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Secondary Prevention of Cardiovascular Disease in the Very Old—A Good Idea Whose Time Has Come
General Cardiology
Secondary Prevention of Cardiovascular Disease in the Very Old—A Good Idea Whose Time Has Come
Focused Review tion of percutaneous interventions or coronary artery bypass graft (CABC) surgery addressed, as these typically are indicated for symptomatic improvement rather than survival benefit.
Nanette K. Wenger, MD, Emory University School of Medicine, Cardiology, Grady Memorial Hospital, Atlanta, Georgia
Smoking Cessation At least half of the decline in overall mortality of 25–50% with smoking cessation following MI is evident in the first year. Important for elderly patients is that benefits of smoking cessation often accrue promptly. Data from the Coronary Artery Surgery Study (CASS) indicate comparable benefit of smoking cessation for morbidity and mortality rates in patients younger and older than age 70 following CABG surgery, with no attenuation of smoking-cessation benefits at advanced age. Inpatient smoking-cessation counseling after MI among smoking Medicare patients decreased immediate and long-term mortality rates. Comparable smoking-cessation interventions appear effective at younger and elderly age and include physician advice, behavioral counseling, buddy support systems, self-help materials, telephone counseling, and use of pharmacologic therapies. Both nicotine replacement therapy and other pharmacologic agents are well tolerated by elderly individuals. Smoking cessation translates into a reduction in cardiovascular morbidity and mortality at least equal to that of other preventive measures such as aspirin or beta-blocker therapy. The 36% reduction in overall mortality resulting from smoking cessation appears greater than that derived from other standard therapies including aspirin, betablockers or ACE inhibitors.
Chronic coronary heart disease (CHD) is present in 217 per 1000 men and 129 per 1000 women older than 75 years of age. Although octogenarians currently comprise about 5% of the US population they represent 20% of all myocardial infarction (MI) hospitalizations and 30% of all MI-related hospital deaths. Approximately 80% of all mortality due to cardiovascular disease occurs in patients older than 65 years of age. Thus, secondary preventive measures are of paramount importance for elderly patients.
Magnitude of the Problem Although almost half of all US octogenarians have some manifestation of cardiovascular illness, they remain underrepresented in or excluded from clinical trials of cardiovascular prevention. The suboptimal representation of patients older than age 65 in randomized studies has resulted in fewer data about the effectiveness of various strategies for elderly patients and virtual absence of clinical trial data for the octogenarian population. Where then does extrapolation appear appropriate to guide clinicians caring for octogenarian patients, given the small numbers of very elderly participants in clinical trials? In the Cardiovascular Health Study (CHS), the prevalence of subclinical atherosclerosis in this population older than 65 years was more than 30%, and it increased further with advancing age, challenging the differentiation of primary and secondary prevention, particularly in octogenarians. Elderly individuals with subclinical evidence of CHD—abnormal ankle-brachial index, ECG abnormalities, echocardiographic abnormalities, abnormal ultrasonographic carotid intima-media thickness, among others— likely warrant management for secondary prevention. A 2002 Scientific Statement from the American Heart Association, “Secondary Prevention of Coronary Heart Disease in the Elderly (with emphasis on patients ⱖ75 years),” advocates control of cigarette smoking, hypertension, abnormal blood lipids, elevated blood glucose, obesity, psychological concerns and physical inactivity as similarly effective as in younger patients. This review does not address the use of aspirin, betablocker therapy and angiotensin-converting enzyme (ACE) inhibitor use, which is recommended for all CHD patients without specific contraindications. Neither is the applica-
Heart-Healthy Diet In the Hale Project, conducted in 11 European countries, adherence to a Mediterranean diet and healthy lifestyle in women and men aged 70 to 90 years was associated with a more than 50% reduction in all-cause and cardiovascular mortality. Addition of soluble fiber to the diet can reduce lowdensity lipoprotein-cholesterol (LDL-C) by up to 20%, without significant impact on high-density lipoproteincholesterol (HDL-C); use of soluble fiber is particularly relevant for elderly patients predisposed to constipation and colon disease.
Obesity/Weight Management The nationwide increase in the prevalence of obesity is likely to result in larger numbers of elderly individuals having the metabolic syndrome, which increases cardiovascular risk. Metabolic syndrome is currently present in more than 40% of elderly persons in the US.
ACC CURRENT JOURNAL REVIEW September 2005 © 2005 by the American College of Cardiology Foundation Published by American College of Cardiology Foundation
11
1062-1458/05/$30.00 10.1016/j.accreview.2005.08.119
Because of the prominent clustering of dyslipidemia, hypertension and insulin resistance in elderly overweight individuals, particularly those with abdominal obesity, weight loss may act as a multifactorial risk-reduction intervention. Weight loss at elderly age related to exercise or dietary regimens effected similar risk-factor improvement and improvement in measures of insulin resistance, suggesting the likelihood of reduction in secondary coronary events. However, few weight-loss studies either of physical activity or of diet involved older patients with CHD.
ical activity than do younger individuals. No significant complications or adverse outcomes of exercise rehabilitation occurred in elderly patients in any study. Moreover, exercise positively impacts coronary risk factors such as obesity, hypertension, dyslipidemia and insulin resistance.
Lipid Management Because of the increased absolute cardiovascular risk at elderly age, lipid-lowering therapy may be more beneficial in moderate to high-risk elderly than in younger patients. Absolute risk reduction in elderly coronary patients with treatment of hypercholesterolemia is greater than that seen at younger age. In a number of randomized clinical trials, pharmacologic lipid control at elderly age effectively reduced cardiovascular events, with benefit of treatment evident as early as the initial year or two of therapy. These benefits are in addition to lifestyle changes that included exercise training and diet. In recent statin studies, intensive lipid lowering in patients older than 65 years of age effectively reduced coronary events and cardiovascular mortality. Identical benefits occurred for those older and younger than 65 years in the Pravastatin Pooling Project. Similar benefit in reduction of major coronary events was evident in coronary patients older and younger than 65 years in the Scandinavian Simvastatin Survival Study (4S). Because mortality rates increase substantially with age, the absolute risk reduction for both all-cause and coronary mortality was twice as great in older patients. In CARE (Cholesterol and Recurrent Events), major coronary events were reduced 19% below age 65 compared with 62% for those older than 65; coronary mortality decreased by 11% in subjects younger than 65 compared with 45% at age older than 65. The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial is the only study specifically to examine the effect of this statin in a population of women and men aged 70 – 82 years. The LDL-C decreased by 34%. Coronary mortality declined by 24% in pravastatin-treated patients, and the risk of recurrent MI was reduced by a fifth with 3 years of therapy. Stroke protection was not evident. The Heart Protection Study, examining patients above and below 65 years of age, showed a significant reduction both for coronary and for cerebrovascular events. Statin use in elderly patients with coronary or vascular disease or diabetes was supported by subgroup analyses of the Heart Protection Study; significant reduction occurred in all-cause mortality and coronary death or nonfatal MI in patients older than 70 years, including those with LDL-C levels ⬍116 mg/dL. Few statin studies involved subjects older than age 75, but there is no evidence for diminishing lipid-lowering effect with age, such that there is no reason that lipidlowering lowering therapy should not be extended to the very elderly as well. In the Treating to New Targets (TNT) trial, with CHD patients enrolled to age 80, age did not significantly interact with benefit. Relevant issues regarding
Physical Activity (Exercise) Recent data suggest that one-fourth of all elderly patients are completely sedentary and about one-half are inadequately active. Studies in both men and women document a lower overall mortality among those with even moderateintensity physical activity done regularly. In the observational Cardiovascular Health Study, which recruited men and women with a mean age of 73 years at enrollment, the level of physical activity independently predicted 5-year survival. An aerobic exercise regimen is recommended in NCEP/ATP-III; in addition to improving functional capacity, exercise training is associated with improvement in lipid levels, which includes a reduction in triglycerides and LDL-C and an increase in HDL-C. Although this is less than the magnitude of benefit seen with lipid-altering drugs, the effects of exercise are additive to pharmacotherapy. Exercise training improves functional capacity from 10 – 60% and reduces myocardial workload with usual activities from 10 –25%; comparable percentage improvement occurs in patients older and younger than 75 years of age, as does improvement in quality of life. In the British Regional Heart study, men with established CHD (albeit a mean age of 63 years) had a significantly decreased risk of all-cause mortality during 5 years of follow-up associated with lightto-moderate physical activity. Physical activity recommendations should address occupational and leisure activities, as well as daily life activities, to allow a diversity of exercise. Particularly after 75 years of age, exercise recommendations should consider comorbidities such as arthritis, pulmonary disease, and peripheral arterial disease. Strength training may improve neuromuscular function and muscular strength and endurance. Participation in cardiac rehabilitation that includes both physical activity and multifactorial risk reduction is optimal. Historically, cardiac rehabilitation has been underutilized by older patients, particularly elderly women, despite comparable benefits evident at younger and elderly age. Because the strength of recommendation of the physician referral is pivotal to subsequent participation, physician recommendations assume major importance. An exercise regimen can improve functional capacity and reduce activity-related symptoms as early as 12 weeks after the initiation of training. Elderly patients achieve significantly greater benefit in total functional scores and life-quality from phys-
ACC CURRENT JOURNAL REVIEW September 2005
12
Blood Pressure Control
pharmacotherapy decisions involve quality of life, concomitant illnesses and remaining life expectancy. The benefit seen in the small percentage of high-risk octogenarians in the Heart Protection Study (HPS) and in the PROSPER trial challenge us to define high risk in the elderly and to treat those with documented cardiovascular disease. Truncation of the Framingham risk score at age 79 poses a challenges for risk ascertainment in octogenarian patients. Statins appear safe and well-tolerated, with a favorable side-effect profile at elderly age. Whether statins exert effects independent of LDL-C lowering remains uncertain. Clinically significant myopathy is uncommon in elderly patients with statin therapy, but has been associated with renal insufficiency. As with all drugs, because of multiple comorbidities and multiple medications used at elderly age, the risk of drug interactions is substantial; thus, statins should be initiated at lower doses at elderly age and titrated to goal LDL-C levels. Fibrates can reduce triglyceride levels as much as 50% and produce a modest increase in HDL-C, but data are not available for patients over 75 years of age. Nicotinic acid (niacin) can lower LDL-C by 10 –15%, triglycerides by 25–30%, and increase HDL-C by 25– 40%. Outcome data are not available for elderly patients. Combination therapies of statin drugs with nicotinic acid and fibrate, as well as the addition of ezetimibe, for LDL-C lowering are not well studied in elderly populations. For statins plus fibrates, close monitoring is warranted for safety concerns. Bile acid sequestrants raise concern in that they inhibit the intestinal absorption of vitamin D, levothyroxin, thiazide diuretics, and other substances important to the management of comorbidities; further, they may worsen constipation. Clinical outcome data are not available for ezetimibe, which has the potential advantage that its coadministration with a statin can enable lower statin doses in elderly highrisk populations yet reach LDL-C goals; LDL-C levels are reduced by 15–20%. The National Cholesterol Education Program Adult Treatment Panel III Update suggests the option of lowering LDL-C to 70 mg/dL for high-risk coronary patients. Recent clinical trials confirmed that high-risk coronary patients are likely to do better with an LDL-C target below 70 mg/dL; a substantial proportion of elderly patients are in this highrisk category, but they have had limited inclusion in the trials that provided an evidence basis for therapy. In the Cardiovascular Health Study, a low level of HDL-C was strongly associated with an increased risk of MI; however, no studies have been reported of interventions designed to raise HDL-C in elderly patients. Lipid management for secondary prevention is a costeffective strategy at elderly age.
Up to 90% of US octogenarians have hypertension, with a substantial percentage having isolated systolic hypertension. Data appear strongest for the benefit of pharmacologic control of isolated systolic hypertension at elderly age. Data are lacking for the benefit of pharmacotherapy of stage 1 hypertension (140 –159 mm Hg systolic blood pressure), but extrapolation of benefit from younger elderly patients appears reasonable. Currently, nearly two-thirds of individuals over 75 years of age have uncontrolled hypertension, using the definition of a systolic blood pressure in excess of 140 mm Hg and/or diastolic blood pressure in excess of 90 mm Hg. Based on meta-analysis, benefits of hypertensive therapy are particularly high in patients aged 60 – 80 years, with greater benefit for stroke and heart failure than for coronary events, although overall mortality is also reduced. The large randomized treatment trials do not allow conclusions for patients older than 80 years, although data from the Systolic Hypertension Europe (SYST-EUR) study and a subgroup metaanalysis of randomized controlled trials support the benefits of therapy. In these studies, benefits of treatment in patients older than 80 years included a significant reduction in the risk of stroke, major cardiovascular events and heart failure, despite lack of reduction of cardiovascular death or total mortality. Nonpharmacologic therapies that include weight reduction, decrease in sodium and alcohol intake, and exercise are more effective in older than younger populations. Conventional pharmacotherapy has favorably impacted cardiovascular mortality and morbidity at elderly age. Cautions for the treating physician are to measure blood pressure both in the seated and standing positions to exclude clinically relevant orthostatic hypotension. As well, postprandial hypotension must be ascertained. In the initial ascertainment of hypertension, blood pressure measurement must be meticulous to exclude psuedohypertension. Application of pharmacologic agents, which might include diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, and/or calcium channel blockers, must begin at low doses with gradual increments in dosage. Attention must be directed to identifying comorbidities that might limit the use of each of these classes of therapy.
Diabetes Both diabetes and insulin resistance increase with increasing age, particularly in association with abdominal obesity. Exercise improves insulin resistance and diabetic control, likely related more to its effect on body fat than on fitness per se. Nutritional counseling should emphasize control of obesity. Patients with CHD should have examination of blood glucose levels for undiagnosed diabetes, and surveillance of individuals already treated should have a goal for hemoglobin A1c of less than 7%.
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Table 1. Risk Intervention at Elderly Age
Despite poor definition of optimal weight-loss strategies at elderly age, management of diabetes through dietary modification, exercise and medications remains similar across age strata.
Psychosocial Interventions Depression has an adverse effect on the morbidity, mortality and functional recovery of patients with cardiovascular disease. Ten percent to 15% of elderly patients are depressed, and a greater percentage have significant anxiety. Elderly patients should be evaluated for depression and offered appropriate management. Social support and social isolation have also been associated with excessive morbidity and mortality in elderly men and women with CHD; interventions to reduce depression and social isolation in an NHLBI study (ENRICHD) with half of patients older than age 65 did not alter outcomes. Elderly patients are particularly prone to depression and social isolation, and their frequently lower socioeconomic status may negatively affect participation in cardiac rehabilitation programs and compliance with medical advice and therapy.
Intervention
Reduction in Mortality
Reduction in Morbidity
Smoking cessation Exercise Therapy of dyslipidemia Therapy of hypertension Control of diabetes mellitus Heart-healthy diet Control of obesity Psychosocial interventions
Yes Yes Yes Yes Yes Yes Uncertain Uncertain
Yes Uncertain Yes Yes Yes Uncertain Uncertain Uncertain
Questions and Answers 1. My octogenarian patient with MI has been smoking for decades. Why should he stop? Half of the 25–50% decrease in mortality with smoking cessation after MI occurs in the first year. Mortality reduction with smoking cessation is equal to or greater than that with aspirin, beta-blockers or ACE inhibitors. 2. Elderly patients are set in their habits. Do diet and lifestyle changes truly matter? Men and women aged 70 –90 had a ⬎50% decrease in all-cause and cardiovascular mortality with adherence to a Mediterranean diet and healthy lifestyle. 3. Is metabolic syndrome important at elderly age? I think of elderly patients as frail and often malnourished. Forty percent of elderly adults in the US have the metabolic syndrome. Dyslipidemia, hypertension and insulin resistance all confer risk. 4. My elderly patients after MI report fatigue and are afraid to exercise. Many have not exercised for years. How is exercise best initiated? Referral to cardiac rehabilitation enables both physical activity initiation and coronary risk reduction. Functional capacity and exercise-related symptoms improve as early as 12 weeks after beginning exercise. Exercise favorably impacts obesity, hypertension, dyslipidemia and insulin resistance. 5. Statins are costly drugs, added to the multidrug regimen of elderly coronary patients. Is the benefit worth the risk and cost? Statin-intensive lipid-lowering in elderly coronary patients decreases cardiovascular events as at younger age, with benefit evident in the first 1 to 2 years of therapy. Some studies have shown a decrease in stroke risk. Statins are safe and well-tolerated, with a favorable side-effect profile at elderly age.
Summary Although the predictive value of traditional cardiovascular risk factors for mortality in middle age is attenuated among elderly adults, the high absolute risk of coronary events at elderly age continues to increase in the oldest old. Effective secondary prevention has the potential to show the greatest benefit in this population. Greater application of secondary preventive interventions is recommended to fully realize the potential of coronary risk reduction in the very elderly. Individuals among the oldest old are markedly disparate in severity of illness, functional status, comorbidities, cognitive status and desires and expectations of both therapeutic and preventive care. Added to their high-risk status, these variables must be incorporated in the secondary preventive care of the very old. Lifestyle modifications are recommended for all patients; these include smoking cessation, a heart-healthy diet, weight management and modest-intensity regular physical activity. Pharmacotherapy relates predominantly to control of blood pressure and lipid abnormalities; control of diabetes is assuming increased importance (Table 1). One might hope that, in an optimal healthcare setting where secondary preventive interventions are instituted across the lifespan, in addition to more CHD patients surviving to elderly age, the application of secondary prevention in the very old will simply remain a component of continuity of care.
Suggested Reading Grundy SM, Cleeman JI, Merz CNB, et al. for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–39. Houston TK, Allison JJ, Person S, Kovac S, Williams OD, Kiefe CI. Post-myocardial infarction smoking cessation counseling: as-
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Study of Pravastatin in the Elderly at Risk. Lancet 2002;360: 1623–30. Williams MA, Fleg JL, Ades PA, et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ⱖ75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation 2002;105:1735– 43.
sociations with immediate and late mortality in older Medicare patients. Am J Med 2005;118:269 –75. Knoops KTB, de Groot LCPGM, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women. The Hale Project. JAMA 2004;292: 1433–9. Lavie CJ. Treatment of hyperlipidemia in elderly persons with exercise training, nonpharmacologic therapy, and drug combinations. Am J Geriatr Cardiol 2004;13:29 –33. Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective
Address correspondence and reprint requests to Nanette K. Wenger, MD, Emory University School of Medicine, Cardiology, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
ACC CURRENT JOURNAL REVIEW September 2005
15
Secondary Prevention of Cardiovascular Disease in the Very Old—A Good Idea Whose Time Has Come
Focused Review tion of percutaneous interventions or coronary artery bypass graft (CABC) surgery addressed, as these typically are indicated for symptomatic improvement rather than survival benefit.
Nanette K. Wenger, MD, Emory University School of Medicine, Cardiology, Grady Memorial Hospital, Atlanta, Georgia
Smoking Cessation At least half of the decline in overall mortality of 25–50% with smoking cessation following MI is evident in the first year. Important for elderly patients is that benefits of smoking cessation often accrue promptly. Data from the Coronary Artery Surgery Study (CASS) indicate comparable benefit of smoking cessation for morbidity and mortality rates in patients younger and older than age 70 following CABG surgery, with no attenuation of smoking-cessation benefits at advanced age. Inpatient smoking-cessation counseling after MI among smoking Medicare patients decreased immediate and long-term mortality rates. Comparable smoking-cessation interventions appear effective at younger and elderly age and include physician advice, behavioral counseling, buddy support systems, self-help materials, telephone counseling, and use of pharmacologic therapies. Both nicotine replacement therapy and other pharmacologic agents are well tolerated by elderly individuals. Smoking cessation translates into a reduction in cardiovascular morbidity and mortality at least equal to that of other preventive measures such as aspirin or beta-blocker therapy. The 36% reduction in overall mortality resulting from smoking cessation appears greater than that derived from other standard therapies including aspirin, betablockers or ACE inhibitors.
Chronic coronary heart disease (CHD) is present in 217 per 1000 men and 129 per 1000 women older than 75 years of age. Although octogenarians currently comprise about 5% of the US population they represent 20% of all myocardial infarction (MI) hospitalizations and 30% of all MI-related hospital deaths. Approximately 80% of all mortality due to cardiovascular disease occurs in patients older than 65 years of age. Thus, secondary preventive measures are of paramount importance for elderly patients.
Magnitude of the Problem Although almost half of all US octogenarians have some manifestation of cardiovascular illness, they remain underrepresented in or excluded from clinical trials of cardiovascular prevention. The suboptimal representation of patients older than age 65 in randomized studies has resulted in fewer data about the effectiveness of various strategies for elderly patients and virtual absence of clinical trial data for the octogenarian population. Where then does extrapolation appear appropriate to guide clinicians caring for octogenarian patients, given the small numbers of very elderly participants in clinical trials? In the Cardiovascular Health Study (CHS), the prevalence of subclinical atherosclerosis in this population older than 65 years was more than 30%, and it increased further with advancing age, challenging the differentiation of primary and secondary prevention, particularly in octogenarians. Elderly individuals with subclinical evidence of CHD—abnormal ankle-brachial index, ECG abnormalities, echocardiographic abnormalities, abnormal ultrasonographic carotid intima-media thickness, among others— likely warrant management for secondary prevention. A 2002 Scientific Statement from the American Heart Association, “Secondary Prevention of Coronary Heart Disease in the Elderly (with emphasis on patients ⱖ75 years),” advocates control of cigarette smoking, hypertension, abnormal blood lipids, elevated blood glucose, obesity, psychological concerns and physical inactivity as similarly effective as in younger patients. This review does not address the use of aspirin, betablocker therapy and angiotensin-converting enzyme (ACE) inhibitor use, which is recommended for all CHD patients without specific contraindications. Neither is the applica-
Heart-Healthy Diet In the Hale Project, conducted in 11 European countries, adherence to a Mediterranean diet and healthy lifestyle in women and men aged 70 to 90 years was associated with a more than 50% reduction in all-cause and cardiovascular mortality. Addition of soluble fiber to the diet can reduce lowdensity lipoprotein-cholesterol (LDL-C) by up to 20%, without significant impact on high-density lipoproteincholesterol (HDL-C); use of soluble fiber is particularly relevant for elderly patients predisposed to constipation and colon disease.
Obesity/Weight Management The nationwide increase in the prevalence of obesity is likely to result in larger numbers of elderly individuals having the metabolic syndrome, which increases cardiovascular risk. Metabolic syndrome is currently present in more than 40% of elderly persons in the US.
ACC CURRENT JOURNAL REVIEW September 2005 © 2005 by the American College of Cardiology Foundation Published by American College of Cardiology Foundation
11
1062-1458/05/$30.00 10.1016/j.accreview.2005.08.119
Because of the prominent clustering of dyslipidemia, hypertension and insulin resistance in elderly overweight individuals, particularly those with abdominal obesity, weight loss may act as a multifactorial risk-reduction intervention. Weight loss at elderly age related to exercise or dietary regimens effected similar risk-factor improvement and improvement in measures of insulin resistance, suggesting the likelihood of reduction in secondary coronary events. However, few weight-loss studies either of physical activity or of diet involved older patients with CHD.
ical activity than do younger individuals. No significant complications or adverse outcomes of exercise rehabilitation occurred in elderly patients in any study. Moreover, exercise positively impacts coronary risk factors such as obesity, hypertension, dyslipidemia and insulin resistance.
Lipid Management Because of the increased absolute cardiovascular risk at elderly age, lipid-lowering therapy may be more beneficial in moderate to high-risk elderly than in younger patients. Absolute risk reduction in elderly coronary patients with treatment of hypercholesterolemia is greater than that seen at younger age. In a number of randomized clinical trials, pharmacologic lipid control at elderly age effectively reduced cardiovascular events, with benefit of treatment evident as early as the initial year or two of therapy. These benefits are in addition to lifestyle changes that included exercise training and diet. In recent statin studies, intensive lipid lowering in patients older than 65 years of age effectively reduced coronary events and cardiovascular mortality. Identical benefits occurred for those older and younger than 65 years in the Pravastatin Pooling Project. Similar benefit in reduction of major coronary events was evident in coronary patients older and younger than 65 years in the Scandinavian Simvastatin Survival Study (4S). Because mortality rates increase substantially with age, the absolute risk reduction for both all-cause and coronary mortality was twice as great in older patients. In CARE (Cholesterol and Recurrent Events), major coronary events were reduced 19% below age 65 compared with 62% for those older than 65; coronary mortality decreased by 11% in subjects younger than 65 compared with 45% at age older than 65. The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial is the only study specifically to examine the effect of this statin in a population of women and men aged 70 – 82 years. The LDL-C decreased by 34%. Coronary mortality declined by 24% in pravastatin-treated patients, and the risk of recurrent MI was reduced by a fifth with 3 years of therapy. Stroke protection was not evident. The Heart Protection Study, examining patients above and below 65 years of age, showed a significant reduction both for coronary and for cerebrovascular events. Statin use in elderly patients with coronary or vascular disease or diabetes was supported by subgroup analyses of the Heart Protection Study; significant reduction occurred in all-cause mortality and coronary death or nonfatal MI in patients older than 70 years, including those with LDL-C levels ⬍116 mg/dL. Few statin studies involved subjects older than age 75, but there is no evidence for diminishing lipid-lowering effect with age, such that there is no reason that lipidlowering lowering therapy should not be extended to the very elderly as well. In the Treating to New Targets (TNT) trial, with CHD patients enrolled to age 80, age did not significantly interact with benefit. Relevant issues regarding
Physical Activity (Exercise) Recent data suggest that one-fourth of all elderly patients are completely sedentary and about one-half are inadequately active. Studies in both men and women document a lower overall mortality among those with even moderateintensity physical activity done regularly. In the observational Cardiovascular Health Study, which recruited men and women with a mean age of 73 years at enrollment, the level of physical activity independently predicted 5-year survival. An aerobic exercise regimen is recommended in NCEP/ATP-III; in addition to improving functional capacity, exercise training is associated with improvement in lipid levels, which includes a reduction in triglycerides and LDL-C and an increase in HDL-C. Although this is less than the magnitude of benefit seen with lipid-altering drugs, the effects of exercise are additive to pharmacotherapy. Exercise training improves functional capacity from 10 – 60% and reduces myocardial workload with usual activities from 10 –25%; comparable percentage improvement occurs in patients older and younger than 75 years of age, as does improvement in quality of life. In the British Regional Heart study, men with established CHD (albeit a mean age of 63 years) had a significantly decreased risk of all-cause mortality during 5 years of follow-up associated with lightto-moderate physical activity. Physical activity recommendations should address occupational and leisure activities, as well as daily life activities, to allow a diversity of exercise. Particularly after 75 years of age, exercise recommendations should consider comorbidities such as arthritis, pulmonary disease, and peripheral arterial disease. Strength training may improve neuromuscular function and muscular strength and endurance. Participation in cardiac rehabilitation that includes both physical activity and multifactorial risk reduction is optimal. Historically, cardiac rehabilitation has been underutilized by older patients, particularly elderly women, despite comparable benefits evident at younger and elderly age. Because the strength of recommendation of the physician referral is pivotal to subsequent participation, physician recommendations assume major importance. An exercise regimen can improve functional capacity and reduce activity-related symptoms as early as 12 weeks after the initiation of training. Elderly patients achieve significantly greater benefit in total functional scores and life-quality from phys-
ACC CURRENT JOURNAL REVIEW September 2005
12
Blood Pressure Control
pharmacotherapy decisions involve quality of life, concomitant illnesses and remaining life expectancy. The benefit seen in the small percentage of high-risk octogenarians in the Heart Protection Study (HPS) and in the PROSPER trial challenge us to define high risk in the elderly and to treat those with documented cardiovascular disease. Truncation of the Framingham risk score at age 79 poses a challenges for risk ascertainment in octogenarian patients. Statins appear safe and well-tolerated, with a favorable side-effect profile at elderly age. Whether statins exert effects independent of LDL-C lowering remains uncertain. Clinically significant myopathy is uncommon in elderly patients with statin therapy, but has been associated with renal insufficiency. As with all drugs, because of multiple comorbidities and multiple medications used at elderly age, the risk of drug interactions is substantial; thus, statins should be initiated at lower doses at elderly age and titrated to goal LDL-C levels. Fibrates can reduce triglyceride levels as much as 50% and produce a modest increase in HDL-C, but data are not available for patients over 75 years of age. Nicotinic acid (niacin) can lower LDL-C by 10 –15%, triglycerides by 25–30%, and increase HDL-C by 25– 40%. Outcome data are not available for elderly patients. Combination therapies of statin drugs with nicotinic acid and fibrate, as well as the addition of ezetimibe, for LDL-C lowering are not well studied in elderly populations. For statins plus fibrates, close monitoring is warranted for safety concerns. Bile acid sequestrants raise concern in that they inhibit the intestinal absorption of vitamin D, levothyroxin, thiazide diuretics, and other substances important to the management of comorbidities; further, they may worsen constipation. Clinical outcome data are not available for ezetimibe, which has the potential advantage that its coadministration with a statin can enable lower statin doses in elderly highrisk populations yet reach LDL-C goals; LDL-C levels are reduced by 15–20%. The National Cholesterol Education Program Adult Treatment Panel III Update suggests the option of lowering LDL-C to 70 mg/dL for high-risk coronary patients. Recent clinical trials confirmed that high-risk coronary patients are likely to do better with an LDL-C target below 70 mg/dL; a substantial proportion of elderly patients are in this highrisk category, but they have had limited inclusion in the trials that provided an evidence basis for therapy. In the Cardiovascular Health Study, a low level of HDL-C was strongly associated with an increased risk of MI; however, no studies have been reported of interventions designed to raise HDL-C in elderly patients. Lipid management for secondary prevention is a costeffective strategy at elderly age.
Up to 90% of US octogenarians have hypertension, with a substantial percentage having isolated systolic hypertension. Data appear strongest for the benefit of pharmacologic control of isolated systolic hypertension at elderly age. Data are lacking for the benefit of pharmacotherapy of stage 1 hypertension (140 –159 mm Hg systolic blood pressure), but extrapolation of benefit from younger elderly patients appears reasonable. Currently, nearly two-thirds of individuals over 75 years of age have uncontrolled hypertension, using the definition of a systolic blood pressure in excess of 140 mm Hg and/or diastolic blood pressure in excess of 90 mm Hg. Based on meta-analysis, benefits of hypertensive therapy are particularly high in patients aged 60 – 80 years, with greater benefit for stroke and heart failure than for coronary events, although overall mortality is also reduced. The large randomized treatment trials do not allow conclusions for patients older than 80 years, although data from the Systolic Hypertension Europe (SYST-EUR) study and a subgroup metaanalysis of randomized controlled trials support the benefits of therapy. In these studies, benefits of treatment in patients older than 80 years included a significant reduction in the risk of stroke, major cardiovascular events and heart failure, despite lack of reduction of cardiovascular death or total mortality. Nonpharmacologic therapies that include weight reduction, decrease in sodium and alcohol intake, and exercise are more effective in older than younger populations. Conventional pharmacotherapy has favorably impacted cardiovascular mortality and morbidity at elderly age. Cautions for the treating physician are to measure blood pressure both in the seated and standing positions to exclude clinically relevant orthostatic hypotension. As well, postprandial hypotension must be ascertained. In the initial ascertainment of hypertension, blood pressure measurement must be meticulous to exclude psuedohypertension. Application of pharmacologic agents, which might include diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, and/or calcium channel blockers, must begin at low doses with gradual increments in dosage. Attention must be directed to identifying comorbidities that might limit the use of each of these classes of therapy.
Diabetes Both diabetes and insulin resistance increase with increasing age, particularly in association with abdominal obesity. Exercise improves insulin resistance and diabetic control, likely related more to its effect on body fat than on fitness per se. Nutritional counseling should emphasize control of obesity. Patients with CHD should have examination of blood glucose levels for undiagnosed diabetes, and surveillance of individuals already treated should have a goal for hemoglobin A1c of less than 7%.
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Table 1. Risk Intervention at Elderly Age
Despite poor definition of optimal weight-loss strategies at elderly age, management of diabetes through dietary modification, exercise and medications remains similar across age strata.
Psychosocial Interventions Depression has an adverse effect on the morbidity, mortality and functional recovery of patients with cardiovascular disease. Ten percent to 15% of elderly patients are depressed, and a greater percentage have significant anxiety. Elderly patients should be evaluated for depression and offered appropriate management. Social support and social isolation have also been associated with excessive morbidity and mortality in elderly men and women with CHD; interventions to reduce depression and social isolation in an NHLBI study (ENRICHD) with half of patients older than age 65 did not alter outcomes. Elderly patients are particularly prone to depression and social isolation, and their frequently lower socioeconomic status may negatively affect participation in cardiac rehabilitation programs and compliance with medical advice and therapy.
Intervention
Reduction in Mortality
Reduction in Morbidity
Smoking cessation Exercise Therapy of dyslipidemia Therapy of hypertension Control of diabetes mellitus Heart-healthy diet Control of obesity Psychosocial interventions
Yes Yes Yes Yes Yes Yes Uncertain Uncertain
Yes Uncertain Yes Yes Yes Uncertain Uncertain Uncertain
Questions and Answers 1. My octogenarian patient with MI has been smoking for decades. Why should he stop? Half of the 25–50% decrease in mortality with smoking cessation after MI occurs in the first year. Mortality reduction with smoking cessation is equal to or greater than that with aspirin, beta-blockers or ACE inhibitors. 2. Elderly patients are set in their habits. Do diet and lifestyle changes truly matter? Men and women aged 70 –90 had a ⬎50% decrease in all-cause and cardiovascular mortality with adherence to a Mediterranean diet and healthy lifestyle. 3. Is metabolic syndrome important at elderly age? I think of elderly patients as frail and often malnourished. Forty percent of elderly adults in the US have the metabolic syndrome. Dyslipidemia, hypertension and insulin resistance all confer risk. 4. My elderly patients after MI report fatigue and are afraid to exercise. Many have not exercised for years. How is exercise best initiated? Referral to cardiac rehabilitation enables both physical activity initiation and coronary risk reduction. Functional capacity and exercise-related symptoms improve as early as 12 weeks after beginning exercise. Exercise favorably impacts obesity, hypertension, dyslipidemia and insulin resistance. 5. Statins are costly drugs, added to the multidrug regimen of elderly coronary patients. Is the benefit worth the risk and cost? Statin-intensive lipid-lowering in elderly coronary patients decreases cardiovascular events as at younger age, with benefit evident in the first 1 to 2 years of therapy. Some studies have shown a decrease in stroke risk. Statins are safe and well-tolerated, with a favorable side-effect profile at elderly age.
Summary Although the predictive value of traditional cardiovascular risk factors for mortality in middle age is attenuated among elderly adults, the high absolute risk of coronary events at elderly age continues to increase in the oldest old. Effective secondary prevention has the potential to show the greatest benefit in this population. Greater application of secondary preventive interventions is recommended to fully realize the potential of coronary risk reduction in the very elderly. Individuals among the oldest old are markedly disparate in severity of illness, functional status, comorbidities, cognitive status and desires and expectations of both therapeutic and preventive care. Added to their high-risk status, these variables must be incorporated in the secondary preventive care of the very old. Lifestyle modifications are recommended for all patients; these include smoking cessation, a heart-healthy diet, weight management and modest-intensity regular physical activity. Pharmacotherapy relates predominantly to control of blood pressure and lipid abnormalities; control of diabetes is assuming increased importance (Table 1). One might hope that, in an optimal healthcare setting where secondary preventive interventions are instituted across the lifespan, in addition to more CHD patients surviving to elderly age, the application of secondary prevention in the very old will simply remain a component of continuity of care.
Suggested Reading Grundy SM, Cleeman JI, Merz CNB, et al. for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227–39. Houston TK, Allison JJ, Person S, Kovac S, Williams OD, Kiefe CI. Post-myocardial infarction smoking cessation counseling: as-
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Study of Pravastatin in the Elderly at Risk. Lancet 2002;360: 1623–30. Williams MA, Fleg JL, Ades PA, et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ⱖ75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation 2002;105:1735– 43.
sociations with immediate and late mortality in older Medicare patients. Am J Med 2005;118:269 –75. Knoops KTB, de Groot LCPGM, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women. The Hale Project. JAMA 2004;292: 1433–9. Lavie CJ. Treatment of hyperlipidemia in elderly persons with exercise training, nonpharmacologic therapy, and drug combinations. Am J Geriatr Cardiol 2004;13:29 –33. Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective
Address correspondence and reprint requests to Nanette K. Wenger, MD, Emory University School of Medicine, Cardiology, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
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