Observational Studies of Statins in Systolic Heart Failure

Heart Failure Clin 4 (2008) 201–208

Observational Studies of Statins in Systolic Heart Failure Wayne C. Levy, MD* University of Washington, Seattle, WA, USA

This article reviews the results of observational statin use in clinical trials of patients with systolic heart failure; post–myocardial infarction with left ventricular dysfunction; and in cardiac device trials (implantable cardioverter defibrillator [ICD], cardiac resynchronization therapy [CRT], and cardiac resynchronization therapy with defibrillator [CRT-D]). This article shows a consistent benefit of statins on mortality (approximately 25%) in heart failure patients of both ischemic and nonischemic etiology. The benefit is not altered by concomitant heart failure medications or device therapy. The benefit of statins in heart failure is being investigated in large prospective trials in a broad range of heart failure patients. Systolic heart failure carries a high and variable risk of death varying from 5% to 75% a year [1]. Heart failure is associated with activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and cytokines. The standard of care for systolic heart failure includes agents to antagonize the sympathetic nervous system (b-blockers, and angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor Dr. Levy has consulted for or participated in speakers bureaus for the following companies in the last 12 months: Pfizer, GlaxoSmithKline, Novartis, BoehringerIngelheim, Thoratec, and Medtronic. He serves on the steering committee for clinical trials by Amgen and Scios. He is on the end point committee for clinical trials by General Electric. He has received research funding from Scios, Medtronic, Vasogen, Astellas, and Thoratec. He has equity in Cardiac Dimensions. The University of Washington holds the copyright for the Seattle Heart Failure Model. * Division of Cardiology, University of Washington, Box 356422, 1959 NE Pacific Street, Seattle, WA 98195. E-mail address: [email protected]

blockers [ARBs]) and the renin-angiotensinaldosterone system (ACEIs, ARBs, and aldosterone blockers), and devices to prevent sudden death (ICDs) and to aid mechanical synchrony (CRT). Each of these individually is associated with approximately 12% to 35% reduction in mortality in patients with systolic heart failure [1]. In combination, agents like an ACEI, bblocker, and aldosterone blocker with an ICD can decrease mortality in systolic heart failure by approximately 80% [1]. Patients treated with these therapies, however, still can have an annual mortality of approximately 5% per year or a life expectancy of approximately 10 years [1]. Compared with a life expectancy in heart failure of less than 5 years before multimodality therapy, this is a tremendous achievement but still leaves substantial room for improvement. Given the marked cytokine and other neurohormonal activation that occurs in heart failure it is not surprising that clinical trials have been performed to antagonize potent vasoconstrictors, such as endothelin-1, and inflammatory cytokines, such as tumor necrosis factor (TNF)-a. Even though agents like bosnetan, an endothelin antagonist, are useful in pulmonary hypertension, they have failed to show benefit in heart failure [2]. TNF-a has been targeted directly by antibodies that bind TNF-a, such as enbrel and infliximab. The RENEWAL program with enbrel was stopped for futility, whereas infliximab may have caused harm [3,4]. Immunomodulation therapy has been attempted with Celacade. This therapy treats 10 mL of autologous blood ex vivo with ultraviolet light, ozone, and heat to induce white blood cell apoptosis. The treated blood is then injected intramuscularly at monthly intervals. Apoptotic

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cell death is thought to suppress T helper cells type 1 (which produce proinflammatory cytokines, such as TNF-a and interferon-g) and increase T helper cells type 2 (which produce anti-inflammatory cytokines, such as interleukin10 and transforming growth factor-b). This concept was evaluated in 2408 heart failure patients in the ACCLIAM trial with no effect on mortality and a nonsignificant 8% reduction in morbidity and mortality. In a post hoc analysis, there may be more benefit in the nonischemic or less symptomatic patients (ie, New York Heart Association [NYHA] II) [5]. Statins are powerful anti-inflammatory agents with pleiotropic effects on endothelial cells, platelets, smooth muscle cells, monocytes and macrophages, vascular inflammation, collagen deposition, and myocardial phenotype [6,7]. One of the most intriguing aspects of statins is down-regulations of the beta myosin heart chain phenotype and suppression of collagen with statin therapy [8]. This was associated with improved left ventricular systolic and diastolic function in rats. These myosin changes also occur with b-blocker therapy in heart failure and are associated with the increase in ejection fraction in humans [9]. Similarly, many statin trials in heart failure have shown an improvement in ejection fraction (6–8 ejection fraction units) in both animals and humans [10–13]. Intriguingly, the negative prospective small trials have been with high-dose statins, such as atorvastatin 80 mg/day, and rosuvastatin 40 mg/day [10,14]. The anti-inflammatory effect of statins can be shown by measuring C-reactive protein (CRP) where equal potent levels of statins (pravastain 40 mg; simvastatin 20 mg; and atorvastatin 10 mg) seemed to all reduce CRP by a similar amount [15]. CRP is a marker of inflammation but also mediates uptake of low-density lipoprotein cholesterol into macrophages, suggesting it may be a mediator of the atherosclerosis [16]. Although CRP is a powerful predictor in coronary disease, it seems to be a less potent predictor in heart failure [17]. High cholesterol and hypertension often coexist. Investigators have shown that high cholesterol levels up-regulate the AT1 receptor and augment the pressor response to angiotensin II infusions. Surprisingly, statins down-regulated the AT1 receptors, resulting in a blunted pressor response to angiotensin II infusions [18]. In heart failure, antagonism of the renin-angiotensin-aldosterone system with ACEI, ARB, and aldosterone

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blockers has been very beneficial. It is uncertain whether statins may have similar effects in human heart failure by down-regulating the AT1 receptor. It is intriguing to speculate whether statins, by a down-regulation of AT1 receptors, may have substantial benefit in the severest heart failure patients who are unable to tolerate neurohormonal blockade (ie, no ACEI, ARB, or b-blockers) because of either low blood pressure or renal dysfunction. Cholesterol is also part of the acute-phase response. Some biomarkers increase with inflammation, such as sedimentation rate, white blood cells, neutrophils, fibrinogen, CRP, and urine albumin. Other markers are suppressed, such as hemoglobin, lymphocytes, albumin, high-density lipoprotein, and total cholesterol [1]. For example, with an acute myocardial infarction CRP and white blood cells are increased, whereas cholesterol is acutely decreased. As the inflammation resolves after a myocardial infarction, the CRP levels decrease and the total cholesterol returns to previous levels [19]. Because heart failure is a chronic inflammatory state, many heart failure patients with more severe heart failure have lower levels of cholesterol than are seen in patients with chronic coronary disease. NCEP Adult Treatment Panel III guidelines stated statins were not indicated in patients with known vascular disease if the low-density lipoprotein was less than 100 mg/dL and were optional with lowdensity lipoprotein of 100 to 129 mg/dL [20]. With the lack of outcome trials of statins in heart failure and the terminal event in heart failure usually being sudden death or pump failure death, rather than an ischemic event, the proportion of patients on statins with moderate or severe heart failure has often been quite low.

Heart failure in randomized statin clinical trials There was some evidence that statins might reduce heart failure hospitalization. This was first seen in 4S, where treatment of severe hypercholesterolemia with simvastatin 20 to 40 mg/day, was associated with a 30% reduction in mortality [21]. Within this trial, the diagnosis of heart failure was reduced by 21% (P!.015). The risk of death in those who developed heart failure was reduced by 19% (25.5% versus 31.9%). There was nonsignificant 42% reduction in the hospital days attributable to heart failure. A nonfatal myocardial infarction, however, preceded the

STATINS IN SYSTOLIC HEART FAILURE

development of heart failure in 40% of statintreated and 52% of placebo-treated patients. It is uncertain if the major benefit was caused by reduction in the risk of nonfatal myocardial infarction and a subsequent reduction in the development of heart failure or a direct effect of statins on heart failure. In the GREACE trial, 1600 patients with coronary disease were titrated on atorvastatin to reduce low-density lipoprotein to the NCEP III goal of less than 100 mg/dL (mean atorvastatin dose was 24 mg/day) [22]. Treatment with the statin reduced heart failure by 50% (P ¼ .02). In the 8% of patients with a previous history of heart failure (NYHA I or II), the combined end point was reduced by 32% (P ¼ .02). Statin use was also associated with an 8% reduction in uric acid, a marker of oxidative stress [23] and a risk factor in heart failure [1]. Renal function, potentially a marker of inflammation, improved with atorvastatin with an 8 mL/min increase in glomerular filtration rate (P!.0001) versus a 3 mL/min decrement in the usual care group [23]. More recently, the PROVE-IT trial randomized 4162 patients with an acute myocardial infarction to pravastatin 40 mg/day, versus atorvastatin 80 mg/day. High-dose statin use was associated with a 45% reduction in heart failure hospitalization (P ¼ .008) [24]. The benefit was reduced to 42% after controlling for recurrent myocardial infarctions. Similar benefits on heart failure hospitalizations were seen in TNT with atorvastatin, 10 mg versus 80 mg (26%); A to Z with simvastatin, 20 mg versus 80 mg (28%); and IDEAL with simvastatin, 20 to 40 mg versus atorvastatin 80 mg (20%). The authors reported a meta-analysis benefit of 27% for prevention of heart failure hospitalization with high-dose versus lower-dose statin (P!.001). In the TNT trial, patients with a previous history of heart failure seemed to have a greater benefit with high-dose statin versus those without a heart failure history (41%, P ¼ .008 versus 13%, P ¼ .34) [25].

Observational statin use in clinical systolic heart failure trials Reports like these led to analysis of heart failure clinical trial and other databases (reviewed in previous article) to determine if statins might be a potential therapy for heart failure as an immune modulator, potentially unrelated to the effects on cholesterol. In observational and clinical trial

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databases, it is always very difficult to adjust for differences between patients who are and those who are not on statins. This may be somewhat less problematic in a clinical trial database where there are uniform entry criteria. For example, a patient who is healthier may have a lower NYHA class and a higher cholesterol level. This patient may be more likely to be started on a statin than an NYHA IV patient with a low cholesterol level caused by high levels of inflammation. In this example, the use of statin may be merely a marker of a healthier patient selection, better health care, or the ability to pay for a statin, rather than a mediator of the lower risk of death. These can be adjusted for using multivariate adjustments, but confounding may remain. The first systolic heart failure clinical trial to publish the observational benefits of statins was the PRAISE trial (Table 1) [26]. This was a 1153patient randomized trial of amlodipine in severe heart failure (NYHA IIIB–IV with ejection fraction !30%) treated with diuretic, digoxin, and ACEI therapy. This trial preceded the use of bblockers in heart failure. There were 134 patients on statins (12%). The mean dose of statins was low (lovastatin 24 mg/day; pravastatin 19 mg/day; and simvastatin 12 mg/day). After adjusting for age, gender, ejection fraction, ischemic etiology, diabetes, smoking, and systolic blood pressure, statin use was associated with 62% lower mortality (P!.001). Statin use was associated with a marked reduction in both sudden death (57%) and pump failure death (70%). As is expected in systolic heart failure trials, there were very few myocardial infarctions (N ¼ 12). In patients who were not on a statin there was a marked increase in the risk of death as the cholesterol level decreased, as noted by previous investigators. This inverse relationship was not present, however, in patients on a statin where the response was flat. After propensity adjustment for the probability of statin use, there was a 48% lower mortality. There were no differential benefits of statins with regard to age, gender, or diabetes. There was a suggestion that smokers might benefit less than nonsmokers. This was the first observational trial to suggest similar benefit of statins in both ischemic (60%) and nonischemic patients (75%). The NYHA IV patients (87%) had as great or greater benefit as the IIIB patients (55%). There was similar benefit above and below the median cholesterol of 203 mg/dL. The ELITE2 trial enrolled 3132 heart failure patients (ejection fraction %40%) who were not

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Table 1 Observational studies of statins in systolic heart failure: subjects from clinical trials

Trial

NYHA

Cholesterol Total patient Ejection mg/dL statin/ Ischemic Mortality (% on statin) fraction (%) no statin etiology (%) benefit

Heart failure PRAISE [26]

CIBIS II [29]

IIIB-IV Amlodipine II-IV ACEI versus ARB II-IV ARB II-IV

2746 (8)

BEST [30]

III-IV

1024 (7)

ELITE 2 [27] Val-HeFT [28]

1153 (12)

21

225/199

74

3132 (13)

31

199/207

74

5010 (32)

27

187/206

57 59

23

62% P!.001 39% P ¼ .0028 19% P ¼ .005 40% P!.005 62% P ¼ .013

199/196

0

221/206

100

26% P!.001

31

81

23

100

21

0

24

52

21

55

36% P ¼ .03 35%a P!.01 77% P ¼ .002 30% P ¼ .001 40% P ¼ .008

Post–myocardial infarction OPTIMAAL [31]

LV dysfunction

5301 (47)

Device AVID [32]

Sudden cardiac death 713 (21) Amiodarone versus ICD MADIT 2 [34] I-III 654 (64) ICD DEFINIT [33] I-III 458 (24) ICD SCD-HeFT [35] II-III 2510 (38) Amiodarone versus ICD COMPANION [36] III-IV 1520 (40) CRT versus CRT-D

Abbreviations: CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy with defibrillator; LV, left ventricular; NYHA, New York Heart Association. a Cardiac death or appropriate ICD discharge.

on renin-angiotensin-aldosterone system inhibitors to captopril or losartan [27]. There were 368 patients (13%) on a variety of statins at baseline (dose not specified). Statin use was associated with a multivariate risk adjusted 39% lower mortality (P ¼ .0028). The authors noted that each millimole per liter increase in total cholesterol (38.6 mg/dL) was associated with a 12.5% lower mortality. This inverse relationship seemed to apply mainly to cholesterol levels below 200 mg/dL, whereas the relationship was flat above this level. They did not test if the relationship differed in patients who were on statin therapy. They also reported a five-center observation study in 2068 patients where 705 patients were on statins (34%) with similar results (36% benefit; P ¼ .005) [27]. In both of these analyses, the benefit of a statin was similar in magnitude to the observational benefit of b-blocker use (35%) and the results of clinical trials of bblockers (35%).

The Val-HeFT trial randomized 5010 heart failure patients (NYHA II–IV, ejection fraction !40%) to valsartan in addition to usual heart failure medications [28]. Because this was a more contemporary trial, 1602 patients (32%) were on a statin. Statin use over the initial 4 months was associated with a reduction in CRP and an attenuation of the rise in norepinephrine. The Cox adjusted benefit for statin use was a 19% reduction in mortality (P ¼ .005) and 13% reduction in morbidity and mortality (P ¼ .02). There was a borderline greater benefit of statins in the ischemic heart failure patients (interaction P value for mortality, P ¼ .07 and 0.044 for morbidity and mortality). There was an inverse relationship between total cholesterol and mortality in patients who were not on statins (P!.001) but no relationship if they were on a statin (P ¼ .95), confirming the previous observation in the PRAISE1 analysis. There was no interaction with valsartan use.

STATINS IN SYSTOLIC HEART FAILURE

CIBIS II was a randomized trial of bisoprolol in 2647 patients with systolic heart failure [29]. There were 226 patients on a statin at baseline (8%). Statin use was associated with a multivariate 40% reduction in mortality (P!.005). In univariate analysis, there was a 31% benefit for cardiovascular death and 57% for noncardiovascular death. There was a 26% benefit for pump failure death, whereas no benefit for sudden death, cardiovascular death, or hospitalization. There was a significant greater benefit of patients who were on both a statin and bisoprolol, with a 91% benefit compared with those on neither a statin nor bisoprolol. The authors suggested the benefit of statins is only present with a b-blocker, but note that statins were very beneficial in PRAISE where there was no b-blocker usage. The BEST trial was a randomized trial of bucindiolol, a nonspecific b-blocker, in 2708 NYHA III to IV heart failure patients with ejection fraction less than or equal to 35%. There were 1024 nonischemic patients in the trial with complete data for analysis. In this subgroup, 74 patients (7%) were on a statin. The benefit of statin in a multivariate adjustment was 62% (P ¼ .013) [30]. Observational statin use in clinical trials of patients with left ventricular systolic dysfunction post–acute myocardial infarction OPTIMAAL was a randomized trial of captopril versus losartan in 5301 patients with left ventricular dysfunction or heart failure after an acute myocardial infarction [31]. Statin therapy was used at hospital discharge in 2467 (47%) of the patients. The low statin usage in this patient population was likely caused by the NCEP recommendation to use these agents if the low-density lipoprotein is greater than 130 mg/dL at the time of the trial [20]. Statin use was associated with a 26% reduction in mortality similar to the 31% reduction with b-blocker use. Combination of statin and b-blocker use was associated with a 48% reduction in mortality (all P!.001). The benefit on mortality was greater than the benefit on hospitalization (9%, P!.05); sudden death (12%, P ¼ NS); stroke (16%, P ¼ NS); or repeat myocardial infarction (18%, P!.05).

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Although the mean ejection fraction was severely reduced at 31%, only 45% had previous heart failure. Those who were on early and consistent statin use (N ¼ 149 out of 713) had a 36% reduction in mortality (P ¼ .03) and a 40% reduction in ventricular tachycardia (P ¼ .003). The DEFINIT trial was a randomized trial of ICD versus no ICD in 458 nonischemic heart failure patients [33]. A total of 110 patients (24%) were on statin therapy. The multivariate benefit of statin treatment was 77% (P ¼ .002). There was a trend for reduction in sudden death (84%, P ¼ .08) with statin therapy, but no reduction in appropriate shocks in the patients with an ICD. The MADIT2 trial was a randomized trial of ICD versus medical therapy in ischemic heart failure patients NYHA I to III with ejection fraction less than or equal to 30% [34]. In the 654 patients randomized to ICD therapy, data for medication use were available to categorize patients to less than or equal to 10%, 11% to 89%, and greater than 90% use of statins during the trial. A total of 64% of patients were on statins in the trial. Cardiac death or appropriate ICD shock was reduced by 35% (P!.01) with statin use with a 28% reduction in first episode of ventricular tachycardia/fibrillation. The SCD-HeFT trial was a randomized trial of amiodarone versus ICD versus placebo in NYHA II and III heart failure patients with an ejection fraction of less than or equal to 35% with 45 months of follow-up [35]. There were 965 patients (38%) on statins at baseline and 47% at last follow-up. Using a time dependent Cox model, there was a 30% reduction in mortality (P ¼ .001). The benefit was consistent in those with ischemic versus nonischemic etiology (31% versus 33%); ICD versus no ICD (34% versus 29%); and NYHA II versus III (38% versus 21%). Statin use in nonischemic patients increased from 18% to 31% during the trial. The COMPANION trial was a randomized trial of 1520 severe heart failure patients (NYHA III–IV, ejection fraction %35%, and QRS R120 milliseconds) treated with CRT versus CRT-D versus medial therapy. At baseline, 603 patients (40%) were on statins. The adjusted risk of death was 28% lower in patients on statins (P ¼ .008) without an interaction between etiology of heart failure or type of device therapy [36].

Observational statin use in clinical device trials of patients with left ventricular systolic dysfunction

Meta-analysis of statins in heart failure

In AVID, sudden cardiac death survivors were treated with amoidarone or an ICD [32].

A recent meta-analysis included PRAISE, ELITE2, CIBIS II, SCD-HeFT, and Val-HeFT

206

trials along with observational databases and the randomized trial, CORONA [37]. There were a total of 30,107 of 131,449 patients on statin therapy (23%). Statin therapy was associated with a 26% reduction in all-cause mortality. In the trials reporting the etiology of heart failure, the benefit was consistent in the patients with an ischemic etiology (27%) or nonischemic etiology (27%) [38].

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TNFR1, TNFR2, BNP, interleukin-6, and ejection fraction [13,41] and reduced mortality in a 110patient randomized single center trial (1 year 16% versus 36%, P ¼ .017) [42]. The results of current clinical trials are discussed elsewhere in this issue. However, the results seen in observational studies of a medication may not be validated in large randomized clinical trials. References

Summary In the observational studies of statin use in clinical trials, the magnitude of benefit has been consistently in the 20% to 60% range for most trials with a 26% benefit in a recent meta-analysis. This is consistent with a meta-analysis of statin use in randomized clinical trials with a 22% reduction in cardiovascular mortality [39]. The magnitude of benefit seems to be similar in both ischemic and nonischemic heart failure patients. Except for the subgroup report with biosoprolol, the benefit does not seem to be altered by ARB, b-blocker, ICD, CRT, or CRT-D use. Statins seem to reduce both sudden death and nonsudden death, although only a few trials have reported cause-specific mortality. Unlike the recent highdose trials of statins in coronary disease, the only trial that reported the dose of statins within clinical trials (PRAISE) found substantial benefit with a dose equivalent to simvastatin 12 mg/day. The dose of statins used in the clinical trials that did report cholesterol achieved a total cholesterol of approximately 200 mg/dL. It is quite likely the dose of statin used was lower than used in the recent trials TNT, IDEAL, PROVE-IT, CORONA-HF, and GISSI-HF. It is uncertain if higher doses of statins are beneficial or harmful in heart failure. The two negative small prospective trials involved atorvastatin 80 mg daily, and rosuvastatin 40 mg daily [10,14]. This contrasts with small positive trials using cerivastatin 0.4 mg, simvastatin 10 mg, or atorvastatin 10 to 20 mg daily. Rosuvastatin 40 mg/day, failed to lower the biomarkers B-type natriuretic peptide, CRP, TNF-a, endothelin-1, norepinephrine, and interleukin-6, or alter ejection fraction [14]. Cerivastatin 0.4 mg/day, lowered troponin T, CRP, plasminogen activator inhibitor–1, and TNF-a [40]. Simvastatin 10 mg/day, lowered BNP, TNF-a, and interleukin-6 and improved flow-mediated vasodilation and ejection fraction in 3 months [12]. Atorvastatin 10 to 20 mg/day, lowered CRP, endothelin-1,

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LEVY

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a systematic review. Arch Intern Med 2005;165(7): 725–30. [40] Laufs U, Wassmann S, Schackmann S, et al. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol 2004;93(2):103–8. [41] Mozaffarian D, Minami E, Letterer RA, et al. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol 2005;96(12): 1699–704. [42] Vrtovec B, Okrajsek R, Golicnik A, et al. Atorvastatin therapy decreases sudden cardiac death in patients with advanced chronic heart failure: a prospective study [abstract 3195]. Vienna (Austria): European Society of Cardiology Congress; 2007.