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

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

Both phenotypes of HF share analogous pathologic mechanisms HF

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% 0-10 -20-30 -40-50 -60-70 -80-90 Reduction in Mortality ( %)

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

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

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

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

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

Proof of Concept Studies Error precedes fact

% OPTIMAAL: non-randomised retrospective data in 5477: those who had HF following 0-10 -20-30 -40-50 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;93:603-606

4S: Retrospective Data 0-10 -20 New HF S Mortality of HF S -30-40 -19% P=0.015-25%

VALHeft STUDY: Cumulative Mortality based upon Statin use Placebo Statins Survival 0.9 0.7 N=3029 Statin=1602 HR=0.81 P=0.029 6 12 18 24 30M 17.9% 20.2% ESC,2004

ELITE II:LOSARTAN in HF 1. Statin use was associated with a 33% relative risk reduction in 1-year mortality ( p=0.038) 0-5 -10-15 8% 12% Statin(n=398) ( control =1294)

TNT study: Hospitalisation for HF 80 mg atorva 10 mg atorva 2.4% 3.3% HR=0.74 P=0.0116 Khush KK et al: 2007, Circulation

Simvastatin in Dilated Cardiomyopathy ( Koichi Node et al, Circ 2003;108:839-843) 100 90 80 70 60 50 40 30 20 10 34% N=51 P<0.05 41% 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% 148 130 Total Cholesterol 10 mg

Swedish Heart Failure Registry Circ Heart Fail. 2015 Jan 9. pii: CIRCHEARTFAILURE.114.001730 Propensity-matched Survival 0.9 0.7 N=21864 with HFrEF HR=0.81 P=0.001 0 3 6 9 12 Statin Placebo 83% 79% FU ( months)

Proof of Evidence Studies great antidote to the poison of enthusiasm

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

Per cent 35 CORONA:Primary endpoint CV death or non-fatal MI or non-fatal stroke Kjekshus J et al. N Engl J Med,2007:357. 30 25 20 LDL -45% to -34% hscrp -25% to -37% Placebo n = 732 (29.3%) Rosuvastatin n = 692 (27.5%) 15 10 5 Hazard ratio = 0.92 95% CI 0.83 to 1.02 p = 0.12 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2497 2315 2156 2003 1851 1431 811 Rosuvastatin 2514 2345 2207 2068 1932 1484 855 Kjekshus J et al. N Engl J Med 2007;357:in press.

Per cent CORONA:Total mortality 35 30 25 20 15 Placebo n = 759 (30.3%) Rosuvastatin n = 728 (28.9%) 10 5 Hazard ratio = 0.95 95% CI 0.86 to 1.05 p = 0.31 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2497 2365 2240 2112 1980 1545 881 Rosuvastatin 2514 2379 2260 2139 2018 1566 907 Kjekshus J et al. N Engl J Med 2007;357:

Per cent CORONA:Nonfatal or fatal MI or stroke 15 (Post hoc analysis) 12 Placebo n = 264 (10.6%) 9 6 3 Rosuvastatin n = 227 (9.0%) Hazard ratio = 0.84 95% CI 0.70 to 1.00 p = 0.05 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2497 2315 2156 2003 1851 1431 811 Rosuvastatin 2514 2345 2207 2068 1932 1484 855 Kjekshus J et al. N Engl J Med 2007;357:

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 30 25 Placebo n = 588 (23.5%) 20 15 10 5 Rosuvastatin n = 554 (21.6%) Hazard ratio = 0.92 95% CI 0.82 to 1.04 p = 0.18 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2497 2299 2127 1974 1819 1405 789 Rosuvastatin 2514 2332 2174 2029 1871 1427 817 Kjekshus J et al. N Engl J Med 2007;357:

4000 4074 (1523) 3694 (1489) 1 CORONA:Number of hospital admissions Placebo Rosuvastatin 3000 2000 1000 0 All cause p=0.007 2 2564 (1164) 2193 (1104) CV cause p<0.001 2 1299 (669) 1109 (622) Heart failure p=0.01 2 90 (71) 74 (65) Unstable angina p=0.30 1 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.

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

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

CORONA:Will Statins work in mild HF better? Third tertile Of nbnp(>2300) 0.90 1.01 First tertile of nbnp (<868 pg/ml) HR=0.74 (p=0.014) Rosuvastatin Placebo John Cleland et al, JACC 2009

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

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;6:635 41. GISSI-HF Investigators. Lancet 2008;doi:10.1016/S0140-6736(08)61240-4.

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 0.90-1.12] 0.94 All-cause mortality or CV hospitalization 1305 (57) 1283 (56) 1.01 [99% CI 0.91-1.11] 0.90 Adapted from GISSI-HF Investigators. Lancet 2008; doi:10.1016/s0140-6736(08)61240-4.

Per cent GISSI-HF: Total mortality 35 30 N=4572 FU=3 yrs Rosuvastatin n = 657 (29%) 25 20 15 10 5 Placebo n = 644 (28%) Hazard ratio = 1.0 95% CI 0.92 to 1.10 p = 0.94 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2287 2265 2240 2112 1980 1545 881 Rosuvastatin 2285 2279 2260 2139 2018 1566 907 LANCET 2008

GISSI-HF: Causes of CV Mortality No. of CV deaths=478 No. of CV deaths= 488 29 31 38 29 198 182 Other CV Stroke Presumed arrhythmic Worsening HF Acute MI 203 231 10 15 Rosuvastatin (n=2285) Placebo (n=2289) Adapted from GISSI-HF Investigators. Lancet 2008;doi:10.1016/S01.40-6736(08)61240-4.

Per cent GISSI-HF: Hospitalisation for HF 35 30 N=4572 FU=3 yrs Rosuvastatin n = 634 (27.7) 25 20 15 10 5 Placebo n = 622 (27.5%) Hazard ratio = 0.97 95% CI 0.92 to 1.10 p = 0.62 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2287 2265 2240 2112 1980 1545 881 Rosuvastatin 2285 2279 2260 2139 2018 1566 907 LANCET 2008

Per cent GISSI-HF: MI+ Stroke 35 30 N=4572 FU=3 yrs 25 20 15 10 P=NS Placebo n = 6.3% 5 0 Rosuvastatin 6%) 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2287 2265 2240 2112 1980 1545 881 Rosuvastatin 2285 2279 2260 2139 2018 1566 907 LANCET 2008

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

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

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.

Effect of Rosuvastatin in HF: Henry Krum et al: EF by RNV No effect on any biomarker Journal of Cardiac Failure 2007 13, 1-7DOI: (10.1016/j.cardfail.2006.09.008) Copyright 2007 Elsevier Inc. Terms and Conditions

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): e89732. doi:10.1371/journal.pone.0089732 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089732

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): e89732. doi:10.1371/journal.pone.0089732 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089732

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

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

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<0.00001 Atorvastatin 4.2% increase in LVEF Placebo Lipinsky MJ et al: AJC 2010

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

Epidemic of heart failure that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs Expert Rev Clin Pharmacol. 2015 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.

Rosuvastatin Impact on Ventricular Remodelling Lipids and Cytokines (UNIVERSE)

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 <0.000 01), 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

Clinical Relevance of hscrp in the CORONA Trial McMurray JJV, et al. Circulation 2009;2188-2196.

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

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

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

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

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

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

Acute coronary findings (%) Autopsy findings in CHF according to baseline CAD and mode of death (ATLAS Study) 60 50 P=0.0001 40 CAD No CAD 30 20 10 0 SD HF HF SD Mode of death Uretsky, et al. Circulation. 2000;102:611-616.

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

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.

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