PROVE IT-TIMI 22

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Cannon CP, et al. "Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes". The New England Journal of Medicine. 2004. 350(15):1495-1504.
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Clinical Question

Among patients with recent ACS, does high-dose atorvastatin reduce the rate of CV events compared to moderate-dose pravastatin?

Bottom Line

After recent ACS, high-dose atorvastatin reduces the rate of CV events compared to moderate-dose pravastatin.

Major Points

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, published in 2004, randomized 4,162 patients with recent ACS to high-dose atorvastatin 80mg daily or moderate-dose pravastatin 40mg daily. Using non-inferiority analysis at a mean follow-up of 2 years, the high-dose atorvastatin group was associated with a reduction in the composite endpoint of death, MI, UA requiring hospitalization, revascularization at ≥30 days, or stroke (22.4% vs. 26.3%). Atorvastatin was associated with a significantly reduced LDL (62 vs. 95 mg/dL) and a nonsignificant reduction in mortality compared to pravastatin (2.2% vs. 3.2%). There were no differences in rates of drug discontinuation due to myalgias, elevated CPK, or rhabdomyolysis.

Interestingly, the study was sponsored by Bristol-Myers-Squibb, the makers of Pravachol (pravastatin), in hopes of demonstrating the non-inferiority of moderate-dose pravastatin compared to high-dose atorvastatin. Just three years prior, MIRACL (2001) demonstrated the efficacy of high-dose atorvastatin after UA/NSTEMI. A follow-up period of 2 years was selected, presumably because most of the differences between statins had taken about 18-24 months to emerge in prior studies.[1] Yet in PROVE IT, the benefits of atorvastatin were seen at 30 days and the efficacy curves for atorvastatin and pravastatin remained separate throughout the follow-up period. Ultimately, this non-inferiority trial demonstrated the superiority of high-dose atorvastatin over moderate-dose pravastatin. Because of the comparatively different dosages, this should not be taken to mean that atorvastatin itself is superior to pravastatin, only that intensive therapy is superior to standard therapy. Moreover, the results of PROVE IT have been used to support LDL targets <70 mg/dL among patients following ACS, but this is a generous interpretation of a study that did not compare different LDL targets.[2]

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[3]

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

ACCF/AHA STEMI (2013, adapted)[4]

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

ACC/AHA Cholesterol treatment to reduce ASCVD risk (2013, adapted)[5]

  • 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

  • Multicenter, double blind, randomized, comparative, non-inferiority study
  • N=4,162
    • Atorvastatin 80mg (n=2,099)
    • Pravastatin 40mg (n=2,063)
  • Setting: 349 centers in 8 countries
  • Enrollment: 2000-2001
  • Mean follow-up: 2 years
  • Analysis: Non-inferiorty and superiority
  • Primary outcome: Composite of all-cause mortality, MI, UA rehospitalization, revascularization in 30 days, or stroke

Population

Inclusion Criteria

  • Age ≥18 and hospitalized for ACS in the prior 10 days
  • Stable condition
  • PCI if indicated
  • TC ≤240 mg/dL or ≤200 if on lipid lowering agents

Exclusion Criteria

  • Expected survival ≤2 years
  • Any statin dosed at 80 mg daily
  • Lipid lowering therapy that could not otherwise be discontinued
  • Use or expected use of strong CYP450 3A4 inhibitors
  • PCI in prior 6 months
  • CABG in prior 2 months
  • CABG scheduled because of index event
  • Factors extending QT segment
  • Obstructive hepatobiliary disease
  • Non-MI-related CPK >3x ULN
  • Creatinine >2 mg/dL

Baseline Characteristics

From the pravastatin group.

  • Demographics: Age 58.3 years, male 78.4%, white race 90.4%
  • PMH: DM 17.5%, HTN 49.2%, Smoker 37.1%, MI 19.1%
  • PCI: Prior 15.5%, on enrollment 69.1%
  • Prior CABG: 10.7%
  • Prior statin: 24.9%
  • Event: UA 29.8%, NSTEMI 36.7%, STEMI 33.4%
  • Median lipids: TC 180 mg/dL, LDL 106 mg/dL, HDL 39 mg/dL, TG 154 mg/dL

Interventions

  • Randomization to atorvastatin 80mg daily (intensive therapy) or pravastatin 40mg daily (standard therapy)
    • Pravastatin could be increased to 80mg daily if LDL remained >125mg/dL (while staying blinded)
    • Doses could be reduced by 50% if LFTs increased
  • Both groups received standard medical therapy for ACS
  • An additional parallel study (not discussed here) randomized patients to gatifloxacin or placebo, hypothesizing that eradication of the atherogenic Chlamydia pneumoniae could similarly reduce CV events

Outcomes

Comparisons are atorvastatin vs. pravastatin.

Primary Outcome

Composite of all-cause mortality, MI, UA rehospitalization, revascularization in 30 days, or stroke
22.4% vs. 26.3% (relative reduction in HR of 16%; 95% CI 5-26%; P=NS for equivalence; P=0.005 for superiority)

Secondary Outcomes

CV mortality, MI, or revascularization
19.7% vs. 22.3% (P=0.029)
All-cause mortality
28% reduction with atorvastatin (P=0.07)
Revascularization
14% reduction with atorvastatin (P=0.04)
Recurrent UA
29% reduction with atorvastatin (P=0.02)
LDL
62 mg/dL vs. 95 mg/dL (P<0.001)
Reduction in statin naive at 30 days: 51% vs. 22% (P<0.001)
Reduction in those previously on statins at 30 days: 32% vs. unchanged (P<0.001)
HDL change
+6.5% vs. +8.1% (P<0.001)
CRP
1.3 mg/L vs. 2.1 mg/L (P<0.001)

Subgroup Analysis

For the primary outcome.

LDL level
≥125 mg/dL: 28.2% vs. 20.1% (P not given but significant)
<125 mg/dL: 25.6% vs. 23.1% (P=NS)

Adverse Events

Discontinuation for adverse event or patient preference
22.8% vs. 21.4% (P=0.30)
Liver studies >3x ULN
1.1% vs. 3.3% (P<0.001)
Discontinuation for myalgias or headaches
2.7% vs. 3.3% (P=0.23)

Criticisms

  • Unclear if statins provide benefits because of an effect other than lipid lowering
  • Dosages of the two statins were not equivalent, so this trial should not be used to determine the relative efficacy of individual statins
  • Insufficient reporting of reasons for drug withdrawal in each group[6]
  • No long-term outcomes

Funding

  • Bristol-Myers Squibb and Sankyo (manufacturer of Pravachol, the brand name of pravastatin)
  • Multiple authors with financial ties

Further Reading

  1. Topol EJ. "Intensive Statin Therapy — A Sea Change in Cardiovascular Prevention." N Engl J Med 2004; 350:1562-1564
  2. Morrissey RP, et al. "Statins in Acute Coronary Syndromes: Do the Guideline Recommendations Match the Evidence?" Journal of the American College of Cardiology2009;54(15):1425-1433.
  3. 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.
  4. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  5. 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.
  6. NEJM letters to the editor