- Email: [email protected]
In the statin era, how important are intense lifestyle changes?
Journal of the American College of Cardiology © 2003 by the American College of Cardiology Foundation Published by Elsevier Science Inc.
EDITORIAL COMMENT
In the Statin Era, How Important Are Intense Lifestyle Changes?* William W. Parmley, MD, MACC San Francisco, California The patient sitting across from me in my office seems to have lipids controlled with a reasonable diet and a daily statin. He asks, “Doctor, can I have an occasional steak, and an occasional hot fudge sundae?” As a believer in the importance of quality of life, I am likely to concur with such a request. In my mind I am probably rationalizing that the statin will easily cover such indiscretions because of its powerful effects in both primary and secondary prevention. In this issue of the Journal, Sdringola et al. (1) suggest that my attitude may be too cavalier. They make a case for intense lifestyle changes bringing added benefit to patients on top of statin therapy. A total of 409 consecutive unselected patients with coronary artery disease (CAD) had baseline positron emission tomography imaging, repeat imaging at about two and half years, with additional follow-up for five more years. The level of treatment during this time was classified as: poor ⫽ no dietary control or lipid-active drugs; moderate ⫽ American Heart Association See page 263 diet plus lipid-lowering drugs or on a strict low fat diet (⬍10% of calories); and maximal ⫽ diet (⬍10% of calories as fat), regular exercise, weight loss, monthly follow-up, and lipid-active drugs dosed to target cholesterol goals (LDL [low-density lipoprotein] ⬍90 mg/dl). Over the five-year period, coronary events occurred in 6.6%, 20.3%, and 30.6% of patients in the maximal, moderate, and poor treatment groups, respectively. This data is first of all an affirmation that lipid-lowering is beneficial in reducing coronary events. Similarly, lipid-lowering improved myocardial perfusion judged by PET scan (2). This effect presumably occurred by improved endothelial function and/or plaque regression. The new question of importance, however, is the potential independent benefit from intense lifestyle changes (3). One of the difficulties in answering the question posed by Sdringola et al. (1) is that this was not a randomized trial. In their introduction, the investigators make a compelling case as to why randomization would be difficult if not impossible. Nevertheless, this remains a major problem with the present study. We have recent examples of how observational studies have been strongly contradicted by subsequent prospective, placebo-controlled, randomized trials. Obser*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Division, University of California, San Francisco, California.
Vol. 41, No. 2, 2003 ISSN 0735-1097/03/$30.00 PII S0735-1097(02)02692-X
vational studies of vitamin E intake strongly suggested benefit from taking this antioxidant vitamin (4 – 6). The rationale seemed intuitive that an antioxidant vitamin would counter the adverse effects of oxidized LDL cholesterol. However, the large placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) (7) and Heart Protection Studies (8) failed to show any benefit from vitamin E. In a similar way, observational studies of hormone replacement therapy (HRT) have suggested considerable benefit in protecting postmenopausal women from cardiovascular events (9 –11). Again, the rationale seems indisputable. Prior to menopause the female hormones seem to be protective, by a number of mechanisms, thus explaining the higher risk in men. After menopause there is a catch-up phenomenon, whereby women have more events than men, a sequence so easily explained by the loss of their protective hormones. Thus, it was quite a surprise when the Heart and Estrogen/progestin Replacement Study (HERS) (12) and the Women’s Health Initiative (13) failed to show protection with HRT in women, and in fact were suggestive of harm. These two recent examples remind us of a major pitfall of nonrandomized observational studies: you simply cannot control for, or know, all of the variables that affect outcome. In the two observational examples cited above, the patients who benefited from vitamin E (4 – 6) or HRT (9 –11) were probably doing other “healthy things,” which improved the outcome. In the present trial (1), intense lifestyle changes may have been the other “healthy things” that improved the outcome, but we cannot prove it by this study design. Missing data in this study are the baseline lipids, although there is a similar distribution of patients in the three groups, those who have “hypercholesterolemia,” hypertriglyceridemia,” and “low high-density lipoprotein (HDL).” When examining the follow-up lipid data, the simplest explanation for the difference in clinical events is the difference in lipids (Table 2 in Sdringola et al. [1]). For the maximal, moderate, and poor treatment groups the total cholesterol levels were 140, 184, and 226 mg%, and the LDL cholesterol levels were 74, 111, and 143 mg%, respectively. This leaves the unanswered question: If lipid levels were the same in all three groups (by adjusting statins), would there have been a similar clinical event rate? In other words, is lowering lipids by intense lifestyle changes to the same extent as statins equally protective? Another question related to the study by Sdringola et al. (1) is whether all the benefit is related to the level of lipids achieved. In the Scandinavian Simvastatin Survival Study (4S) study with simvastatin in patients with known vascular disease and very high levels of LDL cholesterol, there was a similar percentage reduction in clinical events in patients from all quartiles of initial LDL cholesterol (14). Conversely, in the Cholesterol And Recurrent Events (CARE) trial (15) postmyocardial infarction, it appeared that pravachol was beneficial only in patients with an initial baseline
274
Parmley Editorial Comment
LDL cholesterol ⬎125 mg%. However, in the much larger Heart Protection Study (16) there was an equal percent benefit from simvastatin in each tertile of LDL cholesterol, including patients who started below 100 mg%. This suggests that LDL goal levels may be overemphasized since the use of statins may be the key. This may reflect other beneficial effects of statins, such as anti-inflammatory and antithrombotic effects, among other benefits. Relative to the present study, the use of statins in the maximal, moderate, and poor treatment groups was 89%, 64%, and 15%, respectively. Thus, the markedly differing use of statins may have played a role in the results cited by the investigators (1). In contrast, intense lifestyle changes such as exercise, diet, and weight loss may also have other independent benefits besides lowering cholesterol. Conclusions. In summary, the study by Sdringola et al. (1) is very important in emphasizing the benefit of lifestyle changes and risk factor reduction along with lipidlowering therapy. It seems reasonable to employ a broadbased approach to both primary and secondary prevention, rather than to depend only on a pill. Because the study by Sdringola et al. (1) was not randomized, it cannot unequivocally prove the added benefit of lifestyle changes. Nevertheless, I agree with the investigators in their important findings that a combination of lifestyle changes and lipidlowering therapy caused an optimal reduction in clinical events. Reprint requests and correspondence: Dr. William W. Parmley, University of California, San Francisco, Cardiology Division, 350 Parnassus, Room 709, San Francisco, California 94143-0124. E-mail: [email protected].
REFERENCES 1. Sdringola S, Nakagawa K, Nakagawa Y, et al. Combined intense lifestyle and pharmacologic lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared to usual care cholesterol-lowering drugs in coronary artery disease. J Am Coll Cardiol 2003;41:263–72.
JACC Vol. 41, No. 2, 2003 January 15, 2003:273–4 2. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. Circulation 1994;89:1530 –8. 3. Gould KL, Ornish D, Scherwitz L, et al. Changes in myocardial perfusion abnormalities by positron emission tomography after longterm, intense risk factor modification. JAMA 1995;274:894 –901. 4. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444 –9. 5. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450 –6. 6. Knekt P, Reunanen A, Jarvinen R, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180 –9. 7. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high risk patients. HOPE Study Group. N Engl J Med 2000;342:154 –60. 8. MRC/BHF. Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:23–33. 9. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–41. 10. Psaty BM, Heckbert SR, Atkins D, et al. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994;154:1333–9. 11. Petitti D, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol 1987;70:289 –93. 12. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/ progestin Replacement Study follow-up (HERS II). JAMA 2002;288: 49 –57. 13. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. 14. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4,444 patients with coronary artery disease: the 4S Trial. Lancet 1994;344:1383–9. 15. Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. 16. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7–22.
EDITORIAL COMMENT
In the Statin Era, How Important Are Intense Lifestyle Changes?* William W. Parmley, MD, MACC San Francisco, California The patient sitting across from me in my office seems to have lipids controlled with a reasonable diet and a daily statin. He asks, “Doctor, can I have an occasional steak, and an occasional hot fudge sundae?” As a believer in the importance of quality of life, I am likely to concur with such a request. In my mind I am probably rationalizing that the statin will easily cover such indiscretions because of its powerful effects in both primary and secondary prevention. In this issue of the Journal, Sdringola et al. (1) suggest that my attitude may be too cavalier. They make a case for intense lifestyle changes bringing added benefit to patients on top of statin therapy. A total of 409 consecutive unselected patients with coronary artery disease (CAD) had baseline positron emission tomography imaging, repeat imaging at about two and half years, with additional follow-up for five more years. The level of treatment during this time was classified as: poor ⫽ no dietary control or lipid-active drugs; moderate ⫽ American Heart Association See page 263 diet plus lipid-lowering drugs or on a strict low fat diet (⬍10% of calories); and maximal ⫽ diet (⬍10% of calories as fat), regular exercise, weight loss, monthly follow-up, and lipid-active drugs dosed to target cholesterol goals (LDL [low-density lipoprotein] ⬍90 mg/dl). Over the five-year period, coronary events occurred in 6.6%, 20.3%, and 30.6% of patients in the maximal, moderate, and poor treatment groups, respectively. This data is first of all an affirmation that lipid-lowering is beneficial in reducing coronary events. Similarly, lipid-lowering improved myocardial perfusion judged by PET scan (2). This effect presumably occurred by improved endothelial function and/or plaque regression. The new question of importance, however, is the potential independent benefit from intense lifestyle changes (3). One of the difficulties in answering the question posed by Sdringola et al. (1) is that this was not a randomized trial. In their introduction, the investigators make a compelling case as to why randomization would be difficult if not impossible. Nevertheless, this remains a major problem with the present study. We have recent examples of how observational studies have been strongly contradicted by subsequent prospective, placebo-controlled, randomized trials. Obser*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Division, University of California, San Francisco, California.
Vol. 41, No. 2, 2003 ISSN 0735-1097/03/$30.00 PII S0735-1097(02)02692-X
vational studies of vitamin E intake strongly suggested benefit from taking this antioxidant vitamin (4 – 6). The rationale seemed intuitive that an antioxidant vitamin would counter the adverse effects of oxidized LDL cholesterol. However, the large placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) (7) and Heart Protection Studies (8) failed to show any benefit from vitamin E. In a similar way, observational studies of hormone replacement therapy (HRT) have suggested considerable benefit in protecting postmenopausal women from cardiovascular events (9 –11). Again, the rationale seems indisputable. Prior to menopause the female hormones seem to be protective, by a number of mechanisms, thus explaining the higher risk in men. After menopause there is a catch-up phenomenon, whereby women have more events than men, a sequence so easily explained by the loss of their protective hormones. Thus, it was quite a surprise when the Heart and Estrogen/progestin Replacement Study (HERS) (12) and the Women’s Health Initiative (13) failed to show protection with HRT in women, and in fact were suggestive of harm. These two recent examples remind us of a major pitfall of nonrandomized observational studies: you simply cannot control for, or know, all of the variables that affect outcome. In the two observational examples cited above, the patients who benefited from vitamin E (4 – 6) or HRT (9 –11) were probably doing other “healthy things,” which improved the outcome. In the present trial (1), intense lifestyle changes may have been the other “healthy things” that improved the outcome, but we cannot prove it by this study design. Missing data in this study are the baseline lipids, although there is a similar distribution of patients in the three groups, those who have “hypercholesterolemia,” hypertriglyceridemia,” and “low high-density lipoprotein (HDL).” When examining the follow-up lipid data, the simplest explanation for the difference in clinical events is the difference in lipids (Table 2 in Sdringola et al. [1]). For the maximal, moderate, and poor treatment groups the total cholesterol levels were 140, 184, and 226 mg%, and the LDL cholesterol levels were 74, 111, and 143 mg%, respectively. This leaves the unanswered question: If lipid levels were the same in all three groups (by adjusting statins), would there have been a similar clinical event rate? In other words, is lowering lipids by intense lifestyle changes to the same extent as statins equally protective? Another question related to the study by Sdringola et al. (1) is whether all the benefit is related to the level of lipids achieved. In the Scandinavian Simvastatin Survival Study (4S) study with simvastatin in patients with known vascular disease and very high levels of LDL cholesterol, there was a similar percentage reduction in clinical events in patients from all quartiles of initial LDL cholesterol (14). Conversely, in the Cholesterol And Recurrent Events (CARE) trial (15) postmyocardial infarction, it appeared that pravachol was beneficial only in patients with an initial baseline
274
Parmley Editorial Comment
LDL cholesterol ⬎125 mg%. However, in the much larger Heart Protection Study (16) there was an equal percent benefit from simvastatin in each tertile of LDL cholesterol, including patients who started below 100 mg%. This suggests that LDL goal levels may be overemphasized since the use of statins may be the key. This may reflect other beneficial effects of statins, such as anti-inflammatory and antithrombotic effects, among other benefits. Relative to the present study, the use of statins in the maximal, moderate, and poor treatment groups was 89%, 64%, and 15%, respectively. Thus, the markedly differing use of statins may have played a role in the results cited by the investigators (1). In contrast, intense lifestyle changes such as exercise, diet, and weight loss may also have other independent benefits besides lowering cholesterol. Conclusions. In summary, the study by Sdringola et al. (1) is very important in emphasizing the benefit of lifestyle changes and risk factor reduction along with lipidlowering therapy. It seems reasonable to employ a broadbased approach to both primary and secondary prevention, rather than to depend only on a pill. Because the study by Sdringola et al. (1) was not randomized, it cannot unequivocally prove the added benefit of lifestyle changes. Nevertheless, I agree with the investigators in their important findings that a combination of lifestyle changes and lipidlowering therapy caused an optimal reduction in clinical events. Reprint requests and correspondence: Dr. William W. Parmley, University of California, San Francisco, Cardiology Division, 350 Parnassus, Room 709, San Francisco, California 94143-0124. E-mail: [email protected].
REFERENCES 1. Sdringola S, Nakagawa K, Nakagawa Y, et al. Combined intense lifestyle and pharmacologic lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared to usual care cholesterol-lowering drugs in coronary artery disease. J Am Coll Cardiol 2003;41:263–72.
JACC Vol. 41, No. 2, 2003 January 15, 2003:273–4 2. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. Circulation 1994;89:1530 –8. 3. Gould KL, Ornish D, Scherwitz L, et al. Changes in myocardial perfusion abnormalities by positron emission tomography after longterm, intense risk factor modification. JAMA 1995;274:894 –901. 4. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444 –9. 5. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450 –6. 6. Knekt P, Reunanen A, Jarvinen R, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180 –9. 7. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high risk patients. HOPE Study Group. N Engl J Med 2000;342:154 –60. 8. MRC/BHF. Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:23–33. 9. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–41. 10. Psaty BM, Heckbert SR, Atkins D, et al. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994;154:1333–9. 11. Petitti D, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol 1987;70:289 –93. 12. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/ progestin Replacement Study follow-up (HERS II). JAMA 2002;288: 49 –57. 13. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. 14. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4,444 patients with coronary artery disease: the 4S Trial. Lancet 1994;344:1383–9. 15. Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. 16. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7–22.