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Statins and Heart Failure

Statins and Heart Failure. Benjamin M. Scirica MD MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA. Disclosures.

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Statins and Heart Failure

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  1. Statins and Heart Failure Benjamin M. Scirica MD MPH TIMI Study Group Brigham and Women’s Hospital Harvard Medical School Boston, MA

  2. Disclosures TIMI Study Group: Research grant support (significant) via BWH from Accumetrics, Amgen, Astra-Zeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly and Co, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck and Company, Merck-Schering Plough Joint Venture, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, sanofi-aventis, Sanofi-Synthelabo, and Schering-Plough. Dr. Scirica:Honoraria for presentations (modest): sanofi-aventis and Pfizer

  3. Statins in CVD • Well proven benefit of statins in reducing CV events • Primary Prevention – WOSCOPS, AFCAPS/TexCAPs, ALLHAT • Secondary Prevention – 4S, CARE • Intensive statin therapy may be superior to moderate statin therapy • PROVE IT-TIMI 22, TNT, IDEAL, A2Z

  4. Statins and heart failureUnanswered questions • Is low cholesterol associated with poor outcomes in HF? • Could statins actually be detrimental? • Dose the dose of statins matter? (no effect in HF benefit in CARE, PROSPER, ALLHAT, ASCOT)

  5. Statins and heart failureUnanswered questions • If statins are beneficial, is it due to lipid lowering or “pleiotrophic” effects? • Is the benefit similar in ischemic vs. non-ischmemic heart failure? • Who should be treated and is there a a “goal”?

  6. Potential mechanisms of benefit and harm in heart failure van der Harst et al, Card Research 2006

  7. Statins and HFState of current evidence • Several observational studies have shown benefit with statin therapy • Statin therapy improves LV EF compared to placebo in pts with CHF • Large randomized trials in ACS / CAD suggest that intensive statin therapy may improve HF, but few details are known(TNT, IDEAL, A2Z)

  8. Death and HF according to statin therapy – Observational Study in 24,598 pts P<.001 for all comparisons (24,598) (19,705) (4893) (24,598) (19,705) (4893) Hosp for HF DEATH Age and sex-adjusted Go et al, JAMA 2006

  9. Death and HF according to statin therapy – Observational Study in 24,598 pts * Adjusted for age, sex, HTN, prior CVD, DM, non-CVD co-morbidities, concomitant meds, intensity of medical care, GFR and more… Go et al, JAMA 2006

  10. Divergent results of statins in small prospective studies of pts with HF Favor Statin No Difference Kush, et al. J Card Fail 2006

  11. Effect of 1-year of statin therapy on LV dimension and function P=01 P=NS P=0.004 Ejection Fraction Sola, et al. JACC 2006

  12. PROVE IT - TIMI 22: Study Design 4,162 patients with an ACS < 10 days ASA + Standard Medical Therapy Double-blind Standard Therapy (Pravastatin 40 mg) Intensive Therapy (Atorvastatin 80 mg) 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up Primary Endpoint: Death, MI, UA, or Stroke Secondary Endpoint: Re-hospitalization for heart Failure Cannon et al, AHJ 2004

  13. Methods for HF analysis • Endpoint– Hospitalization for new or worsening heart failure that occurred 30 days after randomization • Mean follow-up 24 months • BNP measured at baseline • Statistical Analysis – • Kaplan-Meier estimates with HR comparing pravastatin and atorvastatin Scirica et al, JACC 2006;47:2326-31

  14. Baseline Characteristics Scirica et al, JACC 2006;47:2326-31

  15. Risk of heart failure and statin therapy 4 Pravastatin 40mg • Controlling for prior heart failure • HR 0.55 (0.35, 0.86) p=0.008 • Excluding all pts with MI/RI prior to heart failure • HR 0.47 (0.26, 0.86) p=0.015 • Including the first 30 days after randomization • HR 0.53 (0.35, 0.80) p=0.002 3 HR 0.55 (0.35, 0.85) P=0.008 Hosp for heart failure (%) 2 Atorvastatin 80mg 1 0 30 180 365 540 720 900 Days from Randomization No. at Risk Prava 2063 1930 1846 1785 866 342 Atorva 2099 1959 1869 1826 869 339 Scirica et al, JACC 06

  16. 0.74 (0.58,0.94) 0.72 (0.52,0.98) 0.54 (0.34,0.85) 0.80 (0.61,1.05) Overall (95% CI) 0.73 (0.63,0.84), p<0.001 Meta-analysis of benefit of intensive statin therapy trials on heart failure Odds ratio Treatment Achieved LDL (mg/dl) Study (n) (95% CI) Moderate Intensive TNT (10,001) Atorvastatin 80 77 Atorvastatin 10 101 A to Z (4497) Simvastatin 80 63 Simvastatin 20 77 PROVE IT (4162) Atorvastatin 80 62 Pravastatin 40 95 IDEAL (8888) Atorvastatin 80 81 Simvastatin 20 104 0.5 3.0 1 Intensive statin therapy better Moderate statin therapy better Odds ratio Scirica et al, JACC 2006;47:2326-31

  17. B-type Natriuretic Peptide (BNP) and Mortality 10 Quartile 4 Independent of age, Killip class, HR, BP, DM, anterior MI P < 0.001 8 6 Quartile 3 Mortality (%) 4 Quartile 2 2 Quartile 1 0 0 50 100 150 200 250 300 Time (days) deLemos et al. NEJM 2001; 345:1014-1021

  18. Baseline BNP in patients with heart failure Baseline BNP (pg/ml) Pts Baseline BNP > 80 P<0.001 P<0.001 BNP (pg/ml) Scirica et al, JACC 2006;47:2326-31

  19. Baseline BNP and risk of heart failure p=0.016 Adjusted HR <15 pg/ml 16-32 pg/ml 33-65 pg/ml >65 pg/ml adjusted for age, sex, DM, HTN, BMI, Cr, index dx, and PCI during the index event Scirica et al, JACC 2006;47:2326-31

  20. HR 0.32 (0.13, 0.8) p=0.014 4.7% Abs risk reduction HR 0.59 (0.29, 1.1) p=0.099 Risk of heart failure according to BNP and intensity of statin therapy 8 6 Hospitalization for heart failure (%) 4 2 0 30 200 400 600 800 900 Days from Randomization Scirica et al, JACC 2006;47:2326-31

  21. GISSI – HF Study Design ~7000 patients with diagnosis of HF (NYHA II-IV) Standard Medical Therapy Double-blind n-3 PUFA Placebo ~75% in R2 Rosuvastatin Placebo Rosuvastatin Placebo Duration: 3 year follow-up • Endpoints: • All cause mortality (1252 events) • All cause mortality and hosp for cardiac cause Tavazzi et al, Eur J Heart Fail. 2004

  22. CORONA Study • ~5016 pts > 60yo with • EF <40%(NYHA III-IV) or, • EF <35% (NYHA II) Baseline Characteristics Mean Age 73yo NYHA II 37% NYHA III 62% Mean EF 31% Prior MI 60% HTN 63% DM 30% Double-blind Placebo Rosuvastatin 10mg Duration: 52 months year follow-up • Endpoints: • 1° CV Death, non-fatal MI, stroke • 2°All cause mortality Kjekshus et al, Eur J Heart Fail. 2005

  23. Conclusion • Statins indicated according to current guidelines in pts with CAD • Goal of < 70 mg/dl • Regardless of HF or no HF • In non-ischemic HF, promising early data but need results of RTC • Potential for identification of pts who will benefit most from intensive statin therapy

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