Statins in Acute Coronary Syndromes

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1 Journal of the American College of Cardiology Vol. 54, No. 15, by the American College of Cardiology Foundation ISSN /09/$36.00 Published by Elsevier Inc. doi: /j.jacc VIEWPOINT AND COMMENTARY Statins in Acute Coronary Syndromes Do the Guideline Recommendations Match the Evidence? Ryan P. Morrissey, MD,* George A. Diamond, MD,* Sanjay Kaul, MD* Los Angeles, California On the basis of the evidence obtained from observational studies, randomized controlled trials and their meta-analyses, current guidelines recommend initiating high-dose statin therapy pre-discharge regardless of the baseline low-density lipoprotein (LDL) level in patients with acute coronary syndromes (ACS). Careful review of the evidence indicates that early initiation of high-dose statin therapy reduces recurrent ischemia and may reduce revascularization, but does not confer benefit in terms of hard clinical outcomes such as death or myocardial infarction in any of the randomized controlled trials, and may be associated with increased liver and muscle-related adverse outcomes leading to increased withdrawal and suboptimal long-term adherence. A mortality benefit is apparent in pooled analyses of randomized controlled trials only at long-term (24-month) but not short-term (4-month) follow-up. The critical role of the timing of initiation of therapy (early vs. late) on the benefit-risk profile of statin treatment has not been systematically assessed. It is unclear whether the clinical benefits are attributable to lipid-lowering or lipid-lowering independent effects. Finally, an optimal LDL threshold for initiating treatment or target LDL level for treatment in ACS remains yet to be defined. On the basis of these observations, and despite a compelling pathophysiologic rationale, the justification for current Class I, Level of Evidence: A recommendation for statin therapy in patients with ACS remains open to question. (J Am Coll Cardiol 2009;54: ) 2009 by the American College of Cardiology Foundation There are no facts, only interpretations. Friedrich Nietzsche (1) Each year, nearly 1.5 million people living in the U.S. suffer an acute coronary syndrome (ACS) (2). The administration of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors in patients during ACS has been shown to be beneficial (3 5). The evidence supporting the use of statins, however, is less clear (6). Statins clearly reduce cardiovascular mortality and morbidity in primary and secondary prevention of coronary heart disease (CHD) (7). A majority of the secondary prevention trials have been limited to the timeframe immediately (3 to 6 months) following an index acute coronary event (7). Consequently, over the past decade, a number of investigations have specifically evaluated the role of statins during the course of ACS. Based on the results of these investigations, early intensive statin therapy has become formally endorsed as a treatment guideline (3,4) and a performance measure (5) in patients with ACS. We herein review the evidence base in support of these policy recommendations. From the *Cedars-Sinai Medical Center, Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; and the Cedars-Sinai Heart Institute, Los Angeles, California. Dr. Diamond serves on the speaker s panel of Schering-Plough and Merck. Manuscript received December 23, 2008; revised manuscript received March 25, 2009, accepted April 14, Efficacy of Statin Therapy Statins exhibit a number of biologic effects that may be relevant in the setting of acute ischemic events (8). They act rapidly to improve vascular endothelial function (8 10), attenuate vascular inflammation (8,11), stabilize plaques (12), correct prothrombotic tendencies (8,12), and influence myocardial protection and remodeling (13). These effects may be related to low-density lipoprotein (LDL) reduction or to a variety of LDL-independent mechanisms the so-called pleiotropic effects. The relative importance of these 2 mechanisms continues to be hotly debated. A meta-regression analysis found that the nonstatin (diet, bile acid sequestrants, and ileal bypass surgery) and statin interventions in stable patients appear to reduce CHD risk in a similar manner, consistent with the 1-to-1 relationship with the degree of LDL cholesterol lowering (14). This is true for the ACS trials as well. For example, despite significant reductions in inflammatory markers, a 31% greater reduction in LDL with atorvastatin 80 mg over pravastatin 40 mg was associated with an additional 18% reduction in CHD events in the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial (15). Similarly, a 14% greater reduction in LDL was associated with a 12% better outcome in the aggressive statin treatment arm in the A to Z (Aggrastat to Zocor) trial (16). A meta-analysis of placebo-controlled trials found that statin

2 1426 Morrissey et al. JACC Vol. 54, No. 15, 2009 Statins in ACS Revisited October 6, 2009: Abbreviations and Acronyms ACS acute coronary syndromes CHD coronary heart disease LDL low-density lipoprotein MI myocardial infarction therapy had no significant effect on C-reactive protein, an inflammatory biomarker, after adjustment for change in LDL (17). Multivariate modeling revealed that only 2% to 11% of the C-reactive protein change (28% reduction) could not be accounted by LDL lowering. Thus, these results provide insufficient evidence in support of the pleiotropic effects of statins. Nevertheless, the role of statin therapy in patients with ACS relies more on empirical observation than on mechanism of action. The efficacy of statin therapy in ACS has been evaluated in observational studies, post-hoc analyses of ACS clinical trials performed for other purposes, placeboor active-controlled randomized controlled trials and their meta-analyses. The results of key trials and meta-analyses are summarized in Table 1. Observational studies. A number of observational studies indicate that statins decrease major cardiovascular outcomes including mortality by approximately 30% to 40% in treatment subjects compared with control subjects when initiated before or at discharge after ACS (18 24). In a large Swedish registry, RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions), of nearly 20,000 cardiac intensive care patients, treatment with a statin was associated with significantly lower 1-year mortality (adjusted relative risk: 0.75, 95% confidence interval [CI]: 0.63 to 0.89) (19). These observations were confirmed in a pooled analysis of the GUSTO- IIb (Global Utilization of Streptokinase and TPA for Occluded Arteries IIb) plus PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trials enrolling about 20,000 patients (adjusted mortality hazard ratio [HR]: 0.67, 95% CI: 0.48 to 0.95) (25), the NRMI (National Registry of Myocardial Infarction) 4 database (adjusted in-hospital mortality odds ratio [OR]: 0.58, 95% CI: 0.54 to 0.63) (22), and Nagashima et al. (24) that demonstrated sustained mortality benefit at 5-year follow-up. The benefit associated with early initiation of statin therapy documented in the NMRI-4 registry coupled with the harm associated with suddenly stopping statins after an ACS documented in the NMRI-4 registry (22) and the PRISM (Platelet-Receptor Inhibition for Ischemic Syndrome Management) study (26) further highlight the efficacy of statin treatment. In contrast, pooled analysis of the first and the second SYMPHONY (Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes) trials found no improvement in outcomes (adjusted mortality HR: 0.99, 95% CI: 0.73 to 1.33) (27). The inconsistency among these observational studies is likely related to confounding arising from nonrandomized comparisons and heterogeneity in the timing of statin therapy. Randomized trials. Several placebo-controlled (28 35) and 2 active-control randomized trials (15,16) have evaluated the efficacy and safety of statins in ACS. With the exception of the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) trial (32), none of the placebo-controlled trials showed a significant reduction in the primary end point. These studies were, however, limited by insufficient statistical power to detect differences over placebo due to premature study termination as a consequence of slow enrollment in the PACT (Plasminogen Activator-Angioplasty Compatibility Trial) (33), statin withdrawal in the PRINCESS (Prevention of Ischaemic Events by Early Treatment of Cerivastatin after Acute Myocardial Infarction) trial (34), or low event rates in the FLORIDA (Fluvastatin on Risk Diminishing After Acute Myocardial Infarction) trial (35). In the MIRACL study, the reduction in the primary composite end point was driven by recurrent angina requiring hospitalization without significant effects on death, cardiac arrest, myocardial infarction (MI), or revascularization (32). Furthermore, an unplanned interim analysis was performed in the MIRACL trial without adjustment of p value in the reported results (p 0.048). Whether the primary end point would have reached statistical significance had such an adjustment been made remains unclear. Meta-analyses. A meta-analysis of 12 trials comparing early statin therapy with placebo or usual care demonstrated that initiation of statin therapy within 14 days following onset of ACS did not reduce death, MI, or stroke at 4 months of follow-up (6). Additional meta-analyses of randomized controlled trials demonstrate that early initiation of statins after ACS improves cardiovascular outcomes, although these benefits take 6 months for morbid events (36) and 24 months for fatal events (36,37) to become evident. Safety of Statin Therapy Moderate doses of statins are generally safe and well tolerated (Table 1). Regarding the safety of high-dose statins used in ACS trials, higher doses of simvastatin were associated with a greater incidence of myopathy compared with lower doses in the A to Z trial (Table 1), a finding also observed in the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) study, a recent trial of aggressive versus moderate LDL lowering in more than 12,000 heart attack survivors (38). There were 53 cases of myopathy reported with 80-mg simvastatin compared with only 3 cases with 20-mg simvastatin. Similarly, a greater incidence of liver enzyme elevation was seen with 80 mg/day of atorvastatin compared with 40 mg/day of pravastatin in the PROVE-IT study (15). In the MIRACL study, there was a statistically significant 4-fold increase in liver enzyme elevations with 3 cases of hepatitis (2 of them resolving upon discontinuation) (32). Meta-analyses of intensive- versus moderate-dose statin trials reveal a 2- to 4-fold increase in adverse hepatic and

3 Randomized Table 1 Randomized Control TrialsControl and Meta-Analyses Trials and Meta-Analyses of Statin Therapy of Statin Initiated Therapy for ACS Initiated for ACS Trial (Ref. #) MIRACL (32) Treatment Atorvastatin 80 mg vs. placebo AtoZ(16) Simvastatin 40/80 mg vs. placebo/ simvastatin 20 mg PROVE-IT (15) Atorvastatin 80 mg vs. pravastatin 40 mg Initiation, Days (Mean) Primary End Point 1 4 (2.6) Death, MI, cardiac arrest, RI 5 (3.7) CV death, MI, stroke, ACS 10 (5.7) Death, MI, RI, revasc, stroke Follow-Up, Months On-Treatment LDL (mg/dl) Control Rx Control Randomized Control Trials Rx Efficacy Odds Ratio (95% CI) Control ALT (>3 ULN) Rx Odds Ratio (95% CI) Safety Control CK (>10 ULN) Rx Odds Ratio (95% CI) ( ) ( ) 0 0 Not estimable ( ) ( ) ( ) ( ) ( ) ( ) Meta-Analyses Briel et al. (6) (12 RCTs) Statin vs. placebo 14 (4.3) Death, MI, stroke ( ) NA NA Bavry et al. (37) Early intensive 12 (5.3) Death ( ) ( ) 0.71* 0.97* 1.35 ( ) (7 RCTs) statin vs. control MI ( ) Stroke ( ) RI ( ) Revasc ( ) Afilalo et al. (40) Intensive vs. 10 (4.7) CV death, ACS, ( ) ( ) ( ) (PROVE-IT AtoZ) moderate statin stroke Death ( ) *Reported as myositis; secondary end point; pooled analysis. Efficacy refers to the primary end point. ACS acute coronary syndrome; CI confidence interval; CV cardiovascular; MI myocardial infarction; NA not available; RCT randomized control trial; Revasc coronary artery bypass graft surgery or percutaneous coronary intervention; RI recurrent ischemia requiring hospitalization; Rx prescription; ULN upper limit of normal. JACC Vol. 54, No. 15, 2009 Morrissey et al. October 6, 2009: Statins in ACS Revisited 1427

4 1428 Morrissey et al. JACC Vol. 54, No. 15, 2009 Statins in ACS Revisited October 6, 2009: muscular events, and an increase in adverse events requiring discontinuation of therapy (39 41). In general, the upward titration of statins from 40 to 80 mg is associated with multiple-fold increases in liver or muscle toxicity (likely contributing to lower adherence) while providing only 6% to 7% additional LDL reduction (reflecting the log-linear relationship between LDL reduction and statin dose) (Table 1). Moreover, adverse event rates in real-world clinical practice are likely substantially higher (42) than those reported in clinical trials because of the strict exclusion criteria and run-in phase employed in trials that filter out patients intolerant to statins. Guidelines for Statin Therapy in ACS Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide a Class I, Level of Evidence: A (strong and compelling evidence in favor of benefit outweighing the risk) recommendation for initiating statin therapy pre-discharge regardless of the baseline LDL level (3,4). Furthermore, the guidelines also provide a Class I, Level of Evidence: A recommendation for LDL target of 100 mg/dl and Class IIa, Level of Evidence: A (reasonable but high-quality evidence) for LDL target of 70 mg/dl in ACS (3,4). Let us examine whether these guideline recommendations are supported by evidence. Timing of statin therapy. The critical role of the timing of initiation of statin therapy (i.e., early vs. late during hospitalization or pre- vs. post-discharge) has been formally evaluated in only 2 observational studies and 1 randomized controlled trial. Li et al. (43) compared patients started on statin therapy 2 days versus 2 days after admission for first episode of ACS. After multivariate analysis, there was no significant influence on the primary end point at 4 months or at 12 months. Similarly, Saab et al. (44) observed no significant differences in cardiovascular outcomes at 6 months in patients receiving statin therapy 24 h versus 24 h after admission. These observational data do not suggest a treatment advantage for initiating statin treatment within 24 to 48 h of admission for ACS. The randomized clinical trial A to Z (16) compared early intensive to delayed conservative statin therapy in patients with ACS. Patients were randomized within 5 days of admission to simvastatin 40 mg/day for 1 month followed by simvastatin 80 mg/day versus placebo for 4 months (acute phase) followed by simvastatin 20 mg/day thereafter (chronic phase). No significant differences in outcomes were observed either during the acute phase (primary end point HR: 1.01, 95% CI: 0.83 to 1.25) or at 24 months (HR: 0.89, 95% CI: 0.76 to 1.04). However, the trial was limited by insufficient power as fewer than expected events were accrued in the trial (652 instead of the planned 970) (16). Treatment threshold. The influence of baseline pretreatment LDL on the clinical benefit of lipid-lowering therapy remains controversial. Two observational studies reported favorable outcomes in patients prescribed statin treatment at discharge even in those with LDL levels 100 (45) or 60 mg/dl (46). In contrast, randomized controlled trials have shown inconsistent results. A post hoc analysis of the CARE (Cholesterol And Recurring Events) trial found no significant benefit of LDL lowering with 40-mg pravastatin in individuals whose baseline LDL levels were 125 mg/dl (47). However, in a post hoc analysis of the HPS (Heart Protection Study) trial, significant benefits were seen in high-risk individuals even when their baseline LDL levels were low, that is, 100 mg/dl (48). Data from intensiveversus moderate-ldl lowering trials provide inconsistent information in this regard. A threshold relationship was seen in the TNT (Treatment to New Targets) study (34% reduction in those with baseline LDL 125 mg/dl compared with 7% reduction in those with LDL 125 mg/dl) (49) and the PROVE-IT trial (37% reduction in those with baseline LDL 132 mg/dl compared with 7% reduction in those with LDL 92 mg/dl) (50), but not in the IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering) study (51). In the PROVE-IT (50) and MUSASHI-AMI (Multicenter Study for Aggressive Lipidlowering Strategy by HMG-CoA Reductase Inhibitors in Patients with Acute Myocardial Infarction) (31) trials, the benefit of intensive therapy progressively declined as baseline LDL cholesterol decreased. A post hoc multivariable analysis of the PROVE-IT trial revealed no evidence of benefit in patients with baseline LDL 66 mg/dl (50). A meta-analysis of data from 90,056 patients in 14 trials indicated that the treatment benefit associated with statin was not shown to be related to baseline pre-treatment LDL level but to the reduction in LDL levels a 40-mg/dl reduction in LDL translating into a 20% improvement in outcomes (7). A key limitation is that in none of these trials were patients randomized to statin therapy according to low and high pre-treatment LDL levels. Thus, the guideline recommendation for initiating statin therapy in ACS regardless of the baseline LDL level reflects the current emphasis on risk stratification-based rather than an LDL level-driven approach to treating dyslipidemias. The justification for this approach, however, is based on extrapolation from epidemiologic observations, post hoc review of trial data, expert opinion, and a belief in pleiotropic effects of statins rather than an evidence-based conclusion derived from prospective randomized controlled trials. Treatment target. The current ACC/AHA guideline recommendations for statin treatment target were adapted from LDL targets proposed by National Cholesterol Education Program guidelines that offer an optional LDL goal of 70 mg/dl for patients believed to be at very high risk of atherosclerotic heart disease such as ACS and a mandatory less ambitious target LDL goal of 100 mg/dl for standard high-risk patients (52). The scientific validity of these targets, particularly the ultralow LDL target of 70 mg/dl, has been challenged recently by Hayward et al. (53) as not being based on compelling evidence. Further, they also

5 JACC Vol. 54, No. 15, 2009 October 6, 2009: Morrissey et al. Statins in ACS Revisited 1429 remain unconvinced about the evidence previously cited to support an LDL goal of 100 mg/dl for high-risk patients, pointing out several methodological limitations such as failure to account for known confounders such as a healthy volunteer effect, post-randomization analysis based on observational cohort data, lack of randomization to achieved LDL targets, failure to consider pleiotropic effects of statins, and flaws intrinsic to ecological analyses that drive the guideline recommendations (53). The supporters of the guideline recommendations counter these criticisms by citing a vast body of favorable evidence derived from clinical trials, epidemiological data, anthropological data (54) and experimental laboratory data that cannot be ignored. A critical examination of the data indicates that although angiographic (55), intracoronary ultrasound (56) and carotid intima-media thickness (57) studies have generally shown that lowering LDL to very low levels arrests or even reverses the development of atherosclerosis (a surrogate outcome), there is very little clinical outcome data to support the lower is-better hypothesis. The results of trials of intensive lipid lowering with high-dose statin therapy versus moderate lipid lowering with standard-dose statin therapy the subject of 5 randomized controlled trials, 2 in patients with ACS (PROVE-IT [15], A to Z[16]) and 3 in patients with stable CHD (TNT [49], IDEAL [51], SEARCH [38]) provide important insights. None of these trials was designed to address the treat to target hypothesis but they used a fixed dose of statin (high- vs. standard-dose) throughout. Two of the five trials compared nonequipotent doses of different statins (PROVE-IT and IDEAL). Pooled pre-treatment LDL averaged 130 mg/dl and post-treatment LDL averaged 101 and 75 mg/dl with moderate- and intensive-dose treatment, respectively (39). The guidelinerecommended LDL target of 70 mg/dl was achieved in the 2 ACS trials median LDL of 62 mg/dl in the PROVE-IT trial on atorvastatin 80 mg/day (15), 66 mg/dl in the A to Z trial on simvastatin 80 mg/day (16) (Table 1). The primary end point was significantly reduced in favor of intensive therapy in 2 out of the 5 trials (PROVE-IT and TNT), mostly driven by reductions in revascularization or unstable angina requiring hospitalization in the PROVE-IT trial (which constituted 75% of the composite end point) (15) and nonfatal MI or stroke in the TNT study (49). Pooled analyses of randomized controlled trials of intensive versus moderate LDL lowering failed to reveal a benefit in all-cause or cardiovascular mortality (39 41). Although intensive-dose statin therapy was associated with a reduced risk for important cardiovascular events, it was also associated with an increased risk for statin-induced adverse events. Pooling the results of only ACS trials (A to Z and PROVE-IT), Afilalo et al. (40) reported a reduction in all-cause mortality from 4.6% to 3.5% over 2 years (OR: 0.75, 95% CI: 0.61 to 0.93) with intensive statin therapy. Similar observations were also reported by Josan et al. (58). Despite lack of statistical heterogeneity, there is substantial clinical heterogeneity between the 2 trials with respect to trial design, patient characteristics, treatment protocols, and outcome event rates (Table 2) that argue against pooling, thereby challenging the interpretability of the pooled data. The results from the PROVE-IT trial have been interpreted as providing strong support for aggressive LDL lowering. There are, however, several issues with the design and analysis of the PROVE-IT trial that merit careful consideration. First, the PROVE-IT trial was not designed to prospectively address the lower-is-better hypothesis, Comparison Table 2 Comparison of PROVE-IT of and PROVE-IT A to Z Trials and AoftoEarly Z Trials Intensive of Early Statin Intensive Therapy Statin ACS Therapy in ACS Variable PROVE-IT (n 4,162) A to Z (n 4,497) Treatment Atorvastatin 80 mg vs. pravastatin 40 mg Simvastatin 40/80 mg vs. simvastatin 0/20 mg Placebo-controlled phase No Yes Trial design Active-control noninferiority Active-control superiority, factorial design Time of statin initiation, mean (days) Follow-up, yrs 2 2 Primary end point Death, MI, hospitalization for recurrent ischemia, CV death, MI, stroke, readmission for ACS revascularization, and stroke U.S. enrollment 71% 21% Age, mean (yrs) Females 22% 24% History of diabetes 18% 24% Hypertension 50% 50% Smoker 36% 41% Prior history of CHD 18% MI, 38% CHD, 15% PCI, 11% CABG 17% MI, 45% PCI, 4% CABG Previous statin use 25% 0% Index event 29% UA, 36% NSTEMI, 35% STEMI 40% STEMI, 60% NSTEMI PCI for index event 69% 44% Death rate 2.2% vs. 3.2% 5.5% vs. 6.7% Death or MI rate 8.3% vs. 10.0% 11.1% vs. 12.4% CABG coronary artery bypass graft surgery; CHD coronary heart disease; NSTEMI non ST-segment elevation myocardial infarction; PCI percutaneous coronary intervention; STEMI ST-segment elevation myocardial infarction; UA unstable angina; other abbreviations as in Table 1.

6 1430 Morrissey et al. JACC Vol. 54, No. 15, 2009 Statins in ACS Revisited October 6, 2009: that is, an LDL reduction of 50% would be more beneficial than an LDL reduction of 25%. To the contrary, the primary hypothesis of the trial was to show that moderate lipid lowering with standard-dose pravastatin would be not much worse (noninferior) than aggressive lipid lowering with high-dose atorvastatin. In science, hypothesis should be fixed a priori and tested rather than assumed (hypothesis should drive the data and not vice versa). Second, the difference in favor of aggressive LDL lowering with atorvastatin was largely driven by reduction in soft end points of recurrent angina and revascularization (the most prevalent components of the composite end point) with a nonsignificant impact on the hard end points of death, MI, or stroke. Third, the fact that 2 different statins (atorvastatin 80 mg vs. pravastatin 40 mg) with slightly different effects on the lipid profile and possibly different pleiotropic properties were used makes it difficult to ascertain whether all differences between the 2 regimens can be explained by the intensity of lipid lowering. Finally, post-hoc analysis of the 4-month data in the PROVE-IT trial has been argued to indicate that further benefit is conferred without additional risk for adverse events when LDL is reduced to 40 to 60 mg/dl compared with 61 to 80 mg/dl (59). However, 30% of the patients discontinued drug therapy prematurely, which might have contributed to the reported low rate of side effects. In addition, lack of adequate power to detect adverse events and residual confounding challenge the interpretation of the results. A post hoc analysis of 2-year data in the PROVE-IT trial failed to reveal significant differences in the primary end points in patients with median follow-up LDL concentrations of 53 mg/dl versus 82 mg/dl (50). Therefore, the intensity of statin therapy and the associated target threshold of LDL reduction at which the benefits still outweigh potential adverse effects remain open to question. Thus, it can be argued that the results from the PROVE-IT trial do not provide unequivocal evidence in support of the lower-is-better hypothesis. Based on these observations, there is insufficient evidence to recommend treating to particular LDL targets as advocated by the guidelines. It is interesting to note that the European Society of Cardiology guideline recommendations for statin treatment in ACS are less sanguine than the ACC/AHA guidelines. They recommend early initiation (within 1 to 4 days) of statin treatment with the aim of achieving LDL levels 100 mg/dl (Class I, Level of Evidence: B), and intensive lipid-lowering therapy with target LDL levels 70 mg/dl initiated within 10 days after admission (Class IIa, Level of Evidence: B) (60). Implicit in the Level of Evidence: B recommendations (compared with Level of Evidence: A recommendations endorsed by the ACC/AHA guidelines) is the acknowledgment of lack of high-quality evidence in support of LDL treatment targets. Finally, an analysis of existing data from primary and secondary prevention trials, including the ACS trials, could provide useful insights into the threshold and target issues by documenting the multivariate relationship (or lack thereof) of clinical outcome to baseline LDL and magnitude of LDL reduction. One such hypothetical analysis, demonstrating a graded relationship of treatment benefit according to tertiles of baseline LDL (from 70 to 100 mg/dl) and quartiles of percent LDL lowering (from 10% to 30%), is illustrated in Figure 1. We urge those with access to these data to conduct such analyses. However, given the lack of randomization according to LDL treatment thresholds or to achieved LDL targets in these trials, it is important to keep in mind the exploratory nature of such analyses and the limited ability to draw inferences from them. Only randomized controlled trials that are properly designed to prospectively evaluate LDL threshold and LDL target can provide more valid and persuasive evidence in support of guideline recommendations to inform clinical practice. Statin Adherence After ACS It has been argued that perhaps the most important reason to initiate statin therapy during the hospital phase of the ACS is to ensure that patients receive this critical component of secondary prevention and to improve long-term adherence by taking advantage of a teachable moment when patients are most motivated. Recent registry and observational cohort studies such as the NMRI-4 registry (20) and the CHAMP (Cardiac Hospitalization Atherosclerosis Management Program) (61) and LTAP (Lipid Treatment Assessment Project) (62) trials have demonstrated improved short- and long-term adherence rates when statins, along with other cardioprotective medications, were started early before hospital discharge. However, these studies were limited by lack of randomization and lack of high-dose statin treatment. The drop-out rate associated with high-dose statin treatment in randomized trials is not trivial nearly 11% over 4 months in the MIRACL trial (32) and nearly 30% over 2 years in both the PROVE-IT Figure 1 CHD Risk Reduction According to Baseline LDL-C and LDL Lowering Putative relationship of treatment benefit (% coronary heart disease [CHD] risk reduction) according to baseline pre-treatment LDL (from 70 to 100 mg/dl) and % low-density lipoprotein (LDL) lowering (from 10% to 30%). LDL-C low-density lipoprotein cholesterol.

7 JACC Vol. 54, No. 15, 2009 October 6, 2009: Morrissey et al. Statins in ACS Revisited 1431 (15) and A to Z trials (16). Treatment intolerance and withdrawal rates in real-world clinical practice may be even higher than those reported in clinical trials (63,64). Thus, there is no direct evidence in support of improved adherence with early intensive statin therapy. Nevertheless, one could still make a case for initiating a low- or moderate-dose statin during hospitalization and up-titrating to achieve desired target LDL levels during subsequent post-hospitalization follow-up. This might help optimize adherence (65) and preserve the benefits associated with long-term statin therapy while minimizing the potential for adverse events. Implications In objectively reviewing the evidence on statins in ACS, it is important not to miss the forest for the trees. The rationale for statins in ACS is supported by a large body of evidence derived from basic laboratory, epidemiologic, and clinical trial data. Although unequivocal trial evidence in support of guideline recommendations is arguably lacking at the current time, and because there is the possibility of benefit with little or no likelihood of harm in most patients, it is hard not to acknowledge an important role for statin therapy in ACS. It is prudent to recommend low-tomoderate-dose statin therapy as the most appropriate choice for achieving cardiovascular risk reduction in the majority of individuals without incurring adverse effects, whereas intensive-dose statin therapy may be reserved for those that do not respond to low-to-moderate-dose statins. However, the challenges of obtaining LDL goals in clinical practice compared with clinical trials where less than one-half of the patients achieved LDL 70 mg/dl) (15,16,49,51) and the benefit-risk-cost ratio of aggressive LDL lowering strategy in clinical practice (frequent use of multidrug therapy with its potential harms, frequent monitoring, adherence, and so on) cannot be overlooked. Conclusions In acute coronary syndromes, early initiation of high-dose statin therapy reduces recurrent ischemia; may reduce revascularization, but does not confer benefit in terms of the hard clinical outcomes of MI and stroke; and may be associated with increased liver and muscle-related adverse outcomes leading to increased withdrawal and suboptimal long-term adherence. A mortality benefit is apparent in pooled analyses of trials only at long-term (24-month) but not at short-term (4-month) follow-up. Both clinical benefit and adverse safety outcomes appear to be dose- and statindependent. It is unclear whether the clinical benefits are attributable to lipid-lowering or lipid-lowering-independent effects. The critical role of the timing of initiation of therapy (early vs. late) on the benefit-risk profile of statin treatment has not been systematically assessed. Finally, an optimal LDL threshold for initiating treatment and a target treatment LDL level in ACS remain to be defined. On the basis of these observations, and despite a compelling pathophysiologic rationale, the current evidence is insufficient to justify a Class I, Level of Evidence: A recommendation (as formerly defined) for initiating with ACS. More importantly, these limitations also call into question the recent elevation of this guideline to a performance measure (5), which is typically reserved for the highest level of evidence. Reprint requests and correspondence: Dr. Sanjay Kaul, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California kaul@cshs.org. REFERENCES 1. Nietzsche s Nachlass, A. Danto translation. Available at: theperspectivesofnietzsche.com/nietzsche/ntruth.html. Accessed August 18, Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2008;51: Anderson JL, Adams CD, Antman EM, et al., ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2007;50: Krumholz HM, Anderson JL, Bachelder BL, et al., ACC/AHA 2008 performance measures for adults with ST-elevation and non STelevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for ST-Elevation and Non ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2008;52: Briel M, Schwartz GG, Thompson PL, et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials. JAMA 2006;295: Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: Sposito AC, Chapman MJ. Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit. Arterioscler Thromb Vasc Biol 2002;22: Dupuis J, Tardif JC, Cernacek P, Théroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999;99: Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97: Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005:4: Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279: Xu Z, Okamoto H, Akino M, Onozuka H, Matsui Y, Tsutsui H. Pravastatin attenuates left ventricular remodeling and diastolic dys-

8 1432 Morrissey et al. JACC Vol. 54, No. 15, 2009 Statins in ACS Revisited October 6, 2009: function in angiotensin II-induced hypertensive mice. J Cardiovasc Pharmacol 2008;51: Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol 2005;46: Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350: de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292: Kinlay S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a metaanalysis. J Am Coll Cardiol 2007;49: Bybee KA, Wright RS, Williams BA, Murphy JG, Holmes DR Jr., Kopecky SL. Effect of concomitant or very early statin administration on in-hospital mortality and reinfarction in patients with acute myocardial infarction. Am J Cardiol 2001;87: Stenestrand U, Wallentin L, Swedish Register of Cardiac Intensive Care (RIKS-HIA). Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 2001;285: Walter DH, Fichtlscherer S, Britten MB, et al. Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction. Am J Cardiol 2002;89: Ferrieres J, Cambou JP, Gueret P, et al. Effect of early initiation of statins on survival in patients with acute myocardial infarction (the USIC 2000 Registry). Am J Cardiol 2005;95: Fonarow GC, Wright RS, Spencer FA, et al. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol 2005;96: Lenderink T, Boersma E, Gitt AK, et al. Patients using statin treatment within 24 h after admission for ST-elevation acute coronary syndromes had lower mortality than non-users: a report from the first Euro Heart Survey on acute coronary syndromes. Eur Heart J 2006;27: Nagashima M, Koyanagi R, Kasanuki H, et al. Effect of early statin treatment at standard doses on long-term clinical outcomes in patients with acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology Statin Evaluation Program). Am J Cardiol 2007;99: Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357: Heeschen C, Hamm CW, Laufs U, Snappin S, Bohm M, White HD. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002;105: Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287: Arntz HR, Agrawal R, Wunderlich W, et al. Beneficial effects of pravastatin ( /-colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] study). Am J Cardiol 2000;86: Colivicchi F, Guido V, Tubaro M, et al. Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non-q-wave myocardial infarction. Am J Cardiol 2002;90: Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH study. Circulation 2004;110: Sakamoto T, Kojima S, Ogawa H, et al. Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese. Am J Cardiol 2006;97: Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285: Thompson P, Meredith I, Amerena J, et al., on behalf of Pravastatin in Acute Coronary Treatment (PACT). Effect of pravastatin compared with placebo initiated within 24 hours of onset of acute myocardial infarction or unstable angina: the Pravastatin in Acute Coronary Treatment (PACT) trial. Am Heart J 2004;148:e Wright RS. The Prevention of Ischemic Events by Early Treatment with Cerivastatin (PRINCESS) study. Paper presented at: the Annual Congress of the European Society of Cardiology; August 28 September 1, 2004; Munich, Germany. 35. Liem AH, van Boven AJ, Veeger NJ, et al., on behalf of Fluvastatin on Risk Diminishment after Acute Myocardial Infarction Study Group. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J 2002;23: Hulten E, Jackson JL, Douglas K, George S, Villines TC. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166: Bavry AA, Mood GR, Kumbhani DJ, Borek PP, Askari AT, Bhatt DL. Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials. Am J Cardiovasc Drugs 2007;7: Collins R, Armitage J. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Available at: clintrialresults.org/slides/aha%20search% _final.ppt. Accessed March 18, Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48: Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart 2007;93: Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007;29: Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289: Li Y, Wu H, Yang Y, Tsai H, Chao T. Effect of early versus late in-hospital initiation of statin therapy on the clinical outcomes of patients with acute coronary syndrome. Int Heart J 2007;48: Saab FA, Eagle KA, Kline-Rogers E, et al. Comparison of outcomes in acute coronary syndrome in patients receiving statins within 24 hours of onset versus at later times. Am J Cardiol 2004;94: Spencer FA, Goldberg RJ, Gore JM, et al. Comparison of utilization of statin therapy at hospital discharge and six-month outcomes in patients with an acute coronary syndrome and serum low-density lipoprotein or 100 mg/dl versus 100 mg/dl. Am J Cardiol 2007;100: Leeper NJ, Ardehali R, degoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007;116: Sacks FM, Moye LA, Davis BR, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998;97: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002;360: LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352: Giraldez RR, Giugliano RP, Mohanavelu S, et al. Baseline lowdensity lipoprotein cholesterol is an important predictor of the benefit of intensive lipid-lowering therapy: a PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) analysis. J Am Coll Cardiol 2008;52: Pedersen TR, Faergeman O, Kastelein JJ, et al., on behalf of Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294: Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006;145:

9 JACC Vol. 54, No. 15, 2009 October 6, 2009: Morrissey et al. Statins in ACS Revisited O Keefe JH Jr., Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc 2004;79: Brown BG, Stukovsky KH, Zhao XQ. Simultaneous low-density lipoprotein-c lowering and high-density lipoprotein-c elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials. Curr Opin Lipidol 2006;17: Nissen SE, Nicholls SJ, Sipahi I, et al., on behalf of the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295: Crouse JR III, Raichlen JS, Riley WA, et al., on behalf of the METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA 2007;297: Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008;178: Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy. J Am Coll Cardiol 2005;46: Bassand JP, Hamm CW, Ardissino D, et al., on behalf of the Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Guidelines for the diagnosis and treatment of non-st-segment elevation acute coronary syndromes. Eur Heart J 2007;28: Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). Am J Cardiol 2001;87: Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160: Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang MR, Semchuk WM. Adherence to statins, beta-blockers and angiotensinconverting enzyme inhibitors following a first cardiovascular event: a retrospective cohort study. Can J Cardiol 2005;21: Eagle KA, Kline-Rogers E, Goodman SG, et al. Adherence to evidence-based therapies after discharge for acute coronary syndromes: an ongoing prospective, observational study. Am J Med 2004; 117: Benner JS, Tierce JC, Ballantyne CM, et al. Follow-up lipid tests and physician visits are associated with improved adherence to statin therapy. Pharmacoeconomics 2004;22: Key Words: statins y low-density lipoprotein y unstable angina y myocardial infarction y guidelines y cardiovascular outcomes. APPENDIX Search methodology. We searched EMBASE, MEDLINE, and the Cochrane Library until March 3, We used the following terms: statin(s), HMG-CoA reductase inhibitor(s), acute coronary syndrome(s), myocardial infarction(s), low-density lipoprotein (LDL), adherence, compliance, and guidelines. We focused on the randomized controlled trials and their meta-analyses, nonrandomized evaluations, editorials, and reviews to explore key issues relating to statins in acute coronary syndromes. All articles were limited to the English language.