Week 41 – PROVE IT-TIMI 22

“Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes”

by the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators

N Engl J Med. 2004 Apr 8;350(15):1495-504. [free full text]

Statins are a cornerstone of therapy for the primary and secondary prevention of atherosclerotic cardiovascular disease. In the early 2000s, atorvastatin (Lipitor) was an immensely popular and profitable drug for its maker Pfizer. Notably, the 2001 MIRACL trial demonstrated that early use of high-intensity atorvastatin after UA/NSTEMI significantly reduced the risk of adverse cardiovascular outcomes at 16 weeks. In this context, Bristol-Meyers Squibb designed a non-inferiority trial to compare a relatively low dose of its new drug pravastatin (Pravachol) to high-intensity atorvastatin 80mg for the prevention of adverse cardiovascular outcomes following ACS.

Population: adults with ACS in the preceding 10 days, post-PCI (if planned/applicable), with total cholesterol < 240 (< 200 if already on lipid-lowering therapy)

Intervention: pravastatin 40mg PO daily

Note – the dose of pravastatin could be increased to 80mg daily in a blinded fashion if LDL remained > 125 mg/dL on two consecutive follow-up visits.

Comparison: atorvastatin 80mg PO daily (“intensive therapy”)

Outcome:
Primary – composite of all-cause mortality, MI, UA requiring rehospitalization, revascularization > 30 days after randomization, and stroke

The authors pre-specified an upper limit of non-inferiority as a 17% increase in the hazard ratio for the primary outcome within the pravastatin group at 2 years.

Secondary:

  • composite of death from CAD, non-fatal MI, or revascularization
  • composite of death from CAD or non-fatal MI
  • the individual components of the composite primary outcome

Subgroup analyses of primary outcome: sex, baseline LDL > 125, UA, MI, DM

Results:
4162 patients were randomized. Baseline characteristics were similar among the two groups, aside from a higher rate of peripheral arterial disease among the pravastatin group. Regarding the type of ACS, approximately 1/3 of cases were UA, 1/3 were NSTEMIs, and 1/3 were STEMIs. 69% of patients received PCI prior to randomization. Approximately 25% of patients were taking statins at the time of inclusion. At inclusion, the median LDL level was 106 mg/dL.

During follow-up, the median LDL level among pravastatin patients was 95 mg/dL and 62 mg/dL in the intensive therapy (atorvastatin) patients. Ultimately, 8% of pravastatin patients had their dose uptitrated to 80mg daily due to LDL levels remaining above 125 mg/dL.

At two-year follow-up, the primary composite outcome was noted in 26.3% of patients in the standard-dose pravastatin group but only 22.4% of the intensive-therapy atorvastatin group (ARR = 3.9%, p = 0.005, NNT = 25.6). Pravastatin therapy failed to meet its prespecified non-inferiority criteria; in fact, atorvastatin was decidedly superior.

The composite of death due to CAD, non-fatal MI, or revascularization was reduced by 25% in the atorvastatin group (p < 0.001). The composite of death due to CAD or non-fatal MI was not different among the two groups. Regarding individual components of the primary outcome: there was a 14% reduction in the need for revascularization and a 29% reduction in recurrent UA in the atorvastatin group (p = 0.04 and 0.02, respectively). There were no group differences in all-cause mortality, MI, or stroke. Discontinuation rates were 21.4% in the pravastatin group and 22.8% in the atorvastatin group (p = 0.11).

Implication/Discussion:
Among patients with recent ACS, high-intensity atorvastatin was superior to standard-dose pravastatin in preventing a composite of cardiovascular outcomes.

Bristol-Meyers Squibb had counted on this trial to show the non-inferiority of its new drug pravastatin to high-intensity atorvastatin in the secondary prevention of ASCVD. Instead, this trial established the dominance of high-intensity statin therapy for secondary prevention.

The treatment groups in this trial differed both by drug and by relative dosage intensity of the assigned drug. Whether the improvements in outcomes were from one or both of these factors is unknown. The marked group difference in LDL reduction correlates with these interventions and outcomes, but this paper does not establish a causal relationship between LDL reduction and improved cardiovascular outcomes.

The current standard of care is to initiate high-intensity statin therapy as early as possible after the diagnosis of ACS. Per UpToDate, atorvastatin 80mg is the best-studied high-intensity statin regimen and an excellent default. However, rosuvastatin 20mg or 40mg is an acceptable alternative. Their expert opinion also recommends adding ezetimibe 10mg daily in patients with LDL > 70 mg/dL despite high-intensity statin therapy.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate “Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome”

Summary by Duncan F. Moore, MD

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