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Treating Cholesterol in the Elderly

Monday, September 2, 2013 // Uncategorized

Treating elevated cholesterol in patients with cardiovascular disease is fairly standard, but there is less solid proof  that treating older patients without heart disease is effective.  The following is the abstract of a a meta- analysis published by the American College of Cardiology.  I am following it by a summary of the data from UpToDate.  The bottom line is that more older patients could benefit from taking statins.  Some people may be put of by the definition of elderly, 65 and older:

Clinical Research                         | August 2013

Benefits Of Statins In Elderly Subjects Without Established Cardiovascular Disease. A Meta-Analysis                                                 ONLINE FIRST

Gianluigi Savarese, MD; Antonio M. Gotto, MD, PhD; Stefania Paolillo, MD; Carmen D’Amore, MD; Teresa Losco, MD; Francesca Musella, MD; Oriana Scala, MD; Caterina Marciano, MD; Donatella Ruggiero, MD; Fabio Marsico, MD; Giuseppe De Luca, MD, PhD; Bruno Trimarco, MD, PhD; Pasquale Perrone-Filardi, MD, PhD
J Am Coll Cardiol. 2013;():.                               doi:10.1016/j.jacc.2013.07.069
                        Published online

Objectives      To assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease.

Background      Since ageing of the population is steadily raising, prevention of cardiovascular (CV) disease in the elderly is relevant. In elderly patients with previous CV events, use of statins is recommended by guidelines, whereas benefits of these drugs in elderly subjects without previous CV events are still debated.

Methods      Randomized trials comparing statins versus placebo and reporting all-cause and CV mortality, myocardial infarction (MI), stroke, and new cancer onset in elderly (>65 years old) subjects without established CV disease were included.

Results      Eight trials enrolling 24,674 subjects (42.7% females; mean age 73.0+2.9; mean follow-up 3.5+1.5 years) were included in analyses. Statins, compared to placebo, significantly reduced the risk of MI by 39.4% (relative risk [RR]: 0.606 [95% confidence interval (CI): 0.434 to 0.847]; p=0.003), as well as the risk of stroke by 23.8% (RR: 0.762 [CI: 0.626 to 0.926]; p=0.006). In contrast, the risk of all-cause death (RR: 0.941 [CI: 0.856 to 1.035]; p=0.210) and of CV death (RR: 0.907 [CI: 0.686 to 1.199]; p=0.493) were not significantly reduced. New cancer onset did not differ between statin- compared to placebo-treated subjects (RR: 0.989 [CI: 0.851 to 1.151]; p=0.890).

Conclusions      In elderly subjects at high CV risk without established CV disease, statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term

BENEFITS OF LIPID LOWERING LIPID IN THE ELDERLY

Clinical trials — The secondary prevention trials of LDL-cholesterol lowering therapies have shown a reduction in cardiac events and all cause mortality (see “Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents”). However, these studies had only limited data in older subjects. Nevertheless, subgroup analysis of trials that included elderly individuals suggests that they have a similar benefit from lipid lowering therapy as younger subjects [2,16-21].

  • The Scandinavian Simvastatin Survival Study (4S trial) included 1021 patients greater than 65 years of age with angina or a previous myocardial infarction and hypercholesterolemia (baseline plasma total cholesterol levels between 212 and 309 mg/dL [5.5 and 8.0 mmol/L]) [16]. Similar reductions in serum lipids were observed among elderly and younger individuals. In the older patients, treatment with simvastatin reduced all cause mortality (34 percent lower), mortality from coronary heart disease (43 percent), major coronary events (34 percent), and the number of revascularization procedures (41 percent).
  • The Cholesterol and Recurrent Events (CARE) trial included 1283 patients between the ages of 65 and 75 who had average levels of total, LDL and HDL cholesterol of 209 mg/dL, 139 mg/dL, and 39 mg/dL (5.4, 3.6, and 1.0 mmol/L) [18]. Reductions in coronary events were similar to the 4S trial (figure 4). It was estimated that for every 1000 older patients treated, 225 cardiovascular hospitalizations and 207 cardiovascular events would be prevented compared with 121 hospitalizations and 150 cardiovascular events in 1000 younger patients [18,19].
  • The LIPID trial included 3514 patients between the ages of 65 and 75 years who had a prior infarction or unstable angina in addition to a baseline serum cholesterol of 155 to 271 mg/dL (4 to 7 mmol/L) [20]. Although the risk of all cardiovascular events and all-cause mortality were reduced by pravastatin therapy to a similar degree in older and younger patients, the absolute benefit was greater in the elderly because of a greater risk for these events; fewer elderly patients needed to be treated to prevent one death from any cause (22 versus 46 for younger patients), one death from CHD (35 versus 71), one cardiovascular death (28 versus 61), one fatal or nonfatal MI (30 versus 36), or one stroke (79 versus 170).
  • The Heart Protection Study included over 20,000 patients with varying lipid profiles (33 percent had baseline LDL cholesterol <116 mg/dL [<3 mmol/L], 25 percent had a level of 116 to 135 mg/dL [3 to 3.5 mmol/L], and 42 percent had levels >135 mg/dL [>3.5 mmol/L]) who were randomly assigned to simvastatin or placebo [21]. Entry criteria were age 40 to 80 years, a history of cardiovascular disease (coronary cerebrovascular, or peripheral vascular disease), diabetes mellitus, or treated hypertension. Thus, most patients were treated for secondary prevention. Treatment with simvastatin was associated with a reduction in cardiovascular events that was similar in patients above and below age 65. (See “Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents”, section on ‘Heart Protection Study’.)
  • Similarly, in the CARDS study in patients with type 2 diabetes without known CHD, atorvastatin 10 mg daily reduced first major cardiovascular events by 37 percent in patients younger than 65 and by 38 percent in patients 65 and older [22].
  • In the TNT (Treating to New Targets) study, atorvastatin 80 mg versus 10 mg in 10,001 patients with stable CHD significantly decreased the risk for major cardiovascular events in those both ages 65 and older (n = 3809) and in younger patients [23,24]. (See “Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents”, section on ‘TNT trial’.)

 

Similar findings were noted in an analysis of pooled data from three randomized trials of pravastatin involving 19,768 patients (CARE, LIPID, and WOSCOPS) [25]; two of these are discussed individually above. The relative reduction in the risk of cardiac events was comparable for patients ages <55 years, 55 to 64 years, and 65 to 75 years (32, 21, and 26, respectively).

Subgroup analyses from primary prevention trials of statins, including AFCAPS/TexCAPS, and ASCOT-LLA found similar relative effects of therapy on clinical endpoints in younger and older individuals [26-28]. In JUPITER, a large trial of rosuvastatin in patients with low-to-average LDL-C levels and elevated c-reactive protein levels, although the relative risk reductions were similar in older and younger patients, the absolute reduction in the primary composite cardiovascular endpoint was 0.77 events per 100 patient-years in the 5695 patients ages 70 and older, which was greater than the reduction of 0.52 events per 100 patient-years seen in the 12,107 patients ages 50 to 69 [28].

Other studies that specifically included older adult patients add further evidence that treatment of hypercholesterolemia in older adults provides similar benefits to that of treatment in younger people [29,30]:

  • The PROSPER trial randomly assigned 5804 men and women ages 70 to 82 years with a history of or risk factors for vascular disease to pravastatin (40 mg per day) or placebo [30]. During a mean follow-up of only three years, pravastatin treatment was associated with both significantly lower LDL concentrations and a significantly reduced risk of the primary end point (coronary death, nonfatal myocardial infarction, and fatal or nonfatal stroke, hazard ratio [HR] 0.81, 95% CI 0.74-0.97). Stroke risk alone was unaffected by therapy, but pravastatin was associated with significantly lower risk of coronary death and nonfatal myocardial infarction. There was, however, no significant reduction in all-cause mortality (HR 0.97, CI 0.83-1.14), and there was a significant increase in new diagnoses of cancer (HR 1.25, CI 1.04-1.51). The authors performed a meta-analysis of statin trials including PROSPER and found no overall evidence of an increased risk of cancer with statins (HR 1.02, CI 0.96-1.09). (See “Statins: Actions, side effects, and administration”, section on ‘Side effects’.)
  • The SAGE trial compared intensive and moderate statin therapy in patients with known CHD ages 65 to 85 who had at least one episode of ischemia on baseline screening with 48-hour ambulatory monitoring [31]. Patients were randomly assigned to treatment with atorvastatin 80 mg daily or pravastatin 40 mg daily. There was no difference between the two groups in the primary endpoint of duration of ischemia on ambulatory monitoring at month 12. However, there was a trend toward a reduction in a composite endpoint of major cardiovascular events with intensive therapy (HR 0.71, CI 0.46-1.09), and a post-hoc analysis found a reduction in mortality (HR 0.33, CI 0.13-0.83). In contrast, no similar reduction in mortality was seen with intensive statin therapy in patients ages 65 and older (n = 3809) in the TNT trial (HR 1.08, CI 0.87-1.33) [24,32]. (See “Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents”, section on ‘TNT trial’ and “Intensity of lipid lowering therapy in secondary prevention of coronary heart disease”.)

 

Despite these apparent benefits, compliance with statin therapy declines substantially with time in older adult patients [33,34]. This occurs even when cost is not an issue. The adherence rate is similar to that observed for treatment of hypertension, another asymptomatic condition.

Time course for CHD benefit — The prevention of CHD in elderly subjects has been hindered by the perception that LDL lowering therapy requires many years before the course of atherosclerosis can be altered. This concept has been challenged by the observation that clinical benefits are seen as early as six months to two years (figure 5), in many cases before atherosclerosis regression has occurred [35-37]. In addition, statin therapy can improve endothelial dysfunction within three days of initiating therapy [38]. (See “Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease”.)

Side effects — The safety of lipid lowering agents in older subjects was evaluated in two double-blind, placebo-controlled trials that included 573 patients over the age of 64 [39,40]. Treatment with lovastatin or pravastatin was associated with a fall in cholesterol levels similar to that seen in younger subjects. There was no statistically significant difference in side effects between the treatment and placebo groups. Neither trial provided information regarding the effect of therapy on morbidity and mortality.

An analysis from the CARDS study of atorvastatin 10 mg daily in patients with type 2 diabetes without known CHD found similar rates of adverse events in patients younger than age 65 and in those ages 65 and older [22]. For both younger and older patients, the rates of adverse events were no different with atorvastatin or placebo.

Summary

The decision whether to treat high or high-normal serum cholesterol in an elderly individual needs to be individualized, being based upon both chronological and physiologic age. As an example, a patient with a limited life span from a concomitant illness is probably not a candidate for drug therapy. On the other hand, an otherwise healthy elderly individual should not be denied drug therapy simply on the basis of age alone [2].

The studies described above support the use of lipid lowering therapy for secondary prevention in older patients with established CHD who do not have life-limiting comorbid disease [16-18,20,21]. These patients should be treated similar to younger patients according to the guidelines established by the National Cholesterol Education Program (see “Treatment of lipids (including hypercholesterolemia) in secondary prevention”) [1,2]. There are limited data on the value of treating elderly patients with low HDL-cholesterol (<40 mg/dL [1.03 mmol/L]), but again, presumably the same principles would apply as in younger patients. (See “HDL metabolism and approach to the patient with abnormal HDL-cholesterol levels”.)

In comparison, there are more limited data concerning the use of lipid lowering for primary prevention of CHD in elderly hypercholesterolemic patients. Because of the progressive elevation in total and LDL cholesterol levels with aging (figure 2), it has been estimated 40 percent or more of those above age 65 meet the National Cholesterol Education Program guidelines for treating hypercholesterolemia (see “Treatment of lipids (including hypercholesterolemia) in primary prevention”) This would entail a large annual cost.

On the other hand, over 50 percent of older individuals will eventually die from cardiovascular disease and data from the Cardiovascular Health Study suggest significant benefit from primary prevention in patients ages 65 and older [41]. The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III), published before the results of the Cardiovascular Health Study were available, recommended that therapeutic lifestyle changes are the first line of primary prevention for older individuals, although LDL-cholesterol lowering drugs can be considered when older patients have multiple risk factors for CHD as shown in the table (table 1) [1].

Despite their proven benefit, lipid-lowering drugs are markedly underutilized in elderly patients. This was illustrated in a prospective study of 500 patients with a mean age of 81 years and a Q wave myocardial infarction [42]. Although 67 percent had a serum LDL-cholesterol concentration above 125 mg/dL (3.2 mmol/L); only 5 percent were treated with a lipid-lowering drug. A retrospective cohort study of 396,077 high-risk elderly patients found that prescription of statins decreased with increasing age and also with increasing cardiovascular risk and risk of death; thus, the elderly patients likely to get the greatest absolute benefit from statins appear least likely to receive them [43].

ADDITIONAL ISSUES IN OLDER ADULTS

Secondary causes — Older adult patients commonly have medical conditions that may contribute to dyslipidemia. Etiologies to consider include hypothyroidism, diabetes mellitus, and nephrotic syndrome. Therapies may also contribute to dyslipidemias. As examples, thiazide diuretics can affect lipid metabolism, and antipsychotics used for agitation in dementia can produce weight gain. (See “Secondary causes of dyslipidemia”.)

Dietary modifications — While therapeutic lifestyle changes involving exercise and diet are generally the first line of treatment for dyslipidemias, providers should avoid dietary restrictions in older patients who are at high risk of malnutrition. These include patients with dementia or physical disabilities that limit their access to adequate nutrition. (See “Treatment of dementia”, section on ‘Nutrition’.)

Drug interactions and side effects — Elderly patients are frequently treated with multiple medications and so are at increased risk for complications of drug interactions. As an example, macrolide antibiotics can raise statin levels and thus the risk of muscle toxicity (see “Statins: Actions, side effects, and administration”). Providers should be particularly cautious of such interactions in older patients.

Additionally, older adult patients may have greater susceptibility to medication side effects, such as bloating and constipation with bile acid sequestrants, and hyperglycemia and gout with niacin. (See “Lipid lowering with drugs other than statins and fibrates”, section on ‘Bile acid sequestrants’ and “Lipid lowering with drugs other than statins and fibrates”, section on ‘Nicotinic acid (Niacin)’.)

SUMMARY AND RECOMMENDATIONS

  • Coronary heart disease (CHD) is the most common cause of death in older patients, and, as in younger patients, dyslipidemia is associated with an increased risk of CHD. (See ‘Cardiovascular disease in older adults’ above.)
  • Although the relative risk of hypercholesterolemia is somewhat lower in older patients, the absolute risk is higher than in younger patients. (See ‘Relative risk versus attributable risk’ above.)
  • The relative benefit of lipid lowering therapy in older patients is similar to that in younger patients, and the absolute benefit is typically greater than in younger patients. Particularly in secondary prevention, the absolute benefits are large enough that many older patients with CHD would benefit from lipid-lowering therapy, and older patients with a reasonable life expectancy may also benefit in primary prevention. Side effects of lipid lowering therapy may also be similar in older and younger patients. (See ‘Benefits of lipid lowering lipid in the elderly’ above.)
  • Reductions in events with statin therapy can occur quickly (within weeks to months), and so even in older patients such therapy can be expected to reduce events during a patient’s expected lifespan. (See ‘Time course for CHD benefit’ above.)
  • Secondary causes of dyslipidemia such as hypothyroidism, diabetes, nephrotic syndrome, and drug effects should be considered, particularly in older patients. (See “Secondary causes of dyslipidemia”.)

 

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REFERENCES

 

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