- Email: [email protected]
Cholesterol Lowering in the Management of Coronary Artery Disease: The Clinical Implications of Recent Trials
Cholesterol Lowering in the Management of Coronary Artery Disease: The Clinical Implications of Recent Trials Daniel A. Eisenberg, MD
Atherosclerotic vascular disease is the major cause of death and disability in adult men and women living in the United States, where 13–14 million adults have a history of coronary artery disease (CAD). One-third of the 1.5 million individuals who experience a myocardial infarction (MI) each year will die and one half of these deaths will occur within 60 minutes of the event. The relation between elevated serum lipids and CAD has been corroborated by epidemiologic as well as pathologic evidence. Approximately 96 million people have total cholesterol levels >200 mg/dL, with 38 million of these individuals having values >240 mg/ dL. The National Cholesterol Education Program (NCEP) identified elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for CAD in 1988. This conclusion, along with recommendations for assessment and treatment, was reaffirmed in 1993. The NCEP also recommended that high-risk patients, with or without clinical manifestations of coronary atherosclerosis, should substantially lower their serum cholesterol levels. Specifically, the NCEP recommends that patients with CAD need to maintain serum LDL cholesterol levels of ≤ 100 mg/dL; this means that the vast majority of patients need to decrease LDL cholesterol levels by ≥ 30%. Aggressive dietary and/or drug therapy are recommended to achieve these reductions. In recent years, clinical trials have demonstrated the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) in lowering elevated levels of LDL cholesterol and decreasing the risk for clinical coronary events. Am J Med. 1998;104(2A):2S–5S. © 1998 by Excerpta Medica, Inc.
From the Foothill Cardiology/California Medical Group, University of Southern California, Los Angeles, California. Requests for reprints should be addressed to Daniel A. Eisenberg, MD, University of Southern California, Foothill Cardiology/California Heart Care Medical Group, 2601 West Alameda, Suite 304, Burbank, California 91505. 2S © 1998 by Excerpta Medica, Inc. All rights reserved.
I
n 1988, the identification of elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for coronary artery disease (CAD) was made by the National Cholesterol Education Program (NCEP). This conclusion, along with assessment and treatment recommendations was reaffirmed in 1993.1 Despite the general agreement that total cholesterol is a modifiable risk factor for CAD, there remains some disagreement on the best means of achieving cholesterol reduction.
APPROACHES TO LOWERING BLOOD CHOLESTEROL Two major strategies have been proposed for achieving serum cholesterol reduction: high-risk individuals should be identified and receive intensive intervention therapy; alternatively, the distribution of cholesterol levels in the entire population should be shifted to within a lower range. Although these 2 strategies may appear to be at opposite ends of the spectrum, they are better considered as being complementary approaches representing a coordinated strategy for decreasing coronary risk.
CLINICAL DATA The association between the mortality rate from CAD and serum cholesterol levels follows a curvilinear distribution; consequently, there is no established cut-point in the risk of CAD that is attributable to elevated cholesterol levels. Although there is a marked increase in CAD mortality in patients whose serum total cholesterol is .200 mg/dL (5.17 mmol/L), there is increasing risk in each decile above 140 mg/dL (3.62 mmol/L). Therefore, although 200 mg/dL has been defined as being a desirable serum total cholesterol, there is a reduction in risk associated with decreasing serum cholesterol below this level. The Lipid Research Clinics Coronary Primary Prevention Trial The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was the first randomized, doubleblind study to establish conclusively that lowering serum cholesterol decreased the incidence of heart attacks in humans.2,3 All patients in this study followed a moderate cholesterol lowering diet; the treatment group also received daily doses of the lipid-lowering agent cholestyramine, whereas the control group received a placebo.3 Se0002-9343/98/$19.00 PII S0002-9343(98)00038-2
Symposium on Coronary Artery Disease/Eisenberg
rum LDL cholesterol levels in patients who took cholestyramine decreased by 12% compared with the control group; this was associated with a 19% reduction in the incidence of CAD (p ,0.05).3 The Familial Atherosclerosis Treatment Study The Familial Atherosclerosis Treatment Study (FATS) showed that clinical events can be markedly altered by only minimal changes in the diameter of vessel walls.4 In this 6 year study, individuals with very high lipid values, including a high proportion of patients with CAD, were randomly assigned to receive either colestipol and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (“statin”) lovastatin, or colestipol and niacin, or placebo. After 2.5 years, modest decreases in lumen diameter (mean improvement in proximal stenosis per patient was ,1%) were reflected by significant reductions (73% lower) in the incidence of cardiovascular events.5 Three recent trials have substantiated the claim that CAD progression can be altered by therapies that lower levels of serum lipids. All three of these trials used HMGCoA reductase inhibitors to lower serum lipid levels.6 The Scandinavian Simvastatin Survival Study The Scandinavian Simvastatin Survival Study (4S) was a landmark trial that changed the treatment paradigm in CAD by demonstrating that lowering cholesterol levels can significantly decrease the incidence of death from CAD, even in patients who have already experienced a coronary event7 A total of 4,444 patients with either angina pectoris or prior myocardial infarction (MI), and serum cholesterol levels of 213–310 mg/dL (5.5– 8.0 mmol/L), were enrolled in this double-blind study. Patients were followed for .5 years, during which time simvastatin treatment lowered total cholesterol and LDL cholesterol levels by 25% and 35%, respectively— changes that were paralleled by a 42% reduction in the incidence of death from CAD (Figure 1). The impact of cholesterol lowering was first evident after 1 year of statin therapy. The 4S was the first major trial to show that cholesterol lowering decreases the incidence of major coronary events in both men and women. Patients who were smokers, hypertensives, or diabetics also benefited from lipidlowering therapy. Coronary event reduction was seen across all baseline LDL cholesterol levels. Further subanalysis of the data revealed significant survival benefits for elderly patients; this group experienced a significant reduction in the incidence of MI and other coronary events. These results have particular relevance for the United States, where CAD is now the primary disease afflicting the elderly and is the number one cause of their death and disability, accounting for 75% of all coronary deaths. Although the incidence of death from CAD has
Figure 1. Scandinavian Simvastatin Survival Study (4S): allcause mortality in simvastatin-treated and placebo-treated groups.
decreased in the United States, the total number of deaths from CAD has actually begun to increase after a prior steady decline; this is probably a result of an increasing proportion of middle-aged and elderly individuals in the population. The West of Scotland Coronary Prevention Study The West of Scotland (WOSCOPS) Coronary Prevention Study demonstrated that the incidence of nonfatal MI and death from CAD could be decreased by reducing cholesterol levels with the HMG-CoA reductase inhibitor pravastatin.8 The 6,595 men in this double-blind study were considered to be representative of the general population, with an average age of 45– 64 years, no history of MI, and only moderate hypercholesterolemia (mean LDL cholesterol 192 mg/dL [4.97 mmol/L]). Patients were followed for 3–5 years. Overall, cholesterol levels were lower in patients in the treatment group when compared with those who had received placebo (Figure 2). For example, plasma cholesterol and LDL cholesterol levels were 20% and 26% lower, respectively, whereas corresponding values in the placebo group were unchanged. The risk of death from CAD (definite and suspected) was 33% lower in the group with decreased cholesterol levels compared with the control group (p 5 0.042; Figure 3). There also was a 31% reduction in nonfatal MI (p ,0.001). The Cholesterol and Recurrent Events Study The previous trials clearly demonstrated that lowering cholesterol levels had a significant impact for patients
February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Volume 104 (2A)
3S
Symposium on Coronary Artery Disease/Eisenberg
with hypercholesterolemia. The Cholesterol and Recurrent Events (CARE) trial demonstrated similar benefits in patients with coronary disease who had average LDL cholesterol levels.9 At entry into this double-blind study, 3,583 men and 576 women had total plasma cholesterol values ,240 mg/dL (6.21 mmol/L; mean 209 mg/dL [5.40 mmol/L]), and LDL cholesterol values of 115–174 mg/dL (2.97– 4.50 mmol/L; mean 139 mg/dL [3.59 mmol/L]). Cholesterol levels in most CAD patients who survive myocardial infarction are ,240 mg/dL. After patients were treated with a cholesterol-lowering drug, pravastatin, mean LDL cholesterol levels decreased to 97–98 mg/dL (2.51–2.53 mmol/L)—a 32% reduction that yielded a final mean LDL cholesterol concentration consistent with NCEP treatment goals. Laboratory values were maintained throughout the 5 years of study followup. Cholesterol levels in the treatment group were 28% lower than those in placebo-treated patients and demonstrated a significant reduction in the incidence of fatal coronary events and nonfatal MI (24% risk reduction, p 5 0.003; Figure 4). The individual risk reductions for these events were 20% (p 5 0.10) and 23% (p 5 0.02), respectively. The benefits of cholesterol lowering were first measurable 12–18 months after initiation of therapy.
Figure 2. West of Scotland Coronary Prevention Study (WOSCOPS): effects of pravastatin therapy on plasma LDL cholesterol levels. LDL 5 low-density lipoprotein. (Adapted with permission from N Engl J Med.8)
CONCLUSIONS One in 5 men, and 1 in 17 women living in the United States will eventually develop CAD, the financial costs of which are staggering. Estimates for 1996 alone are in excess of $60 billion. The evidence summarized above clearly establishes that cholesterol lowering with an HMG-CoA reductase inhibitor can alter the natural history of CAD in a number of diverse populations, including those patients who have already experienced a coronary event. At this time, national treatment and practice patterns do not parallel the treatment guidelines established by the NCEP.2 Consequently, most individuals who have hypercholesterolemia do not receive any treatment. Only 1 of 4 of those who need lipid-lowering therapy actually receive it, and, only 4% of those identified as requiring treatment actually reach target cholesterol levels. In a group of 2,000 patients requiring treatment, this would mean that only 500 patients (25%) would be identified and given cholesterol-lowering therapy, of which only 125 would reach their NCEP goal for LDL cholesterol. With the introduction of the HMG-CoA reductase inhibitors, we have now entered an era of safe and effective lipid-lowering therapy. Statins are now first-line drug therapy for the primary and secondary prevention of CAD. As summarized in Figure 5, the clinical benefits from lipid-lowering therapy seem to be proportionate to the magnitude of the reduction. Clinical benefit has been demonstrated in a variety of patient populations including women, the elderly, smokers, hypertensives, diabet4S February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Figure 3. West of Scotland Coronary Prevention Study (WOSCOPS). Time to nonfatal myocardial infarction or coronary artery disease death in pravastatin-treated and placebotreated groups. (Adapted with permission from N Engl J Med.8)
Figure 4. The Cholesterol and Recurrent Events (CARE) study. Incidence of coronary events in pravastatin-treated and placebo-treated groups. (Adapted with permission from N Engl J Med.9)
Volume 104 (2A)
Symposium on Coronary Artery Disease/Eisenberg
more potent HMG-CoA reductase inhibitors may have even greater clinical benefit than the currently available agents.
REFERENCES
Figure 5. Future goals: decrease LDL cholesterol to reduce CAD risk. 4S 5 Scandinavian Simvastatin Survival Study; CARE 5 Cholesterol and Recurrent Events trial; CAD 5 coronary artery disease; LDL 5 low-density lipoprotein; LRC-CPPT 5 Lipid Research Clinics Coronary Primary Prevention Trial; MI 5 myocardial infarction; WOSCOPS 5 West of Scotland Coronary Prevention Study.
ics, and patients with impaired left ventricular function. The 10 –13% lipid reduction in the LRC-CPPT trial after cholestyramine treatment was associated with a 20% reduction in nonfatal MI. Pravastatin reduced lipid levels in the WOS primary prevention trial by .20%, which was reflected by a greater reduction in the incidence of MI than was seen in the LRC-CPPT trial. In the 4S, simvastatin lowered cholesterol levels by 35%, thereby providing the greatest reduction in coronary risk to date. These landmark clinical trials clearly demonstrate the safety and efficacy of statin therapy in decreasing the risk of a first or subsequent coronary event. The introduction of new,
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA. 1993;269:3015–3023. 2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in the incidence of coronary heart disease. JAMA. 1984;251: 351–364. 3. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 251:365–374. 4. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid lowering therapy in men with high levels of apoliprotein B. N Engl J Med. 1990;323:1289 –1298. 5. Brown GB, Zhao X-Q, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781–1791. 6. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal. Drug Safety. 1996;14:11–24. 7. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 8. Shepherd J, Cobbe ST, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307. 9. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335:1001–1009.
February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Volume 104 (2A)
5S
Atherosclerotic vascular disease is the major cause of death and disability in adult men and women living in the United States, where 13–14 million adults have a history of coronary artery disease (CAD). One-third of the 1.5 million individuals who experience a myocardial infarction (MI) each year will die and one half of these deaths will occur within 60 minutes of the event. The relation between elevated serum lipids and CAD has been corroborated by epidemiologic as well as pathologic evidence. Approximately 96 million people have total cholesterol levels >200 mg/dL, with 38 million of these individuals having values >240 mg/ dL. The National Cholesterol Education Program (NCEP) identified elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for CAD in 1988. This conclusion, along with recommendations for assessment and treatment, was reaffirmed in 1993. The NCEP also recommended that high-risk patients, with or without clinical manifestations of coronary atherosclerosis, should substantially lower their serum cholesterol levels. Specifically, the NCEP recommends that patients with CAD need to maintain serum LDL cholesterol levels of ≤ 100 mg/dL; this means that the vast majority of patients need to decrease LDL cholesterol levels by ≥ 30%. Aggressive dietary and/or drug therapy are recommended to achieve these reductions. In recent years, clinical trials have demonstrated the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) in lowering elevated levels of LDL cholesterol and decreasing the risk for clinical coronary events. Am J Med. 1998;104(2A):2S–5S. © 1998 by Excerpta Medica, Inc.
From the Foothill Cardiology/California Medical Group, University of Southern California, Los Angeles, California. Requests for reprints should be addressed to Daniel A. Eisenberg, MD, University of Southern California, Foothill Cardiology/California Heart Care Medical Group, 2601 West Alameda, Suite 304, Burbank, California 91505. 2S © 1998 by Excerpta Medica, Inc. All rights reserved.
I
n 1988, the identification of elevated low-density lipoprotein (LDL) cholesterol as a primary risk factor for coronary artery disease (CAD) was made by the National Cholesterol Education Program (NCEP). This conclusion, along with assessment and treatment recommendations was reaffirmed in 1993.1 Despite the general agreement that total cholesterol is a modifiable risk factor for CAD, there remains some disagreement on the best means of achieving cholesterol reduction.
APPROACHES TO LOWERING BLOOD CHOLESTEROL Two major strategies have been proposed for achieving serum cholesterol reduction: high-risk individuals should be identified and receive intensive intervention therapy; alternatively, the distribution of cholesterol levels in the entire population should be shifted to within a lower range. Although these 2 strategies may appear to be at opposite ends of the spectrum, they are better considered as being complementary approaches representing a coordinated strategy for decreasing coronary risk.
CLINICAL DATA The association between the mortality rate from CAD and serum cholesterol levels follows a curvilinear distribution; consequently, there is no established cut-point in the risk of CAD that is attributable to elevated cholesterol levels. Although there is a marked increase in CAD mortality in patients whose serum total cholesterol is .200 mg/dL (5.17 mmol/L), there is increasing risk in each decile above 140 mg/dL (3.62 mmol/L). Therefore, although 200 mg/dL has been defined as being a desirable serum total cholesterol, there is a reduction in risk associated with decreasing serum cholesterol below this level. The Lipid Research Clinics Coronary Primary Prevention Trial The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was the first randomized, doubleblind study to establish conclusively that lowering serum cholesterol decreased the incidence of heart attacks in humans.2,3 All patients in this study followed a moderate cholesterol lowering diet; the treatment group also received daily doses of the lipid-lowering agent cholestyramine, whereas the control group received a placebo.3 Se0002-9343/98/$19.00 PII S0002-9343(98)00038-2
Symposium on Coronary Artery Disease/Eisenberg
rum LDL cholesterol levels in patients who took cholestyramine decreased by 12% compared with the control group; this was associated with a 19% reduction in the incidence of CAD (p ,0.05).3 The Familial Atherosclerosis Treatment Study The Familial Atherosclerosis Treatment Study (FATS) showed that clinical events can be markedly altered by only minimal changes in the diameter of vessel walls.4 In this 6 year study, individuals with very high lipid values, including a high proportion of patients with CAD, were randomly assigned to receive either colestipol and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (“statin”) lovastatin, or colestipol and niacin, or placebo. After 2.5 years, modest decreases in lumen diameter (mean improvement in proximal stenosis per patient was ,1%) were reflected by significant reductions (73% lower) in the incidence of cardiovascular events.5 Three recent trials have substantiated the claim that CAD progression can be altered by therapies that lower levels of serum lipids. All three of these trials used HMGCoA reductase inhibitors to lower serum lipid levels.6 The Scandinavian Simvastatin Survival Study The Scandinavian Simvastatin Survival Study (4S) was a landmark trial that changed the treatment paradigm in CAD by demonstrating that lowering cholesterol levels can significantly decrease the incidence of death from CAD, even in patients who have already experienced a coronary event7 A total of 4,444 patients with either angina pectoris or prior myocardial infarction (MI), and serum cholesterol levels of 213–310 mg/dL (5.5– 8.0 mmol/L), were enrolled in this double-blind study. Patients were followed for .5 years, during which time simvastatin treatment lowered total cholesterol and LDL cholesterol levels by 25% and 35%, respectively— changes that were paralleled by a 42% reduction in the incidence of death from CAD (Figure 1). The impact of cholesterol lowering was first evident after 1 year of statin therapy. The 4S was the first major trial to show that cholesterol lowering decreases the incidence of major coronary events in both men and women. Patients who were smokers, hypertensives, or diabetics also benefited from lipidlowering therapy. Coronary event reduction was seen across all baseline LDL cholesterol levels. Further subanalysis of the data revealed significant survival benefits for elderly patients; this group experienced a significant reduction in the incidence of MI and other coronary events. These results have particular relevance for the United States, where CAD is now the primary disease afflicting the elderly and is the number one cause of their death and disability, accounting for 75% of all coronary deaths. Although the incidence of death from CAD has
Figure 1. Scandinavian Simvastatin Survival Study (4S): allcause mortality in simvastatin-treated and placebo-treated groups.
decreased in the United States, the total number of deaths from CAD has actually begun to increase after a prior steady decline; this is probably a result of an increasing proportion of middle-aged and elderly individuals in the population. The West of Scotland Coronary Prevention Study The West of Scotland (WOSCOPS) Coronary Prevention Study demonstrated that the incidence of nonfatal MI and death from CAD could be decreased by reducing cholesterol levels with the HMG-CoA reductase inhibitor pravastatin.8 The 6,595 men in this double-blind study were considered to be representative of the general population, with an average age of 45– 64 years, no history of MI, and only moderate hypercholesterolemia (mean LDL cholesterol 192 mg/dL [4.97 mmol/L]). Patients were followed for 3–5 years. Overall, cholesterol levels were lower in patients in the treatment group when compared with those who had received placebo (Figure 2). For example, plasma cholesterol and LDL cholesterol levels were 20% and 26% lower, respectively, whereas corresponding values in the placebo group were unchanged. The risk of death from CAD (definite and suspected) was 33% lower in the group with decreased cholesterol levels compared with the control group (p 5 0.042; Figure 3). There also was a 31% reduction in nonfatal MI (p ,0.001). The Cholesterol and Recurrent Events Study The previous trials clearly demonstrated that lowering cholesterol levels had a significant impact for patients
February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Volume 104 (2A)
3S
Symposium on Coronary Artery Disease/Eisenberg
with hypercholesterolemia. The Cholesterol and Recurrent Events (CARE) trial demonstrated similar benefits in patients with coronary disease who had average LDL cholesterol levels.9 At entry into this double-blind study, 3,583 men and 576 women had total plasma cholesterol values ,240 mg/dL (6.21 mmol/L; mean 209 mg/dL [5.40 mmol/L]), and LDL cholesterol values of 115–174 mg/dL (2.97– 4.50 mmol/L; mean 139 mg/dL [3.59 mmol/L]). Cholesterol levels in most CAD patients who survive myocardial infarction are ,240 mg/dL. After patients were treated with a cholesterol-lowering drug, pravastatin, mean LDL cholesterol levels decreased to 97–98 mg/dL (2.51–2.53 mmol/L)—a 32% reduction that yielded a final mean LDL cholesterol concentration consistent with NCEP treatment goals. Laboratory values were maintained throughout the 5 years of study followup. Cholesterol levels in the treatment group were 28% lower than those in placebo-treated patients and demonstrated a significant reduction in the incidence of fatal coronary events and nonfatal MI (24% risk reduction, p 5 0.003; Figure 4). The individual risk reductions for these events were 20% (p 5 0.10) and 23% (p 5 0.02), respectively. The benefits of cholesterol lowering were first measurable 12–18 months after initiation of therapy.
Figure 2. West of Scotland Coronary Prevention Study (WOSCOPS): effects of pravastatin therapy on plasma LDL cholesterol levels. LDL 5 low-density lipoprotein. (Adapted with permission from N Engl J Med.8)
CONCLUSIONS One in 5 men, and 1 in 17 women living in the United States will eventually develop CAD, the financial costs of which are staggering. Estimates for 1996 alone are in excess of $60 billion. The evidence summarized above clearly establishes that cholesterol lowering with an HMG-CoA reductase inhibitor can alter the natural history of CAD in a number of diverse populations, including those patients who have already experienced a coronary event. At this time, national treatment and practice patterns do not parallel the treatment guidelines established by the NCEP.2 Consequently, most individuals who have hypercholesterolemia do not receive any treatment. Only 1 of 4 of those who need lipid-lowering therapy actually receive it, and, only 4% of those identified as requiring treatment actually reach target cholesterol levels. In a group of 2,000 patients requiring treatment, this would mean that only 500 patients (25%) would be identified and given cholesterol-lowering therapy, of which only 125 would reach their NCEP goal for LDL cholesterol. With the introduction of the HMG-CoA reductase inhibitors, we have now entered an era of safe and effective lipid-lowering therapy. Statins are now first-line drug therapy for the primary and secondary prevention of CAD. As summarized in Figure 5, the clinical benefits from lipid-lowering therapy seem to be proportionate to the magnitude of the reduction. Clinical benefit has been demonstrated in a variety of patient populations including women, the elderly, smokers, hypertensives, diabet4S February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Figure 3. West of Scotland Coronary Prevention Study (WOSCOPS). Time to nonfatal myocardial infarction or coronary artery disease death in pravastatin-treated and placebotreated groups. (Adapted with permission from N Engl J Med.8)
Figure 4. The Cholesterol and Recurrent Events (CARE) study. Incidence of coronary events in pravastatin-treated and placebo-treated groups. (Adapted with permission from N Engl J Med.9)
Volume 104 (2A)
Symposium on Coronary Artery Disease/Eisenberg
more potent HMG-CoA reductase inhibitors may have even greater clinical benefit than the currently available agents.
REFERENCES
Figure 5. Future goals: decrease LDL cholesterol to reduce CAD risk. 4S 5 Scandinavian Simvastatin Survival Study; CARE 5 Cholesterol and Recurrent Events trial; CAD 5 coronary artery disease; LDL 5 low-density lipoprotein; LRC-CPPT 5 Lipid Research Clinics Coronary Primary Prevention Trial; MI 5 myocardial infarction; WOSCOPS 5 West of Scotland Coronary Prevention Study.
ics, and patients with impaired left ventricular function. The 10 –13% lipid reduction in the LRC-CPPT trial after cholestyramine treatment was associated with a 20% reduction in nonfatal MI. Pravastatin reduced lipid levels in the WOS primary prevention trial by .20%, which was reflected by a greater reduction in the incidence of MI than was seen in the LRC-CPPT trial. In the 4S, simvastatin lowered cholesterol levels by 35%, thereby providing the greatest reduction in coronary risk to date. These landmark clinical trials clearly demonstrate the safety and efficacy of statin therapy in decreasing the risk of a first or subsequent coronary event. The introduction of new,
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA. 1993;269:3015–3023. 2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in the incidence of coronary heart disease. JAMA. 1984;251: 351–364. 3. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 251:365–374. 4. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid lowering therapy in men with high levels of apoliprotein B. N Engl J Med. 1990;323:1289 –1298. 5. Brown GB, Zhao X-Q, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781–1791. 6. Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: a reappraisal. Drug Safety. 1996;14:11–24. 7. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. 8. Shepherd J, Cobbe ST, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307. 9. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335:1001–1009.
February 23, 1998
THE AMERICAN JOURNAL OF MEDICINEt
Volume 104 (2A)
5S