High-Dose Statin Therapy Reduces Recurrent Cardiovascular Events

December 16, 2009 (Boston, Massachusetts and Helsinki, Finland) — Exploratory analyses from two large cholesterol-lowering trials show that intensive statin therapy is more effective than standard therapy in preventing recurrent cardiovascular disease events [1,2].

The results, from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI 22) and Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) studies, highlight the need for clinicians to continue to prescribe high-dose statin therapy to patients experiencing a first cardiovascular event, say researchers.

"These findings suggest continued therapy with a regimen that maintains low LDL cholesterol is central to preventing additional atherosclerotic development and cardiovascular events, including recurrent events," write lead PROVE-IT investigator Sabina Murphy (Brigham and Women's Hospital, Boston, MA) and colleagues in the December 15–22, 2009 issue of the Journal of the American College of Cardiology.

Similar conclusions are reached by the IDEAL investigators, led by Dr Matti Tikkanen (Helsinki University Central Hospital, Finland), as they write that "clinicians should not hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent cardiovascular events."

Commenting on the studies for heartwire , Dr Steven Nissen (Cleveland Clinic, OH), who also wrote an editorial accompanying the analyses [3], said the results confirm the paradigm shift that occurred with the original PROVE-IT paper in 2004, a study that showed high-dose atorvastatin reduced cardiovascular events 16% compared with standard therapy in patients who recently had an acute coronary syndrome.

"Basically, almost everybody I know intensifies therapy after the patient has an acute event," said Nissen. "In fact, what we do is go with the highest dose of atorvastatin because of the PROVE-IT trial."

Exploratory Analysis

In both PROVE-IT and IDEAL, the prespecified efficacy analysis, like other clinical trials, was based on the time to first cardiovascular event. In this approach, the cardiovascular events occurring after the first event are ignored, or censored, and do not contribute to the statistical analysis.

In the newest analyses, the PROVE-IT and IDEAL investigators utilized a different approach and included these previously censored clinical events in the analysis. The PROVE-IT investigators used the same clinical end point in the original trial--death, MI, unstable angina requiring hospitalization, stroke, or revascularization within 30 days--and measured all events that occurred in the two-year follow-up period. The IDEAL investigators, on the other hand, expanded the primary end point to include a broader spectrum of cardiovascular disease.

From PROVE-IT, investigators showed that intensive lipid-lowering therapy with atorvastatin 80 mg after an acute coronary syndrome reduced subsequent cardiovascular events 19% compared with individuals treated with pravastatin 40 mg. Overall, there were 138 fewer primary end-point events with high-dose atorvastatin, a benefit that was driven primarily by reductions in unstable angina requiring hospitalization.

PROVE IT: Primary End-Point Events by Therapy

End point	Initial events, pravastatin 40 mg	Initial events, atorvastatin 80 mg	Additional events, pravastatin 40 mg	Additional events, atorvastatin 80 mg	p*
Any primary end point	537	464	340	275	0.009
Death	49	32	18	15	0.568
MI	121	103	64	57	0.472
Unstable angina	77	66	46	18	0.001
Revascularization within 30 d	276	246	205	177	0.127

*Additional events, atorvastatin vs pravastatin

In IDEAL, the investigators used a statistical analysis known as the Wei, Lin, and Weissfeld method, which allowed them to analyze the repeated occurrence of clinical events. Based on this analysis, treatment with atorvastatin 80 mg reduced the relative risk of a second and third cardiovascular event 24% and 19%, respectively, both of which were statistically significant reductions. Fourth and fifth cardiovascular events were also reduced, although the reduction was not statistically significant, likely because of the smaller number of events, according to investigators.

Tikkanen and colleagues believe the results provide new insights into the treatment of patients with cardiovascular disease. After a first event, they write, a physician might question whether to continue with high-dose statin therapy, possibly out of concern over drug-drug interactions. "Our results seem to indicate that, especially for such patients, intensive statin therapy is preferable to standard therapy."

Changing the Course of Clinical Trials

Although the results are exploratory and post hoc, the PROVE-IT investigators suggest that an expanded analysis of total events might warrant consideration for future clinical trials, given that "all events are important to patients, clinicians, and payers." Similarly, a cost-effectiveness analysis that incorporates all events in the model would provide a more comprehensive estimate of the total cost-effectiveness of a given therapy when the drug is shown to reduce events beyond the first occurrence.

Speaking with heartwire , Nissen said that while there are arguments to be made in favor of that approach, he does not believe trials should stray from the "time-honored approach" of analyzing efficacy based on the time to a first cardiovascular event.

"My thinking is that these studies are interesting, but it shouldn't really change how we do studies in the future," said Nissen. "There are too many risks in using total number of events. The big problem is that you end up counting individual patients on multiple occasions. So if a single individual has a whole bunch of events, they can really dominate the outcome in a clinical trial. The more conservative approach, which is to censor events after the first event and to look at the time to first event, is much more rigorous and should remain the gold standard."

Nissen also said that the approach used by the IDEAL investigators, where they analyzed a broader composite of clinical events--any cardiovascular disease, including coronary heart disease death, nonfatal MI, and resuscitated cardiac arrest, plus stroke, revascularization, unstable angina, hospitalization for heart failure, and peripheral artery disease--might reduce the need for the mega-20 000-plus-patient trials that are needed because cardiovascular event rates have declined dramatically in recent years. He remains steadfast, however, that hard clinical outcomes--death, MI, and stroke--should retain their prominence in clinical trials, especially since they are "irrevocable events with permanent consequences." Also, adjudicating softer events can be problematic, he said.

"Going to a lot of softer events also has risks, especially in international trials, because the indications--for revascularization, for example--are very different in different parts of the world," said Nissen. "I'm very cautious. I think they're very interesting, exploratory post hoc analyses, but they really would not, or should not, change how we do things in the future."

Heartwire from Medscape © 2009  Medscape, LLC

Cite this: High-Dose Statin Therapy Reduces Recurrent Cardiovascular Events - Medscape - Dec 16, 2009.