Early Intensive vs a Delayed Conservative Simvastatin Strategy in Patients With Acute Coronary Syndromes:  Phase Z of the A to Z Trial FREE

Long-term therapy with statin drugs has been shown to reduce the risk for death, myocardial infarction (MI), and stroke among patients with established coronary artery disease, even when low-density lipoprotein (LDL) cholesterol levels are not elevated.^1- 4 Most of the landmark clinical trials evaluating statins for secondary prevention enrolled patients who were stable for at least several months after an index acute coronary syndrome (ACS) event.^1- 3 More recently, 2 randomized controlled trials have evaluated earlier initiation of statin therapy following an ACS event and have noted a corresponding early reduction in major cardiovascular events.^5- 6

Phase Z of the A to Z trial was designed to evaluate a strategy of early initiation of intensive treatment with simvastatin in ACS patients compared with a delayed, less intensive strategy.

Details of the study design have been reported previously.⁷ The A to Z trial is an international trial consisting of 2 overlapping phases. Phase A was an open-label noninferiority trial comparing enoxaparin with unfractionated heparin in patients with non–ST-elevation ACS who were treated with tirofiban and aspirin. Patients were required to have chest pain at rest lasting 10 minutes or longer within the previous 24 hours, which was associated with either ST elevation or depression of 0.5 mm or higher, or with elevated levels of creatine kinase–MB or troponin. Results of phase A have been reported.⁸

Phase Z is a double-blind trial comparing 2 statin regimens in patients with ACS. Patients between the ages of 21 and 80 years with either non–ST-elevation ACS or ST-elevation MI were eligible for enrollment if they had a total cholesterol level of 250 mg/dL (6.48 mmol/L) or lower. Initially, patients were entered into phase Z only if they presented with non–ST-elevation ACS, were stabilized during phase A of the trial for at least 12 consecutive hours within 5 days after symptom onset, and met at least 1 of the following high-risk characteristics: age older than 70 years; diabetes mellitus; prior history of coronary artery disease, peripheral arterial disease, or stroke; elevation of serum creatine kinase–MB or troponin levels; recurrent angina with ST-segment changes; electrocardiographic evidence of ischemia on a predischarge stress test; or multivessel coronary artery disease determined by coronary angiography. Patients enrolled in phase A who did not meet stability and high-risk criteria were not eligible for continuation to phase Z. All patients provided written informed consent and the protocol was approved by the local institutional review board of each participating hospital.

The protocol was amended to allow patients with non–ST-elevation ACS who were not enrolled in phase A and patients with ST-elevation MI to enter directly into phase Z. Patients in the latter category were required to receive fibrinolytic therapy or primary percutaneous coronary intervention (PCI) if they presented within 12 hours of symptom onset and no reperfusion therapy if symptom onset was longer than 12 hours prior to presentation. Patients were also required to meet criteria for stability and have at least 1 high-risk feature in addition to cardiac biomarker elevation.

Patients were excluded from enrollment if they were receiving statin therapy at the time of randomization, if coronary artery bypass graft surgery was planned, or if PCI was planned within the first 2 weeks after enrollment. Patients also were excluded for having an alanine aminotransferase (ALT) level higher than 20% above the upper limit of normal (ULN); for having an increased risk for myopathy due to renal impairment (serum creatinine level >2.0 mg/dL [176.8 µmol/L]) or concomitant therapy with agents known to enhance myopathy risk, such as fibrates, cyclosporine, macrolide antibiotics, azole antifungals, amiodarone, or verapamil; or for having a prior history of nonexercise-related elevations in creatine kinase level or nontraumatic rhabdomyolysis.

All patients were encouraged to adopt an American Heart Association Step I diet. They were randomized to either an early intensive statin treatment strategy (40 mg/d of simvastatin for 30 days and then 80 mg/d of simvastatin thereafter) or a less aggressive strategy (placebo for 4 months and then 20 mg/d of simvastatin thereafter). Each center was assigned 1 or more blocks of 4 allocation numbers and blinded study supplies corresponding to these allocation numbers. Treatments were assigned randomly to the allocation numbers using a blocked randomization scheme. A patient was randomized by being assigned to the next available allocation number at that site.

Clinical and laboratory assessments (lipid levels, high-sensitivity C-reactive protein serum chemistries, liver function tests, creatine kinase level, and urine pregnancy tests) were performed prior to study drug initiation and at months 1, 4, and 8 and every 4 months thereafter until trial completion. Patients were followed up for at least 6 months and up to 24 months. Patients who had LDL cholesterol levels that were higher than 130 mg/dL (3.37 mmol/L) at month 8 or any subsequent visit were provided additional dietary, lifestyle, and compliance counseling. If after 6 weeks the LDL cholesterol level remained higher than 130 mg/dL (3.37 mmol/L), the investigator could either add a bile acid sequestrant or discontinue the study drug and initiate open-label statin therapy. The study drug was discontinued if the LDL cholesterol level was 40 mg/dL (1.04 mmol/L) or lower.

Patients with levels of ALT or aspartate aminotransferase (AST) that were higher than 3 times the ULN and creatine kinase levels higher than 5 times the ULN were required to have a repeat measurement within 3 days. Protocol-mandated withdrawal from study treatment was required for patients with any consecutive elevations in ALT or AST levels higher than 3 times the ULN, a single measurement of creatine kinase level higher than 10 times the ULN with muscle symptoms, or a consecutive measurement of creatine kinase level higher than 10 times the ULN without symptoms.

The primary efficacy end point of the trial was a composite of cardiovascular death, nonfatal MI, readmission for ACS (requiring new electrocardiographic changes or cardiac marker elevation), and stroke. All primary end points were adjudicated by an independent clinical end point committee blinded to treatment assignment. Secondary end points included individual components of the primary end point, revascularization due to documented ischemia, all-cause mortality, new-onset congestive heart failure (requiring admission or initiation of heart failure medications), and cardiovascular rehospitalization.

Adverse events were recorded at each study visit, and safety data were reviewed by an independent data and safety monitoring board. The primary safety outcomes were elevations in levels of AST or ALT higher than 3 times the ULN or myopathy (defined as creatine kinase level >10 times the ULN and associated with muscle symptoms).⁹ Rhabdomyolysis was defined as a creatine kinase level higher than 10 000 units/L with or without muscle symptoms.¹⁰

Sample size calculations were based on the following assumptions: (1) a 1-year event rate of 20% in the placebo plus 20 mg/d of simvastatin group based on the observed event rate between 4 and 180 days in the tirofiban plus unfractionated heparin group in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Angina Signs and Symptoms (PRISM PLUS) study¹¹; (2) a 15% discontinuation rate; and (3) a 20% reduction in the primary end point rate in the simvastatin only group (40 mg/d and then 80 mg/d). Based on these assumptions, 970 patients experiencing a primary end point event would yield 90% power at the 2-sided 5% significance level and 80% power to detect a 17.5% reduction in the hazard ratio.

The sample size of 4500 patients (2250 per treatment group) was selected to yield 970 events within 1 year after enrollment. The protocol permitted a sample size adjustment to achieve the projected number of 970 total primary end point events, but the executive committee elected to halt enrollment after the planned 4500 patients were enrolled. During the course of the trial, data emerged to support statin initiation early after ACS,⁵ and practice patterns in participating hospitals changed considerably, so that it became increasingly difficult to enroll patients into the placebo-controlled portion of the trial. Moreover, the investigators believed that lengthening the follow-up period beyond 2 years to accrue more events would fundamentally alter the hypotheses being tested in the trial.

All efficacy and safety analyses were performed on an intent-to-treat basis. The cumulative incidence of the primary end point was determined using the Kaplan-Meier product-limit method. Patients who did not achieve expected follow-up were censored at the time they withdrew consent or were lost to follow-up. Statistical comparison between treatment groups was performed using a Cox proportional hazards model that included covariates for treatment group and age. Although a significant treatment × time interaction (P = .03) was observed, all end point analyses were performed as prespecified using the Cox proportional hazards model. The primary end point analysis required a 2-sided α level of .046 for significance to account for 2 interim data and safety monitoring board analyses. All other analyses required a significance level of .05. Comparisons of adverse safety events were performed using the Fisher exact test. Statistical analyses were performed using SAS software (version 8.0, SAS Institute Inc, Cary, NC).

Between December 29, 1999, and January 6, 2003, 4497 patients were enrolled at 322 centers in 41 countries (Figure 1). The mean time from symptom onset to randomization in phase Z was 3.7 days. Baseline characteristics were similar between the 2 treatment groups (Table 1). Treatment with guideline-recommended therapies, such as angiotensin-converting enzyme inhibitors, β-blockers, and aspirin, was high and similar between the 2 treatment groups (Table 1). There were 1958 (44%) patients who underwent PCI to treat the index ACS event prior to enrollment. Treatment was discontinued prematurely in 711 patients (32%) in the placebo plus 20 mg of simvastatin group and 765 (34%) in the simvastatin only group (40 mg/d and then 80 mg/d). The median follow-up period was 721 days and 22 patients in each treatment group were lost to follow-up (Figure 1).

In the placebo plus simvastatin group, median LDL cholesterol levels increased by 11% during the 4-month placebo period from 111 mg/dL (2.87 mmol/L) to 124 mg/dL (3.21 mmol/L) and then decreased to 77 mg/dL (1.99 mmol/L) at month 8 after the initiation of 20 mg of simvastatin (31% change from baseline). In the simvastatin only group, the median LDL cholesterol levels decreased by 39% to 68 mg/dL (1.76 mmol/L) over the first month during treatment with 40 mg/d of simvastatin and then decreased an additional 6% to 62 mg/dL (1.61 mmol/L) at month 4 following the increase to the 80 mg/d of simvastatin (Table 2). Changes in lipid and C-reactive protein values are shown in Table 2. The latter were equivalent in the 2 groups at baseline and at month 1, but became significantly lower in the simvastatin only group subsequently.

The primary end point of cardiovascular death, MI, readmission for ACS, and stroke occurred in 343 patients (16.7%) in the placebo plus simvastatin group compared with 309 (14.4%) in the simvastatin only group (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.76-1.04; P = .14; Figure 2). Outcomes for selected secondary end points are shown in Table 3. Cardiovascular death occurred in 109 patients (5.4%) in the placebo plus simvastatin group compared with 83 (4.1%) in the simvastatin only group (HR, 0.75; 95% CI, 0.57-1.00; P = .05; number needed to treat to prevent 1 cardiovascular death, 77). No significant differences were observed between treatment groups with regard to the secondary end points of MI, readmission for ACS, revascularization due to documented ischemia, or stroke. New-onset congestive heart failure was reduced from 5.0% in the placebo plus simvastatin group to 3.7% in the simvastatin only group (HR, 0.72; 95% CI, 0.53-0.98; P = .04; number needed to treat to prevent 1 episode of new-onset congestive heart failure, 77; Table 3).

In a post hoc analysis, no difference between treatment groups in the primary end point was evident over the first 4 months following randomization, which corresponded to the placebo-controlled comparison period (HR, 1.01; 95% CI, 0.83-1.25; P = .89). However, from 4 months through the end of the study, the primary end point was reduced from 9.3% in the placebo plus simvastatin group to 6.8% in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P = .02; Figure 3).

No significant treatment interactions were detected in subgroups defined by demographic variables, index diagnosis, baseline lipid and C-reactive protein levels, or use of early PCI. There was no evidence of a greater relative treatment effect among patients with higher baseline levels of LDL cholesterol (Figure 4).

Rates of adverse events according to treatment assignment and time since randomization are summarized in Table 4. The proportion of patients with consecutive elevations in AST or ALT levels of more than 3 times the ULN was 0.4% (8/2068) in the placebo plus simvastatin group and 0.9% (19/2132) in the simvastatin only group (P = .05).

Discontinuation of the study drug due to a muscle-related adverse event occurred in 1.5% (34/2230) of patients in the placebo plus simvastatin group and 1.8% (41/2263) in the simvastatin only group (P = .49). A total of 10 patients developed myopathy (creatine kinase level >10 times the ULN with associated muscle symptoms); 1 patient was in the placebo plus simvastatin group and 9 patients were in the simvastatin only group (while taking the 80 mg/d dose) (P = .02). Three of the 9 patients with myopathy had creatine kinase levels higher than 10 000 units/L and met the definition for rhabdomyolysis. Of these 3 patients, 1 patient had contrast-induced renal failure and 1 patient was receiving concomitant verapamil, which is a known inhibitor of CYP3A4. In addition, 1 patient receiving 80 mg of simvastatin had a creatine kinase level higher than 10 times the ULN without muscle symptoms, which was associated with alcohol abuse. There were no cases of myopathy when patients were taking 20 mg of simvastatin or 40 mg of simvastatin.

Among patients with ACS who were stabilized with guideline-based acute therapies, the early initiation of an intensive simvastatin regimen resulted in a trend toward reduction in the rate of the primary composite end point of death, MI, readmission for ACS, and stroke when compared with the delayed initiation of a less intensive simvastatin regimen. However, the trial did not achieve the prespecified end point and the 11% relative (2.3% absolute) reduction in the rate of the primary end point in the early intensive statin group was not statistically significant. While no differences were observed between treatment groups with regard to the secondary end points of MI and readmission for ACS, the early intensive statin regimen was associated with a reduction in cardiovascular mortality of 25% (absolute reduction, 1.3%; P = .05) and congestive heart failure of 28% (absolute reduction, 1.3%; P = .04). These findings are qualitatively consistent with results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22)⁶ and the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL)¹² trials, which demonstrated improved clinical outcomes and reduced progression of atherosclerosis with a more intensive statin regimen (80 mg/d of atorvastatin) compared with a less intensive statin regimen (40 mg/d of pravastatin).

Several factors may explain the absence of a statistically significant benefit with respect to the primary end point in the early intensive statin group of the A to Z trial. First, the clinical benefit was delayed and of a smaller magnitude than was anticipated. Second, the trial had less statistical power than was originally planned due to a lower than expected number of end points and a higher than expected rate of study drug discontinuation. Although the study reached its projected enrollment number of 4500 participants, the primary end point rate was considerably lower than projected, resulting in only 652 primary end point events, which is short of the 970 events required to provide adequate power. The 33% rate of study drug discontinuation in the present study is higher than in previous secondary prevention trials^1- 4 but similar to the rate observed in PROVE IT, a trial that also enrolled patients early after ACS and followed up patients for up to 2 years.⁶ These trials highlight challenges in maintaining long-term adherence to even well-tolerated therapies when they are initiated during the acute phase of illness.

Realizing that there are limitations when making direct comparisons between clinical trials, the magnitude of clinical benefit observed at the end of the 2-year follow-up period in the A to Z trial appeared to be less than was observed in PROVE IT-TIMI 22, a finding that may relate to the smaller between-group difference in LDL cholesterol level lowering in the A to Z trial compared with PROVE IT. While the LDL cholesterol levels achieved in the aggressive statin treatment groups were similar between the 2 trials, the median LDL cholesterol level in the standard care treatment group of the A to Z trial was 77 mg/dL (1.99 mmol/L) at 8 months compared with 95 mg/dL (2.46 mmol/L) in the group receiving 40 mg/d of pravastatin in PROVE IT. Thus, from months 4 through 24, the median difference in LDL cholesterol levels between treatment groups was approximately 14 mg/dL (0.36 mmol/L) in the A to Z trial (18% relative difference) compared with 33 mg/dL (0.85 mmol/L) in PROVE IT (33% relative difference). This difference may in part explain the smaller relative reduction in the primary end point rate of 11% in the A to Z trial compared with 16% in PROVE IT. These findings are consistent with analyses included in the recent update to the National Cholesterol Education Program Adult Treatment Panel III Guidelines, which support a direct proportional relationship between the magnitude of LDL cholesterol level lowering and coronary heart disease risk reduction.¹³

Until recently, information regarding the timing of initiation of statin agents following ACS had been limited to observational studies and post hoc analyses of clinical trials performed for other purposes.^14- 17 Including the A to Z trial, 3 trials have evaluated early initiation of statins after ACS. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study reported a 16% lower rate of death and nonfatal major cardiac events 4 months after ACS in patients receiving 80 mg/d of atorvastatin compared with placebo (P = .05).⁵ No early differences in mortality or MI were evident in MIRACL, but rehospitalization for recurrent ischemia was significantly reduced—a finding that is in contrast to the A to Z trial, in which no effect of aggressive statin therapy was observed for the end point of readmission for ACS. Because MIRACL excluded patients with recent or planned revascularization, the use of glycoprotein IIb/IIIa inhibitors and clopidogrel was low. In contrast to the MIRACL trial, PROVE IT included an active comparison group (40 mg/d of pravastatin), patients with both ST-elevation MI and non–ST-elevation ACS, and patients who were treated with PCI for their index ACS event. A significant benefit with regard to the primary end point of death, MI, and total revascularization favoring high-dose atorvastatin was evident within the first 6 months of PROVE IT and a strong trend was observed at 30 days.

In the A to Z trial, no early divergence in event rates was noted between treatment groups despite marked differences in LDL cholesterol levels. However, the primary end point rate was significantly lower in the aggressive simvastatin group between 4 and 24 months. A number of factors related to patient characteristics and concomitant treatment strategies may have contributed to the delay in clinical benefit observed in the A to Z trial. In contrast with the MIRACL study, glycoprotein IIb/IIIa inhibitor use was mandated in phase A of the A to Z trial and more than 50% of the patients were treated with an early invasive management strategy.⁸ These therapies may have competed with statin therapy to reduce early nonfatal recurrent ischemic events.

Differences between the A to Z trial and PROVE IT with regard to the timing of patient enrollment and practice patterns in the enrolling sites also may have contributed to differences in early outcomes between the 2 trials. In PROVE IT, patients were enrolled an average of 7 days after ACS (largely from centers in the United States) with the consequence that 69% of patients had undergone revascularization to treat the ACS event prior to randomization. The culprit lesion and acute thrombotic process may have been stabilized prior to enrollment in PROVE IT, which is a hypothesis supported by the extremely low cardiovascular mortality rate (<1.5% at 2 years) observed in both treatment groups in this trial.⁶ In contrast, in the A to Z trial, patients were enrolled 3 to 4 days earlier, were selected to have higher risk features, and were less likely to undergo PCI prior to enrollment. These features may have resulted in more patients entering phase Z of the trial with an ongoing active thrombotic process that was relatively less responsive to statin therapy.

In contrast with the PROVE IT study,⁶ the C-reactive protein concentrations in the A to Z trial did not differ between the treatment groups at 30 days despite marked differences in LDL cholesterol levels. The lack of a concurrent anti-inflammatory effect may also have contributed to the delayed treatment effect that was observed. Patients in the aggressive simvastatin arm of the A to Z trial were not titrated up to 80 mg/d of simvastatin until after the first month. It is possible that more intensive therapy is required immediately after the onset of ACS during the period of greatest clinical instability to achieve a more rapid clinical benefit.

No difference in treatment effect was evident across subgroups defined by LDL cholesterol levels. These findings are consistent with those from the Heart Protection Study, which found no interaction based on initial LDL cholesterol levels in the reduction of major vascular events with 40 mg/d of simvastatin.⁴

The incidence of consecutive elevations in AST or ALT levels higher than 3 times the ULN was low in both treatment groups. Muscle-related adverse events occurred infrequently, including those that led to study drug discontinuation. Myopathy (creatine kinase level >10 times the ULN with muscle symptoms) occurred in 9 patients (0.4%) receiving 80 mg/d of simvastatin, which included 3 patients who developed rhabdomyolysis (creatine kinase level >10 000 units/L); these rates are consistent with the long-term safety of this dose in patients with hypercholesterolemia.⁹ There were no cases of myopathy in patients receiving 20 mg/d or 40 mg/d doses of simvastatin, which is also consistent with the overall safety of these doses reported in other long-term outcome trials.^1,4 Clinicians should be aware that the 80-mg/d dose of simvastatin is associated with a higher risk of myopathy than lower dosages of the drug and should educate patients receiving the 80-mg/d dose of simvastatin to pay close attention to muscle-related symptoms.

The traditional approach to lipid management following ACS has been to begin with dietary management and then to initiate a statin agent at a low dose and increase the dose stepwise to achieve target LDL cholesterol levels. The findings from the A to Z trial, as well as from MIRACL and PROVE IT, support a strategy of aggressive LDL cholesterol lowering following ACS to prevent death and major cardiovascular events. Statins should be initiated early after ACS, with consideration of dosages well above the typical starting dose, and they should be down-titrated or discontinued if important adverse effects, such as myopathy or significant liver abnormalities, develop.