PROVE-IT: Atorvastatin 80 mg reduces major CV events by 16% compared with pravastatin 40 mg in ACS patients

March 08, 2004

New Orleans, LA - Intensive lipid lowering with atorvastatin (Lipitor®, Pfizer) 80 mg daily provided greater protection from death and cardiovascular events compared with pravastatin (Pravachol®, Bristol-Myers Squibb) 40 mg daily in patients recently hospitalized with acute coronary syndromes (ACS)[1].

The findings, from the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study, presented during a late-breaking clinical trials session at the American College of Cardiology 2004 Scientific Sessions and published online the same day in the New England Journal of Medicine, suggest that in ACS patients, lowering LDL cholesterol levels substantially below current target levels is beneficial.

"Among patients who had recently been hospitalized for an acute coronary syndrome, the more intensive regimen resulted in a lower risk of death from any cause or major cardiac events than did a more moderate degree of lipid lowering with the use of a standard dose of statin," write Dr Christopher P Cannon (Brigham and Women's Hospital, Boston, MA) and colleagues. "Although prior placebo-controlled studies have shown that a standard-dose statin is beneficial, we demonstrated that more intensive lipid lowering significantly increased this clinical benefit."

In an accompanying editorial[2], Dr Eric Topol (Cleveland Clinic, OH) says the findings herald a shake-up in the field of cardiovascular prevention. What was considered optimalto lower LDL cholesterol to less than 100 mg/dLhas come "under serious question," he says, "because we know that atherosclerotic progression and clinical outcomes will be ameliorated by much more aggressive use of statins."

Superior benefit of atorvastatin

PROVE-IT was a 24-month study testing the hypothesis that a lower absolute LDL cholesterol level in patients with ACS is associated with a reduced risk of CVD events, while also evaluating the efficacy and safety of aggressive LDL cholesterol lowering. The noninferiority study was designed to test the equivalence of pravastatin 40 mg daily vs atorvastatin 80 mg daily for use in preventing death or major CV events in patients following an ACS.

To address the critical "is-lower-better" question, investigators sought to compare the effect of a reduction of LDL cholesterol to approximately 100 mg/dL with pravastatin 40 mg daily or to 70 mg/dL daily with atorvastatin 80 mg daily on the primary composite end point of all-cause mortality, MI, documented unstable angina requiring hospitalization, revascularization requiring PCI or CABG, and stroke. Secondary end points included death due to CHD, MI, or revascularization, death due to CHD/MI, as well as individual components of the primary end point.

PROVE-IT randomized 4162 patients hospitalized for an acute MI and unstable angina to an intensive lipid-lowering regimen or to standard statin therapy. Patients had to have a total cholesterol level of <240 mg/dL, measured within the first 24 hours after ACS onset. Patients receiving long-term statin therapy at the time of their index ACS were included in the study if total cholesterol measured at screening was <200 mg/dL. Most patients were concomitantly administered aspirin (93%), beta blockers (85%), clopidogrel/ticlodipine (72%), and ACE inhibitors (69%) during treatment.

As expected, atorvastatin lowered LDL cholesterol more than pravastatin. In patients already receiving statin therapy, LDL cholesterol levels were unchanged from baseline in the pravastatin arm, but fell by an additional 32% in the atorvastatin arm (p<0.001).

PROVE-IT: Final LDL cholesterol level

LDL cholesterol level

Pravastatin 40 mg (IQR) (n=1973)

Atorvastatin 80 mg (IQR) (n=2003)

 

Final LDL cholesterol (mg/dL)

95 (79-113) 62 (50-79) <0.001

IQR=Interquartile range

At 24 months, the primary composite end point for patients receiving standard statin therapy with pravastatin was 26.3% compared with 22.4% in the high-dose atorvastatin arm, representing a 16% relative risk reduction favoring atorvastatin. As a result, pravastatin failed to meet the criteria for equivalence.

PROVE-IT: Primary composite end point

Primary end point

Pravastatin 40 mg (n=1973)

Atorvastatin 80 mg (n=2003)

Relative risk reduction, %

p

All-cause mortality/MI/unstable angina/revascularization (PCI or CABG)/stroke (%)

26.3 22.4 16 0.005
 

These data suggest that this population of patients with acute coronary syndromes...can derive particular benefit from early and intensive lipid lowering with statins.

 

The benefit of atorvastatin compared with pravastatin emerged as early as 30 days and was consistent over time.

"This early reduction in event rates in patients with acute coronary syndromes contrasts with the lag of approximately one to two years in prior studies of statins in patients with chronic atherosclerosis," write Cannon and colleagues. "These data suggest that this population of patients with acute coronary syndromes, who have a culprit lesion and frequently multiple additional vulnerable plaques as well, can derive particular benefit from early and intensive lipid lowering with statins."

Among the individual components of the primary end point, there was a consistent benefit favoring high-dose atorvastatin over standard-dose pravastatin, with the exception of stroke, which showed little difference. Moreover, the benefit was consistent across the prespecified subgroups, including men and women; in patients with unstable angina or MI; and those with and without diabetes mellitus.

PROVE-IT: Secondary end points

Secondary end points

Pravastatin 40 mg (n=1973)

Atorvastatin 80 mg (n=2003)

Relative risk reduction, %

p

CHD death, nonfatal MI, or revascularization (%)

22.3 19.7 14 0.029

All-cause mortality (%)

3.2 2.2 28 0.07

Death/nonfatal MI (%)

10.0 8.3 18 0.06

Unstable angina (%)

5.1 3.8 29 0.02

Revascularization (%)

18.8 16.3 14 0.04

Rates of discontinuation for adverse events, patient preference, or other reasons were not statistically different between the two study arms at 12 months or at 24 months. The percentage of patients who developed abnormal liver elevations, defined as alanine aminotransferase (ALT) >3 times the upper limit of normal, were 1.1% for pravastatin and 3.3% for atorvastatin (p<0.001).

No major differences in CRP

The PROVE-IT results follow the recently published REVERSAL study, another comparative statin trial that attracted considerable attention. Previously reported by heartwire , REVERSAL showed that intensive lipid lowering with atorvastatin 80 mg halted the progression of atherosclerosis, whereas pravastatin 40 mg was associated with continued atherosclerosis progression.

Despite both trials demonstrating the superiority of atorvastatin, the two studies reported disparate results with regard to C-reactive protein (CRP) reduction. In REVERSAL, involving a patient population with stable CAD, there was a marked difference in CRP lowering between the two drugs, with atorvastatin reducing CRP 36% compared with just 5% with pravastatin. In PROVE-IT, however, there was relatively little difference in CRP lowering between the two statin regimens.

Cannon and colleagues say that the study was not designed to determine the mechanism for atorvastatin's clinical benefit but suggest that in addition to the differences in LDL lowering, non-lipid-related pleiotropic effects should not be excluded.

The investigators conclude that "given the substantially lower LDL cholesterol levels achieved in the group given 80 mg of atorvastatin daily, our results suggest that after an ACS, the [target] LDL cholesterol level may be lower than recommended in the current guidelines."

"Sea change" in cardiovascular prevention

In the editorial, Topol writes that the results from both PROVE-IT and REVERSAL are expected to usher in a new era of aggressive lipid lowering.

"The implications of this turning point—that is, of the new era of intensive statin therapy—are profound. Even today, only a fraction of the patients who should be treated with a statin are actually receiving such therapy," says Topol, noting that more than 200 million people worldwide meet the criteria for treatment, but fewer than 25 million take statins.

 
The implications of this turning point—that is, of the new era of intensive statin therapy—are profound.
 

In addition to likely changes in practice, Topol also notes that the combination of a clinical-outcomes trial, PROVE-IT, and an imaging study, REVERSAL, yields a compelling validation of IVUS as a surrogate measure of clinical benefit with atherosclerotic agents. Moreover, the two studies strongly reinforce the need for more head-to-head trials of drugs within the same class. Taken together, the results will bring about a sea change in the prevention and management of atherosclerotic vascular disease, he predicts.

"The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials," concludes Topol. "Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines."

Topol notes that with differences in anti-inflammatory effects seen in the two studies, more investigation is needed to unravel the independent and interdependent effects of statins on LDL cholesterol and arterial inflammation.

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