonstrated Val Superior to Cap Cap Superior to Val Favors Valsartan Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Favors Captopril

14 VALIANT Mortality in SAVE, TRACE, AIRE, VALIANT Hazard Ratio for Mortality SAVE TRACE AIRE Combined VALIANT (imputed placebo) Valsartan preserves 99.6% of mortality benefit of captopril. 0.5 Favors 1 Favors 2 Active Drug Placebo Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

15 Captopril Valsartan VALIANT CV Death, MI, or HF by Treatment 0.4 Prob bability of Event Valsartan + Captopril Valsartan vs. Captopril: HR = 0.96; P = Valsartan + Captopril vs. Captopril: HR = 0.97; P = Months Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

16 VALIANT 0.4 Study Drug Discontinuation Captopril Valsartan Pro bability of Even nt Valsartan + Captopril * * * Overall Due to Adverse Events Months *P < 0.05 vs Captopril Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

17 CMS/JCAHO Now Recommend Either ARB or ACEI for HF and AMI Premise for changes based on expert opinion: accumulating g evidence has provided the impetus to include ARBs as acceptable alternatives to ACE inhibitors. all patients with HF and LVSD, including those post-mi, should be treated with either an ACEI or an ARB unless there is documentation of a specific absolute contraindication or drug intolerance to both ACEIs and ARBs. CMS=Centers for Medicare & Medicaid Services. JCAHO=Joint Commission on Accreditation of Healthcare Organizations. Joint Commission on Accreditation of Healthcare Organizations. Change in ACEI for LVSD measures (HF-3, AMI-3): Incorporation of ARBs. Accessed at on February 1, 2005.

18 Val-HeFT Study Design 5010 patients 18 years; EF <40%; NYHA II IV Receiving background therapy ACE inhibitors (n = 4644), diuretics (n = 4300), digoxin (n = 3374), -blockers (n = 1784) Randomized to Valsartan 40 mg bid titrated to 160 mg bid Placebo Cohn JN et al. For the Valsartan Heart Failure Trial Investigators. N Engl J Med. 2001;345:

19 Val-HeFT Combined Morbidity Endpoint* Eve ent-fre ee Prob babilit ty Valsartan Placebo 13% Risk Reduction P = Months *All-cause mortality, sudden death with resuscitation, hospitalization for worsening HF, or therapy with IV inotropes or vasodilators. (Cohn JN, et al. N Engl J Med. 2001)

20 Val-HeFT Heart Failure Hospitalizations* Event-f free Pr robabil lity 100 Valsartan 95 Placebo % Risk Reduction 70 P < Months *First hospitalization. Cohn JN, et al. N Engl J Med. 2001

21 Val-HeFT Subgroup Combined Mortality/Morbidity All patients 100 < Male 80 Female 20 EF <27 50 EF IHD (yes) 57 IHD (no) 43 ACEI (yes) 93 ACEI (no) 7 BB (yes) 35 BB (no) 65 Patients (%) Favors valsartan Favors placebo Cohn JN. Circulation. 2000;102: Hazard ratio

22 Val-HeFT Subgroup not Receiving ACE-Is: Reduction in Mortality 100 Propo ortion su urvived (%) Valsartan 90 (n=185) Placebo (n=181) Risk reduction = 33.1% p value (log-rank) = Time since randomisation (months) Hazard ratio (Cox model): Maggioni AP et al. J Am Coll Cardiol 2002;40:

23 Val-HeFT Subgroup not Receiving ACE-Is: Reduction in Combined Morbidity Endpoint* lity Even nt-free probabi Subgroup without ACE-I background therapy Placebo (n=181) Risk reduction = 44.0% Valsartan (n=185) p value (log-rank) = Time since randomisation (months) *p< for morbidity/mortality; 33% relative risk (RR; p=0.017) for all-cause mortality Randomised, double blind, parallel group trial Maggioni AP et al. J Am Coll Cardiol 2002;40:

24 Val-HeFT AF Sub-study Risk of New Onset AF Estimated pr robability of AF Placebo (n=2,205) Valsartan (n=2,190) Time post-randomization (months) 37% risk reduction p=0.003 Maggioni AP et al. Am Heart J 2005;149:548 57

25 The RAAS Cascade: Formation of Angiotensin II

26 The RAAS Cascade: Formation of Angiotensin II

27 Aliskiren Binds to the Active Site of the Renin Molecule Renin Aliskiren Angiotensinogen g Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I Adapted from Wood JM, et al. 2003

28 Drug Effects on the RAS Class PRA Ang I Ang II ACEI ARB Direct Renin Inhibitor (DRI) Increased peptide levels have not been shown to overcome the blood pressure lowering effect of these agents. ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; PRA,,plasma renin activity. 1. Johnston CI. Blood Press Suppl. 2000;1:9(suppl 1): Widdop RE et al. Hypertension. 2002;40: Lin C et al. Am Heart J. 1996;131:

29 Primary objective: ALOFT: Objectives Evaluate the safety and tolerability of aliskiren 150 mg when given in addition to standard therapy in patients with hypertension and stable HF Secondary objectives included: Effect of aliskiren on BNP, N-terminal probnp (NT- probnp) and aldosterone Effect of aliskiren on echocardiographic measures of left ventricular (LV) function Effect of aliskiren on improvement in signs and symptoms of HF Effect of aliskiren on BP McMurray JJV. Circ Heart Failure. 2008;1:17-24

30 ALOFT Reductions in BNP levelsl Optimal HF therapy + Optimal HF therapy + Aliskiren 150 mg Placebo p= Mean change from baseline in BNP at Week 12 (pg/ml) Baseline BNP concentration = 301 pg/ml for aliskiren and 273 for placebo. McMurray JJV. Circ Heart Failure. 2008;1:17-24

31 ALOFT Reductions in NT-proBNP levelsl Mean change from baseline in NT-proBNP at Week 12 (pg/ml) p= Optimal HF therapy + Optimal lhfth therapy + Aliskiren 150 mg Placebo McMurray JJV. Circ Heart Failure. 2008;1:17-24

32 Perspectives from other 10 Outcome Studies ALOFT Val-HeFT RALES A-HeFT 3 months 4 months 3 months 6 months (pg/ml) Change in BNP Baseline BNP conc. (pg/ml) n=137 n=148 n=1850 n=51 n=50 n=340 n= n= p= p< p= p= ~70 ~300 Placebo Aliskiren Valsartan Spironolactone 39 Hydralazine-isosorbide dinitrate

33 ALOFT: Echo End-points Optimal HF therapy + Aliskiren 150 mg (n=156) Placebo (n=146) Adjusted p (between Groups) EDV index, ml/m (6.7) 3.4(12.9) 0.56 ESV index, ml/m (8.1) 4.3 (10.7) 0.67 LVEF, % 17(31) 1.7 (3.1) 16(29) 1.6 (2.9) MR/LA area ratio 4.1 (10.1) 1.3 (10.1) *E/E 0.83 (8.0) 0.11 (6.9) *Post hoc analysis. EDV, End diastolic volume; ESV, End systolic volume; MR, mitral regurgitation; LA, left atrial; E, early diastolic peak transmitral flow velocity; E mitral annular relaxation velocity McMurray JJV. Circ Heart Failure. 2008;1:17-24

34 Proportion of patients (%) NS non-significant p=ns ALOFT Adverse events p=ns p=ns 3.2 Optimal HF therapy + Aliskiren 150 mg (n=156) Placebo (n=146) Renal Symptomatic Hyperkalemia dysfunction hypotension McMurray JJV. Circ Heart Failure. 2008;1:17-24

35 Summary Conclusions Ang II plays an important t role in the pathogenesis of CV diseases. AT 1 receptor blockade with valsartan is equally effective as an ACEI in reducing mortality in patients with post-mi LVD. AT 1 receptor blockade with valsartan improves outcomes in heart failure patients with LVD. DRIs provide a new strategy for blocking the effects of the RAS. Emerging data indicates that aliskiren will favorably affect outcomes in hypertension and heart failure.