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Emerging Clinical Challenges in the Use of Statins

      In randomized trials and meta-analyses, statins decrease myocardial infarction, stroke, vascular death, and total mortality.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      The totality of evidence indicates no threshold below which there are no net benefits, including primary prevention subjects at low risk.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      In this commentary, we present some consequent new and emerging clinical challenges.
      The early landmark trials used lovastatin, pravastatin, and simvastatin in a wide range of patients from high-risk secondary to low-risk primary prevention. Statins produced net benefits that began after 1 or more years. These findings were expected because the primary mechanism was antiatherogenic via reductions in low-density lipoprotein (LDL) cholesterol. The subsequent availability of 2 more potent statins, atorvastatin and rosuvastatin, led to more patients reaching the goals.
      • Hennekens C.H.
      • Schneider W.R.
      The need for wider and appropriate utilization of statins and aspirin in treatment and prevention of cardiovascular disease.
      After demonstrating clinical benefits against placebo, recent statin trials tested whether more intensive lipid-lowering produces incremental clinical benefits when compared with usual statin regimens.
      The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial was the first to directly test this hypothesis by comparing the highest marked dose of atorvastatin with the efficacious and acceptably safe pravastatin. In 4162 high-risk patients post-acute coronary syndrome treated and followed for 2 years, the achieved LDL levels were 62 mg/dL in the 80 mg atorvastatin group and 97 mg/dL in the 40 mg pravastatin group, which was just below the goal of 100 mg/dL. The patients assigned at random to 80 mg atorvastatin had a statistically significant and clinically important 16% reduction in the primary prespecified composite end point of all-cause mortality and major cardiovascular events that were not offset by drug-associated safety concerns.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.M.
      • et al.
      for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      The Treatment to New Targets (TNT) trial randomized 10,002 patients with chronic stable coronary disease to 80 mg atorvastatin or 10 mg atorvastatin over 5 years of treatment and follow-up. In these secondary prevention patients, who had experienced an event at least 1 year previously, the achieved LDL levels were 77 mg/dL in the 80 mg atorvastatin group and 100 mg/dL in the 10 mg atorvastatin group. There were statistically significant and clinically important relative reductions in the primary composite end point (death from coronary heart disease, nonfatal myocardial infarction, resuscitation after cardiac arrest, fatal or nonfatal stroke) of 22% and in several components, including major coronary events (20%) and cerebrovascular events (23%). Serious adverse events were 8.1% in the high-dose group and 5.8% in the low-dose group, a difference not attributable to muscle aches but to reversible elevations in liver function tests.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Treating to New Targets (TNT) Investigators
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial randomized 19,802 primary prevention subjects without elevated LDL levels. Nonetheless, these subjects had a 10-year risk of a first event of approximately 16% to 18%, because 41% had metabolic syndrome. The selection criterion of risk was an elevation of high-sensitivity C-reactive protein. Their baseline LDL levels indicated that these moderate-risk primary prevention subjects would not be prescribed statins. After randomization, the achieved LDL levels were 55 mg/dL in the 20 mg rosuvastatin group and 109 mg/dL in the placebo group. The trial was scheduled to terminate after 5 years, but after 1.9 years the independent Data and Safety Monitoring Board unanimously recommended the early termination of JUPITER. Subjects assigned to rosuvastatin 20 mg compared with placebo experienced a statistically extreme (P < .001) 44% reduction in the primary prespecified combined end point of myocardial infarction, stroke, unstable angina, revascularization, or cardiovascular death, as well as the individual components of myocardial infarction, stroke, and revascularization and a significant 20% reduction in total mortality. There were no significant differences in serious adverse events between the 2 groups.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.H.
      • et al.
      JUPITER Study Group
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      A small increased risk of diabetes was exceeded by the morbidity and mortality benefits of rosuvastatin, including among those at high risk of developing diabetes.
      • Ridker P.
      • Pradhan A.
      • MacFadyen J.
      • Libby P.
      • Glynn R.J.
      Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
      The LDL levels achieved in these 3 landmark trials showed statistically significant and clinically important benefits of achieving lower LDL levels, and the magnitude of the clinical benefits were apparent within 1 month of starting therapy (Table 1).
      Table 1Low-Density Lipoprotein Cholesterol Levels Achieved in Three Landmark Trials of Intensive Statin Therapy
      Name of TrialLDL Achieved (mg/dL)
      High DoseUsual Dose
      PROVE-IT (atorvastatin 80 mg)6297
       High-risk secondary prevention
      TNT (atorvastatin 80 mg)77101
       Usual-risk secondary prevention
      JUPITER (rosuvastatin 20 mg)55109
       Moderate-risk primary prevention
      JUPITER = Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin; LDL = low-density lipoprotein; PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; TNT = Treatment to New Targets.
      A meta-analysis of low-risk primary prevention subjects includes individual participant data from 22 trials of statin versus control among 134,537 subjects with a median follow-up of 4.8 years with a mean LDL cholesterol difference of approximately 40 mg/dL and 5 trials of more versus less statin and 39,612 subjects with a median follow-up of 5.1 years with a mean LDL cholesterol difference of approximately 20 mg/dL. In individuals with a 5-year risk of major vascular events less than 10%, which corresponds to a 10-year risk of major coronary events less than 10%, each 38 mg/dL reduction in LDL cholesterol produced an absolute reduction in major vascular events of approximately 11 per 1000 over 5 years. This absolute benefit greatly exceeds any known risks of statin therapy. Under present goals, such low-risk primary prevention subjects typically would not be regarded as suitable for LDL lowering with statins.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      This hypothesis is being directly tested in Heart Outcomes Prevention Evaluation (HOPE-3) trial, a placebo-controlled trial of rosuvastatin in middle-aged primary prevention subjects at usual risk. A total of 12,705 participants have been recruited and will be treated and followed for 5 years.

      Heart Outcome Protection Evaluation 3 (HOPE 3). Available at: clinicaltrials.gov/ct2/show/NCT00468923. Accessed October 14, 2012.

      Meanwhile, the current totality of evidence provides clinicians the opportunity to consider statin therapy in low-risk primary prevention subjects previously considered ineligible. The evidence suggests that more widespread and appropriate use of statins, as adjuncts, not alternatives to therapeutic lifestyle changes, will yield net benefits in low-risk primary prevention subjects, including those unwilling or unable to adopt therapeutic lifestyle changes.

      References

        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        • Cholesterol Treatment Trialists' (CTT) Collaboration
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Mihaylova B.
        • Emberson J.
        • Blackwell L.
        • et al.
        • Cholesterol Treatment Trialists' (CTT) Collaborators
        The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
        Lancet. 2012; 380: 581-590
        • Hennekens C.H.
        • Schneider W.R.
        The need for wider and appropriate utilization of statins and aspirin in treatment and prevention of cardiovascular disease.
        Expert Rev Cardiovasc Ther. 2008; 6: 95-107
        • Cannon C.P.
        • Braunwald E.
        • McCabe C.M.
        • et al.
        for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
        N Engl J Med. 2004; 350: 1495-1504
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        • Treating to New Targets (TNT) Investigators
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Engl J Med. 2005; 352: 1425-1435
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.H.
        • et al.
        • JUPITER Study Group
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008; 359: 2195-2207
        • Ridker P.
        • Pradhan A.
        • MacFadyen J.
        • Libby P.
        • Glynn R.J.
        Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
        Lancet. 2012; 380: 561-571
      1. Heart Outcome Protection Evaluation 3 (HOPE 3). Available at: clinicaltrials.gov/ct2/show/NCT00468923. Accessed October 14, 2012.