Q J Med 2001; 94: 457-463
© 2001 Association of Physicians
Review |
Cholesterol lowering in the older population: time for reassessment?
1 From the Department of Geriatrics and 2 Metabolic Service, Kaplan Medical Centre, Rehovot, and The Hebrew University Hadassah Medical School of Medicine, Jerusalem, Israel
 |
Summary |
|---|
 Top Summary IntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
Hypercholesterolaemia is an established major risk factor for coronary heart disease (CHD) in the general population. In the vast majority of studies that focused on this particular age group and carefully eliminated other confounding factors such as co-morbid conditions, hypercholesterolaemia was a risk factor for CHD in the older population. Because the prevalence of CHD increases with advancing age, studies that consider not only the relative risk attributed to cholesterol but also the absolute numbers of people affected, show hypercholesterolaemia to be an even stronger risk factor in the elderly. Large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) in the elderly have shown a reduction in major coronary events similar to that observed in the younger age group. The role of hypercholesterolaemia as a risk factor for stroke is less clear, and a major limitation is the heterogeneous nature of the disease. Nevertheless, most studies that evaluated non-haemorrhagic strokes separately showed a positive association with cholesterol levels, and statin therapy is effective in preventing stroke. These data provide a rationale for treating older hypercholesterolaemic people with statins, not only to prevent CHD, but also to prevent stroke.
|
Introduction |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
Cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, is the leading cause of morbidity and mortality in elderly men and women.1 Hypercholesterolaemia is an established major risk factor for CVD in the general population, and the need to treat according to specific guidelines has produced a consensus.2 However, the role of hypercholesterolaemia as a risk factor for CVD in older people, and whether to treat it with lipid-lowering medications, remain controversial issues.3 The relationship between serum cholesterol and stroke incidence is debatable, both in general and in older populations,4 although recent lipid-lowering trials have clearly shown a beneficial effect of HMG-CoA reductase inhibitors (statins) in reducing strokes in all age groups.5–7 We review current data regarding the role of cholesterol as risk factor for CVD and the results of major clinical trials with statins, in the older population, based on a search of the Medline and Cochrane Library (1989 to present).
|
Cholesterol as a risk factor for CHD in the older population |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
Hypercholesterolaemia is a major risk factor for CHD in the general population, according to many epidemiological and intervention studies.3,5–8 However in older people, the association between high serum cholesterol levels and CHD is still disputed, because of the results of some of the earlier studies.3,9 For example, the Framingham Heart Study showed a reduction of the CHD risk ratio between the highest and lowest quartiles for total cholesterol, for men 50 years and older, compared to younger men.3 The first report from the EPESE study, which included results for one of the three centres participating, failed to show that cholesterol was a risk factor for CHD in men and women aged >70 years.9
CHD is the major cause of morbidity and mortality in older people, and the age group >65 years represents an increasing percentage of the population treated for CHD by the health-care systems.1 The importance of identifying CHD risk factors in this specific population has led in recent years to a re-examination of the role of cholesterol, in large-scale studies focusing on older subjects. In Table 1
, we summarize the data from seven large-scale prospective studies, including 22 656 older men and women. Five of the seven studies demonstrated that a high level of serum total cholesterol was a risk factor for CHD in elderly men.10–15 Three out of five studies found that total cholesterol was a significant predictor in women.10,12,14 Two important lessons emerge from these studies. The first, demonstrated by the third report from the EPESE study,10 is the significant effect of adjusting for indicators of health status (serum albumin and iron) and exclusion of first-year events. Only after these adjustments were made did the association between total cholesterol levels and death from CHD become significant. As co-morbid conditions are common in the geriatric population, these results may explain why previous reports from the EPESE study,9,14 and some of the other studies that did not perform these adjustments, showed conflicting results. The second lesson, from the Kaiser Permanente CHD in the Elderly Study, is that the effect of high cholesterol levels with advancing age, may be better estimated by evaluation of the increase in absolute mortality from CHD than by relative risk measures.13 In this study both relative risk and excess risk were used, and while the first statistical analysis remained fairly constant with increasing age, the second showed a marked increase, reaching an excess rate of 11.3 deaths per 1000 person-years in men 75–79-years-old. Manolio et al. analysed data of 25 different populations and found that although relative risks were generally lower in older subjects, the absolute risks were greater.16
|
Low levels of high-density lipoprotein cholesterol (HDL-C) are another risk factor for CHD in the general population. As shown in Table 1
, three of the six studies that reported data on HDL-C levels found that low HDL-C was associated with increased risk for CHD in older men and women.10,12,14 The Dubbo Study found it to be a predictor of CHD in men only.11 The FINE Study, which included only men from three countries, found low HDL-C to be related to CHD mortality in Finnish men, as well as in lean Italian men who drank <40 g alcohol daily.15
|
Statin therapy for prevention of CHD in the older population |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
The advent of statins has revolutionized the treatment of hypercholesterolaemia, as these drugs are highly effective in reducing low-density lipoprotein cholesterol (LDL-C) levels and are generally well tolerated. Most of the data on the effect of statins on preventing CHD in the elderly are derived from secondary-prevention trials. Three of the large secondary-prevention trials, The Scandinavian Simvastatin Survival Study (4S),5,17 Cholesterol and Recurrent Events (CARE)6 and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID),7 included men and women aged >65 years. The results of these studies are shown in Table 2
. A marked reduction in coronary events in the older age group was found, similar to the reduction observed in patients aged <65 years.5–7,17 Based on these data, statin therapy may be regarded as part of the standard care of elderly hypercholesterolaemic patients with CHD, along with aspirin, beta-blockers and other accepted therapies. The major limitation of these studies is that they included ‘young’ elderly patients, up to age 75. However, as the results of statin therapy do not show a tendency to decrease with advancing age, it is reasonable to extrapolate these results to the ‘older’ elderly, as long as the patient is in relatively general good health.
|
Only one primary-prevention trial with statins included a large number of older people: the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).18 The 6605 participants in the trial included 1416 men and women aged
65 years. The results (Table 2) showed a marked reduction of 37% in major coronary events in the whole group, and similar results were observed in the older age group. No significant adverse events were reported related to drug therapy in this study. The study suggests that primary prevention with statin therapy is beneficial in the elderly, at least in the ‘young’ elderly, without significant adverse effects. Based upon these data, a recent statement article was published by the Committee of the National Cholesterol Education Program,19 suggesting consideration of drug therapy for primary prevention in elderly patients with significant hypercholesterolaemia, according to: (i) the general health status and functional capacity of the elderly individual; and (ii) CHD risk stratification. According to these guidelines, drug therapy should be considered in elderly patients without debilitating diseases with a very high LDL-C, 190 mg/dl (corresponding roughly to a total cholesterol of >270 mg/dl), or in patients with an LDL-C in the range of 160–189 mg/dl (corresponding roughly to a total cholesterol 240–269 mg/dl) with two or more CHD risk factors. Total cholesterol may serve as a screening measure; however, we recommend that in cases in which total cholesterol is 240 mg/dl, HDL-C and LDL-C should be determined before deciding upon appropriate therapy.
|
Cholesterol as a risk factor for stroke in the older population |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
The prevalence of stroke, the third leading cause of death and the most prevalent disabling disorder, increases with age and doubles every decade after age 55.20 The relationship between serum cholesterol and stroke incidence is controversial. One of the major limitations in analysing the possible relationship is the heterogeneous nature of the disease, which includes haemorrhagic and non-haemorrhagic stroke. About 80% of first strokes are non-haemorrhagic, and can be further divided into atherothrombotic, cardioembolic, lacunar, etc.21 The results from the Kaiser Permanente Medical Care program showed that in men aged 65 or older, low serum cholesterol levels compared with high levels, were associated with a relative risk of 2.7 (95%CI 1.4–5) of intracerebral haemorrhage.22 Therefore meta-analysis studies such as the Prospective Studies Collaboration, which included studies with no reference to stroke subtype,4 are difficult to interpret. The heterogeneous nature of non-haemorrhagic stroke may also obscure the possible association with cholesterol, as strokes caused by atherothrombotic process involving extracranial vessels may be more likely to be associated with high cholesterol levels than cardioembolic or lacunar strokes.23 Determining precisely the aetiology of stroke is technically difficult and not carried out routinely, and therefore data from most existing studies are incomplete.
In Table 3a, we summarize three case-control studies that include data on older patients with ischaemic strokes, and all of them showed significant correlation between cholesterol and stroke.24–26 The majority of the patients in these studies underwent computed tomography, and in the study of Hachinski et al., even cases with cardiac source for emboli were excluded.26 These data may indicate that future studies using sophisticated diagnostic modalities may demonstrate more compelling evidence for the association between stroke and cholesterol. One limitation of case-control studies can be a drop in cholesterol levels during hospitalization;27 however this would tend to underestimate the association between cholesterol and stroke. Another limitation in some studies is the exclusion of fatal cases.26
|
In Table 3b
, we summarize two prospective observational studies that included elderly people.28,29 The Honolulu Heart Project,28 an epidemiological study of men of Japanese ancestry, evaluated the association between cholesterol and CHD and thromboembolic stroke in a large cohort aged 51–74 years, including 2872 men aged 60–74 years. In the older age group, there was a significant correlation between total cholesterol and stroke. The Copenhagen City Heart Study, another large prospective observational study that included men and women aged 20–80, did not show a linear correlation between total cholesterol and stroke.29 The only correlation found was between cholesterol levels >300 mg/dl and non-haemorrhagic stroke. This association decreased with advancing age. However, a limitation of this study is that the diagnosis of non-haemorrhagic and haemorrhagic stroke was based on the results of computed tomography or autopsy in fewer than half of the cases. In conclusion, although the role of hypercholesterolaemia in stroke is still inconclusive, most studies that carefully evaluated non-haemorrhagic strokes have shown a positive association with cholesterol levels.
|
|
Trials on stroke prevention with statins in older patients with CHD |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
Trials in the pre-statin era did not show beneficial effect of treatment on stroke risk in middle-aged men, and studies using clofibrate even showed an increased risk of fatal strokes.30 The large statin trials have conclusively demonstrated for the first time a marked stroke reduction: a meta-analysis of 12 primary and secondary intervention trials with statins showed an overall reduction of 27% (p=0.001).31 The strongest evidence comes from the secondary prevention trials including patients with CHD.5–7 In the Scandinavian Simvastatin Survival Study, which included 4444 men and women aged 35–70, a 30% relative risk reduction for stroke was found in patients receiving simvastatin compared to the placebo group.5 The LIPID trial included 9014 men and women with a mean age of 61 years, and showed a 19% relative risk reduction for stroke in patients receiving pravastatin.7 In the CARE study, a separate analysis of 2129 men and women aged
60 years showed a 35% relative risk reduction for stroke and TIAs. Notably, patients in the older age group benefited more than patients <60 years of age.6 The data from these three large trials show a risk reduction of stroke by statins that is comparable to that achieved by conventionally accepted treatments such as anti-platelet or anti-hypertensive medications. The marked decrease in stroke rate in these studies caused by statins, which is not fully explained by cholesterol reduction alone, and the discrepancy between the therapeutic efficacy achieved with statins and the lack of beneficial effect with the other lipid-lowering treatments, has led to consideration of other possible mechanisms beyond cholesterol reduction.32 The other possible beneficial effects include: plaque stabilization, suppression of inflammation, improving endothelial dysfunction and effects on platelet function and coagulation. As statins may reduce stroke by mechanisms that go beyond cholesterol reduction, further studies are needed in determining their role in normocholesterolaemic patients who are at high risk for developing stroke.
|
Notes |
|---|
Address correspondence to Dr H. Knobler, Metabolic Service, Kaplan Medical Centre, Rehovot, Israel
|
References |
|---|
|
TopSummaryIntroductionCholesterol as a risk...Statin therapy for prevention...Cholesterol as a risk...Trials on stroke prevention...References |
|---|
1. Thorn TJ, Epstein FH. Heart disease, cancer and stroke mortality trends and their interrelations: an international perspective. Circulation1994; 90:574–82.
2.
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. JAMA1993; 269:3015–23.
3.
Kronmal RA, Cain KC, Ye Z, Omenn GS. Total serum cholesterol levels and mortality risk as a function of age: a report based on Framingham data. Arch Intern Med1993; 153:1065–73.
4. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Lancet1995; 346:1647–59.[Web of Science][Medline]
5. The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet1994; 344:1383–9.[Web of Science][Medline]
6.
Lewis SJ, Moye LA, Sacks FM, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med1998; 129:681–9.
7.
The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med1998; 339:1349–57.
8. Menotti A, Keys A, Blackburn H, et al. Comparison of multivariate predictive power of major risk factors for coronary heart diseases in different countries: results from eight nations of the Seven Countries Study, 25-year follow-up. J Cardiovasc Risk1996; 3:69–75.[Medline]
9.
Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA1994; 272:1335–40.
10.
Corti MC, Guralnik JM, Salive ME, et al. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med1997; 126:753–60.
11. Simons LA, Friedlander Y, McCallum J, Simons J. Risk factors for coronary heart disease in the prospective Dubbo Study of Australian elderly. Atherosclerosis1995; 117:107–18.[Web of Science][Medline]
12. Housterman S, Verschuren WM, Hofman A, Witteman JC. Serum cholesterol is a risk factor for myocardial infarction in elderly men and women: the Rotterdam Study. J Intern Med1999; 246:25–33.[Web of Science][Medline]
13. Rubin SM, Sidney S, Black DM, Browner WS, Hulley SB, Cummings SR. High blood cholesterol in elderly men and the excess risk for coronary heart disease. Ann Intern Med1990; 113:916–20.
14.
Corti MC Guralnik JM, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA1995; 274:539–44.
15. Houterman S, Verschuren WMM, Giampaoli S, et al. Total but not high-density lipoprotein cholesterol is associated with coronary heart disease mortality in elderly men in Finland, Italy and the Netherlands. Epidemiology2000; 11:327–32.[Web of Science][Medline]
16. Manolio TA, Pearson TA, Wenger NK, Barret-Connor E, Payne GH, Harlan WR. Cholesterol and heart disease in older persons and women: review of an NHLBI workshop. Ann Epidemiol1992; 2:161–76.[Medline]
17.
Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation1997; 96:4211–18.
18.
Downs GR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/Tex CAPS. JAMA1998; 279:1615–22.
19.
Grundy SM, Cleeman JI, Rifkind BM, Kuller LH. Cholesterol lowering in the elderly population. Coordinating Committee of the National Cholesterol Education Program. Arch Intern Med1999; 159:1670–8.
20.
Kalache A, Aboderin I. Stroke: the global burden. Health Policy Plan1995; 10:1–21.
21. Adams RD, Victor M. Cerebrovascular disease. In: Principles of Neurology. New York, McGraw-Hill, 1977.
22.
Iribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? Stroke1996; 27:1993–8.
23.
Reed DM. The paradox of high risk of stroke in populations with low risk of coronary heart disease. Am J Epidemiol1990; 131:579–88.
24. Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischemic strokes. Br Med J1991; 303:605–9.
25. Di Mascio R, Marchioli R, Vitullo F, Di Pasquale A, Cavasinni L, Tognoni G. Serum cholesterol and risk of ischemic stroke: results of a case-control study. Prev Med1995; 24:128–33.[Web of Science][Medline]
26.
Hachinski V, Graffagnino C, Beaudry M, et al. Lipids and stroke: a paradox resolved. Arch Neurol1996; 53:303–8.
27. Brugada R, Wenger NK, Jacobson TA, Clark WS, Cotsonis G, Iglesias A. Changes in plasma cholesterol levels after hospitalization for acute coronary events. Cardiology1996; 87:194–9.[Web of Science][Medline]
28. Benfante R, Yano K, Hwang LJ, Curb JD, Kagan A, Ross W. Elevated serum cholesterol is a risk factor for both CHD and thromboembolic stroke in Hawaiian Japanese men: implications of shared risk. Stroke1994; 25:814–20.[Abstract]
29.
Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high-density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. Br Med J1994; 309:11–15.
30.
Atkins D, Psaty BM, Koepsell TD, Longstreth WT Jr, Larson EB. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med1993; 119:136–45.
31.
Crouse JR, Byington RP, Hoen HM, Furberg CD. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med1997; 157:1305–10.
32.
Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reductions. JAMA1998; 279:1643–50.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. M. Gotto Jr Statin Therapy and the Elderly: SAGE Advice? Circulation, February 13, 2007; 115(6): 681 - 683. [Full Text] [PDF]
|
|
|
|
 |
|
 G. McGwin Jr, S. McNeal, C. Owsley, C. Girkin, D. Epstein, and P. P. Lee Statins and Other Cholesterol-Lowering Medications and the Presence of Glaucoma Arch Ophthalmol, June 1, 2004; 122(6): 822 - 826. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||