Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes. Can We Expect a MIRACL from Cholesterol Lowering Therapy?

Original Citation

Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.

Overall Study Question

The MIRACL Study was a prospective, randomized, placebo controlled trial conducted in 122 centres.  This study was designed to determine whether early initiation of atorvastatin 80 mg/d would reduce the occurrence of death and non-fatal ischemic events.

Patients were included if they were at least 18 years of age, with prolonged chest pain within 24 hours of admission to hospital and objective evidence of ischemia (dynamic ECG changes, new wall motion abnormalities, new reversible ischemia on myocardial perfusion imaging, or elevation of cardiac troponin or CK/CKMB).  Exclusion criteria were: total cholesterol > 7 mmol/L; planned or anticipated revascularization; Q-wave myocardial infarction within 4 weeks; coronary artery bypass surgery (CABG) within 3 months or percutaneous coronary intervention (PCI) within 6 months; a left bundle-branch block or paced ventricular rhythm; severe congestive heart failure (NYHA class IIIb or IV); concurrent therapy with lipid lowering agents (other than niacin at doses of 500 mg/d), vitamin E (except doses <400 IU/d), or drugs associated with the development of rhabdomyolysis in combination with statins; severe anemia; renal dialysis; hepatic dysfunction (ALT twice the upper limit of normal [ULN]); insulin-requiring diabetes; and pregnancy or lactation.

Patients were randomized to either atorvastatin 80 mg or placebo within 24-96 hours of admission, and then were followed for 16 weeks.  The primary endpoint for the trial was the combined occurrence of death, nonfatal acute myocardial infarction (AMI), resuscitated cardiac arrest and recurrent symptoms with objective evidence of myocardial ischemia requiring readmission.  Secondary endpoints were the occurrence of each primary endpoint component, as well as nonfatal stroke, new or worsening congestive heart failure (CHF) requiring hospitalization, worsening angina without objective evidence of ischemia requiring hospitalization, revascularization (CABG or PCI), time to first occurrence of any endpoint, and percentage change in lipids from baseline to the end of the study.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes. From May 1997 to September 1999, 3086 patients were randomized (stratified by centre) to receive atorvastatin 80 mg/day or placebo. This article and a previous publication describing the rationale and design of the trial do not specifically address issues such as the number of patients screened, nor the specific details of randomization (i.e. on-site vs. centrally).

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  A total of 3086 patients were enrolled, 1548 received placebo and 1538 received atorvastatin 80 mg/d. Withdrawal of study medication occurred in 10.4% of the placebo group and 11.4% of patients treated with atorvastatin.  Analysis was conducted by a intention-to-treat strategy. Eleven patients were lost to follow-up. Patients who did not experience an endpoint were censored, with their survival time made to correspond to the day of final study contact.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes. Local investigators were blinded, and all physicians involved in the care of the patients were asked not to perform serum lipid studies at local laboratories.  All lipid measurements were done at a central laboratory.  The endpoint adjudication committee, consisting of 6 cardiologists, was also blinded to treatment assignment of all patients.

4. Were the groups similar at the start of the trial?

Yes.  Both groups of patients had similar baseline demographics, including serum lipid levels. They were also similar in terms of cardiovascular medication use prior to the index hospitalization.

5. Aside from the experimental intervention, were the groups treated equally?

Yes.  Both groups were managed similarly in terms of additional medical therapy after randomization.  Open label lipid lowering agents were used in 3.0% of the placebo group and 2.0% of the atorvastatin group following the premature discontinuation of study medication.  In addition, all patients received instruction to promote compliance with a National Cholesterol Education Program (NCEP) Step 1 diet.

6. Overall, are the results of the study valid?

Yes.

What were the Results?

1. How large was the treatment effect? 

During the 16-week follow-up period, a primary end point occurred in 14.8% of the atorvastatin group and 17.4% of the placebo group (p=0.48), ARR = 2.6% (95% CI 0% to 5.2%), NNT = 38 (95% CI 20 to 11,893).  There was no difference in the incidence of death, non-fatal MI, or resuscitated cardiac arrest between the two groups.

Recurrent symptoms with objective evidence of ischemia occurred in 6.2% of the atorvastatin group and 8.4% of the placebo group (p=0.02), ARR = 2.2% (95% CI 0.4% to 4%), NNT = 46 (95% CI 25 to 273).  Non-fatal stroke occurred in 0.6% of the atorvastatin group and 1.4% of the placebo group (p=0.02, ARR = 0.8%, NNT=125) and either fatal or nonfatal stroke occurred in 0.8% of the atorvastatin group and 1.6% of the placebo group (p=0.045, ARR = 0.8%, NNT= 125).  The NNT to prevent 1 primary end point event or nonfatal stroke was 33.

There were no interactions between treatment assignment and baseline demographic variables.  During the course of follow-up, patients in the atorvastatin group experienced a 40% decline in serum LDL, and a 16% reduction in triglycerides, compared with increases of 12% and 9%, respectively, in the placebo group.  No change in the HDL occurred in either group. However, the occurrence of an endpoint event was not related to baseline lipid levels, or to the changes in these levels.

There were no documented cases of myositis; however, 2.5% in the atorvastatin group experienced abnormal elevation of liver transaminases (ALT >3 times the upper limit of normal (ULN)) compared to 0.6% of the placebo group (p<0.001, ARI = 1.9%, NNH = 53).

2. How precise was the estimate of the treatment effect?

The combined primary endpoint was reduced from 17.4% in the placebo to 14.8% in the atorvastatin treated group (p=0.049).  This endpoint just achieved statistical significance at the a priori level of p=0.049 which was adjusted to preserve the overall type I error rate at p=0.05 with the 3 protocol interim analyses of safety and efficacy performed by the data safety monitoring board.  While the 95% confidence intervals for the point estimate of the absolute risk reduction does not cross zero (i.e. the point of unity), the lower limit falls directly on zero.  Consequently, the possibility exists that early intervention with atorvastatin 80 mg/d offers no benefit over placebo in reducing this primary combined endpoint.  While the NNT for this endpoint appears to be acceptable, the 95% confidence interval around this point estimate are extremely wide (NNT = 38; 95% CI 20 to 11,893).  Consequently, while atorvastatin treatment resulted in a statistically significant reduction in the primary endpoint, it is unclear whether or not it provides a clinically significant reduction in this endpoint.

This study was underpowered to detect differences between treatment groups for the individual components of the primary endpoint.  Nevertheless, a statistically significant reduction in recurrent symptomatic ischemia requiring hospitalization was observed [(p = 0.02), ARR = 2.2% (95% CI 0.4% to 4%), NNT = 46 (95% CI 25 to 273)].  This reduction in the secondary endpoint is what contributed to the main benefit observed for the primary endpoint.  However, the 95% confidence intervals for this secondary event are narrow and the lower boundary includes a minimally important clinical difference.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes.  The broad range of lipid levels allowed in this trial would suggest general applicability.  However, the patients enrolled in this study are at high risk of recurrent events on the basis of their presentation to hospital with either non-ST segment elevation MI, or unstable angina with objective evidence of ischemia.  Recent literature supports an aggressive, early invasive management strategy for these patients, with angiography and revascularization if appropriate. Therefore, in contemporary clinical practice, the majority of these high-risk individuals would not have received the study intervention employed in the MIRACL trial.  In the setting where there is no rapid access to a cardiac catheterization laboratory, it would be appropriate to consider initiation of statin therapy as demonstrated by the results of this study.

2. Were all clinically important outcomes considered?

Yes.  All outcomes were clearly defined and are of significant importance.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes.  While the clinical significance of the reduction observed for the combined primary endpoint is unclear, early atorvastatin treatment provided both statistically and clinically significant reductions in a couple of secondary endpoints (recurrent symptomatic ischemia requiring hospitalization, non-fatal strokes and the combination of fatal and non-fatal strokes).  No other secondary endpoints were significantly reduced by treatment with atorvastatin.  In addition, atorvastatin was generally well tolerated in this patient population.  While there were no documented cases of myositis, elevations of serum transaminases (>3 times ULN) occurred in 2.5% of patient receiving atorvastatin patients compared to 0.6% of placebo treated patients (p<0.001). Also, 3 of the 38 atorvastatin treated patients with elevated liver enzymes were hospitalized with a diagnosis of hepatitis.The long-term benefits of therapy with statin agents have already been proven in patients with coronary artery disease, and those at high risk to develop it.  These agents are expensive, but provide considerable savings over time with regards to hospitalization and vascular morbidity and mortality.  Nevertheless, the cost-effectiveness of early, short-term treatment with atorvastatin 80 mg/day for patients with acute coronary syndromes remains to be clarified.

Commentary

This trial involved the assessment of short-term drug administration in a high risk population of patients with ischemic heart disease.  The most substantial benefit of these agents has been seen in trials of much longer duration (i.e. five to seven years), using different agents.  Currently there is no evidence for long term morbidity and mortality benefit with the use of atorvastatin.  The short term results in this underpowered study are certainly encouraging but further study is needed, both in the high risk patients who are treated with aggressive early invasive strategies, and for the long-term effects of atorvastatin on outcomes.

Even if we accept the beneficial role of early statin therapy for patients with and acute coronary syndrome, we are left with a number of unanswered questions.  For example, can these results be extrapolated to contemporary clinical practice where a significant number of these patients undergo early coronary intervention (PCI) and/or receive a glycoprotein IIB/IIIA receptor antagonist ?  Can these results be extrapolated to patients with non-ST-segment myocardial infarctions (Q-wave MI’s)?  Would the same results occur with a lower dose of atorvastatin or another statin with proven long-term outcome benefits?

Methodological limitations and unanswered clinical questions notwithstanding, the results of this current trial should be viewed optimistically. vEven with only the potential for short-term benefits, our knowledge of the definite long-term benefits and absence of significant harm should provide sufficient evidence for all patients hospitalized for an acute coronary event to be initiated on a statin prior to their discharge.  Prescribing lipid-lowering therapy with a statin in this manner may help to ensure that this important secondary prevention measure in not overlooked later in the patient’s management.  Additionally, initiating this therapy early may serve to emphasize to both the patient and their other primary care providers the importance of this treatment for cardiovascular risk reduction.

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