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COMMENTARIES |
Geriatric Services, Palmetto Health & Division of Geriatrics, University of South Carolina School of Medicine, Columbia.
Address correspondence to Victor A. Hirth, MD, Nine Medical Park, Suite 630, Columbia, SC 29203. E-mail: victor.hirth{at}palmettohealth.org
Significant progress has been achieved in the study of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in the secondary prevention of coronary heart disease (CHD). Caution should be exercised before advocating their use in patient populations that have not been well studied. Rather than overgeneralizing the findings of well-designed trials, we should be advocating the study of these at-risk populations in whom the potential benefits have yet to be determined and strive to improve compliance in those in whom trial evidence suggests the most benefit.
The National Cholesterol Education Program (NCEP) has recently revised the treatment guidelines for hyperlipidemia in adults "at high risk" based on the results of newer statin trials (1). The NCEP report was written by a working group of nine experts, eight of whom have or had financial relationships with Merck, the producer of the number two selling statin (simvastatin, Zocor), and seven of whom have or had financial relationships with Pfizer, the producer of the top-selling statin (atorvastatin, Lipitor). These recommendations will significantly alter the landscape of provider prescribing for years to come. The recent recommendations change the goal LDL from less than 100 to less than 70 in high-risk individuals. Unfortunately, these recommendations, even before this change, are being overgeneralized to the treatment of seniors without underlying CHD. Pharmaceutical company funding and direct-to-consumer marketing may be pushing this trend.
Based on the ATPIII Goals and Cut points, a 75- to 79-year-old male, nonsmoker, with a total cholesterol of 240 mg/dl, an HDL of 49 mg/dl, and an untreated systolic blood pressure of 130–139 mmHg would qualify as "high risk." A woman with the same cholesterol profile as the male above but with a treated blood pressure of 130–139 mmHg would also meet the 10-year risk threshold of >20% risk of a CHD event, based on Framingham data (2). Are we really ready to advocate the use of these medicines to the millions of seniors who have age, prehypertension, and dyslipemia as their only risk factors?
Few studies have enrolled a significant proportion of seniors, particularly older than 80, an age group from which both primary care physicians and geriatricians are experiencing ever-greater numbers of office visits. The Heart Protection Study (HPS) trials and those of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), which studied elderly individuals at risk for vascular disease, showed benefit in lowering LDL in patients up to age 82 with underlying CHD or cerebrovascular disease (3,4). Both studies demonstrated improved outcomes for both CHD and stroke. Subgroup analysis from other studies that included subjects in their 70s with CHD have also demonstrated benefit (3,5,6).
Trials involving CHD risk factors, but without established CHD, have been severely lacking in the statin arena, particularly in seniors who have age alone as their most potent risk factor. One study, the ASCOT lipid-lowering arm, enrolled subjects to the age of 79 with hypertension, total cholesterol less than 251 mg/dl, and at least three other risk factors and found that fatal and nonfatal CHD was reduced by 36% at 3.3 years (6). Subjects had an average of 3.7 risk factors in addition to hypertension, making this a very high-risk group. Subgroup analysis in women showed no benefit, although female numbers were small.
The primary prevention arm of the PROSPER trial showed no effect from lipid lowering in any of the outcome measures including fatal or nonfatal myocardial infarction or fatal or nonfatal stroke (4). Another study with negative findings was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which had a lipid-lowering arm using pravastatin (7). Unfortunately, because of low event rates and crossover of usual care patients to statin treatment, conclusions based on this trial are limited.
Other studies such as the West of Scotland pravastatin trial, which has been touted as a primary prevention trial, limited the age of enrollment to those persons younger than 65; included men who had angina, peripheral vascular disease, or diabetes mellitus; and had subjects with plasma cholesterols in the highest quartile found in the British population (8). Most likely a substantial proportion of subjects had underlying CHD, and there are serious questions about the generalizability of these findings to seniors living in the United States. The only true primary prevention trial showing benefit with statin therapy is the West Texas AFCAPS/TexCAPS trial (9). This trial limited enrollment to subjects 65 or younger and used an agent, lovastatin, no better than fourth in its share of new prescriptions filled in the United States (10). Whether negative trial publishing bias exists in the statin field is unknown, but given the experience in numerous other fields, there is no reason to think otherwise.
Much of the available data in the treatment of dyslipemia with statins come from enrolled subjects who were predominately white and male, had underlying CHD, and were between 44 and 65 years old. Extensive subgroup analysis has now led to the recommendations that seniors, women, and some ethnic group members will benefit from cholesterol-lowering therapy. Optimally, these analyses should be used to prompt further research in this area as opposed to generalizing recommendations to other groups on the basis of findings not related to the original study design and hypothesis.
Particularly, dealing with the "old-old" life expectancy and comorbidity should be an important consideration in the recommendation for or against statin therapy. A 90-year-old male has a life expectancy of 4.1 years (11). The time to benefit for primary prevention in this age group is unknown and for secondary prevention would be at about the limit of where studies have shown benefit in those persons with CHD. Another factor, not well understood, is the dogma that statins are "well tolerated." In research trials, side effects have been minor and generally have not led to drug discontinuation. Adherence to therapy in trials has been excellent, with discontinuation rates of only 6%–30% over 5 years (3,4,8). However, community studies of compliance with statin therapy show that compliance at 1 year is 50% or less, and at 5 years is less than 30% (12,13). Cost of medication seems to be an unlikely explanation, particularly when the two trials that reached these conclusions provided free medication or only required a $2 copayment. Poor compliance is not a reason to deny therapy when secondary prevention evidence is so strong. However, there may be other undetermined factors adversely affecting compliance, resulting in these findings.
Finally, the issue of coexisting comorbidity is not well understood either. In the population of seniors, comorbid conditions increase in frequency with an increase in age. Most of the statin trials excluded subjects who had significant underlying pulmonary, renal, or neurologic disease. The effect of these comorbidities on outcomes will remain undetermined until studied.
Substantial progress has been made in determining the potent benefits of statin therapy in patients with underlying CHD (14). Unfortunately, the same cannot be said for the use of statins in primary prevention, particularly in seniors. Marketing pressure, direct-to-consumer advertising, and potential conflicts of interest of expert panels are all clouding effective decision making based on patient outcomes in regard to the prescription of statins. Until trials properly designed to address these specific issues are performed, physicians should concentrate on improving medication compliance in those settings in which statins have shown their most robust benefit.
References
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