MIRACL

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Schwartz GG, et al. "Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes". Journal of the American Medical Association. 2001. 285(13):1711-1718.
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Clinical Question

In patients with UA/NSTEMI, does early treatment with atorvastatin reduce rates of early CV events when compared with placebo?

Bottom Line

Early initiation of atorvastatin post-UA/NSTEMI reduced the combined endpoint of death, nonfatal MI, cardiac arrest, and ACS requiring hospitalization at 16 weeks, when compared to placebo.

Major Points

The use of statins had previously been shown to reduce mortality from chronic cardiovascular disease. This trial aimed to evaluate whether early initiation of therapy may also be of benefit.

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial randomized 3,086 patients to either atorvastatin 80mg or placebo daily, starting within 4 days of hospitalization for UA/NSTEMI. Patients were excluded if they were on a statin at baseline. At 16 weeks, atorvastatin reduced the combined endpoint of all-cause mortality, nonfatal MI, cardiac arrest with resuscitation, and rehospitalization for ACS (14.8% vs. 17%; NNT 38), driven mostly by a reduction in rehospitalization for ACS. High-dose atorvastatin was compared with moderate-dose pravastatin in the subsequent PROVE IT-TIMI 22 study (2004), which demonstrated superiority to high-dose atorvastatin.

The trial detected a significant reduction in stroke among those on atorvastatin. This finding was confirmed in the follow-up SPARCL trial (2006).

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[1]

  • If no contraindications, a high-intensity statin should be started and continued for all patients (class I, level A)

ACC/AHA Cholesterol treatment to reduce ASCVD risk (2013, adapted)[2]

  • Secondary prevention with high-intensity statin therapy for patients ≤75 years in age with clinical ASCVD (i.e. stable CAD) unless contraindicated (grade A, class I, level A)
  • Moderate-intensity therapy for above group if contraindication to high-intensity statin therapy or risk for statin-associated adverse events (grade A, class I, level A)
  • For patients ≥75 years with clinical ASCVD, evaluate risks and benefits when initiating high- or moderate-intensity statin therapy (grade E, class IIa, level B)
  • No recommendation for specific targets for LDL- and non-HDL-cholesterol for primary or secondary prevention of ASCVD.
  • Definition of intensity of statin therapy as:
    • High-intensity (LDL reduction ≥50%): Atorvastatin 40-80 mg, rosuvastatin 20-40 mg
    • Moderate-intensity (LDL reduction 30-<50%): Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg BID, pitavastatin 2-4 mg
    • Lower-intensity (LDL reduction <30%): Simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, pitavastatin 1 mg

Design

  • Randomized, double-blind, placebo-controlled trial
  • N=3,086 patients with UA/NSTEMI
    • Atorvastatin (n=1,538)
    • Placebo (n=1,548)
  • Setting: 122 sites in Europe, North America, South Africa, Australia, and New Zealand
  • Enrollment: 1997-1999
  • Analysis: Intention-to-treat
  • Primary endpoint: All-cause mortality, nonfatal MI, cardiac arrest, or rehospitalization for ACS
  • Follow-up: 16 weeks

Population

Inclusion Criteria

  • Age ≥18 years
  • Chest pain/discomfort ≥15 min at rest or with little exertion in the 24h before hospitalization that differed from usual symptomatology
  • UA or NSTEMI (non-Q-wave AMI), defined by:
    • UA, ≥1 of the following:
      • New or dynamic ST-wave or T-Wave changes in ≥2 continuous EKG leads
      • New wall motion abnormality on echo
      • New and reversible perfusion defect by scintigraphy
      • Elevation of troponins ≤2x ULN
    • NSTEMI, ≥1 of the following:
      • CK or CK-MB ≥2x ULN
      • Troponin ≥2x ULN

Exclusion Criteria

  • Screening total cholesterol >270 mg/dL except >310 mg/dL in Poland and South Africa
  • Anticipated/planned coronary revascularization
  • Q-wave MI in prior 4 weeks
  • CABG in prior 3 months
  • PCI in prior 6 months
  • LBBB or paced ventricular rhythm
  • NYHA class IIIB or IV symptoms
  • Treatment with lipid-regulating medications other than niacin or vitamin E
  • Medications associated with rhabdomyolysis
  • Severe anemia
  • Dialysis
  • AST >2x ULN
  • Insulin-dependent diabetes
  • Pregnancy/lactation

Baseline Characteristics

From the atorvastatin group.

  • Demographics: Age 65 years, female 36%
    • Race: White 86%, Black 3%, Asian 3%, other 9%
    • Geographic region: Australia or New Zealand 6%, Europe 50%, North America 33%, South Africa 11%
  • Inclusion event type: UA 47%, NSTEMI 53%
  • Time from event to randomization: 63 hours
  • PMH: CHF 9%, cerebrovascular disease 9%, PVD 10%, prior MI 25%
    • CAD risk factors: Current smoker 28%, HTN 55%, DM 22%
  • PSH: CABG 7%, PCI/angioplasty 3%
  • Medications before hospitalization: ASA 18%, other antiplatelet 1%, heparin 1%, oral anticoagulants 2%, fibrinolytics <1%, nitrates 15%, beta blocker 11%, CCB 8%, ACE-inhibitor/ARB 12%, digoxin 4%, lipid-lowering agent 1%

Interventions

  • Patients randomly assigned to receive atorvastatin 80mg PO daily or placebo
  • Drug given within 96 of hospitalization
  • All patients received diet counseling
  • Follow up at 2, 6, and 16 weeks
  • Laboratory testing at enrollment, 6, and 16 weeks

Outcomes

Comparisons are atorvastatin vs. placebo

Primary Outcome

All-cause mortality, nonfatal MI, cardiac arrest with resuscitation, or rehospitalization for ACS
14.8% vs. 17.4% (HR 0.84, 95% CI 0.70-1.00, P=0.048; NNT 38)

Secondary Outcomes

All-cause mortality
4.2% vs. 4.4% (HR 0.94, 95% CI 0.67-1.31)
Nonfatal MI
6.6% vs. 7.3% (HR 0.90, 95% CI 0.69-1.16)
Cardiac arrest with resuscitation
0.5% vs. 0.6% (HR 0.82, 95% CI 0.33-2.06)
Recurrent symptomatic myocardial ischemia requiring hospitalization
6.2% vs. 8.4% (HR 0.74, 95% CI 0.57-0.95; NNT 45)
Any stroke
0.8% vs. 1.6% (HR 0.50, 95% CI 0.26-0.99; NNT 125)
Nonfatal stroke
0.6% vs. 1.4% (HR 0.41, 95% CI 0.20-0.87; NNT 125)
New or worsening CHF requiring hospitalization
2.6% vs. 2.8% (HR 0.94, 95% CI 0.62-1.43)
Worsening angina requiring hospitalization
5.9% vs. 6.8% (HR 0.86, 95% CI 0.66-1.13)
Coronary revascularization (PCI or surgical)
16.5% vs. 16.1% (HR 1.02, 95% CI 0.87-1.20)
PCI
9.8% vs. 9.2% (HR 1.06, 95% CI 0.85-1.32)
Surgical coronary revascularization
6.9% vs. 7.1% (HR 0.97, 95% CI 0.75-1.25)

Adverse Events

Liver transaminase level elevations >3x ULN
2.5% vs. 0.6% (P<0.001)
Of note, these all resolved with cessation of the medication.
Myositis
No episodes reported

Criticisms

  • Excluded patients with Q-wave AMIs and those undergoing planned revascularization
  • Not powered to detect the individual components of the primary end point
  • Cannot conclude that it is safe for patients to be on high-dose atorvastatin for more than 16 weeks [3]
  • Unclear if this is more than a marginal benefit when compared to interventions like GPIIb/IIIa inhibitors [4]
  • High loss of follow-up, primary outcome was increased due to decrease in unstable angina, atorvastatin has not been proven to reduce events related to cardiovascular disease, prevent myocardial infarction, or have a survival benefit [5]
  • High loss to follow-up in comparison to other studies [5]

Funding

Pfizer provided a grant and the medications. Authors with multiple disclosures.

Further Reading

  1. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  2. Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.
  3. Schwartz GG, et al. "Atorvastatin for Acute Coronary Syndromes." JAMA. 2001;286(5):532-535.
  4. Wierzbicki AS, et al. "Atorvastatin for Acute Coronary Syndromes." JAMA. 2001;286(5):532-535.
  5. 5.0 5.1 Sacks FM. "Lipid-Lowering Therapy in Acute Coronary Syndromes." JAMA. 2001;285(13):1758-1760.

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