Abstract & Commentary
Synopsis: High-dose atorvastatin protects patients with acute coronary syndrome from death and major cardiovascular events better than usual dose pravastatin.
Source: Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
In a head-to-head smackdown, Cannon and colleagues in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial enrolled 4162 patients from around the world in a prospective, double-blinded, randomized, controlled trial of pravastatin (Pravachol®) 40 mg daily vs atorvastatin (Lipitor®) 80 mg daily. These doses were chosen because, on average, pravastatin (PRA) 40 mg is able to reduce low-density lipoprotein cholesterol (LDL-C) to approximately 100 mg/dL and atorvastatin (ATOR) 80 mg can drop it to 70 mg/dL, provided total cholesterol is in the neighborhood of 240 mg/dL.
These are the same drugs used in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study1 where patients taking ATOR had no progression, or in some cases regression, of atheroma, while patients taking PRA had progression. While these results are impressive, the PROVE IT researchers heeded the cry of physicians for primary, patient-oriented outcomes rather than secondary, disease-oriented end points. Adult patients who had been hospitalized within 10 days of either acute myocardial infarction or high-risk unstable angina were enrolled if they were in stable condition, if any planned percutaneous revascularization procedures had been completed, and if their total cholesterol levels were < 240 mg/dL. If they were already on lipid-lowering therapy, the cholesterol cut off was 200 mg/dL. There were multiple exclusion criteria.
For instance, life expectancy < 2 years, current use of 80 mg of any statin, current use of a fibric acid derivative or niacin that could not be discontinued before randomization, and use of drugs that inhibit cytochrome P-450 3A4 (ATOR’s metabolic pathway) all would have eliminated candidates. Other exclusion criteria included having undergone a percutaneous coronary procedure within the last 6 months or coronary bypass surgery within the last 2 months, and other conditions that would have precluded use of the study medications. All patients received aspirin and dietary education. Some received clopidogrel or warfarin. All other lipid-lowering drugs were discontinued. Patients were seen and blood samples obtained at randomization, 30 days, and 4 months, and every 4 months after that until the study ended. Average follow up was 24 months. Only 8 patients were lost to follow up. Primary end points were: death from any cause, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, and stroke.
The 2 groups were well matched. The patients on average were 58 years old, three-quarters male, and 90% white. Slightly better than one-sixth had diabetes, half suffered from hypertension, and more than one-third smoked. The only clinically and statistically difference between the 2 groups was the presence of peripheral vascular disease (6.6% in the PRA group, 5.0% in the ATOR group). At the start of the study, both groups had average LDL-C values of 106 mg/dL. As expected, the LDL-C values at the end of the study averaged 95 in the PRA group and 62 in the ATOR group. The average high-density lipoprotein cholesterol levels before the study were 39 in the PRA group and 38 in the ATOR group. At study’s end they had risen 8.1% in the PRA group and 6.5% in the ATOR group (statistically significant). C-reactive protein reduction was significantly greater in the ATOR group.
More patients in the PRA group had a primary end point by the end of the study than ATOR patients (26.3% vs 22.4%). Except for stroke and death from any cause, there were similar reductions for the individual elements of the primary end point. There was no difference in the stroke rate and a statistically insignificant trend favoring ATOR for death from any cause. ATOR worked well in all groups, but especially in patients with LDL-C > 125 mg/dL. Discontinuation rates for both drugs were similar. Fewer patients taking PRA had liver enzyme levels >3-time normal than patients taking ATOR (1.1% vs 3.3). Neither group experienced rhabdomyolysis.
Comment by Allan J. Wilke, MD
It wasn’t that long ago (2002) that the National Cholesterol Education Program2 set 100 mg/dL as the LDL-C goal for high-risk patients. The bar has been lowered. The atorvastatin pharmaceutical representatives will be visiting you soon (if they haven’t already) and will spin these results as a 16% reduction in the hazard ratio. While they technically speak the truth, a better way to look at the results is the absolute reduction of 3.9%. This works out to a number-needed-to-treat of 25. If they push the issue, you can point out that the ATOR patients had a 300% increased risk of elevated liver enzymes (instead of an absolute increase of 2.2%, number-needed-to-harm 45)!
This study raises more questions than it answers:
1. How long will the beneficial effects last? What I found most impressive about this study was how soon (at 2 months) the 2 curves on the Kaplan-Meier graph began to separate. What would have happened if the study had been extended beyond the 2-year mark? Eventually, because death comes to us all, the curves have to meet again at the 100% point.
2. Was this a fair fight? In other words, could the pravastatin dose have been pushed to a level that would have achieved the same results as atorvastatin? As it turns out, the study was designed to allow a blinded increase in PRA to 80 mg daily, if the LDL-C didn’t fall below 125 mg/dL. Only 8 patients ended up taking this dose, and there were no data presented on these patients. I suspect that an 8-patient group isn’t large enough to do subgroup analysis.
3. Were these patients that you see? I think so, but it’s a pretty small crowd. More importantly, can you extrapolate the findings to patients who don’t make the inclusion or exclusion criteria?
4. Is there a point at which further reduction of LDL-C confers no additional benefit? How much LDL-C, if any, is necessary to maintain good health?
5. Does it matter how you get to a low LDL-C? The makers of the other statins (fluvastatin [Lescol®], lovastatin [Mevacor®], simvastatin [Zocor®]), ezetimibe (Zetia®), and (soon) torcetrapib*3 hope you won’t think so.
* The next new thing—an inhibitor of cholesteryl ester transfer protein
6. Are the statins all the same? Some, like atorvastatin, are lipophilic, others, hydrophilic, like pravastatin. There is evidence,4 based on simvastatin’s ability to reduce coronary events even in patients with LDL-C < 100 mg/dL, that the statins’ mechanism of action may be something more than LDL-C reduction.
7. Should we just put a statin in the water? Last year, Wald and Law5 proposed the Polypill, a medication containing a statin, a thiazide, a ß-blocker, an ACE inhibitor, folic acid, and aspirin. They claimed it would prevent heart attacks and stroke if use by everyone over 55 years of age and those patients with existing heart disease.
You may be wondering about the "Infection" in PROVE IT. This study had a 2 × 2 factorial design where the patients also received gatafloxacin or placebo. The results of that study are yet to be published. Stay tuned.
Dr. Wilke, Assistant Professor of Family Medicine, Medical College of Ohio, Toledo, OH, is Associate Editor of Internal Medicine Alert.
1. Nissen SE, et al. JAMA. 2004;291:1071-1080.
2. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002;106:3143-3421.
3. Brousseau ME, et al. N Engl J Med. 2004;350: 1505-1515.
4. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
5. Wald NJ, Law MR. BMJ. 2003;326:1419-1424.