Lipid-Lowering Medications in the Elderly
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Valid November 1, 2005- January 31, 2006. Estimated time: 1 hour
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1. To identify the indications for statin therapy
2. To identify the contraindications for statin therapy
3. To be able to recommend appropriate lipid management for elderly patients
4. To identify risk factors for rhabdomyolysis in patients taking combination therapy
The final report of the Adult Treatment Panel III (ATP III) guidelines was published in 2001 and provided specific targets and treatment strategies for patients with dyslipidemia.1 Although the target values for lipid levels were not age-specific, ATP III acknowledged that the majority of major coronary events occur in individuals older than 65 years of age.2 Results from the Framingham Heart Study showed that the lifetime risk of coronary heart disease (CHD) increased with rising total cholesterol (TC) levels.3 The lifetime risk for men and women with TC lower than 200 mg/dL and age 60 years was 34% and 20%, respectively, whereas the risk was 51% and 36% for men and women with TC higher than 240 mg/dL. In 2002, the American Heart Association Council on Clinical Cardiology Subcommittee issued a scientific statement emphasizing the importance of secondary prevention of CHD in elderly individuals, including those older than 75 years of age.4 The evidence showed that older persons as compared with individuals younger than 65 years of age derived equal benefit from interventions and treatments known to reduce risk for cardiovascular and cerebrovascular disease.
Interventions such as coronary artery bypass grafting and angioplasty reduced relative risk in older men and women, and treatments such as antihypertensive medications have also been shown to be cardioprotective in this population. With regard to lipid-lowering therapies, post-hoc analysis of large clinical trials, such as the Scandinavian Simvastatin Survival Study (4S),5 the Cholesterol And Recurrent Events (CARE) trial,6 and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study,7 have demonstrated that persons 65 years and older also derived benefit by using these medications. Most recently, the results from the PROspective Study of Pravastatin in the Elderly at Risk of vascular disease (PROSPER) trial8 have shown that pravastatin therapy significantly reduced absolute risk for coronary artery disease (CAD) in an elderly population. Nonpharmacological therapies have been shown to be of benefit in the elderly (weight reduction, smoking cessation, and exercise activity), and none of these would be considered risky treatments in an older population. However, health care providers are reluctant to initiate lipid-lowering treatment in older individuals due to concerns of increased risk without convincing evidence of benefit. Therefore, this review assesses the efficacy and safety of statins (monotherapy and combination with fibrates/niacin) in older persons.
Statin therapies HMG CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitors are the most widely used class of lipid-lowering medications. Low-density lipoprotein cholesterol (LDL-C) reductions are seen due to inhibition of the hepatic enzyme responsible for the rate-limiting step in cholesterol synthesis. Triglycerides (TGs) are reduced to a lesser extent, and high-density lipoprotein (HDL) rises minimally in response to medication. Common adverse events leading to drug discontinuation include myopathy and elevated transaminases. Rhabdomyolysis occurs more rarely, usually when statins are prescribed in combination with fibrates. Contraindications to therapy include pregnancy, breastfeeding, and active liver disease. Likely due to perceived increased risk of adverse events, more comorbid conditions, concerns over polypharmacy, and lower perceived mortality benefit from lipid lowering, the elderly are well-documented to be under-prescribed statins.
Several studies published in the last few years have demonstrated not only that older patients benefit from statins and have no more adverse events than younger patients, but also that the absolute risk reduction for cardiac events and mortality is greatest in the elderly. The PROSPER trial8 is the only randomized, controlled trial to date that specifically and exclusively enrolled older subjects. Subjects ages 70-82 years with pre-existing CAD or at high risk for CAD were randomized to pravastatin or placebo. Over an average of more than three years follow-up of 5804 subjects, the pravastatin group had significantly fewer combined cardiovascular outcomes (CHD death or nonfatal or fatal myocardial infarction [MI], fatal or nonfatal stroke). There was no effect on cerebrovascular events or coronary revascularization rates when analyzed separately. Subanalyses of older subjects from three large clinical trials have shown similar results. The CARE,6 LIPID,7 and 4S5 trials together enrolled 5818 subjects 65 years and older.
The 4S study was a secondary prevention trial randomizing subjects to simvastatin or placebo. Subjects 65 years and older as well as subjects under 65 years had significant reductions in all-cause mortality, CHD mortality, major cardiovascular events, nonfatal MI, and any acute CHD-related event, atherosclerotic endpoint, and revascularization rates. All-cause and CHD mortality rates in older subjects were more than twice those of younger subjects, and therefore the absolute risk reductions in the older subjects were far greater than in the younger subjects. Simvastatin was tolerated similarly to placebo in the older and younger subgroups. Minor elevations in transaminases were more common in older subjects, but the rate of discontinuation of study medication due to markedly elevated transaminases was the same in the simvastatin group and placebo group, both of which were similar to rates in the younger population. The CARE and LIPID trials were also secondary prevention trials, randomizing subjects to pravastatin or placebo. Subgroup analyses of elderly subjects in both trials showed significant reductions in fatal or nonfatal MI, coronary bypass surgery rates, coronary deaths, and coronary deaths combined with nonfatal MI in the treated compared with placebo group.
The CARE trial, but not the LIPID trial, showed a significant reduction in stroke rates in the elderly treated population. The LIPID trial also demonstrated a significant decrease in all-cause mortality and cardiovascular death in the elderly. The LIPID trial elderly subgroup analysis showed a higher risk of all cardiovascular outcomes in the older group compared to younger subjects, except for revascularization rates that were lower in the older subjects, possibly due to the more conservative management often practiced in the elderly. For both CARE and LIPID subgroup analyses, the number needed to treat to prevent cardiovascular events was lower in older than in younger subjects, reflecting the increased baseline risk of such events in the older subjects. The LIPID trial reported similar adverse events rates among elderly subjects in treated and placebo groups. There are no randomized, controlled trials of statins in the very elderly; however, an observational study of patients admitted to the hospital and found to have angiographically significant CAD included 655 subjects age 80 years and older as well as younger subjects (under 65 years and 65-79 years).9 Across all age groups, statins were prescribed for only 20-28% of patients in this 2002 study. Of subjects age 80 years and older, 80% were discharged without statin prescription, and 35% of these subjects had hyperlipidemia. Follow-up all-cause mortality data were obtained on 100% of patients, with a mean follow-up of 3.3 years.
In multivariable regression analysis, the two oldest groups had significantly fewer deaths in the statin-prescribed groups than in the group not discharged on a statin. The treated and untreated groups were not randomized, thus there are limitations to interpreting these data. Low-density lipoprotein treatment goals have been progressively lowered as trials are published, demonstrating continued benefit of more aggressive lipid lowering. High-dose atorvastatin (80 mg/day) in the post-MI period was proven to reduce combined cardiovascular endpoints compared to placebo in the Myocardial Ischemia Reductions with Aggressive Cholesterol Lowering (MIRACL) trial.10 Mean patient age was 65 years; however, no elderly subanalysis was offered to confirm that they benefit equally compared to younger patients. The PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial11 showed that high-dose statin therapy in patients immediately post-MI reduces combined cardiovascular endpoints as well as some individual cardiovascular endpoints, compared to less aggressive statin therapy. However, a subgroup analysis of subjects age 65 years and older showed no reductions in the primary outcome of combined cardiovascular events. The Treating to New Targets (TNT) trial12 showed significant reductions in cardiovascular outcomes in subjects with stable CAD treated with aggressive lipid lowering. No interaction was observed with age, but the age groups analyzed were not described. Although no dedicated trials or post-hoc analyses have examined the role of high-dose lipid-lowering therapy in high-risk elderly, there is no reason to suspect that older subjects would respond less well to aggressive statin therapy compared to younger subjects.
The cumulative experience of publications dedicated to elderly response to statins highlights the increased benefit of treating the elderly, as they are at highest absolute risk for cardiovascular events; this is also a reasonable expectation for aggressive lipid lowering. It should be noted that all of the trials described above, as well as the observational study, examined subjects with known CAD or who were at high risk for CAD. The role of lipid lowering in older persons as primary prevention of CAD has not been explored in dedicated clinical trials. Statin-fibrate therapies In 2001, Shek et al13 conducted a literature review regarding the safety of combining statins plus fibrates in the treatment of mixed hyperlipidemia. The authors identified 29 case reports and 36 clinical trials for patients/subjects using combination therapy and reporting occurrences of rhabdomyolysis, myopathy, myalgia, elevated creatine kinase (CK), or serum transaminases. Of the 29 published case reports of rhabdomyolysis, the ages ranged from 42-79 years (mean age, 63.1 ± 10.3 years), 70% of cases were female, and 28% had chronic renal impairment or kidney disease. Gemfibrozil was the prescribed fibrate in all of these cases, and the statin medications varied (lovastatin [72%], simvastatin [14%], cerivastatin [withdrawn from the U.S. market in 2001] [10%], and atorvastatin [3%]).
Of the 36 clinical trials, there were no reported cases of rhabdomyolysis; mean ages from the trials ranged from 44-64 years (mean age for all trials, 53.3 ± 5.6 years). The incidence of myopathy was 0.12% (defined as CK levels > 10 times upper limits of normal), musculoskeletal symptoms was 1.9% (defined as myalgia, muscle weakness, musculoskeletal pain, or myositis), subclinical elevations of CK was 2.1% (defined as elevations of CK < 10 times upper limits of normal), and subclinical elevations of serum transaminases was 3.2% (defined as elevations of transaminases < 3 times upper limits of normal). Gemfibrozil was the most prescribed fibrate (56%), whereas fenofibrate usage was 6% of the total (remainder of fibrates used [bezafibrate, ciprofibrate] are not available in the United States). Doses of statins varied between studies, and several trials used more than one statin. Lovastatin, pravastatin, and simvastatin were used most commonly (in 10, 11, and 12 trials, respectively), and fluvastatin and atorvastatin were used less commonly (in 8 and 2 trials, respectively). Overall, the authors suggested that the presence of increased age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise increased risk for myopathy. Since 2000, there have been seven randomized studies of statin-fibrate therapy (Table I).14-20
The reasons for not considering the remaining studies are that most were review articles, the studies were retrospective chart reviews, or the study population did not contain individuals older than 65 years of age. In all of these statin-fibrate studies, combination therapy significantly reduced TC and TG levels and increased HDL-C levels, as compared to baseline levels. As shown in Table I, there were few significant side effects, including severe myositis or transaminitis. Statin-niacin therapies Four randomized studies of statin-niacin therapy have been published since 2000 (Table II).21-24 The ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study21 was a randomized, placebo-controlled study that examined the effect of adding niacin (1000 mg/day) to statin therapy (majority of subjects used simvastatin) in persons with known CAD. The mean age of the study population was 67 ± 10 years, with the vast majority being men. The primary outcome was change in carotid intimal-medial wall thickening (CIMT), and secondary endpoints were changes in lipid levels and adverse and clinical cardiovascular events. The results showed that progression of CIMT was significantly less in subjects using statin-niacin combination versus statin alone. Low-density lipoprotein cholesterol levels were lower than 100 mg/dL in both groups, while HDL-C increased significantly (17%, P = 0.003) and TG decreased significantly (18%, P = 0.03) in the statin-niacin group. Adverse events included significantly increased fasting glucose levels in both groups and flushing in the statin-niacin group.
Hecht et al22 examined the effects of statin-niacin on calcified plaque progression (measured by electron beam computed tomography [EBCT]) in study participants without known CAD. The investigators found no difference in calcium burden between statin-only or statin-niacin therapy. High-density lipoprotein cholesterol significantly increased in the statin-niacin group, while levels of LDL-C, non–HDL-C, TG, and TC/HDL-C decreased significantly. Wink et al23 reported a similar trend in HDL-C in subjects who had been on stable doses of statins and were treated with either placebo or low-dose, immediate-release niacin. Low-dose niacin significantly increased HDL-C but did not significantly change TC or LDL-C levels. Capuzzi et al24 examined the effects of rosuvastatin and extended-release niacin in subjects with mixed dyslipidemia. These investigators found that rosuvastatin/extended-release niacin was well-tolerated and significantly reduced TC and TG levels while increasing HDL-C levels. Elevation in creatine kinase levels were seen in one patient on niacin monotherapy.
Ezetimibe is a new lipid-lowering agent that inhibits gastrointestinal cholesterol absorption. Ezetimibe co-administered with statins reduces LDL-C further than statins alone and allows for lower statin doses. Studies including older subjects have shown equivalent LDL-C reduction in subjects over 65 years of age25-28 and over 75 years of age28 compared to younger patients. Adverse event rates were equivalent in the combination therapy groups compared to the statin-only groups.25-28 A study incorporating data from four trials of combination therapy versus statin-only therapy found that older subjects in the combination therapy group were more likely to experience adverse events leading to discontinuation of study medication compared to the younger subjects. However, there were no cases of elevated transaminases or CK in older subjects.28 Importantly, as ezetimibe interferes with gastrointestinal absorption of cholesterol, there has been no demonstrated difference in serum levels of vitamins A, D, and E, and no difference in cosyntropin response or in prothrombin time in the treatment group after 12 weeks of monotherapy.29 Although the lipid-lowering effect of ezetimibe in combination with statins is an important new tool, there are no data on cardiovascular outcomes.
Medications raising HDL—Meta-analysis of niacin/fibrate studies In 2005, Birjmohun et al30 performed a meta-analysis of randomized, controlled clinical trials of niacin and fibrate medications on the efficacy of lipid lowering and clinical outcomes. The meta-analysis was generated from data extracted from 30 trials of niacin monotherapy (immediate-release acipimox, extended-release niacin, and wax matrix sustained-release niacin) and from 53 trials of fibrate monotherapy (gemfibrozil, fenofibrate, bezafibrate, clofibrate, and ciprofibrate). The mean age for these pooled studies was 58 years for the niacin studies and 56 years for the fibrate studies, with a predominance of male subjects (male-to-female ratio, 7:1 for niacin studies and 16:1 for fibrate studies). The average study duration was 8 months for the niacin studies and 12 months for the fibrate studies. The results showed that niacin significantly reduced TC and TG levels (range for TC reduction, 13-15%; range for TG reduction, 20-26%), whereas HDL-C levels were significantly increased (range, 13-23% [with immediate-release niacin causing the most robust responses]; P < 0.00001). In order of decreasing prevalence, the most common adverse effects of niacin treatment were flushing, gastrointestinal symptoms, skin reactions, hyperglycemia, hepatotoxicity, and musculoskeletal symptoms.
Only one clinical trial with niacin monotherapy has been conducted, the Coronary Drug Project,31 which showed a significant reduction in major coronary events. However, the dropout rate was high (70%), owing to the use of immediate-release niacin and the high side-effect profile of this formulation. In all fibrate studies, TC and TG decreased significantly (9-13% for TC reduction and 18-48% for TG reduction; P < 0.00001), whereas the effect on LDL-C reduction was variable (bezafibrate, fenofibrate, and ciprofibrate reduced LDL-C by 13% [P < 0.04], 11% [P < 0.01], and 8% [P < 0.005], respectively; clofibrate and gemfibrozil had no significant effect on LDL-C reduction). Overall, the fibrates significantly increased HDL-C, with the exception of clofibrate (bezafibrate 11%, gemfibrozil 11%, fenofibrate 10%, and ciprofibrate 10%; all P < 0.00001). In decreasing order of prevalence, the most common adverse effects of fibrate medications were gastrointestinal symptoms, skin reactions, hepatotoxicity, and musculoskeletal symptoms. In terms of clinical outcomes, the pooled results showed that fibrate therapy significantly reduced risk from major coronary events by 25% (P < 0.001), but had no statistically significant effect on all-cause or coronary mortality. The reduction in major coronary events was significant in two studies, Veterans Affairs HDL Intervention Trial (VA-HIT)32 and Helsinki Heart Study,33 and trended toward significant in three studies, BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT),34 Bezafibrate Infarction Prevention (BIP) study,35 and Lower Extremity Arterial Disease Event Reduction (LEADER) trial.36
The absolute risk for cardiovascular and cerebrovascular disease in persons over the age of 65 years is considerably greater than in those younger than 65 years. Nonpharmacological therapies have been shown to provide benefit in older persons. The current review and meta-analysis results strongly suggest that lipid-lowering therapies, particularly statins, should be offered to all older persons at risk for cardiovascular disease. For the very elderly (over the age of 75 years) and for those who are frail and have comorbidities such as renal or liver impairment, clinical judgment is required in balancing benefit versus risk of statin monotherapy or combination therapies. Data to support treatment of dyslipidemia in the elderly for primary prevention of coronary or cerebrovascular events in groups at low or moderate risk are lacking.