Sara Faber, PGY3
Evidence Based Medicine
February 26, 2010
ARTICLE
Cannon Christopher P, et al. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary
Syndromes. NEJM 2004; 350(15): 1495-1504. (The PROVE IT-TIMI 22 trial)
PURPOSE OF STUDY
Establish the noninferiority of pravastatin 40 mg as compared with atorvastatin 80 mg with respect to
the time to an end-point event.
BACKGROUND
 In various randomized placebo-control trials, statins demonstrated to reduce risk of death or
cardiovascular events whether or not patients have h/o CAD.
 Based on these studies, NIH/NCEP ATPIII: The goal for high risk patients is an LDL of < 100
mg/dL.
 Based on this (and other) studies, ATPIII updated in July 2004: For “very high risk” patients, a
therapeutic option is to treat to < 70 mg/dL.
METHODS
 Design: Randomized, double blind, active control trial
 Patients: 4162 enrolled at 349 sites in 8 countries (see table 1, p 1498)
o Inclusion criteria:
 patients who had been hospitalized for an acute coronary syndrome (unstable
angina, NSTEMI, STEMI) in preceding 10 days
 enrolled after PCI
 total cholesterol 240 mg/dL or less measured within 24 hours of ACS onset or
during previous 6 months OR if pt was already on lipid lowering therapy,
starting total cholesterol 200 mg/dL or less
o Exclusion criteria:
 Coexisting condition with expected survival < 2 years
 On statin of 80 mg or on fibric acid derivatives or niacin which could not be
discontinued
 On med or likely to require a med that interferes with Cytochrome P-450 3A4
 Undergone PCI in previous 6 mo; CABG in previous 2 mo; or scheduled for CABG
 Prolonged QT
 Hepatobiliary disease or other hepatic disease
 Unexplained elevation in CK or baseline serum creatinine > 2 mg/dL
 Intervention: Pravastatin 40 mg or atorvastatin 80 mg (also randomized to receive 10 day course
of gatifloxacin versus placebo in factorial design)
o Dose of pravastatin increased to 80 mg if LDL > 125 at follow up visits x 2 (~8% pts)
o Dose of either statin halved if elevated LFTs/CK or myalgias (1.4-1.9% of pts)
 Follow up: 18-36 months (mean 24 mo)
 Outcomes:
o Primary (composite) end point: death from any cause; MI; documented USA requiring
hospitalization; PCI or CABG > 30 days after randomization; stroke.
o Secondary end point: risk of death from CHD, nonfatal MI or revascularization; risk of
death from CHD or nonfatal MI; risk of components of primary end point.
 Statistics:
o Noninferiority: upper limit of the one sided 95% CI of the relative risk at 2 years < 1.17
o Superiority: analysis requiring 2 sided confidence intervals – study not designed for this
o Intention to treat analysis
o Study powered to show difference with 95 primary outcome events
VALIDITY
Was the assignment of patients to treatments randomized? YES.
Was follow up of patients sufficiently long and complete? YES.
Were all the patients analyzed in the groups to which they were randomized? YES.
Were patients and clinicians kept “blind” to treatment? Not sure who was blinded…
Were the groups treated equally, apart from the experimental treatment? YES, though note that
patients were also randomized to receive antibiotics or placebo and data is not shown.
Were the groups similar at the start of the trial? YES.
RESULTS
 LDL levels achieved (Figure 1, p 1499)
o Pravastatin: 95 mg/dL (22% drop in statin-naïve pts; no change in pts previously on
statin)
o Atorvastatin: 62 mg/dL (51% drop in statin-naïve pts; 32% drop in pts previously on
statin)
 Primary end point (Figures 2-4, pp 1500-01)
o Composite: “…a 16% reduction in the hazard ratio favoring atorvastatin”
o Individual endpoints: cannot be assessed, but endpoints of (1) need for revascularization
and(2) risk of unstable angina appear to have largest effect on composite endpoint
Primary
endpoint
95% CI
Pravastatin 40mg
(control event
rate)
Atorvastatin 80mg
(experimental
event rate)
Relative risk
reduction
26.3
22.4
14.8
Absolute
risk
reduction
# needed to
treat
3.9
1.3-6.5
25.6
15-77
CONCLUSION: In this subset of patients, atorvastatin 80 mg decreases cardiovascular events compared
to pravastatin 40 mg. Noninferiority was NOT proven.
DISCUSSION
Limitations: Planned as a noninferiority trial but data presented as superiority trial; Composite
endpoints; Different statins used in each group; Study population limited and not our UNC patient
population.
Strengths: Overall, a good study; active-control study rather than placebo control
Thoughts: mechanism of decreased rate of cardiovascular events not clear, but based on this study, LDL
goals changed; given that benefit appeared greater in pts with starting LDL > 125, should goal have
changed? (See Figure 5, p 1502)
In the real world: So now that we’re aiming for an LDL < 70, what do we do with patients who are maxed
out on their statins?