2nd October 2004
ANAHEIM, Calif.-- Leading cardiovascular experts from around the world Wednesday issued the following comments regarding the West of Scotland study, the latest research on aggressive cholesterol-lowering in people at high risk for heart disease, following a presentation at the American Heart Association annual meeting:
Terje R. Pedersen, M.D., coordinator of the Scandinavian Simvastatin Survival Study
"This study has major implications for clinical practice, the start of treating high cholesterol in the same dimension as treating hypertension today. The results of the West of Scotland (WOS) study confirm what we observed in the Scandinavian Simavastatin Survival Study, that cholesterol-lowering is of substantial value in reducing the risk of coronary heart disease. These benefits are not isolated to the agent used in the WOS trial."
J. Sanford Schwartz, M.D., executive director of the Leonard Davis Institute of Health Economics at the University of Pennsylvania
"The WOS study is an important study for several reasons. First it confirms and extends previous findings on the impact of cholesterol-lowering on cardiac morbidity and overall mortality. Prior to WOS there have been other trials that showed that if you take patients who have elevated cholesterol and who are at risk coronary heart disease and lower their cholesterol level you can reduce heart attacks and deaths from coronary heart disease.
"Last year 4S demonstrated that in addition to reducing in cardiac morbidity and cardiac mortality, you also get significant increases in overall survival. WOS confirms and extends those findings beyond patients who have coronary heart disease to people with elevated cholesterol and multiple risk factors for heart disease.
"What was demonstrated in 4S and has been demonstrated in the trials is the greater the extent of cholesterol lowering that is achieved the greater the benefit. The National Cholesterol Education Program guidelines recommend treating to goal -- driving cholesterol down to 100 mg/dl in patients with CHD.
"The WOS results that have been made available thus far do not report what level these patients got down to, but they do report a 26 percent reduction in LDL cholesterol. Based on previous trials, one would expect that those patients who achieve a greater reduction in LDL cholesterol will achieve a greater benefit.
"If that's true, that would suggest that drugs that are more effective in lowering cholesterol, like simvastatin, will have an even greater impact. In 4S LDL cholesterol was reduced by 35 percent, as compared to WOS where LDL cholesterol was reduced by 26 percent.
"Most experts believe that these are primarily class effects and that they are a result of primarily if not solely LDL reduction. All the data suggests that the more effectively you lower LDL , the more benefit you'll see. There is no reason to believe that this is only restricted to the drug that was used in WOS.
"My take away for clinicians is that we now have two very well designed, very well run, large randomized clinical trials in the last two years that provide us with rock solid evidence that in patients with elevated cholesterol that have either CHD or multiple risk factors that lowering cholesterol aggressively with statins reduces cardiac mortality, cardiac morbidity and it reduces overall mortality. And therefore, the controversy which is surrounding this area, with these clear results, should really be put to rest.
Suzanne Oparil, professor of medicine at the University of Alabama at Birmingham
"This is a dramatic study. We learned last year from the 4S study that lipid lowering with a statin drug lowers coronary disease mortality, lowers the incidence of non-fatal heart attack, does not adversely affect non-coronary mortality, and therefore, decreased all cause mortality dramatically. Other findings were the need for hospitalizations decreased, the need for revascularization decreased, and cardiovascular endpoints of all causes such as sudden death decreased.
"The 4S study was done in individuals who already had heart attacks -- 92% of them already had heart attacks, the others had angina. One thing the 4S study had that the West of Scotland doesn t is women, and the women seemed to benefit as much as the men, although there were smaller numbers there.
"In the West of Scotland Study, only men were looked at who did not have established myocardial infarction, pre-existing myocardial infarction, and it was shown that lowering cholesterol with pravastatin, which is another statin agent, decreased non-fatal MI or cardiovascular death, coronary heart disease death, by 31% which is a pretty dramatic effect. This was accomplished by lowering total cholesterol by 20% and LDL cholesterol by 26%.
"We believe that the beneficial effects of the statins are related to the cholesterol lowering, there is no evidence for another mechanism although another mechanism has not been ruled out. And it s reasonable to extrapolate that if the cholesterol had been lowered further, that the benefit might have been greater.
"The clinical implications are if you are a man, and you have a high cholesterol level, you probably should be on a cholesterol-lowering agent and at present the statins seem to be the best tolerated of the cholesterol-lowering agents.
"In the literature, cholesterol-lowering with other agents such as resins, has not decreased all cause mortality, suggesting that this may be due to increases in non-cardiovascular mortality with some of the other classes of drugs.
"Statins seem to do nothing adversarial, at least in a high-risk population over a five year follow-up. No major adverse affects were seen with either of the statins over this period of time, which is quite impressive.
"I believe in vigorous cholesterol-lowering with medication. I think one very convincing piece of evidence to practitioners, particularly non-cardiologists, is that cholesterol-lowering does have a beneficial effect in the prevention of fatal cardiovascular events. It should extend the use of these agents (statins) to patients who have very high risk because they have very high cholesterol levels, but have not had heart attacks.
"Since these results are so similar to the results that were seen in the 4S study, they are somewhat less dramatic in that the magnitude of the savings of life and the prevention of MI was smaller and the extent to which cholesterol was lowered was less, it seems that this is a class effect.
"Since meta-analyses have shown that the magnitude of benefit from HMG-CoA reductase treatment, or statin treatment, seems to be proportionate to cholesterol-lowering, one would wish to use high doses, or the most potent agent available. This is a class effect.
"The development of atherosclerotic disease is gradual. The benefit of pravastatin in the West of Scotland is that after six months of treatment there was a statistically significant benefit. That means those men getting benefits from the treatment had established advanced atherosclerotic disease already, which was manifested by a heart attack or death within the first six months of treatment."
Scott Grundy, M.D., director and chairman, Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas
"WOS is one more study that shows that cholesterol-lowering is highly effective for preventing CHD and its complications. This study has to be taken as one of several important studies done recently, and it is particularly in line with the 4S trial, which was a secondary prevention trial that showed if you lower LDL cholesterol, dramatic reduction in coronary in recurrent coronary events follows.
"This trial was a primary prevention trial and similar results were obtained. So I think this is confirmation that dramatic cholesterol-lowering with the statin drugs will significantly reduce coronary events whether in the secondary prevention setting or in the primary prevention setting. The most urgency is for patients in secondary prevention, people who have established coronary disease: they should have their cholesterol lowered, but also high risk patients are candidates for cholesterol lowering drugs.
"The greater the cholesterol lowering the greater the reduction in clinical events. This is been shown by taking all the trials and putting the results together. The more recent trials with the statin drugs, we can lower cholesterol much better than with older drugs, and get much better results.
CONTACT: Merck & Co. Inc., West Point, Pa. | Michael Seggev, 215/652-6931
Terje R. Pedersen, M.D., coordinator of the Scandinavian Simvastatin Survival Study
"This study has major implications for clinical practice, the start of treating high cholesterol in the same dimension as treating hypertension today. The results of the West of Scotland (WOS) study confirm what we observed in the Scandinavian Simavastatin Survival Study, that cholesterol-lowering is of substantial value in reducing the risk of coronary heart disease. These benefits are not isolated to the agent used in the WOS trial."
J. Sanford Schwartz, M.D., executive director of the Leonard Davis Institute of Health Economics at the University of Pennsylvania
"The WOS study is an important study for several reasons. First it confirms and extends previous findings on the impact of cholesterol-lowering on cardiac morbidity and overall mortality. Prior to WOS there have been other trials that showed that if you take patients who have elevated cholesterol and who are at risk coronary heart disease and lower their cholesterol level you can reduce heart attacks and deaths from coronary heart disease.
"Last year 4S demonstrated that in addition to reducing in cardiac morbidity and cardiac mortality, you also get significant increases in overall survival. WOS confirms and extends those findings beyond patients who have coronary heart disease to people with elevated cholesterol and multiple risk factors for heart disease.
"What was demonstrated in 4S and has been demonstrated in the trials is the greater the extent of cholesterol lowering that is achieved the greater the benefit. The National Cholesterol Education Program guidelines recommend treating to goal -- driving cholesterol down to 100 mg/dl in patients with CHD.
"The WOS results that have been made available thus far do not report what level these patients got down to, but they do report a 26 percent reduction in LDL cholesterol. Based on previous trials, one would expect that those patients who achieve a greater reduction in LDL cholesterol will achieve a greater benefit.
"If that's true, that would suggest that drugs that are more effective in lowering cholesterol, like simvastatin, will have an even greater impact. In 4S LDL cholesterol was reduced by 35 percent, as compared to WOS where LDL cholesterol was reduced by 26 percent.
"Most experts believe that these are primarily class effects and that they are a result of primarily if not solely LDL reduction. All the data suggests that the more effectively you lower LDL , the more benefit you'll see. There is no reason to believe that this is only restricted to the drug that was used in WOS.
"My take away for clinicians is that we now have two very well designed, very well run, large randomized clinical trials in the last two years that provide us with rock solid evidence that in patients with elevated cholesterol that have either CHD or multiple risk factors that lowering cholesterol aggressively with statins reduces cardiac mortality, cardiac morbidity and it reduces overall mortality. And therefore, the controversy which is surrounding this area, with these clear results, should really be put to rest.
Suzanne Oparil, professor of medicine at the University of Alabama at Birmingham
"This is a dramatic study. We learned last year from the 4S study that lipid lowering with a statin drug lowers coronary disease mortality, lowers the incidence of non-fatal heart attack, does not adversely affect non-coronary mortality, and therefore, decreased all cause mortality dramatically. Other findings were the need for hospitalizations decreased, the need for revascularization decreased, and cardiovascular endpoints of all causes such as sudden death decreased.
"The 4S study was done in individuals who already had heart attacks -- 92% of them already had heart attacks, the others had angina. One thing the 4S study had that the West of Scotland doesn t is women, and the women seemed to benefit as much as the men, although there were smaller numbers there.
"In the West of Scotland Study, only men were looked at who did not have established myocardial infarction, pre-existing myocardial infarction, and it was shown that lowering cholesterol with pravastatin, which is another statin agent, decreased non-fatal MI or cardiovascular death, coronary heart disease death, by 31% which is a pretty dramatic effect. This was accomplished by lowering total cholesterol by 20% and LDL cholesterol by 26%.
"We believe that the beneficial effects of the statins are related to the cholesterol lowering, there is no evidence for another mechanism although another mechanism has not been ruled out. And it s reasonable to extrapolate that if the cholesterol had been lowered further, that the benefit might have been greater.
"The clinical implications are if you are a man, and you have a high cholesterol level, you probably should be on a cholesterol-lowering agent and at present the statins seem to be the best tolerated of the cholesterol-lowering agents.
"In the literature, cholesterol-lowering with other agents such as resins, has not decreased all cause mortality, suggesting that this may be due to increases in non-cardiovascular mortality with some of the other classes of drugs.
"Statins seem to do nothing adversarial, at least in a high-risk population over a five year follow-up. No major adverse affects were seen with either of the statins over this period of time, which is quite impressive.
"I believe in vigorous cholesterol-lowering with medication. I think one very convincing piece of evidence to practitioners, particularly non-cardiologists, is that cholesterol-lowering does have a beneficial effect in the prevention of fatal cardiovascular events. It should extend the use of these agents (statins) to patients who have very high risk because they have very high cholesterol levels, but have not had heart attacks.
"Since these results are so similar to the results that were seen in the 4S study, they are somewhat less dramatic in that the magnitude of the savings of life and the prevention of MI was smaller and the extent to which cholesterol was lowered was less, it seems that this is a class effect.
"Since meta-analyses have shown that the magnitude of benefit from HMG-CoA reductase treatment, or statin treatment, seems to be proportionate to cholesterol-lowering, one would wish to use high doses, or the most potent agent available. This is a class effect.
"The development of atherosclerotic disease is gradual. The benefit of pravastatin in the West of Scotland is that after six months of treatment there was a statistically significant benefit. That means those men getting benefits from the treatment had established advanced atherosclerotic disease already, which was manifested by a heart attack or death within the first six months of treatment."
Scott Grundy, M.D., director and chairman, Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas
"WOS is one more study that shows that cholesterol-lowering is highly effective for preventing CHD and its complications. This study has to be taken as one of several important studies done recently, and it is particularly in line with the 4S trial, which was a secondary prevention trial that showed if you lower LDL cholesterol, dramatic reduction in coronary in recurrent coronary events follows.
"This trial was a primary prevention trial and similar results were obtained. So I think this is confirmation that dramatic cholesterol-lowering with the statin drugs will significantly reduce coronary events whether in the secondary prevention setting or in the primary prevention setting. The most urgency is for patients in secondary prevention, people who have established coronary disease: they should have their cholesterol lowered, but also high risk patients are candidates for cholesterol lowering drugs.
"The greater the cholesterol lowering the greater the reduction in clinical events. This is been shown by taking all the trials and putting the results together. The more recent trials with the statin drugs, we can lower cholesterol much better than with older drugs, and get much better results.
CONTACT: Merck & Co. Inc., West Point, Pa. | Michael Seggev, 215/652-6931