Is there a role for Statins in Heart Failure? JC Mohan New Delhi

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1 Is there a role for Statins in Heart Failure? JC Mohan New Delhi

2 HF/CHF Neuro-humorally mediated inflammatory disorder Demand- Inappropriate Cardiac output ( HRX SV) Elevated filling pressures

3 Both phenotypes of HF share analogous pathologic mechanisms HF

4 15 10 RAAS Inhibition + Beta-Blockade+AA SOLVD-P 16% ACE-I in HFrEF BB NNT=15 For Combo ACE-I+BB 5 ACE-I+BB+AA 0 Val-HEFT 5% Reduction in Mortality ( %)

5 ACE-I AA BB Angiotensin II Aldosterone Norepinephrine Inflammation,matrix degradation,oxidative stress, Hypertrophy, apoptosis, ischaemia, arrhythmia, remodelling, fibrosis

6 There is a large body of evidence indicating that inflammation and MMP are involved in the pathogenesis of HF

7 An Innocent Hypothesis Statins possess antiinflammatory and matrix stabilizing properties of potential relevance to their cardioprotective effects in HF

8 Inflammatory Cytokines in HF hscrp Activin IL-6 TNFalpha Inverse correlation with LVEF

9 Increased Turn-over of Matrix Metalloproteases MMP-9 MMP-1 MMP-3

10 Proof of Concept Studies Error precedes fact

11 % OPTIMAAL: non-randomised retrospective data in 5477: those who had HF following Statin -26% 2004: Hogenstad et al:therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) MI Total Mortality BB alone -30.6% -48.3% Statin+ BB Am J Cardiol, 2004;93:

12 4S: Retrospective Data New HF S Mortality of HF S % P= %

13 VALHeft STUDY: Cumulative Mortality based upon Statin use Placebo Statins Survival N=3029 Statin=1602 HR=0.81 P= M 17.9% 20.2% ESC,2004

14 ELITE II:LOSARTAN in HF 1. Statin use was associated with a 33% relative risk reduction in 1-year mortality ( p=0.038) % 12% Statin(n=398) ( control =1294)

15 TNT study: Hospitalisation for HF 80 mg atorva 10 mg atorva 2.4% 3.3% HR=0.74 P= Khush KK et al: 2007, Circulation

16 Simvastatin in Dilated Cardiomyopathy ( Koichi Node et al, Circ 2003;108: ) % N=51 P< % 0 EF at 3M Randomised trial, NYHA 2.32 to 2.04, EF and TNF-a and IL-6 had inverse correlation ( r=-0.69) Functional class improved in 39% vs 16% Total Cholesterol 10 mg

17 Swedish Heart Failure Registry Circ Heart Fail Jan 9. pii: CIRCHEARTFAILURE Propensity-matched Survival N=21864 with HFrEF HR=0.81 P= Statin Placebo 83% 79% FU ( months)

18 Proof of Evidence Studies great antidote to the poison of enthusiasm

19 CORONA Controlled rosuvastatin multinational trial in heart failure 5000 patients with HFrEF with mean age 73 on optimal medical treatment and class II-III, mean FU of 2.7 yrs

20 Per cent 35 CORONA:Primary endpoint CV death or non-fatal MI or non-fatal stroke Kjekshus J et al. N Engl J Med,2007: LDL -45% to -34% hscrp -25% to -37% Placebo n = 732 (29.3%) Rosuvastatin n = 692 (27.5%) Hazard ratio = % CI 0.83 to 1.02 p = Months of follow-up No. at risk Placebo Rosuvastatin Kjekshus J et al. N Engl J Med 2007;357:in press.

21 Per cent CORONA:Total mortality Placebo n = 759 (30.3%) Rosuvastatin n = 728 (28.9%) 10 5 Hazard ratio = % CI 0.86 to 1.05 p = Months of follow-up No. at risk Placebo Rosuvastatin Kjekshus J et al. N Engl J Med 2007;357:

22 Per cent CORONA:Nonfatal or fatal MI or stroke 15 (Post hoc analysis) 12 Placebo n = 264 (10.6%) Rosuvastatin n = 227 (9.0%) Hazard ratio = % CI 0.70 to 1.00 p = Months of follow-up No. at risk Placebo Rosuvastatin Kjekshus J et al. N Engl J Med 2007;357:

23 Per cent CORONA: Any coronary event endpoint Sudden death, fatal or non-fatal MI, PCI, CABG, defibrillation by an ICD, resuscitation after cardiac arrest or hospitalization for unstable angina Placebo n = 588 (23.5%) Rosuvastatin n = 554 (21.6%) Hazard ratio = % CI 0.82 to 1.04 p = Months of follow-up No. at risk Placebo Rosuvastatin Kjekshus J et al. N Engl J Med 2007;357:

24 (1523) 3694 (1489) 1 CORONA:Number of hospital admissions Placebo Rosuvastatin All cause p= (1164) 2193 (1104) CV cause p< (669) 1109 (622) Heart failure p= (71) 74 (65) Unstable angina p= Number of patients hospitalized within brackets 2 p-value refers to total number of hospital admissions and not patients 1510 (840) 1501 (839) Non-CV cause Kjekshus J et al. N Engl J Med 2007;357:in press.

25 If the facts don't fit the theory, change the facts. Albert Einstein

26 CORONA:Will Statins work in better if hs-crp is > 2 mg/l? CRP < 2mg/L HR=1.10 ( p=0.28) CRP > 2mg/L HR=0.87 (p=0.0062) Rosuvastatin Placebo John McMurray, Circ 2009

27 CORONA:Will Statins work in mild HF better? Third tertile Of nbnp(>2300) First tertile of nbnp (<868 pg/ml) HR=0.74 (p=0.014) Rosuvastatin Placebo John Cleland et al, JACC 2009

28 CORONA:Will Statins work in better with low Galectin-3 level ( < 19ng/mL) Galectin-3 < 19 HR=0.72 ( p=0.017) Low galectin Low nt-pro BNP 9, 868) Rosuvastatin HR=0.33 (p=0.001) Placebo Gullestad et al:ehj 2012, september

29 GISSI-HF The Gruppo Italiano per lo Studio della Sopravvivenza nell Insufficienza Cardiaca Heart Failure (GISSI-HF) trial Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: GISSI-HF Investigators. Lancet 2008;doi: /S (08)

30 GISSI-HF Co-primary End Points Rosuvastatin (n=2285) n (%) Placebo (n=2289) n (%) HR* CI P value Primary end points All-cause mortality 657 (29) 644 (28) 1.00 [95.5% CI ] 0.94 All-cause mortality or CV hospitalization 1305 (57) 1283 (56) 1.01 [99% CI ] 0.90 Adapted from GISSI-HF Investigators. Lancet 2008; doi: /s (08)

31 Per cent GISSI-HF: Total mortality N=4572 FU=3 yrs Rosuvastatin n = 657 (29%) Placebo n = 644 (28%) Hazard ratio = % CI 0.92 to 1.10 p = Months of follow-up No. at risk Placebo Rosuvastatin LANCET 2008

32 GISSI-HF: Causes of CV Mortality No. of CV deaths=478 No. of CV deaths= Other CV Stroke Presumed arrhythmic Worsening HF Acute MI Rosuvastatin (n=2285) Placebo (n=2289) Adapted from GISSI-HF Investigators. Lancet 2008;doi: /S (08)

33 Per cent GISSI-HF: Hospitalisation for HF N=4572 FU=3 yrs Rosuvastatin n = 634 (27.7) Placebo n = 622 (27.5%) Hazard ratio = % CI 0.92 to 1.10 p = Months of follow-up No. at risk Placebo Rosuvastatin LANCET 2008

34 Per cent GISSI-HF: MI+ Stroke N=4572 FU=3 yrs P=NS Placebo n = 6.3% 5 0 Rosuvastatin 6%) Months of follow-up No. at risk Placebo Rosuvastatin LANCET 2008

35 Science is organized common sense where many a beautiful theory was killed by an ugly fact. Thomas Huxley

36 Meta-analysis of Stains in HF 10 randomised studies,n=10192 Death 1.0 Hospitalisation for worsening HF 0.67 P=0.008 Statins 4.2% increase in LVEF Placebo Lipinsky MJ et al: AJC 2010

37 Retrospective analysis vs Randomised Trials 1. Statin use may be a marker of better health care 2. Despite an extensive adjustment for baseline characteristics, unaccounted bias inherent to retrospective studies may explain the discrepancy in the results.

38 Effect of Rosuvastatin in HF: Henry Krum et al: EF by RNV No effect on any biomarker Journal of Cardiac Failure , 1-7DOI: ( /j.cardfail ) Copyright 2007 Elsevier Inc. Terms and Conditions

39 Changes in left ventricular ejection fraction and LDL cholesterol in 71 patients with IDCM: 6 month data. Broch K, Askevold ET, Gjertsen E, Ueland T, et al. (2014) The Effect of Rosuvastatin on Inflammation, Matrix Turnover and Left Ventricular Remodeling in Dilated Cardiomyopathy: A Randomized, Controlled Trial. PLoS ONE 9(2): e doi: /journal.pone

40 Changes in markers of inflammation and extracellular matrix turnover. Broch K, Askevold ET, Gjertsen E, Ueland T, et al. (2014) The Effect of Rosuvastatin on Inflammation, Matrix Turnover and Left Ventricular Remodeling in Dilated Cardiomyopathy: A Randomized, Controlled Trial. PLoS ONE 9(2): e doi: /journal.pone

41 Why statins are neutral? 1.Reduction in Co-enzyme Q 10 ( mitochondrial toxin) 2.Increased extra-cellular fibrosis by laying down more Procollagen III ( UNIVERSE Trial) 3.Decreased seleno-protein levels 4.Cholesterol is natural buffer to endo-toxins 5.Hydrophobic vs hydrophilic statin

42 Do we need more trials with hydrophobic statins in HF? Insanity: doing the same thing over and over again and expecting different results. Albert Einstein

43 Meta-analysis of Atorvastatin in HF 10 randomised studies,n=10192 Death HR =0.39 P=0.004 Hospitalisation for worsening HF HR=0.30 P< Atorvastatin 4.2% increase in LVEF Placebo Lipinsky MJ et al: AJC 2010

44 Class III Statins for HF without any other indication for their use ACC/AHA 2013 Guidelines

45 Epidemic of heart failure that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs Expert Rev Clin Pharmacol Feb 6:1-11. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Okuyama H 1, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H.

46 Rosuvastatin Impact on Ventricular Remodelling Lipids and Cytokines (UNIVERSE)

47 Although statins have been shown to improve outcomes in retrospective analyses of patients with heart failure (HF), recent randomized placebo-controlled trials have shown mixed results. The goal of this study was to systematically review randomized trials comparing statins to placebo for HF and compare the impact of different statins. CENTRAL, mrct, and PubMed were searched for eligible studies that prospectively randomized patients with HF to statins or placebo. Primary end points were all-cause mortality, cardiovascular mortality, hospitalization for worsening HF, adverse drug events, and changes in left ventricular ejection fraction (LVEF). Pooling was performed with random effect methods with summary effect estimates (95% confidence intervals). Ten studies (10,192 patients) with follow-up from 3 to 47 months were included. Three trials randomized patients to rosuvastatin, 1 to simvastatin, and 6 to atorvastatin. Overall, statins did not affect all-cause or cardiovascular mortality but did significantly decrease hospitalization for worsening HF during follow-up (odds ratio [OR] 0.67, p = 0.008). Patients randomized to statins had a significant 4.2% increase in LVEF at follow-up (95% confidence interval 1.3 to 7.1, p = 0.004). Furthermore, post hoc analyses showed heterogeneity among different statins and demonstrated that randomization to atorvastatin significantly decreased all-cause mortality (OR 0.39, p = 0.004), decreased hospitalization for worsening HF (OR 0.30, p < ), and randomization to atorvastatin and simvastatin led to a significant improvement in LVEF, whereas these benefits were not observed in patients randomized to rosuvastatin. In conclusion, meta-analysis of randomized controlled trials demonstrated that statins are safe and improve LVEF and decrease hospitalization for worsening HF. Lipinsky MJ et al: AJC 2010

48 Although statins have been shown to improve outcomes in retrospective analyses of patients with heart failure (HF), recent randomized placebo-controlled trials have shown mixed results. The goal of this study was to systematically review randomized trials comparing statins to placebo for HF and compare the impact of different statins. CENTRAL, mrct, and PubMed were searched for eligible studies that prospectively randomized patients with HF to statins or placebo. Primary end points were all-cause mortality, cardiovascular mortality, hospitalization for worsening HF, adverse drug events, and changes in left ventricular ejection fraction (LVEF). Pooling was performed with random effect methods with summary effect estimates (95% confidence intervals). Ten studies (10,192 patients) with follow-up from 3 to 47 months were included. Three trials randomized patients to rosuvastatin, 1 to simvastatin, and 6 to atorvastatin. Overall, statins did not affect all-cause or cardiovascular mortality but did significantly decrease hospitalization for worsening HF during follow-up (odds ratio [OR] 0.67, p = 0.008). Patients randomized to statins had a significant 4.2% increase in LVEF at follow-up (95% confidence interval 1.3 to 7.1, p = 0.004). Furthermore, post hoc analyses showed heterogeneity among different statins and demonstrated that randomization to atorvastatin significantly decreased all-cause mortality (OR 0.39, p = 0.004), decreased hospitalization for worsening HF (OR 0.30, p < ), and randomization to atorvastatin and simvastatin led to a significant improvement in LVEF, whereas these benefits were not observed in patients randomized to rosuvastatin. In conclusion, meta-analysis of randomized controlled trials demonstrated that statins are safe and improve LVEF and decrease hospitalization for worsening HF. Lipinsky MJ et al: AJC 2010

49 Clinical Relevance of hscrp in the CORONA Trial McMurray JJV, et al. Circulation 2009;

50 Clinical Relevance of hscrp in the CORONA Trial McMurray JJV, et al. Circulation 2009;

51 Statins: HFrEF vs HFpEF There are no systematic studies in HFpEF with Statins

52 GISSI-HF Co-primary End Points Rosuvastatin (n=2285) n (%) Placebo (n=2289) n (%) HR* CI P value Primary end points All-cause mortality 657 (29) 644 (28) 1.00 [95.5% CI ] 0.94 All-cause mortality or CV hospitalization 1305 (57) 1283 (56) 1.01 [99% CI ] 0.90 Adapted from GISSI-HF Investigators. Lancet 2008; doi: /s (08)

53 In the UNIVERSE trial [37], assessing the effect of rosuvastatin in DCM, an increase in PIIINP was observed in the rosuvastatin group. The authors speculated that an on-treatment increase in extracellular fibrosis might offset other, potentially beneficial effects of rosuvastatin, explaining the neutral result on LVEF in this study

54 Although a low serum coenzyme Q 10 concentration is associated with worse outcomes in heart failure, that is because it is a marker of more advanced disease and is not an independent predict or of prognosis. CORONA, JACC 2010

55 Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet 2000;356:930 3.

56 The mevalonate pathway also produces isoprenoids (farnesyl pyrophosphate and geranylgeranyl phosphate) as intermediates7 which mediate the activation of various signaling molecules via the prenylation of small guanosine triphosphate (GTP) binding proteins: Rho, Ras, and Rac. Rho is involved in the activation of inflammatory cytokines and the formation of the actin cytoskeleton which affects intracellular transport, messenger ribonucleic acid (mrna) stability, and gene transcription.8,9 The Ras proteins regulate cell proliferation and hypertrophy, whereas Rac are involved in reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. By inhibiting HMG-CoA reductase, statins decrease isoprenoid production and consequently downregulate Rho, Ras, and Rac mediated signaling pathways

57 Premise for Statins Pleiotropism can reduce the bioavailability of inflammatory cytokines and oxidative stress potentially leading to increased survival in HF patients.

58 Acute coronary findings (%) Autopsy findings in CHF according to baseline CAD and mode of death (ATLAS Study) P= CAD No CAD SD HF HF SD Mode of death Uretsky, et al. Circulation. 2000;102:

59 Prevalence of HF in Olmsted County EF>50% EF<50% Redfield MM etal; JAMA 2003 N=2042, 2.2% prevalence > 45 yrs

60 A meta-analysis, including the CORONA and GISSI trials, recently concluded that there is evidence to suggest that in patients with HF, statins may improve LV ejection fraction (LVEF) and reduce the number of hospitalizations for worsening HF [11]. It is unclear, however, if these effects are related to changes in immunological parameters or remodeling of the extracellular matrix.

61 There are too few acute ischemic events (heart attacks and strokes) in heart failure patients for a statin to show a benefit.