The PROVE IT Study

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The PROVE IT Study

• Craig M. Hileman, M.D.
• Journal Club
• May14th, 2004

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The Article

• Comparison of Intensive and Moderate Lipid
  Lowering with Statins after Acute Coronary
  Syndromes, NEJM April 8, 2004
• PROVE IT-TIMI 22 (Pravastatin or Atorvastatin
  Evaluation and Infection Therapy-Thrombolysis in
  Myocardial Infarction 22)

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The Goals

• To determine whether lowering lipid levels below
  recommended values would increase the clinical
  benefit of statins
• shhhalso to prove nonsuperiority of Atorvastatin
  over Pravastatin (sponsored by Bristol-Myers
  Squibb)

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VS
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The Methods

• 4162 pts from 349 hospitals in 8 countries
• Inclusion criteria
• gt18 years old
• Hospitalized for ACS (AMI or unstable angina) in
  the last 10 days
• Total cholesterol lt240 if not on lipid meds
• Total cholesterol lt200 if already medicated

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The Methods

• Exclusion criteria
• Less than 2 years to live
• On 80mg of any statin, or niacin, or fibric acid
• On cytochrome P450 inhibitors
• Cath in the last 6 months or CABG in the last 2
  months (or needed CABG b/c of ACS event)
• Long QT
• Obstructive liver disease
• CK gt3xs normal (not related to MI)
• Creatinine gt2

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Protocol

• Double Blinded, Double Dummy
• 40mg of Pravastatin (Pravachol) or 80mg of
  Atorvastatin (Lipitor)
• Followed up _at_ 30days, and 4, 8, 12, 16, up to 36
  months
• In Addition
• If 2 visits had LDL gt125, increase pravastatin to
  80mg
• Halve the dose of either drug if abnl LFTs,
  myalgias or inc CK
• Trial pre-planned to stop when 925 events
  reported (adequate power)
• No prespecified rules to stop if superiority
  determined

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Outcomes

• Primary Outcome
• Time from enrollment to occurrence of
• Death (from any cause)
• MCVE
• MI
• Unstable angina needing hospitalization
• Cath gt30 days after enrollment
• CABG gt30 days after enrollment
• Stroke

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Outcomes

• Secondary outcomes
• Risk of death from
• CAD
• Non-fatal MI
• Revascularization

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Validity

• These results are valid
• Patients were randomized and all patients were
  accounted for
• Study personnel were double blinded, the groups
  were similar and were treated equally

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Relevance

• These results are relevant
• The outcomes were patient oriented, they were
  similar to our patients, and had a significant
  measurable difference

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Results

• Patient Comparison
• Well matched except for more PAD in pravastatin
  group
• Averages
• Age-58
• Sex-78 male
• Race-90 white
• See Table

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Table 1
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Table 1 (cont.)
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Results

• Lipid Lowering Effect
• Pravastatin
• changed LDL from 106 to 95 (11)
• If statin naïve- dec by 22 in 1st 30 days
• If prior statin-no change
• Atorvastatin
• Changed LDL from 106 to 62 (42)
• If statin- naïve dec by 51 in 1st 30 days
• If prior statin-dec by 32

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Figure 1
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Results

• Primary Outcomes
• Pravastatin-26.3 event rate
• Atorvastatin-22.4 event rate
• 16 reduction in the hazard ratio (relative
  risk/time) favoring atorvastatin
• NNT is 50
• The benefit was noted as early as 30 days

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Results

• Secondary Outcomes
• Pravastatin-22.3 event rate
• Atorvastatin-19.7 event rate
• The risk of death, MI, or urgent
  revascularization was reduced by 25 in the
  atorvastatin group
• NNT is 100

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Figure 2
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Figure 3
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Figure 4
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Figure 5

• Subgroups
• The subgroup with a baseline LDLgt125 had a
  greater benefit that the subgroup with a baseline
  LDLlt125. Hmmm?

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Conclusions

• After ACS, high dose atorvastatin resulted in a
  lower mean LDL than moderate dose pravastatin
• Authors feel that this correlates well to the
  results from the Heart Protection Study in Lancet
  in 2002
• Effects were seen as soon as 30 days
• Maybe after ACS we should have lower LDL goals
• But

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But

• Could not exclude that the difference in outcomes
  could be more related to the pleiotropic effects
  of the statins than their lipid lowering ability
• The continued long term benefit may be due to
  lower LDL or the fact that these patients
  unstable plaques were now stabilized
• The REVERSAL trial from Nissen et al (JAMA 2004)

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Positives/Negatives

• Positives
• Good validity and relevance
• Patient population mostly similar to ours

• Negatives
• Short duration of follow up
• Per exclusion criteria, a lot of our pts would
  not qualify

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Should this change my practice?

• Probably not too much
• Only about a 1/3 of people who need a statin are
  on one
• Cost
• 40mg Pravastatin
• 120.00
• 80mg Atorvastatin
• ????
• Statins account for the largest portion of
  prescription drug expenditure
• More side effects with Atorvastatin
• Future studies pending

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Summary

• High dose Atorvastatin lowers LDL more that mod
  dose Pravastatin
• This LDL lowering may affect mortality or future
  events after ACS
• OR it could be the plaque stabilizing factors
• More studies need to be done correlating LDLlt100
  with better prognosis

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Questions or Comments?