Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure
Subgroup Analysis of the Treating to New Targets (TNT) Study
Background— Statins reduce the rate of major cardiovascular events in high-risk patients, but their potential benefit as treatment for heart failure (HF) is less clear.
Methods and Results— Patients (n=10 001) with stable coronary disease were randomized to treatment with atorvastatin 80 or 10 mg/d and followed up for a median of 4.9 years. A history of HF was present in 7.8% of patients. A known ejection fraction <30% and advanced HF were exclusion criteria for the study. A predefined secondary end point of the study was hospitalization for HF. The incidence of hospitalization for HF was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The treatment effect of the higher dose was more marked in patients with a history of HF: 17.3% versus 10.6% in the 10- and 80-mg arms, respectively (hazard ratio, 0.59; 95% confidence interval, 0.4 to 0.88; P=0.009). Among patients without a history of HF, the rates of hospitalization for HF were much lower: 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34). Only one third of patients hospitalized for HF had evidence of preceding angina or myocardial infarction during the study period. Blood pressure was almost identical during follow-up in the treatment groups.
Conclusions— Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF. In a post hoc analysis, this benefit was observed only in patients with a history of HF. The mechanism accounting for this benefit is unlikely to be due primarily to a reduction in interim coronary events or differences in blood pressure.
Received March 8, 2006; accepted November 3, 2006.
In randomized clinical trials, statins have been shown to reduce cardiovascular events in patients with and without known coronary heart disease (CHD). Patients with heart failure (HF) were generally excluded from these studies. Thus, despite the common clinical coexistence of CHD and HF, the effect of statin therapy on outcomes in HF patients remains largely unexplored.
Clinical Perspective p 583
Several observations suggest that statins could be a useful treatment for HF, a pathophysiological state characterized by neurohormonal activation, inflammation, and endothelial dysfunction.1 In small studies, statins have been shown to improve endothelial function2 and to decrease plasma levels of proinflammatory cytokines in patients with CHD and hyperlipidemia.3 Statins may exert antihypertrophic,4,5 antioxidant,6 and antifibrotic7 effects directly on the myocardium and may alter immune function, macrophage metabolism, and cell proliferation independently of changes in low-density lipoprotein (LDL) cholesterol concentrations.8 Finally, by preventing recurrent ischemia in patients with coronary atherosclerosis, statins may prevent the development or worsening of HF.
On the other hand, concerns have been raised about potential adverse effects of statin therapy in HF patients.9 Observational studies have detected an association between low cholesterol levels and adverse outcomes in advanced HF.10 It has been suggested that the decrease in ubiquinone levels caused by statin therapy may have deleterious consequences because ubiquinone is a potential antioxidant and HF 2 is a state of pro-oxidant stress.11,12 Dietary ubiquinone supplementation improved exercise tolerance in HF patients in some studies but not in others.13
The Treating to New Targets (TNT) trial randomized 10 001 patients with stable CHD (both with and without a history of HF) to 10 or 80 mg/d atorvastatin and followed them up for a mean of 4.9 years. The primary end point, a composite of cardiac death, nonfatal myocardial infarction (MI), and stroke, was reduced by 22%, from 10.9% to 8.7%, in the 80-mg group (hazard ratio, 0.78; 95% confidence interval, 0.69 to 0.89; P<0.001).14 A predefined secondary end point of TNT was hospitalizations with a primary diagnosis of HF. The purpose of this article is to report in detail the results from TNT for this outcome.
The design of the TNT study has been described in detail previously.14,15 Eligible patients were men and women 35 to 75 years of age with clinically evident CHD, defined as previous MI, prior or current angina with objective evidence of CHD, or a history of coronary revascularization. Major exclusion criteria included significant liver disease; uncontrolled diabetes, hypothyroidism, or hypertension; unexplained creatine phosphokinase levels >6 times the upper limit of normal; concurrent therapy with lipid-modifying drugs not specified as study treatment in the protocol; or an acute coronary syndrome within 1 month of screening. History of HF and other comorbidities was determined through questionnaires administered at the time of study enrollment. Importantly, patients with New York Heart Association class IIIb or IV HF or with a left ventricular ejection fraction known to be <30% also were excluded. Patients did not undergo an assessment of left ventricular function as part of their baseline evaluation for the trial. The institutional review board at each participating center approved the study, and all patients gave written informed consent.
Any lipid-lowering drugs were discontinued at the time of screening. Patients with LDL cholesterol levels between 130 and 250 mg/dL and triglyceride levels ≤600 mg/dL off treatment entered an 8-week run-in period of open-label treatment with atorvastatin 10 mg/d. On completing the run-in phase, patients with a mean LDL cholesterol level <130 mg/dL were randomly assigned to double-blind therapy with either 10 mg (low-dose) or 80 mg (high-dose) atorvastatin daily. Follow-up visits occurred at 3, 6, 9, and 12 months after initiation of therapy and every 6 months thereafter. The median follow-up period was 4.9 years.
Hospitalization for a primary diagnosis of HF was a predefined secondary efficacy outcome of the study. The primary efficacy outcome was the occurrence of a major cardiovascular event, defined as CHD death; nonfatal, non–procedure-related MI; resuscitated cardiac arrest; or stroke. Hospitalization for HF was defined according to the following criteria16: (1) Patient was hospitalized with an admission diagnosis of HF and demonstrated symptoms and signs consistent with this clinical diagnosis; (2) the cause of HF was related to impaired left ventricular emptying or filling characteristics; and (3) the cause of HF was not temporally related to an acute MI. An independent end point committee adjudicated blindly all potential end-point events.
All analyses were performed on an intention-to-treat basis, and all 10 001 patients who were dispensed randomized study drug were included in the analysis. Using the Kaplan-Meier method, we analyzed end points from the time of the first randomized dose of study drug to the end-point event. Hospitalization for HF was a predefined secondary outcome of TNT; however, the other HF analyses presented here were part of an analysis plan developed after the main results of the trial were known. Although the primary analyses were Kaplan-Meier (log-rank) tests comparing the time-to-event distributions by randomized treatment arm, Cox proportional-hazards models were used to assess the influence of various factors on our end point of interest, as well as on treatment-factor interactions. We did not test for nonproportionality of the Cox model.
We initially examined the factors predictive of hospitalization for HF in a univariate analysis. We subsequently examined the effect of high-dose atorvastatin versus the low dose in patients with and without a history of HF, adjusting for variables found to predict HF hospitalizations in the univariate model. To determine whether the prevention of hospitalizations for HF at the higher dose may have been a consequence of preventing coronary events, we examined the proportion of patients with HF admissions who had an MI or angina after study enrollment and before their HF admission. Subjects were classified as having an acute MI if they had a prespecified combination of abnormal levels of cardiac enzymes (troponin I or T, creatine kinase-MB), ischemic symptoms, and an ECG pattern consistent with MI. Angina was defined as chest pain associated with evidence of myocardial ischemia based on ECG, stress test, or new angiographic findings or on a history of typical chest pain similar to previous documented episodes of myocardial ischemia. We compared blood pressure in the treatment groups because lower blood pressure might contribute to HF prevention. Finally, we compared the incidence of HF hospitalizations using on-treatment LDL cholesterol levels as a predictor.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
The treatment groups had similar baseline characteristics, as shown in Table 1. The mean age of the study patients was 61 years; most were white men. More than half had experienced an MI, more than half had undergone a percutaneous coronary intervention, and nearly half had undergone coronary bypass surgery. A history of HF was reported by 8.1% of the patients in the 10-mg group and 7.5% in the 80-mg group. Patients with and without a history of HF are compared in Table 2. These 2 groups were similar with respect to age, body mass index, and blood pressure. Patients with a history of HF had more comorbidities, including hypertension (67% versus 53%; P<0.0001), diabetes mellitus (27% versus 14%; P<0.0001), peripheral arterial disease (24% versus 11%; P<0.0001), prior MI (74% versus 57%; P<0.0001), and stroke (11% versus 5%; P<0.0001). As expected, these patients had higher levels of angiotensin-converting enzyme inhibitor (61% versus 26%; P<0.0001), angiotensin receptor blocker (10% versus 5%; P<0.0001), and diuretic (54% versus 12%; P<0.0001) use at baseline. The baseline lipid profiles were similar between patients with and without a history of HF.
During treatment with 10 mg/d atorvastatin in the run-in period, LDL cholesterol was reduced by 35% in the overall population, from a mean of 164 mg/dL to a mean of 98 mg/dL (P<0.0001). Similarly, the mean high-density lipoprotein cholesterol level decreased by 1 mg/dL (P<0.0001), and triglycerides decreased by a mean of 52 mg/dL (P<0.0001). Mean LDL cholesterol levels during the study were 101 mg/dL in the 10-mg group and decreased to 77 mg/dL in the 80-mg group. High-density lipoprotein cholesterol levels were identical in the treatment groups during follow-up, whereas mean triglyceride levels were 158 mg/dL in the 10-mg group and 134 mg/dL in the 80-mg group.
Hospitalization for HF
During a mean follow-up period of 4.9 years, 286 of the 10 001 study patients (2.86%) were hospitalized with a primary diagnosis of HF. The incidence of hospitalization for HF was 14.1% in the 781 patients with a history of HF and 1.9% in the 9220 patients without a history of HF (P<0.001). As shown in Table 3, the factors predictive of hospitalization for HF were a history of HF, diabetes, cerebrovascular disease, hypertension, smoking, age >65 years, and female sex. Female sex was not significant in a multivariate analysis because it was strongly correlated with other predictive factors. After patients with a history of HF were excluded, diabetes, a history of cerebrovascular disease, hypertension, smoking, and age >65 years remained significant predictors of HF hospitalizations.
As expected, HF conferred a poor prognosis. Among the 781 patients with a history of HF at baseline, 117 died during the study compared with 449 of the 9220 patients without a history of HF (15.0% versus 4.9%; hazard ratio, 3.28; 95% confidence interval, 2.67 to 4.02; P<0.001). Among the 286 patients who were hospitalized with HF during the study, the subsequent mortality rate was 28%.
Effect of Study Treatment on HF Hospitalizations
During the follow-up period, 122 of the 4995 patients in the 80-mg group (2.4%) were hospitalized with a primary diagnosis of HF compared with 164 of the 5006 patients (3.3%) in the 10-mg group (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). The Kaplan-Meier curves for this outcome are shown in Figure 1. In patients with a history of HF, the incidence of HF hospitalization was 10.6% in the 80-mg group and 17.3% in the 10-mg group (hazard ratio, 0.59; 95% confidence interval, 0.40 to 0.88; P=0.008), as shown in Figure 1. In patients without a history of HF, the rates of hospitalization for HF were much lower, 1.8% in the 80-mg group and 2.0% in the 10-mg group (hazard ratio, 0.87; 95% confidence interval, 0.64 to 1.16; P=0.34; Figure 2). Thus, the absolute risk reduction in hospitalization for HF for the 80-mg group was much greater in patients with than without a HF history. The protective effect of high-dose atorvastatin on preventing HF hospitalizations, however, remained independent of the baseline history of HF. A negative (P=0.13) test of atorvastatin treatment–HF history interaction (in a proportional-hazards model) supports this conclusion. Finally, high-dose atorvastatin reduced HF hospitalizations in subgroups stratified according to gender, smoking, or presence of diabetes or hypertension.
Relationship Between HF Hospitalizations and Other Parameters
To determine whether HF hospitalizations were a consequence of myocardial ischemia or MI, we examined the time period after study enrollment and before each HF hospitalization. During this interval, 42 of the 286 patients hospitalized with HF had an MI (14.7%), and 65 had evidence of angina (22.7%); 94 patients (32.9%) had one or both of these diagnoses. Of those patients with antecedent myocardial ischemia or MI, only 45 (15.7%) experienced their MI or angina in the 3 months before HF hospitalization. No obvious ischemic precipitant of HF was found in 192 of the 286 patients (67%). In comparison, 1469 of the 9715 study participants (15.1%) without HF hospitalizations had documented angina or MI. Thus, although a greater proportion of patients hospitalized with HF had a preceding ischemic coronary event, the majority of HF hospitalizations did not appear to be precipitated by myocardial ischemia or MI.
Compared with patients with no HF hospitalizations, those who were hospitalized with HF during the trial had lower rates of β-blocker (45.1% versus 54.0%) and aspirin (74.1% versus 86.9%) use at baseline and higher rates of angiotensin-converting enzyme inhibitor (50.3% versus 26.5%), angiotensin receptor blocker (10.5% versus 5.1%), aldosterone antagonist (1.4% versus 0.3%), and diuretic use (50.3% versus 13.3%).
Patients were grouped into quintiles according to their LDL cholesterol levels after 3 months of study treatment, as shown in Table 4. A stepwise decrease in major cardiovascular events from 11.9% in the highest to 7.7% in the lowest quintile was seen (P<0.0001). Fewer hospitalizations for HF also occurred among patients in the lower quintiles of on-treatment LDL cholesterol. For each 1-mg/dL reduction in LDL cholesterol, the risk of hospitalization for HF decreased by 0.6% (P=0.007).
At baseline, mean systolic and diastolic blood pressures were identical in the 2 treatment groups: 131±17 and 78±10 mm Hg, respectively. At last follow-up, systolic blood pressure had decreased by 1.2±15.4 mm Hg in the 10-mg arm and by 1.2±15.1 mm Hg in the 80-mg arm; diastolic pressure decreases were 0.7±9.3 mm Hg in the 10-mg arm and 0.7±9.4 mm Hg in the 80-mg arm. A differential blood pressure response between the 2 treatment groups does not account for the discrepancy in HF hospitalizations.
In this study, high-dose compared with low-dose atorvastatin significantly reduced the incidence of hospitalization for HF in patients with stable CHD. The benefit was most pronounced in patients with a history of HF and did not appear to be mediated through a reduction in preceding ischemic events in most cases. Other mechanisms may be responsible for the beneficial effects of statin therapy in preventing HF hospitalizations. Although we did not test for nonproportionality, the benefit appeared to be consistent during the follow-up period.
The initial reports of the effects of statin therapy on the development of HF were retrospective analyses of placebo-controlled trials of statins to prevent coronary events in patients with CHD. These trials, the Scandinavian Simvastatin Survival Study17 and the Cholesterol and Recurrent Events18 trial, excluded patients with preexisting symptomatic or severe HF. Nevertheless, statin therapy reduced the development of HF. Whether this effect was due to the prevention of recurrent ischemia or to noncoronary mechanisms was not known. More recently, the Pravastatin or Atorvastatin Evaluation and Infection Trial–Thrombolysis in Myocardial Infarction 22 investigators have shown that intensive statin therapy reduces the risk of future hospitalization for HF to a greater extent than does moderate-dose statin therapy in patients with acute coronary syndromes.19
Several small-scale prospective trials have been performed to investigate the effects of statin therapy in patients with known HF. In 2 studies, patients with dilated cardiomyopathy treated with statins had fewer HF symptoms and improved left ventricular function, along with lower plasma levels of proinflammatory cytokines and natriuretic peptides, compared with those given placebo.20,21 Similarly, cerivastatin was shown to improve quality of life and exercise capacity in patients with nonischemic cardiomyopathy.22 Tumor necrosis factor-α and C-reactive protein levels decreased, and there was a trend toward improved left ventricular function in the statin-treated patients. These small studies provided preliminary evidence for the potential benefits of statin therapy in patients with HF.
The present study demonstrates that high-dose statin therapy reduces HF hospitalizations to a greater extent than low-dose statin therapy. This study, which is the first to compare 2 doses of the same statin formulation, suggests that high-dose statin therapy may therefore provide incremental benefit in preventing HF hospitalizations, with a relative risk reduction of 26% among patients treated with 80 mg atorvastatin compared with those treated with 10 mg atorvastatin. For each 1-mg/dL reduction in LDL cholesterol on treatment, the risk of hospitalization for HF was reduced by 0.6% (P=0.007). Although lower levels of LDL cholesterol are associated statistically with fewer HF hospitalizations, lower LDL cholesterol levels are highly correlated with being in the 80-mg atorvastatin group, so the observed benefit might be attributed not only to LDL cholesterol lowering but also to other effects of the high-dose atorvastatin.
The progression of HF is closely tied to recurrent ischemic events.23 The antiatherothrombotic effects of statins thus benefit patients with coronary artery disease–associated HF. For instance, statins promote atherosclerotic plaque stabilization, reduce myocardial necrosis, preserve myocardial viability, and improve ventricular function.24 Statins thus appear to reduce the development of HF, at least in part, through lipid lowering and other antiatherothrombotic mechanisms.17
Several other mechanisms have been proposed to account for the observation that statins benefit patients with HF. For instance, statins appear to improve endothelial function through reduced production of the vasoconstrictor endothelin-1 and enhanced synthesis of nitric oxide, a potent vasodilator.8,25 Several small studies also have shown that statins reduce levels of tumor necrosis factor-α, other proinflammatory cytokines,26 and C-reactive protein27 in a manner largely independent of LDL cholesterol. In contrast to these reports, however, other trials have failed to show a reduction in cytokine levels in response to statin therapy28 and have demonstrated a lack of benefit of anticytokine therapy in treating HF patients. In the Anti-TNF Therapy Against Congestive Heart Failure trial, for instance, treatment with infliximab, a monoclonal antibody to tumor necrosis factor-α, did not improve the clinical condition of patients with moderate to severe HF.29 Similarly, the Randomized Etanercept Worldwide Evaluation study, using the soluble tumor necrosis factor-α receptor etanercept, did not show a clinically relevant benefit on HF hospitalizations.30
Experimental evidence also suggests a role for statins in counteracting sympathetic upregulation in acute and chronic HF by decreasing plasma norepinephrine levels and reducing renal sympathetic nerve activity.31 These observations, however, remain to be validated in clinical studies. Finally, animal models suggest that statins may inhibit ventricular remodeling; rats with acute MI demonstrated reductions in left ventricular size and end-diastolic pressure after statin therapy. In contrast, a recent prospective trial of rosuvastatin therapy in patients with chronic HF failed to demonstrate a significant change in LV function or dimensions after 6 months of therapy.32
This study suggests a role for high-dose atorvastatin in preventing HF hospitalizations in patients with preexisting HF. This effect is of paramount importance given the large population of patients with HF and the high readmission rate associated with this condition. That high-dose atorvastatin confers greater protection against HF than low-dose statin therapy is the major novel finding of this study. The mechanism responsible for this dose-related effect remains unknown and may be distinct from the lipid-lowering effects of statin therapy. Prospective, randomized clinical trials of statin therapy in patients with HF are needed to clarify these putative mechanisms.
This study has limitations. History of HF was determined by the study investigators through patient interviews at the time of study enrollment. Neither systolic nor diastolic function was assessed systematically at baseline in the patients, and no follow-up studies were done to monitor potential changes in ventricular function. Because patients with advanced HF were excluded, our results should not be extrapolated to these groups.
Although hospitalization for HF was a prespecified secondary end point of the TNT trial, the other analyses presented here were not prespecified and therefore should be interpreted with caution. Furthermore, our study does not provide insight into the potential mechanisms through which high-dose atorvastatin benefits patients with HF other than that it is not due to a reduction in blood pressure and is unlikely to be due to prevention of ischemic events in most cases. It is possible, however, that not all preceding ischemic events were identified, as in the case of “silent” ischemia or ischemia manifesting as HF without symptoms and signs of typical angina. Although a reduction in LDL cholesterol levels did correlate with reduced HF hospitalizations, this correlation does not prove a cause-and-effect relationship. Indeed, LDL cholesterol reductions may simply be a marker of other as-yet-undefined mechanisms by which statins prevent HF hospitalizations. Finally, unrecognized baseline differences between the 2 treatment groups may have influenced our results.
Intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces subsequent hospitalizations for HF compared with low-dose therapy. This benefit was most pronounced in patients with a history of HF. HF hospitalizations were not usually preceded by an ischemic coronary event, suggesting that high-dose statin therapy may confer this benefit through other as-yet-undefined mechanisms. Randomized clinical trials of statins in patients with HF such as the on-going Controlled Rosuvastatin Multinational Study in Heart Failure32 and Gruppo Italiano por lo Studio della Sopravvivenza nell’Insufficienza Cardiaca33 HF studies will likely yield important and useful findings.
Source of Funding
The TNT trial was funded by Pfizer Inc.
Dr Khush has served as a consultant for Pfizer. Dr Waters has received research funding from Merck and Johnson & Johnson; has served as a consultant for Anthera, Atherogenics, CSL Ltd, Eli Lilly, and Pfizer; and has received honoraria for lectures from Merck, Novartis, and Pfizer. Dr Bittner has received research funding from Atherogenics and Pfizer; has served as a consultant for CV Therapeutics, Pfizer, and Reliant; and has received honoraria for lectures from Kos, Merck, Merck-Shering-Plough, and Pfizer. Dr Deedwania has served as a consultant for and has received honoraria for lectures from AstraZeneca and Pfizer. Dr Kastelein has received research funding from, served as a consultant for, and received honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Schering Plough, and Sankyo. Dr Lewis has received research funding from AstraZeneca and Pfizer and has received honoraria for lectures from AstraZeneca, Merck, Novartis, and Pfizer. Dr Wenger has received research funding from AstraZeneca, Eli Lilly, and Pfizer; has served as a consultant for Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, Glaxo SmithKline, and NitroMed; and has received honoraria for lectures from Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, Merck, NitroMed, Novartis, and Pfizer.
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Previous studies have shown that statins reduce cardiovascular events in patients with coronary heart disease. Patients with heart failure (HF), however, generally were excluded from these trials. Statins may exert beneficial effects in HF; they have been shown to improve endothelial function, to decrease inflammatory cytokine levels, and to inhibit adverse left ventricular remodeling. However, concerns have been raised about the potential adverse effects of statins in HF patients. This study is a predefined secondary analysis of the Treating to New Targets trial, in which 10 001 patients with coronary heart disease were randomized to high-dose (80 mg/d) or low-dose (10 mg/d) atorvastatin and followed up for 5 years. High-dose statin therapy reduced the incidence of hospitalization for HF, which was 2.4% in the 80-mg arm and 3.3% in the 10-mg arm (hazard ratio, 0.74; 95% confidence interval, 0.59 to 0.94; P=0.0116). Patients with a history of HF were more likely to be hospitalized for HF than those with no history of HF, and the treatment effect of high-dose atorvastatin was more pronounced in these patients. The majority of patients hospitalized with HF had no evidence of preceding myocardial ischemia, suggesting that statins may confer benefits beyond a reduction of atherothrombotic events. Prospective trials studying the role of statin therapy in the treatment of HF are now underway.
Presented in part at the 2005 American Heart Association Annual Scientific Sessions, Dallas, Tex, November 13–16, 2005.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00327691.