doi: 10.1161/CIRCULATIONAHA.106.678300
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(Circulation. 2007;115:681-683.)
© 2007 American Heart Association, Inc.
Editorial |
Statin Therapy and the Elderly
SAGE Advice?
From Weill Cornell Medical College, New York, NY.
Correspondence to Antonio M. Gotto, Jr, c/o Jesse Jou, Weill Cornell Medical College, 445 E 69th St, OH205, New York, NY 10021. E-mail amg_editorial{at}med.cornell.edu
Key Words: Editorials • aging • coronary disease • drugs • prevention • risk factors • statins
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Introduction |
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In the United States, the prevalence of coronary and other cardiovascular diseases increases with age, reflecting in part the cumulative effect of lifetime exposure to cardiovascular risk factors.1 Coronary and cerebrovascular atherosclerosis in the elderly (
65 years of age) is a growing clinical problem because of the population’s increasing longevity. Despite this evidence, cardiovascular risk in elderly patients is demonstrably undermanaged according to several epidemiological studies.2–4 In a Canadian study, paradoxically, elderly coronary patients who were at the highest risk for recurrent disease appeared to be the least likely to receive preventive treatment.4 Several factors may contribute to this poor level of management, such as confusion surrounding the relevance of certain modifiable risk factors to this age group, the cost-effectiveness of preventing coronary heart disease (CHD) in older patients, and concerns about the impact of therapies on safety and quality of life.
Article p 700
Despite early studies that questioned the association of cholesterol with coronary risk in the elderly, the available epidemiology now favors the perspective that cholesterol remains an important modifiable risk factor in patients 65 years of age, especially after adjustment for the presence of comorbid conditions.5 Growing evidence demonstrates the benefit of treating higher-risk older patients. In this issue of Circulation, Deedwania et al6 present the results of the Study Assessing Goals in the Elderly (SAGE), which compares the effect of intensive (atorvastatin 80 mg/d) compared with moderate (pravastatin 40 mg/d) cholesterol lowering with statins in a cohort of 893 men and women 65 to 85 years of age with coronary artery disease. SAGE evaluated the absolute change in total duration of ischemia as measured by 48-hour Holter monitoring from baseline to 1 year. Although total ischemia duration was reduced significantly in both arms compared with baseline, the intensive strategy was not superior to the moderate approach in affecting this end point. A nonsignificant trend toward fewer major coronary events in the intensive treatment arm was detected, and an intriguing post hoc finding was a significant reduction in all-cause mortality favoring intensive treatment (77% risk reduction; P=0.01), but the clinical implication of these results may be minimal. Despite questions about how to interpret its findings, SAGE, in the context of the overall knowledge base, affirms that cholesterol management with a statin should be considered in higher-risk elderly patients.
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Statin Therapy in Older Patients |
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TopIntroductionStatin Therapy in Older...DiscussionReferences |
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Before 2002, clinical evidence on the effects of statins in patients
65 years of age came mainly from subgroup analyses of larger studies. LaRosa et al7 performed a meta-analysis of 5 landmark statin trials: the secondary-prevention Scandinavian Simvastatin Survival Study, the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID), and the Cholesterol and Recurrent Events, plus the primary-prevention West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study. Data from >30 000 patients were included, but the percentage of each study’s cohort that was 65 years of age ranged from 0% in WOSCOPS to 39% in LIPID. When the odds for coronary events were stratified by age, the overall proportional reductions for coronary events in persons 65 years of age (32%; 95% confidence interval [CI], 23 to 39) and persons <65 years of age (31%; 95% CI, 24 to 36) were similar. The absolute risk reduction, however, was slightly higher in persons 65 years of age (44 per 1000; 95% CI, 30 to 58 per 1000) than in persons <65 years of age (32 per 1000; 95% CI, 24 to 40 per 1000) because of the higher absolute risk for a CHD event over a short interval that can be found in older patients. Thus, meta-analysis of older subgroups in the large statin trials indicated that relative risk reductions for older patients on statin therapy were similar to those for younger patients, although absolute risk reduction was greater for those 65 years of age. Nevertheless, conclusively extrapolating this to all elderly patients was controversial, in part because most of these trials had entrance criteria that defined an upper age limit (usually 
75 years of age) that favored the inclusion of only "younger" elderly patients.
The Medical Research Council/British Heart Foundation Heart Protection Study evaluated the role of simvastatin 40 mg/d versus placebo in 20 536 patients selected on the basis of either documented coronary atherosclerosis or a risk factor profile that conveyed CHD risk equivalence.8 These high-risk patients were 40 to 80 years of age and had total serum cholesterol concentrations of 135 mg/dL (3.5 mmol/L). A good proportion (28.3%) of randomized patients were 70 years of age. Simvastatin treatment reduced the relative risk for any major vascular event by 24% (P<0.0001). The clinical benefit of statin treatment was consistent across subgroups defined by age. Among the 1263 individuals 75 to 80 years of age at study entry, the difference in the rate of major coronary events in the simvastatin group versus placebo group (23.1% versus 32.3%; P=0.0002) was highly statistically significant. In the overall cohort, statin therapy was associated with a 13% reduction in all-cause mortality (P=0.0003), largely because of the definite 17% reduction in death rate from vascular causes.
A trial that also included "older" elderly patients but focused on an exclusively elderly cohort was the Prospective Evaluation of Pravastatin in the Elderly (PROSPER), which investigated the impact of treatment with pravastatin 40 mg/d versus placebo in 5804 men and women 70 to 82 years of age with a history of vascular disease or a high-risk profile.9 Participants in this study had plasma total cholesterol between 155 and 350 mg/dL (4.0 and 9.0 mmol/L) and triglyceride concentrations <531 mg/dL (6.0 mmol/L). More than half of the individuals in PROSPER were women. After a mean follow-up of 3.2 years, pravastatin treatment reduced the relative risk for coronary death, nonfatal myocardial infarction, and fatal or nonfatal stroke significantly by 15% (P=0.014) (2.1% absolute risk reduction) and CHD death by 24% (P=0.043). The benefit of treatment was similar across subgroups, except that participants in the lowest tertile of baseline high-density lipoprotein cholesterol (<43 mg/dL [1.11 mmol/L]) experienced greater benefit than those in the higher tertiles.
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Discussion |
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The Heart Protection Study, PROSPER, and SAGE illustrate the benefit of statin treatment on coronary or surrogate end points in higher-risk elderly patients, although the data are still somewhat controversial, particularly for individuals
80 years of age. An observational study of acute-care hospitals in the United States identified no association between statin use at discharge and improved survival rate in acute myocardial infarction patients 80 years of age, although it did find benefit in patients <80 years of age.10 Further randomized clinical trials are necessary to determine the optimal treatment approach for those in the growing population of octogenarians, nonagenarians, and beyond. In addition, the PROSPER study reported no reduction with pravastatin in the risk for stroke, an important end point in the elderly population, whereas the proportional reduction in rate of first stroke was 25% in the Heart Protection Study, regardless of the participant’s age.9,11 Whereas the Heart Protection Study and PROSPER compared statin treatment with placebo, SAGE compared higher-dose statin treatment with lower-dose statin treatment. Thus, another issue to consider is its failure to detect a difference between aggressive and moderate lipid modification on the surrogate end point of Holter-monitored duration of ischemia, despite the former’s reducing low-density lipoprotein cholesterol to a significantly greater extent than the latter. This null finding contradicts other intensive-versus-moderate strategy studies that endorse the intensive approach because of significant effects on clinical events or on surrogate end points such as atheroma volume by intravascular ultrasound. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, post–acute coronary syndrome patients treated with a regimen of either pravastatin 40 mg/d or atorvastatin 80 mg/d—the same treatments used in SAGE—experienced a 16% reduction (P=0.005), favoring atorvastatin, in the hazard ratio for the composite end point of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization, and stroke.12 There was a nonsignificant reduction in death from all causes (28%, P=0.07). The same agents and dosages were evaluated in the Reversal of Atherosclerosis With Aggressive Lipid Lowering study of patients who had had an acute coronary syndrome; intensive atorvastatin appeared to halt atheroma progression as measured with intravascular ultrasound, whereas moderate pravastatin therapy did not.13
Whether these outcomes denote that duration of ischemia may be a poor correlate with clinical events, that the elderly may respond differently to aggressive lipid reduction than other age groups, or that there is some other effect at work is unclear. Thus, vagaries remain about the optimal use and targeting of statins in the elderly patient group.
In the US Adult Treatment Panel guidelines, the patient’s overall risk for developing CHD in the next 10 years determines the intensity of lipid intervention in patients who do not have manifest CHD.14 This global risk is estimated with an algorithm that considers not only total cholesterol but also high-density lipoprotein cholesterol, smoking, age, hypertension, and sex. Indeed, age has a significant influence on the overall point total in this risk-scoring paradigm derived from the Framingham Heart Study. In older adults, the Adult Treatment Panel III recognizes that substantial evidence of subclinical atherosclerosis may indicate the presence of high risk. The Adult Treatment Panel III guidelines place no age restrictions on who may receive statin treatment, and it seems reasonable to extrapolate the greater reduction in absolute risk for CHD events found in patients 65 years of age to those who are very old but still in reasonably good health.15 Although therapeutic lifestyle changes are the first line of therapy, elderly patients who appear to be at high risk on the basis of the above factors or who have CHD or other cardiovascular disease should be considered candidates for risk-reducing drug therapies.
On the other hand, those managing an older population must consider the functional age of the patient and the impact of long-term drug therapy on safety and quality of life. Caution is recommended when statins are used in frail elderly patients, who may be more susceptible to drug-related myopathy and other side effects,16 but Jacobson17 has reviewed safety issues of statins in older patients and argues that the potential benefits of treatment should not be denied to higher-risk patients. Indeed, statins were well tolerated in the Heart Protection Study and SAGE, and the only major concern in PROSPER was an increase in cancer incidence in pravastatin-treated patients, which may have been an artifact of randomization.9 A cost-effectiveness analysis of the LIPID trial suggests that pravastatin therapy was more cost-effective for older coronary patients (65 to 74 years of age), despite their shorter life expectancy, because of their higher baseline risk and greater cost offsets from lower rates of hospitalization resulting from preventive treatment compared with younger patients.18
In summary, older chronological age in and of itself should not exclude patients from receiving therapy, especially if an otherwise healthy older patient’s remaining years of life may benefit from prevention of the morbidity associated with a coronary event. SAGE provides additional evidence that statins can benefit older patients but raises questions about the optimal intensity of treatment or the best measures of benefit. Further research is warranted, but in the interim, judicious application of statin therapy to higher-risk elderly patients is appropriate.
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Acknowledgments |
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The author would like to acknowledge the editorial assistance of Jennifer Moon, PhD, in the preparation of this manuscript.
Sources of Funding
None.
Disclosures
Dr Gotto has consulted with the following companies with interests in lipid-modifying drugs within the past 2 years: Aegerion; Arisaph; AstraZeneca; Bristol Myers-Squibb, Co; Dupont; Johnson & Johnson Merck; Kos Pharmaceuticals; Kowa; Merck & Co, Inc; Pfizer; Novartis; and Reliant Pharmaceuticals.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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