Intensive Cholesterol Lowering With Atorvastatin Halts Progression Of Heart Disease, Cleveland Clinic-Led Study Shows

The REVERSAL trial, directed by Cleveland Clinic cardiologist Steven Nissen, M.D., compared the highest doses available at the time of two popular statin drugs, pravastatin and atorvastatin. Both medications work to block the liver’s ability to produce harmful cholesterol, which can clog coronary arteries. Complete trial results will be published March 3 in the Journal of the American Medical Association.

“When we analyzed the results of REVERSAL, we realized that we had found an approach to coronary disease treatment that could literally stop heart disease in its tracks,” Dr. Nissen said. “Additional research must be done to verify our conclusions, but this is potentially life-altering news for millions of people suffering from heart disease.”

The REVERSAL study randomly split 502 patients into equal-sized groups to receive either 40-mg doses of pravastatin or 80-mg doses of atorvastatin for 18 months of treatment. The progression of their heart disease was measured using intravascular ultrasound, which allows scientists to see plaque buildup in coronary arteries over time.

“The results were striking,” Dr. Nissen said, “demonstrating a complete halting of coronary disease progression in the atorvastatin-treated patients and continued progression of disease in the pravastatin-treated group.”

The more intensively treated atorvastatin patients reached an LDL-C level (the bad cholesterol) of 79 milligrams per deciliter (mg/dL), while the more moderately treated pravastatin patients achieved an LDL-C of 110 mg/dL.

The pravastatin-treated patients experienced a 2.7 percent increase in the volume of atherosclerotic plaque, while the atorvastatin-treated patients showed a 0.4 percent decrease. The 0.4 percent decrease in plaque was statistically “no change” from baseline, meaning that no progression had occurred in the atorvastatin-treated group.

Current guidelines set by the National Cholesterol Education Program suggest treating patients to an LDL-C target level of 100 mg/dL. “The REVERSAL trial demonstrates that if we want to prevent the progression of coronary disease, we need to treat patients to much lower levels,” Dr. Nissen said.

Although he emphasized that a single study does not necessarily provide enough evidence to alter these treatment guidelines, “physicians may want to consider these results in deciding how intensively to treat patients.” Tens of millions of Americans currently take one of the statin drugs.

The two drug regimens had a similar incidence of side effects, demonstrating that “more intensive treatment using 80 mg of atorvastatin can reduce the progression of disease without compromising patients,” Dr. Nissen said.

Another important finding of REVERSAL was the effect of atorvastatin and pravastatin on C-reactive protein (CRP), an important measure of artery inflammation linked to an increased risk of heart attack. In the REVERSAL study, patients treated with pravastatin showed a 5.2-percent reduction in CRP, while those treated with atorvastatin showed a 36.4-percent decrease.

The study was conducted at 34 centers in the United States, with preliminary results presented at the annual Scientific Sessions of the American Heart Association in November. Participating patients were identified at the time of cardiac catheterization. Eligibility requirements included an LDL cholesterol level between 125 mg/dL and 210 mg/dL and the presence of at least one coronary artery narrowing at cardiac catheterization.

In addition to demonstrating that “lower is better” for cholesterol, the REVERSAL study provided several surprises for the investigators. “The choice of statin drugs had a major effect on outcome, regardless of the level of LDL-C reduction,” Dr. Nissen said.

Patients who reached a low LDL-C level on pravastatin continued to show disease progression. For any degree of reduction of cholesterol achieved during treatment, the progression rate was slower if the patient reached that cholesterol level by taking atorvastatin. The REVERSAL authors suggest that the greater reduction in CRP may partially explain the better results observed in the atorvastatin-treated patients.

Dr. Nissen and co-authors also comment in JAMA on the limitations of the REVERSAL study. They offer the perspective that studies measuring the effect of statin drugs on the risk of heart attack and death are the ultimate test of whether more aggressive lipid-lowering therapy can save lives.

“I am very confident that clinical outcome trials will confirm the REVERSAL findings, that more intensive cholesterol reductions using a more potent statin that effectively lowers CRP will save lives and prevent heart attacks,” Dr. Nissen said. “Until such studies report, physicians will want to consider the results of the REVERSAL trial in deciding how intensively to treat cholesterol elevations in patients with coronary artery disease,” Dr. Nissen said.

The study was funded by Pfizer, maker of atorvastatin, but was conducted independently by The Cleveland Clinic Cardiovascular Coordinating Center. All measurements were performed by the Intravascular Ultrasound Core Laboratory at The Cleveland Clinic, and the manuscript generated by Dr. Nissen and co-authors.

The Cleveland Clinic Foundation, located in Cleveland, Ohio, is a not-for-profit multispecialty academic medical center that integrates clinical and hospital care with research and education. The Cleveland Clinic was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. U.S. News & World Report consistently names The Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. In 2003, The Cleveland Clinic was ranked fifth overall. Approximately 1,200 full-time salaried physicians at The Cleveland Clinic and Cleveland Clinic Florida represent more than 100 medical specialties and subspecialties. In 2002, there were nearly 2.5 million outpatient visits to The Cleveland Clinic and more than 52,000 hospital admissions. Patients came for treatment from every state and from more than 90 countries. The Cleveland Clinic website address is http://www.clevelandclinic.org.