DALLAS, April 21 -- Do individuals gain progressive benefits in heart attack protection as the drugs, called statins, take cholesterol levels to "new lows?" This is the topic of three reports and an editorial appearing in today's Circulation: Journal of the American Heart Association.
"An important question is how much additional benefit do individuals who have had a heart attack get from reducing their low-density lipoprotein, (LDL), or 'bad' cholesterol levels from low to very low levels, (below the recommended 100 milligrams/deciliter)? Is it considerable, small amounts or none?" asks Scott M. Grundy, M.D., Ph.D., who wrote an accompanying editorial in Circulation. He is director of the center for human nutrition at the University of Texas Southwestern Medical Center in Dallas.
In one report researchers found that the benefits of the popular statin drugs -- shown to sharply reduce heart attack risk in individuals with elevated blood levels of cholesterol -- taper off, indicating a "threshold" effect when LDL reaches 125 mg/dL, according to Frank M. Sacks, M.D., associate professor of medicine, and other researchers at Brigham and Women's Hospital and Harvard Medical School, Boston.
Another report in the same issue however suggested continued benefit down to a level of 100 mg/dL, although there was some lessening of benefit as LDL approached the lower levels.
Even though the data suggest that there may be attenuation in the benefit of cholesterol lowering below 125 mg/dL, Grundy stresses that these reports should not be taken as the final word on the issue. "For the present, the guidelines by the National Cholesterol Education Program (NCEP), endorsed by the American Heart Association, offer the most reliable basis for physicians' decisions regardless of the optimal lower limit for LDL cholesterol," says Grundy. A new statin trial, the Treating to New Target (TNT) study, should provide the answers concerning lower limit of benefit, but results are not expected for another five years.
NCEP guidelines call for individuals with elevated cholesterol -- but no evidence of coronary heart disease or other atherosclerosis -- to reduce their LDL levels to at least 130 mg/dL. For individuals with heart disease, the NCEP goal is 100 mg/dL, or below, says Grundy. LDL cholesterol is called the "bad" cholesterol because it helps form the obstructions inside the blood vessels, setting the stage for a heart attack or stroke.
Sacks and his colleagues report data from the Cholesterol and Recurrent Events (CARE) trial, in which 4,159 individuals with coronary heart disease and blood levels of cholesterol averaging about 139 mg/dL received either 40 mg of pravastatin daily or a placebo, an inert pill. Individuals who had been on pravastatin for an average of five years, lowered LDL levels to an average of 98 mg/dL. In comparison to the control group, the drug-treated group had 24 percent fewer heart attacks.
In a new analysis of their study, the researchers found that the incidence of heart attacks and surgeries to restore blood flow to the heart apparently fell progressively as LDL levels were reduced from 175 to 125 mg/dL. However, further reductions to as low as 71 mg/dL had little impact on risk, says Sacks.
"This report suggests that the effect of pravastatin to lower LDL to less than 125 mg/dL is responsible for most of the reduction in heart attacks and surgery," says Sacks. "A conservative clinical application of these findings could be to suggest a range for optimal LDL concentrations during therapy of 100-125 mg/dL."
In a second journal report, Scandinavian researchers led by Terje R. Pedersen, M.D., of the cardiology department at the Aker Hospital in Oslo, Norway, reviewed the findings of the Scandinavian Simvastatin Survival Study (4S) of 4,444 individuals with coronary heart disease and total cholesterol in the 210-310 mg/dL range.
Individuals received either 20-40 mg simvastatin daily or a placebo for about five years. On average, drug therapy lowered LDL levels by 35 percent and reduced the incidence of heart attacks by 34 percent. The goal was to reduce total cholesterol below about 200 mg/dL. However, many patients achieved greater reductions, which produced continuing, but progressively smaller reductions in heart attack risk. The scientists concluded that more might be gained by reducing LDL to very low levels, such as below 100 mg/dL, but this needs confirmation in new trials.
In another journal report, Chris Packard, FRCPath, D.Sc., and colleagues describe their test of a daily 40-mg dose of pravastatin to prevent first heart attacks in individuals who had no prior heart disease, but had elevated cholesterol levels in the West of Scotland Coronary Prevention Study (WOSCOPS).
Individuals' LDL levels averaged 197 mg/dL before treatment and fell to about 142 mg/dL with pravastatin. The study included 6,595 individuals.
According to the new analysis, the maximum benefit of a 45 percent reduction in heart attack risk was observed in those whose LDL levels dropped 24 percent.
However, further reductions of up to 39 percent were not associated with reduced risk. The analysis "did not yield the predicted results," according to the researchers, who expected continued lowering of LDL to produce a corresponding reduction in heart attack risk.
According to Grundy, "These three trials are all landmark trials in the cholesterol field. All show that effective cholesterol lowering with statins produce striking reductions in coronary heart disease," he says. "The results of the new 4S analysis generally support the goal of reducing LDL cholesterol to 100 mg/dL to prevent second heart attacks, although the data suggested that benefits slowly taper off as LDL approaches the recommended goal of 100 mg/dL."
The benefits from lowering LDL in the CARE followed a different pattern. Researchers found there was a "threshold effect" in which further cholesterol lowering beyond a certain "cutoff" (100-125 mg/dL) offered little benefit in reducing risk of second heart attacks.
The trials do emphasize the need to employ clinical judgment whether to intensify therapy in patients with heart disease whose LDL levels are already nearing these goals, says Grundy.
"For individuals with very high cholesterol levels but no evidence of coronary heart disease, the WOSCOPS study provides strong confirmation of the beneficial effect of cholesterol-lowering drugs," he adds.
In WOSCOPS, pravastatin drugs significantly reduced heart attacks among patients with LDL levels of 160 mg/dL or higher, and other risk factors for heart disease.
Although current NCEP guidelines do not recommend cholesterol-reducing drug therapy for preventing first heart attacks in high-risk patients with LDL levels in the 130-159 mg/dL range, there is "a strong argument for using statin therapy in selected patients at very high risk," Grundy says.
Overall, the three reports send an important message that the statin drugs can saves lives and that more individuals with heart disease need to take them, he says.
"Most coronary heart disease patients whose LDL cholesterol concentrations exceed this (130 mg/dL) level should receive cholesterol-lowering drugs," he advises. "A delay in drug treatment for a trial of dietary therapy in such patients is not necessary nor warranted."
It may take more research to answer the questions about what are the upper limits of benefit for statins. In the meantime, physicians need to make sure patients who need the drugs are getting them, says Grundy.
"Unfortunately, a great many coronary heart disease patients are not receiving the lifesaving benefits of statin therapy and extension of this therapy to untreated patients is urgently needed," he says.
Co-authors of the study, "Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study," are Anders G. Olsson, M.D.; Ole Faergeman, M.D.; John Kjekshus, M.D.; Hans Wedel, Ph.D.; Kare Berg, M.D.; Lars Wilhelmsen, M.D.; Torben Haghfelt, M.D.; Gudmundur Thorgeirsson, M.D.; Kalevi Pyorala, M.D.; Tatu Miettinen, M.D.; Bjorn Christophersen, Ph.D.; Jonathan A Tobert, M.D., Ph.D.; Thomas A. Musliner, M.D.; and Thomas J. Cook, M.S.
Co-authors of the study, "Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events Trial," are Lemuel A. Moye, M.D., Ph.D.; Barry R. Davis, M.D.; Thomas G. Cole, Ph.D.; Jean L Rouleau, M.D.; David Nash, M.D.; Marc A. Pfeffer, M.D., Ph.D.; and Eugene Braunwald, M.D.
Co-authors of the study, "Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study," are the West of Scotland Coronary Prevention Study Group (WOSCOPS).
Media advisory: Dr. Packard of the WOPCOPS study can be reached at 44-141-211-4979 or 4322 or by fax at 44-141-553-2558. Dr. Pedersen of the 4S study can be reached at 47-22-89-44-25 or fax 47-22-15-94-93. Dr. Sacks of the CARE trial can be reached at (617) 432-1420. Dr. Grundy can be reached at (214) 648-2890. (Please do not publish numbers.)