Medical evidence suggests that

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1 COMBINATION THERAPY TO ACHIEVE LIPID GOALS David G. Robertson, MD* ABSTRACT Coronary heart disease (CHD) remains the leading cause of death in the United States despite recent advances in treatment and prevention. Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for CHD as well as being associated with development of atherosclerosis. The National Cholesterol Education Program has issued a new set of guidelines for management of elevated LDL-C levels and other lipid disorders, setting lower LDL-C goals than previously recommended for patients at risk for heart disease and for those with heart disease risk equivalents. Clinical trial investigators continue to evaluate whether patients with a low baseline LDL-C may benefit from achieving LDL-C concentrations even lower than those currently recommended. This article evaluates the relationship between LDL-C and risk reduction, explores issues related to patient compliance, and defines the role of combination therapy in achieving target goals for both LDL and highdensity lipoprotein cholesterol. (Advanced Studies in Medicine 2002;2(13): ) *Assistant Clinical Professor, Emory University School of Medicine; Atlanta Diabetes Associates, Atlanta, Georgia. Address correspondence to David G. Robertson, MD, Atlanta Diabetes Associates, 77 Collier Rd NW, Suite 2080, Atlanta, GA Medical evidence suggests that HMG-CoA reductase inhibitor (statin) therapy, traditionally used to treat hypercholesterolemia, may also benefit patients whose lowdensity lipoprotein cholesterol (LDL-C) levels fall well within the normal range. However, whether a low baseline LDL-C limits the benefits of statin therapy remains a focus of scientific inquiry. The Cholesterol and Recurrent Events (CARE) study suggested that statin therapy may be of limited benefit to patients with pretreatment LDL-C levels <130 mg/dl and that other treatments may prove to be more beneficial. 1 The Heart Protection Study, conducted in private practice settings throughout the United Kingdom, included many subjects whose total cholesterol level was as low as 135 mg/dl in order to evaluate the therapeutic benefits from simvastatin, 40 mg daily, vitamin therapy (C, E, or beta-carotene), or both, versus placebo over a 5-year period. 2 Despite the overall success of the Heart Protection Study, a major concern is that among the subjects who participated in the study, 20% withdrew before the study s end. Such a large attrition rate raises some pertinent questions, particularly because it occurred within the setting of a highly supervised clinical trial designed to systematically encourage patient compliance and offer continuous follow-up. Issues that need to be addressed include whether this attrition was related to a lack of provider or patient conviction about the benefits of therapy, if it was associated with poor tolerance of designated therapies, or if it involved other factors that need to be identified. While virtually all of the clinical trials with statin therapy demonstrate convincing evidence that treat- 472 Vol. 2, No. 13 September 2002

2 ment is generally quite safe and without serious adverse consequences, the percentage of subjects who discontinue therapy is significant, ranging from a low of about 3% to as many as 20%, depending on the study. Reasons for discontinuation vary; patients are either uncomfortable with the therapy, uncomfortable with the concept of the therapy, or have the perception of feeling less healthy while undergoing therapy. Clearly, the medical community needs to address both the issue of long-term compliance with lipid-lowering therapy as well as factors related to noncompliance. The high incidence of noncompliance suggests that therapeutic alternatives be strongly considered, with the goal of boosting compliance. The Heart Protection Study demonstrated a substantial therapeutic benefit from statin therapy, with an average reduction in LDL-C from study baseline of 40 mg/dl. 2 After adjusting for noncompliance, simvastatin, 40 mg daily, safely reduced the risk of myocardial infarction (MI), stroke, and revascularization each by at least one third. Regardless of cholesterol level, age, or sex, 5 years of statin treatment typically prevented major vascular events in study participants as follows: 100 per 1000 with previous MI 80 per 1000 with coronary heart disease (CHD) other than MI 70 per 1000 ( 40 years of age) with diabetes 70 per 1000 with previous stroke 70 per 1000 with other peripheral vascular disease (PVD) The expanding armamentarium of statin therapies coming to market should allow clinicians to expect patients undergoing therapy to achieve an absolute reduction of LDL-C of 40 mg/dl. With the emergence of newer and more powerful drugs, most patients are expected to be able to achieve therapeutic goals on monotherapy, with only a minority not reaching those goals. The question that remains is, how many of the patients achieving those goals will continue monotherapy for the long term, and what reasons will they have for discontinuing their therapy? While the data suggest that the magnitude of benefit improves with long-term compliance, a particular point at which statin monotherapy is capable of eradicating disease has not been determined; the cardiac event rate for subjects taking drug therapy and those taking placebo becomes linear 6 years into the study (Figure 1). The rate of decline of event-free survival Figure 1. Simvastatin:Vascular Event by Follow-up Duration Adapted from HPS Slideshow Presentation. 2 Table 1.The Scandanavian Simvastatin Survival Study (4S): CHD Event Rates by Achieved LDL-C *Deaths or nonfatal MI. MI = myocardial infarction; LDL-C = low-density lipoprotein cholesterol. Adapted with permission from Pedersen, TR et al. Circulation 1997;96(8): Advanced Studies in Medicine 473

3 appears to be fairly linear over time. These results suggest that statin therapy may primarily delay cardiac events, which is certainly a therapeutic benefit, but it illustrates the limitations inherent in this strategy. THE ARGUMENT FOR COMBINATION THERAPY Numerous studies suggest that even in the era of more powerful and efficacious statins, the use of multiple agents is still necessary to achieve the LDL-C goal in some patients. The Scandinavian Simvastatin Survival Study (4S) study demonstrated incremental benefit in CHD events associated with LDL-C reductions (Table 1). 3 The lower the LDL-C, the greater the absolute benefit and relative risk reduction in patients. Similar findings were reported 1 year earlier in the CARE study. 1 The message from both 4S and CARE is that for patients whose LDL-C is 130 mg/dl, statin therapy achieved results no better than placebo, possibly suggesting a threshold for significant LDL-C reduction. Therefore, for patients undergoing statin monotherapy, if the maximum achievable or tolerated dose does not reduce LDL-C levels to <130 mg/dl, providers are obligated to add a second agent to therapy. The 4S study also suggests an opportunity for further benefit if LDL-C is reduced to a goal of <100 mg/dl, with or without combination therapy. Three large trials are under way to determine specifically how much of a reduction below 100 mg/dl can be achieved and to what benefit, but results are not yet available. Until those results are available, striving to achieve an LDL-C goal of <100 mg/dl is absolutely appropriate for these high-risk patients. a placebo group or were treated with gemfibrozil, 600 mg twice daily, showed no statistically significant reduction in LDL-C over a 7-year period, although those in the treatment group were found to have a 20% reduction in risk of cardiovascular events (Figure 2). 5 This study suggests that an absolute change in LDL-C levels is not always necessary to achieve an absolute change in absolute or relative risk for coronary events. These results, considered along with those from 4S and CARE, demonstrate that a wide range of mechanisms is most likely responsible for patients benefiting from drug therapies; a straightforward treatment approach based on event reduction as a function of LDL-C reduction simply cannot be extracted from research to date. These studies represent 3 different approaches with 3 different, possibly unique opportunities for benefit. Although the Heart Protection Study strongly suggests that every patient should consider reducing LDL cholesterol to reduce risk for cardiovascular events, it does not imply that no new knowledge can be obtained from future Figure 2.VA-HIT: Favorable Effects of Fibrate on Cardiovascular Events in CHD Patients With Isolated Low HDL-C THE RELATIONSHIP BETWEEN LDL-C LEVELS AND RISK REDUCTION What data supports the notion that the lower the LDL-C, the greater the benefit? This is, in fact, a very complicated question. Findings from the Lipid Research Clinics Coronary Primary Prevention Trial (LRC- CPPT) in the early 1980s indicated that a 2:1 ratio existed between LDL-C and risk reduction; a 1% reduction in LDL-C yielded a 2% reduction in the risk of coronary events. 4 However, the more recent Heart Protection Study modified this conclusion, showing a 0.5% reduction in relative risk for every 1% reduction in LDL-C. 2 The Veterans Affairs HDL Intervention Trial (VA-HIT) of 2531 men with CHD who were randomized to either Subjects: 2531 men; Aged 74 (avg 64) yrs; Baseline lipids: Mean TC: 175 mg/dl; Mean LDL-C: 111 mg/dl; Mean HDL-C: 32 mg/dl; Mean TG: 161 mg/dl; Duration: 7 yr.. Intervention: Gemfibrozil 600 mg bid. *P <.01; P =.006; P =.05. P=placebo group; RX=treated group; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; TC = total cholesterol; TG = triglycerides. Reprinted with permission from Rubens HB, et al. N Engl J Med. 1999; 341: Vol. 2, No. 13 September 2002

4 studies or that any single approach will provide greatest benefit to the majority of patients. PREDICTING BENEFIT The somewhat surprising results of the VA-HIT trial showing cardiovascular benefits even in the absence of any change in LDL-C and only small increases in high-density lipoprotein cholesterol (HDL-C) prompted investigators to explore what factors predicted benefit in study subjects. They found that the best predictor of outcome improvement was observed in patients whose baseline HDL-C was below 30 mg/dl before treatment and was elevated to above 35 mg/dl after treatment. 5 Baseline triglyceride levels and triglyceride reductions were not predictive of benefit, although patients whose triglyceride levels remained higher than 158 mg/dl did not benefit from therapy, even in the presence of improved HDL-C levels. These findings confirm the conclusions drawn by the National Cholesterol Education Program (NCEP), which sets a triglyceride goal of <150 mg/dl. Yet in the VA-HIT study, a change in triglyceride levels did not predict benefit. How could the presence of high triglyceride levels limit the benefit, but the change in triglyceride levels not predict benefit? The question is baffling, and becomes more so when researchers explore the CARE study data relating to particle size and coronary event rates. Researchers examined the CARE trial data to determine whether LDL size independently predicts recurrent coronary events in patients with known CHD, as opposed to a marker for other lipid abnormalities. 6 LDL-particle size was evaluated in 416 patients who had cardiac events and 421 age- and sexmatched patients who were event-free. The prevalence of LDL pattern B, defined conventionally as a predominance of small LDL particles (less than 254 Å), was not higher in CHD patients (39%) compared with controls (40%). Large LDL size independently predicted coronary events in a typical population with MI, increasing risk nearly 4-fold in the placebo study arm. However, there was no relationship between particle size and outcomes among patients who were treated with pravastatin. The puzzling questions about the role of triglycerides, particle size, and particle numbers as predictors of benefit need to be further analyzed both retrospectively and prospectively in clinical trial data. In the absence of such conclusive data that would allow for highly targeted and specialized treatment of individual patients, the NCEP Adult Treatment Panel III suggests that LDL-C reduction be used as the primary treatment goal while recognizing that low HDL-C and elevated triglyceride levels should also be considered as secondary treatment goals. 7 Clearly, the opportunities to address multiple contributors to risk simultaneously are only beginning to emerge. The HDL-Atherosclerosis Treatment Study (HATS) demonstrated that the combination of simvastatin and an immediate-release form of niacin produced an 80% reduction in coronary events, although this combination appears to cause adverse interaction with antioxidants. 8 In considering other combination therapy options, the bile acid sequestrant-statin combination offers a potential mechanism for addressing the implications of the 20% dropout rate of the Heart Protection Study discussed earlier. Possibly, a significant portion of those patients who dropped out would have remained on therapy if they simply could have reduced their statin dose and added a bile acid sequestrant, making the statin more tolerable while increasing effectiveness with the additional drug. In theory, such a combination provides an ideal interaction. The statin blocks the ability of the liver to respond to bile acid sequestrant therapy by increasing HMG-CoA reductase activity. An obligate loss of cholesterol in a nonsystemic action that poses no risk to patients occurs during treatment with bile acid sequestrants. The only route for cho- Table 2.A 10-Year Follow-up of the FATS Cohort: Events Outcomes Rx n % Death % CVE Triple Therapy Usual Care Triple Therapy: lovastatin, niacin, and colestipol FATS = familial atherosclerosis treatment study; CVE = cardiovascular event. B. Greg Brown, MD, PhD, presented AHA Meeting, Dallas, TX. November Advanced Studies in Medicine 475

5 lesterol to leave the body is through conversion to bile, and by extracting that bile on a daily basis and preventing the liver from using HMG-CoA to increase the available cholesterol for replacement of bile, an upregulation of the LDL-C receptor is the only possible response for the liver. And to the extent that apolipoprotein B (apo B) is a consistent marker of cardiovascular risk, the interaction of low-dose and full-dose bile acid sequestrants with statins achieves greater reductions than statin monotherapy. To the degree that apo A increases are an important component of the benefit predictor conundrum, highdose statin therapy falls short in its ability to increase apo A levels. COST-BENEFIT CONSIDERATIONS Clinical evidence does suggest therapeutic benefits of statin therapy even for patients with near-normal cholesterol levels. But as the appropriate range for treatment becomes lower, as intervention takes place in a younger patient population, and as the absolute risk prior to initiating therapy becomes lower, how do these factors affect the tradeoff of risk and benefit for the pharmaceuticals that we might use? The 4S study findings included an effective cost analysis showing that 1 of every 12 patients needed to be treated in order to achieve cost efficiency. 9 The absolute risk of a CHD event in 4S was approximately 25%; thus, a reduction in absolute risk of 7% to 8% was found to be cost effective. Although the cost for treatment of CHD has risen in the 10 years since the 4S trial, the cost of intervention has been reduced. Considering cost within the US population, standards differ and therapy is recommended for any person whose 10-year absolute risk is 20% or higher. In order to achieve cost effectiveness, absolute risk must be reduced to as low as 3% to 10% (assuming a total absolute risk of 10% to 15%, and cost effectiveness with an absolute risk reduction of 7% to 8%, as was seen in 4S). Whether relative risk reductions of 60% to 80% can be achieved is not known at this point. The Familial Atherosclerosis Treatment Study (FATS) allows speculation as to whether such significant relative risk reductions would be within reach of clinical practice. 10 Comparing the standard of care with optimal care, FATS found that monotherapy, which is usual care, achieved LDL-C reductions from 188 mg/dl to only 166 mg/dl; HDL-C levels barely changed; and triglycerides actually increased (Table 2). In the triple therapy study arm, subjects who underwent therapy with lovastatin, niacin, and colestipol were able to approach the LDL-C target of <100 mg/dl from a baseline of 202 mg/dl; increase HDL-C by 20%; and achieve substantial improvements in triglyceride levels to 134 mg/dl from a baseline of 210 mg/dl. In an 8-year follow-up of the FATS cohort, investigators found that nearly 19% of the usual care patients had a cardiovascular event, with a 1 in 5 death rate. In subjects undergoing the 3-drug regimen, the cardiovascular event rate was 5%, and the death rate was 1 in 75. Although this analysis is not a randomized clinical trial and patients did have known CHD, it nonetheless suggests an opportunity to see a greater than 90% reduction in mortality and essentially an 80% reduction in events following a 3-drug regimen compared with monotherapy. CONCLUSION Although achieving demonstrable cost effectiveness is definitely possible, it requires increased spending on pharmacotherapy. But as the lack of investment in pharmacotherapy grows ever more costly in health and human terms, and as drug-coated stents become the standard of care for diabetic patients and in other situations in which a high risk of restenosis after angioplasty is seen, the argument that prevention is in fact cost effective becomes even more convincing. REFERENCES 1. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med. 1996;335: MRC/BHF Heart Protection Study. HPS Info-Slideshow Presentation. Available at: ~hps/hps_slides.shtml. Accessed July 8, Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study. Circulation. 1998;97: LRC-CPPT Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251: Vol. 2, No. 13 September 2002

6 5. Bloomfield RH, Davenport J, Babikian V, et al. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation. 2001;103: Campos H, Moye LA, Glasser SP, Stampfer MJ, Sacks FM. Low-density lipoprotein size, pravastatin treatment, and coronary events. JAMA. 2001;286: Summary of the second report of the National Cholesterol Education (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269: Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001; 345: Johannesson M, Jonsson B, Kjekshus J, et al. Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian Simvastatin Survival Study Group. N Engl J Med. 1997;336: Brown BG. Triple therapy: lovastatin, niacin, and colestipol. Paper presented at: The 71st Scientific Sessions of the American Heart Association; November 8-11, 1998; Dallas, Tex. Advanced Studies in Medicine 477