
  
    
      
        The problem
        Three published [ 1 2 3 ] and one recently presented [ 4
        ] randomized placebo-controlled clinical trial have
        unequivocally demonstrated that 3-Hydroxy-3-methylgluatryl
        coenzyme A (HMG CoA) reductase inhibitors (statins) reduce
        the morbidity and mortality associated with coronary
        disease. These trials found that when compared with
        placebo, statins significantly reduced the incidence of
        death, myocardial infarction, unstable angina, percutaneous
        and surgical coronary revascularization, and stroke in
        persons with 
        stable coronary disease. Because
        patients who had experienced an acute coronary syndrome
        within three to six months of enrollment were excluded,
        these trials did not assess the effect of lipid-lowering
        therapy on adverse cardiovascular events in those with
        recently 
        unstable coronary disease. Whether
        lipid-lowering therapy would provide incremental benefit if
        initiated immediately following an acute coronary syndrome
        is an important issue as the risk of a recurrent adverse
        cardiac events is much greater in patients with unstable
        coronary disease than in the stable setting. The Myocardial
        Ischemia Reduction with Aggressive Cholesterol Lowering
        (MIRACL) trial set out to answer this question.
      
      
        The answer?
        MIRACL enrolled 3,086 patients within 24-96 hours (mean
        63 hours) of admission for unstable angina or a non-Q-wave
        myocardial infarction and randomized them to 16 weeks of
        atorvastatin 80 mg or placebo once daily [ 5 ] . The major
        exclusion criteria were: total cholesterol level greater
        than 270 mg/dL; Q-wave myocardial infarction on admission
        or during the previous month; and, coronary
        revascularization in the months before admission, during
        the index hospitalization or anticipated following hospital
        discharge. The primary efficacy endpoint was a composite of
        death, non-fatal myocardial infarction, resuscitated sudden
        cardiac death or emergent rehospitalization for worsening
        symptomatic myocardial ischemia. Secondary endpoints
        included stroke, worsening heart failure, need for coronary
        revascularization and change in lipid levels throughout the
        study. On average, patients were 65 years of age,
        approximately 65% were men, 86% Caucasian and the mean
        baseline low density lipoprotein (LDL) cholesterol level
        was 124 mg/dL. Atorvastatin treatment was associated with a
        2.6% absolute reduction in the risk of the primary endpoint
        (14.8% vs. 17.4%; RR relative risk [RR] 0.84, 95%
        confidence interval [CI] 0.70-1.00, p = 0.048). This
        reduction was primarily driven by the 2.2% absolute
        reduction in incidence of emergent rehospitalization for
        symptomatic myocardial ischemia (6.2% vs. 8.4%; RR 0.74,
        95% CI 0.57-0.95, p = 0.02). The risk of death, nonfatal
        myocardial infarction and resuscitated sudden cardiac death
        were each no different between the two groups. While there
        were no significant differences in the incidence of
        worsening heart failure or need for coronary
        revascularization, atorvastatin did reduce the incidence of
        fatal or non-fatal stroke by 0.8% (0.8% vs. 1.6%; RR 0.50,
        95% CI 0.26-0.99, p = 0.045). Atorvastatin also
        significantly reduced total and LDL cholesterol and
        triglyceride levels but did not significantly change high
        density lipoprotein (HDL) cholesterol by 16 weeks. By 16
        weeks, the adjusted mean LDL cholesterol decreased to 72
        mg/dL in atorvastatin-treated patients but increased to 135
        mg/dL among placebo-treated patients. No serious adverse
        events occurred as the result of treatment with
        atorvastatin, although reversible liver transaminase
        elevation more than three times the upper limit of normal
        occurred in 2.5% of atorvastatin-treated versus 0.6% of
        placebo-treated patients (p < 0.001).
      
      
        The MIRACuLous
        The efficacy and safety findings from MIRACL were unique
        for a number of reasons. Although lipid-lowering therapy
        was associated with a significantly lower mortality when
        initiated early after an acute coronary syndrome in two
        large observational studies [ 6 7 ] , MIRACL was the first
        randomized trial to suggest that statins confer clinical
        benefits in this setting. It was also the first trial to
        identify a short-term (ie, within 16 weeks) clinical
        benefit from statin therapy; in previous secondary
        prevention trials, the benefit of statin therapy was not
        evident for one to two years. And, while clinical trial
        safety endpoints may be considered less glamorous, MIRACL's
        most important contribution may have been that high-dose
        statin therapy was not associated with serious harm,
        despite its use in the unstable setting. Earlier secondary
        prevention statin trials had excluded patients with
        unstable coronary syndromes largely out of theoretical
        concern that statin-mediated reductions in vascular smooth
        muscle cell proliferation might destabilize healing plaque.
        That no harm resulted from this aggressive treatment
        strategy should allay theoretical fears and by doing so
        remove a major obstacle to the inpatient initiation of
        lipid-lowing therapy after coronary events.
      
      
        The not so MIRACuLous
        Despite these unique and important findings, there were
        a number of inherent study limitations worth noting. First
        and foremost, the possibility of a null treatment effect
        cannot be ignored given the wide confidence intervals (and
        hence marginally significant p value of 0.048) for the
        effect of atorvastatin on the primary efficacy endpoint.
        Furthermore, while the number of patients lost to follow up
        was small, if adverse events had occurred in those treated
        with atorvastatin (n = 3) but not placebo (n = 8), the
        overall trial results may have been neutral rather than
        positive.
        The types of events prevented in MIRACL are also worth
        noting. While rehospitalization for recurrent myocardial
        ischemia is an important determinant of quality of life and
        health care costs, other important endpoints were not
        significantly affected (eg, death, myocardial infarction,
        resuscitated sudden cardiac death, worsening heart failure,
        need for coronary revascularization, etc). The question of
        whether statins can prevent these and other adverse events
        when initiated soon after an acute coronary syndrome will
        require further study.
        The short duration of follow-up is also particularly
        troubling. While it is impressive that a clinical benefit
        was realized after only 16 weeks of statin therapy, the
        increased risk of adverse clinical events persists
        throughout the year following an acute coronary syndrome.
        Without longer clinical follow up, it is not possible to
        assess the intermediate-term effect (if any) of
        atorvastatin on hard endpoints such as death or myocardial
        infarction. To do so would be critical in light of the lack
        of effect on these important endpoints at 16 weeks.
        Unfortunately, no late clinical follow up is planned.
        There were also a number of limitations that may have
        hampered the study's generalizability. First, patients who
        underwent recent revascularization or in whom it was
        planned were excluded. Specifically, patients who underwent
        percutaneous transluminal coronary angioplasty (PTCA) or
        coronary artery bypass graft (CABG) surgery within the
        previous three or six months respectively were not eligible
        for inclusion. The investigators reasoned that recurrent
        ischemic events in this population were likely to result
        from restenosis or bypass graft closure and that statins
        would be less likely to affect these processes [ 8 ] .
        Nevertheless, a number of trials have established the
        benefits of statin therapy 
        early after coronary
        revascularization [ 9 10 11 ] . Furthermore, a number of
        recent trials have suggested that higher risk patients with
        non-ST elevation acute coronary syndromes fair better when
        an early invasive strategy is applied [ 12 13 14 ] and it
        is not uncommon for patients to be treated in this fashion.
        Second, patients with Q-wave myocardial infarction were not
        eligible for enrollment because it was felt that statins
        would not influence the development of important prognostic
        determinants such as left ventricular systolic dysfunction,
        ventricular arrhythmias or mechanical complications [ 5 ] .
        Nevertheless, patients who develop electrocardiographic
        Q-waves represent a substantial proportion of all patients
        with myocardial infarction. While their short-term risk
        following hospital discharge is lower relative to those
        with a non-Q-wave myocardial infarction, it is still much
        greater than in patients with stable coronary disease, and
        the need for secondary prevention in this population is
        equally important. Third, despite the high risk nature of
        enrolled patients (ie, electrocardiogram [ECG] changes
        and/or other objective evidence of ischemia), the rate of
        platelet glycoprotein IIb/IIIa inhibitor utilization was
        quite low (1.1%). Such therapy appears to be cost effective
        [ 15 16 ] , especially among high risk patients and is
        recommended under current American College of
        Cardiology/American Heart Association guidelines [ 17 ] .
        Fourth, it may not be possible to ascertain whether these
        findings apply to all patients with recent acute coronary
        syndromes regardless of baseline lipid levels. The small
        difference in number of primary endpoint events between
        atorvastatin and placebo groups make it difficult to
        dissect the relationship between baseline lipid levels and
        treatment effect further. Consequently, it remains
        uncertain whether one can extrapolate the MIRACL trial
        results to those who undergo coronary revascularization
        shortly before or after a coronary event, who present with
        a Q-wave myocardial infarction, who are treated with
        platelet glycoprotein IIb/IIIa inhibitors, or who have
        relatively low admission LDL cholesterol levels.
      
      
        Time to change current practice
        Although MIRACL and the two aforementioned cohort
        studies suggest that lipid-lowering agents exert short-term
        clinical benefits when initiated soon after an acute
        coronary syndrome, this remains an open question. Even if
        these findings are not confirmed after further study, one
        could still make a compelling argument that lipid-lowering
        therapy (barring contraindications) should be initiated
        early and universally in patients who present with an acute
        coronary syndrome: First, the long-term safety and
        effectiveness of statins for the secondary prevention of 
        stable coronary disease is
        well-established [ 1 2 3 ] ; Second, as evidenced by
        MIRACL, these agents are safe when initiated at the time of
        hospitalization for an acute coronary syndrome; Third, the
        in-hospital initiation of lipid-lowering therapy appears to
        promote greater long-term utilization of these agents [ 18
        19 20 21 ] . Finally, although lipid levels may be
        unreliable in the setting of an acute coronary syndrome
        (excepting total :HDL and LDL:HDL cholesterol ratios [ 22 ]
        ) the overwhelming majority of patients with coronary
        disease will ultimately require both pharmacologic and
        non-pharmacologic lipid-lowering interventions to attain
        recommended cholesterol targets [ 23 24 25 ] ; newer
        guidelines are even more stringent [ 26 ] . Furthermore,
        data from the recently presented Heart Protection Study
        suggest that clinical benefits may accrue independent of
        baseline cholesterol level [ 4 ] . Thus, to withhold
        lipid-lowering therapy from patients who present with an
        acute coronary syndrome would be to accept the status quo,
        and to date our efforts at cholesterol lowering in the
        secondary prevention setting have been dismal [ 27 28 ]
        .
      
      
        More MIRACLes ahead?
        The ascertainment and quantification of any incremental
        benefit conferred by statin therapy initiated early after
        an acute coronary syndrome will require confirmation. There
        is currently only one ongoing randomized placebo-controlled
        trial of early versus delayed statin therapy in this
        setting, A-2-Z (Aggrastat to Zocor, Merck) [ 29 ] . The
        A-2-Z study is evaluating the efficacy of early treatment
        with simvastatin in 4,500 patients following an episode of
        unstable angina or a non-Q wave myocardial infarction. In
        the first four months, patients will be randomized to
        simvastatin 40 mg daily or placebo. Thereafter, those
        patients treated with simvastatin in the first phase will
        receive 80 mg of simvastatin daily and those treated with
        placebo, 40 mg of simvastatin daily. The primary composite
        endpoint is the occurrence of cardiovascular death,
        non-fatal myocardial infarction, or rehospitalization for
        an acute coronary syndrome (ACS) at one year. If A-2-Z
        demonstrates significant reductions in the incidence of
        adverse events during the first four months, it would
        suggest an incremental clinical benefit from initiating
        these agents early after an acute coronary syndrome. If
        benefits accrue, but do so later during follow up, it would
        be difficult to discriminate between the effects of more
        aggressive vs. earlier lipid lowering therapy.
        The Pravastatin or Atorvastatin Evaluation and Infection
        Therapy (PROVE IT) trial is looking at 4,000 patients
        within 10 days of an acute coronary syndrome and
        randomizing them to either pravastatin 40 mg or
        atorvastatin 80 mg daily [ 29 ] . Patients will be observed
        over at least 1.5 years for the occurrence of myocardial
        infarction or other cardiovascular events. Unlike, MIRACL
        and the A-2-Z trials, this study will not assess the
        efficacy of early statin therapy after an acute coronary
        syndrome; rather, it will examine the role of 
        more vs. 
        less aggressive lipid-lowering in
        this setting.
        In 2002, many would consider it unethical to withhold
        statins from patients with established coronary disease.
        This makes it unlikely that additional placebo-controlled
        trials will be carried out in this area. Future secondary
        prevention studies should look at patients with stable 
        or unstable disease and will need to
        address the comparative efficacy of different statins (or
        newer agents), assess the incremental benefit of
        combination therapy [ 30 ] and determine whether there is a
        serum cholesterol 'floor' below which reductions are
        unlikely to provide further clinical benefit.
      
      
        Competing interests
        Dr Aronow has received honoraria as a speaker and
        advisory board member for Pfizer and as a speaker for
        Merck.
      
      
        Abbreviations
        HMG CoA = 3-Hydroxy-3-methylgluatryl coenzyme A; MIRACL
        = Myocardial Ischemia Reduction with Aggressive Cholesterol
        Lowering; LDL = low density lipoprotein; RR = relative
        risk; CI = confidence interval; HDL = high density
        lipoprotein; PTCA = percutaneous transluminal coronary
        angioplasty; CABG = coronary artery bypass graft; ECG =
        electrocardiogram; A-2-Z = Aggrastat to Zocor; ACS = acute
        coronary syndrome; PROVE IT = Pravastatin or Atorvastatin
        Evaluation and Infection Therapy.
      
    
  
