Schwartz GG, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001;285:1711-8.
Bottom line: In patients with ACS (without Q wave formation & not treated with PCI), high-dose atorvastatin reduced the short-term risk of symptomatic ischemia (NNT 46) or stroke (NNT 125).
Reporting of safety events was limited, but high-dose atorvastatin increased the likelihood of liver enzyme elevation >3x ULN, which has unknown clinical significance.
Patients (n=3086)
- Included
- Age 18+ y
- Within 24-96h after hospital admission for ACS (unstable angina or non-Q-wave MI)
- Excluded
- Total cholesterol >7 mmol/L
- Coronary revascularization planned or anticipated
- Hx of Q-wave MI within 4 weeks, CABG within 3 months, PCI within 6 months
- LBBB or paced ventricular rhythm
- HF with NYHA functional class IIIb-IV
- Treatment with other lipid-lowering agents or vitamin E
- Severe anemia, renal failure requiring dialysis, ALT >2x ULN, insulin-dependent diabetes
- ? screened -> 3086 randomized & analyzed
- Typical patient in study
- Age 65 y
- Female 35%
- ACS: UA 46%, non-Q-wave MI 54%
- PMHx
- Prior MI 25%, CABG 7%, PCI 3%
- HF 8%
- CVA 9%
- Peripheral vascular disease 9%
- Smoker 28%
- HTN 55%
- Diabetes 23%
- Meds
- ASA ~90%, OAC 8%
- ACEI or ARB ~50%
- Beta-blocker 77%
- Used in hospital: Heparin 75%, fibrinolytic 8%
Intervention
- I: Atorvastatin 80 mg PO once daily
- Patients on average took 86% of all doses
- 11.2% discontinued prematurely
- C: Matching placebo
- 10.3% discontinued prematurely
Results @ 4 months
- LDL
- @ baseline: 3.2 mmol/L
- @ 4 months: Atorvastatin 1.9 mmol/L, placebo 3.5 mmol/L (46% reduction vs placebo)
- Statistically significant reduction in
- Primary outcome (death, non-fatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization): 14.8% vs 17.4% (hazard ratio 0.84, 0.70-1.00), NNT 39
- Symptomatic ischemia with objective evidence: 6.2% vs 8.4% (HR 0.74, 0.57-0.95), NNT 46
- Stroke (fatal or non-fatal): 0.8% vs 1.6% (HR 0.50, 0.26-0.99), NNT 125
- No statistically significant difference in
- Coronary revascularization: 16.5% vs 16.1%
- Non-fatal MI: 6.6% vs 7.3%
- Worsening angina without new objective evidence of ischemia: 5.9% vs 6.8%
- Death: 4.2% vs 4.4%
- New/worsening HF requiring hospitalization: 2.6% vs 2.8%
- Resuscitated cardiac arrest: 0.5% vs 0.6%
- Safety
- Liver enzymes >3x ULN at any time: 2.5% vs 0.6% (NNH 53)
- Myalgias, muscle weakness, CK changes or rhabdo: Not reported
Generalizability
- Representative ~intermediate-risk ACS population
- Despite exclusion of patients Q-wave MI, likely included some STEMI patients, particularly since ~8% received lytic therapy
- Likely included an ACS population at low-intermediate risk by excluding Q-wave MI, patients planned for revascularization, recent CV event, or any significant non-CV comorbidity
- Short-term follow-up intended only to evaluate acute effects of high-dose statin therapy; 4-month follow-up precludes meaningful evaluation of long-term benefit, particularly for "secondary prevention"
Internal validity
- Allocation & performance bias
- Insufficient description of random-sequence generation, allocation concealment - likely low risk
- Low risk of detection bias
- Assuming proper allocation concealment & blinding, though not sufficiently described
- Endpoints adjudicated by committee of cardiologists unaware of treatment allocation
- Low risk of attrition bias
- Intention-to-treat analysis including all randomized patients
- <1% lost to follow-up
Corroborating evidence from other studies
- A secondary analysis of the PROVE IT trial evaluating the early and late benefit of high-intensity statin (atorvastatin 80 mg/d) versus low-intensity statin (pravastatin 40 mg/d) found a statistically significant improvement in the first 30 days:
- 30-day risk of composite CV outcome (death, MI or ACS hospitalization): High-intensity 3.0% vs low-intensity 4.2%, HR 0.72 (0.52-0.99)
