The treatment of coronary heart disease (CHD) The Health Economics of the Treatment of Hyperlipidemia and Hypertension J. McMurray

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1 AJH 1999;12:99S 104S The Health Economics of the Treatment of Hyperlipidemia and Hypertension J. McMurray In the current economic climate it is important to demonstrate that healthcare resources are being used efficiently. As a consequence, pharmacoeconomic analyses are invaluable for assessing the costeffectiveness of new therapeutic strategies. A condition with recurrent morbid events that are costly to treat provides the greatest potential for cost savings. In contrast, there is less opportunity to redeem original treatment costs when a condition is associated with infrequent and inexpensive morbidity. Consequently, treatment strategies that have a rapid onset and substantial impact on disease progression are likely to be the most highly cost-effective forms of therapy. Elevated blood pressure in the elderly and established coronary heart disease (CHD) are both associated with high rates of costly cardiovascular events (eg, stroke, myocardial infarction, and heart failure). Clinical trials have shown that The treatment of coronary heart disease (CHD) places a substantial financial burden on healthcare resources. As a consequence, pharmacoeconomic analyses of management and prevention strategies for CHD are a valuable tool for comparing the cost-effectiveness of new medical interventions, allowing healthcare decision-makers to contain costs by choosing those interventions that are most efficient. However, for healthcare planners and providers to make optimal use of pharmacoeconomic evidence, it is From the Department of Cardiology, Western Infirmary, Glasgow, Scotland, United Kingdom. Address correspondence and reprint requests to: Professor J. Mc- Murray, Department of Cardiology, Western Infirmary, Glasgow G11 6NT, U.K. administration of blood-pressure lowering agents to elderly hypertensives and the treatment of hypercholesterolemia with statins in the secondary prevention of CHD are highly effective strategies for reducing this morbidity. Pharmacoeconomic analyses of the data from these clinical trials now provide an additional assessment of their costeffectiveness. The results of these analyses suggest that blood-pressure lowering therapy for the elderly and the use of statins to control hypercholesterolemia in patients at high risk of CHD are extremely cost-effective, compared with many other routine medical interventions. Am J Hypertens 1999;12:99S 104S 1999 American Journal of Hypertension, Ltd. KEY WORDS: Cost-effectiveness, hyperlipidemia, hypertension, pharmacoeconomics. important to understand how these analyses are conducted. Here, the basics of pharmacoeconomics are discussed in relation to two major therapeutic regimens for the prevention of CHD: blood-pressure lowering therapy and cholesterol-lowering therapy. GENERAL PRINCIPLES When treating an illness with a particular therapeutic strategy, cost-effectiveness analyses not only consider the direct costs incurred but also the cost savings (so-called offsets ) that are made after the implementation of that strategy. In other words, such analyses determine the extent to which a given treatment is able to pay for itself through the subsequent offsetting of costs. Clearly, in a condition that has a frequently occurring and costly morbidity (eg, hospital admis by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 100S MCMURRAY AJH OCTOBER 1999 VOL. 12, NO. 10, PART 2 TABLE 1. ECONOMIC ASSESSMENT OF TREATMENT: CONSIDERATIONS FOR A TREATMENT THAT PROLONGS LIFE Costs Cost savings Direct Drug and drug-related Improved quality of life/reduced disease progression Related to adverse effects of treatment Extension of life continued GP visits/hospitalizations/ procedures/operations fewer GP visits fewer events fewer hospitalizations fewer surgical procedures and operations Indirect Continued pension payments Continued employment/productivity/taxes Fewer benefit payments GP, general practitioner. sion, expensive surgical procedure) there is enormous potential to redeem the cost of treatment. Conversely, in a condition characterized by infrequent and inexpensive morbidity there is much less opportunity to offset costs. Thus, a basic principle is that a treatment is least cost-effective where life expectancy is long and morbid events are few and inexpensive. Inevitably, this means that primary prevention strategies are likely to be less cost-effective than secondary prevention strategies. For a treatment strategy to significantly reduce costs it should have a rapid and substantial impact upon the disease process, ie, it must be highly efficacious. The importance of efficacy of treatment on cost-effectiveness is clearly seen in the area of cholesterol lowering and in the era of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). In some of the older cholesterol lowering trials, a fairly weak effect of treatment was achieved and this was often reflected in the modest reductions in morbid events reported. 1 3 More recently, with more efficacious cholesterol-lowering drugs, such as the statins, greater reductions in cholesterol have been achieved, resulting in substantial beneficial effects on morbidity occurring within 6 to 12 months of starting therapy. 4 8 When conducting cost-effectiveness analyses there is a tendency to ignore the indirect costs of treatment. One reason for this may be that direct costs (eg, the cost of a bypass operation or the cost of caring for a patient who has suffered a stroke) are usually quite easy to measure, whereas indirect costs (eg, productivity losses and sickness benefit payments associated with a worker unable to continue employment) are much harder to quantify. Nevertheless, when considering middle-aged people who might have many years of productive life ahead of them, a stroke or a heart attack that prevents work and requires longterm sickness payment can generate indirect costs to the state that might significantly affect the outcome of a cost-effectiveness analysis. Essentially, the cost-effectiveness of a therapeutic agent can be estimated by balancing the total treatment costs, including additional costs incurred during the posttreatment period, against the total cost savings (Table 1). Examples of additional costs might be those resulting from the monitoring of lipid levels after the administration of a cholesterol-lowering agent or those associated with the treatment of drug-attributable adverse events. As already discussed, cost savings are usually most significant when the treatment produces a decrease in morbid events. There are several outcome units that can be used to measure the cost-effectiveness of different therapies. These include cost per life-year gained (LYG); cost per quality-adjusted life-year gained (QALY); and number needed to treat (NNT). The cost per LYG assesses the benefit of treatment purely in terms of mortality. Quite simply, it can be thought of as the amount of money that must be paid, usually by a country s health service, to extend the life of a patient by 1 year. It can be argued that a good treatment should also improve, or at the very least maintain, a patient s quality of life. The QALY, therefore, not only measures cost-effectiveness in terms of longevity but also takes into account improvements in lifestyle. It has become a standard measure in many economic analyses. NNT analysis, although not actually a direct measure of cost, is a strong predictor for cost-effectiveness. For a particular medical intervention, an NNT study will calculate the number of individuals who need to be treated for a period of time (usually 5 years) to prevent the occurrence of one major morbid event. The smaller the NNT, the more likely the treatment is to be cost-effective. COST-EFFECTIVENESS AND THE TREATMENT OF HYPERLIPIDEMIA Patients with established CHD have a high rate of expensive morbidity. 4,6,7,9 Recent studies have demonstrated that the use of statins in the secondary preven-

3 AJH OCTOBER 1999 VOL. 12, NO. 10, PART 2 HEALTH ECONOMICS OF CHD 101S FIGURE 1. Total days spent in hospital during the 4S study by placebo-treated patients and simvastatin-treated patients (data taken from reference 10). *Significantly different from placebo (P.0001). tion of CHD is dramatically effective, in terms of both extending life and of reducing cardiovascular events. As a direct consequence of this decreased morbidity, significant cost savings are achieved that allow some of the costs associated with the statin therapy to be negated. This can be demonstrated by analyzing results from the Scandinavian Simvastatin Survival Study (4S), a randomized trial of cholesterol-lowering therapy in 4444 patients with established CHD. 4 During the 5.5 years of the study, patients who received simvastatin spent approximately 6000 fewer days in hospital (including coronary care units and acute medical wards) than patients treated with placebo (Figure 1). 10 Keeping a patient in hospital, especially in coronary or intensive care units, is extremely expensive. Therefore, any reduction in the number of days a patient is hospitalized (34% in the case of the 4S study) will result in considerable cost savings. As previously discussed, the use of lipid-lowering strategies in the primary prevention of CHD will inevitably be less cost-effective than their use in the secondary prevention of CHD because patients at less risk provide less potential for offsetting costs. The difference in cost-effectiveness between primary and secondary prevention strategies is well illustrated by NNT analysis (Table 2). In the West of Scotland Coronary Prevention Study (WOSCOPS), 5 a primary CHD prevention trial of pravastatin in hypercholesterolemic men (total cholesterol 272 mg/dl [7.0 mmol/l]), approximately 40 men needed to be treated for 5 years to prevent one CHD death or nonfatal myocardial infarction (MI). By comparison, in the 4S trial, only 10 to 16 patients needed to be treated for 5 years to prevent one cardiovascular event. Formal pharmacoeconomic assessments of the 4S and WOSCOPS studies have been conducted and their results confirm that there is less return on treatment investment in the primary prevention of CHD than there is in the secondary prevention of CHD (Raikou, McMurray, and McGuire, unpublished data) In the original analysis of 4S, performed by Jönsson and colleagues, the estimated cost of simvastatin therapy per LYG as applied to the UK was only Using data from WOSCOPS, however, Caro et al showed TABLE 2. ASSESSMENT OF THE BENEFITS OF VARIOUS CARDIOVASCULAR TREATMENTS IN TERMS OF NUMBER NEEDED TO TREAT (NNT) Treatment Events Prevented NNT for 5 Years to Prevent One Event Antihypertensive therapy in elderly Fatal and nonfatal cardiovascular events 6 (STOP trial) Aspirin for TIA Death, CVA 6 Warfarin for AF CVA 7 ACE inhibitor for mild heart failure Cardiovascular death, hospitalization for 8 CHF Statin, post-mi (4S trial) CHD death, MI, arrest 10 Aspirin, post-mi Cardiovascular death, MI, CVA 12 Statin, angina (4S trial) CHD death, MI, arrest 16 Antihypertensive therapy in elderly Fatal and nonfatal cardiovascular events 18 (SHEP trial) Statin, post-mi (CARE trial) CHD death, MI 33 Statin, asymptomatic men with raised LDL-C (WOSCOPS trial) CHD death, MI 42 TIA, transient ischemic attack; AF, atrial fibrillation; CHD, coronary heart disease; CVA, cerebrovascular accident; ACE, angiotensin converting enzyme; CHF, congestive heart failure; MI, myocardial infarction; LDL-C, low-density lipoprotein cholesterol.

4 102S MCMURRAY AJH OCTOBER 1999 VOL. 12, NO. 10, PART 2 TABLE 3. COST PER QUALITY-ADJUSTED LIFE-YEAR GAINED (QALY) FOR VARIOUS MEDICAL TREATMENTS Treatment (1995) ACE inhibitor for CHF 610 Valve replacement for aortic stenosis 1385 CABG (left, main, and severe angina) 2539 Kidney transplant 5720 Cholesterol reduction, statin for secondary prevention ,000 ACE inhibitor post-mi (SAVE trial) ,000 Heart transplant 9522 Home hemodialysis 20,963 CABG (one vessel and moderate angina) 22,859 CAPD 24,133 Hemodialysis 26,583 Erythropoietin for anemia (dialysis) 153,385 ACE, angiotensin converting enzyme; CHF, congestive heart failure; MI, myocardial infarction; CABG, coronary artery bypass graft; CAPD, continuous ambulatory peritoneal dialysis. that the cost of statin therapy can rise to approximately 20,000 per LYG. 13 Notably, if the same WOSCOPS analysis is confined to patients at the highest risk of CHD (those who have an absolute risk of 20% over 10 years and the type of patient that the Second Joint Task Force of European and other Societies on Coronary Prevention 14 recommends for intensive risk factor modification), then the cost per LYG drops to about 14, These data indicate that primary prevention strategies for CHD can probably be made more acceptable, in terms of cost-effectiveness, by concentrating mainly on those individuals who are at the greatest risk. Although the use of statins in the secondary prevention of CHD may be more cost-effective than their use in primary prevention, how expensive is statin therapy when compared with other routine medical interventions? Table 3 shows a number of treatment strategies and their relative cost-effectiveness as measured by cost per QALY. As a generally agreed international standard, most countries will provide hemodialysis, or dialysis of some description, to patients with end-stage renal failure. It is commonly accepted that a treatment strategy that is more cost-effective than hemodialysis (approximately 26,500 per QALY) is acceptable. With an estimated cost per QALY of 5000 to 10,000, the use of statins to treat established CHD can, therefore, be considered an economically viable treatment. COST-EFFECTIVENESS AND THE TREATMENT OF HYPERTENSION TABLE 4. PLACEBO GROUP EVENTS PER 1000 PATIENT YEARS OF FOLLOW-UP FOR CLINICAL TRIALS CONDUCTED IN ELDERLY HYPERTENSIVES OR PATIENTS WITH HYPERCHOLESTEROLEMIA Trial CVA CHF MI SHEP* STOP* S WOSCOPS CVA, cerebrovascular accident; CHF, congestive heart failure; MI, myocardial infarction. * Elderly hypertensives. Patients with hypercholesterolemia. Many physicians, including some cardiologists, fail to realize that elderly hypertensive patients are an extremely high-risk patient population whose condition is associated with high rates of morbidity. In fact, the rates of morbid cardiovascular events in elderly hypertensives are not dissimilar to those in patients with established cardiovascular disease and are considerably greater than in patients within other primary prevention CHD categories (Table 4). In addition to stroke and MI, elderly hypertensive patients are at particular risk from congestive heart failure (CHF), an extremely disabling disorder. 15,16 Because stroke, MI, and CHF are all very expensive cardiovascular events to treat, the use of antihypertensive medications to reduce blood pressure in the elderly provides immense potential to offset costs. Once again, by using NNT analysis as a surrogate for cost-effectiveness, the economic benefits of treating hypertension in the elderly can be evaluated. Analyzing data from the Swedish Trial in Old Patients with Hypertension (STOP Hypertension), 15 a randomized trial comparing antihypertensive therapy with placebo, it has been estimated that only six patients would need to be treated for 5 years to prevent one major cardiovascular event. In the Systolic Hypertension in the Elderly Program (SHEP), 16 another placebo-controlled trial of antihypertensive therapy, one major cardiovascular event was prevented for every 18 patients treated for 5 years. These NNT values for the STOP and SHEP trials compare favorably with other secondary preventive therapies (Table 2). Formal pharmacoeconomic analysis of the STOP study supports the notion that the treatment of high blood pressure in older individuals is a highly costeffective strategy. 17 For male patients, the cost per LYG was estimated to be about 500 (Table 5). This value is one of the lowest cost-effectiveness ratios observed for any treatment in cardiovascular medicine, or indeed in any other branch of medicine, and may in part be due to the fact that the STOP study used an inexpensive thiazide diuretic. In contrast, the cost per LYG for antihypertensive treatment in a 40-year-old man is approxi-

5 AJH OCTOBER 1999 VOL. 12, NO. 10, PART 2 HEALTH ECONOMICS OF CHD 103S TABLE 5. COST-EFFECTIVENESS OF TREATING HYPERTENSION IN THE ELDERLY Treatment Approximate Cost per LYG ( ) Antihypertensive therapy in elderly (STOP)* Men 500 Women 1500 Antihypertensive therapy in 40-year-old man with DBP of 95 mm Hg* 49,000 Cholesterol lowering, secondary prevention (4S)* ,000 Cholesterol lowering, primary prevention (WOSCOPS) 20,000 * All from same health economics group. LYG, life-year gained; DBP, diastolic blood pressure. mately 100 times as much, at 49,000, 18 indicating that the treatment of younger hypertensives is a far greater drain on healthcare resources. Care should be exercised when drawing conclusions from economic analyses conducted by different research groups, especially if they have employed different methods. However, three of the cost-effectiveness analyses listed in Table 5 were conducted by the same group 11,17,18 and the fourth, the analysis of the WOSCOPS study, 13 followed similar principles. On this basis, it is reasonable to conclude from these data that antihypertensive treatment in the elderly is more cost-effective than in the young and compares favorably with other secondary and primary preventive strategies for the treatment of CHD. CONCLUSIONS In comparison with other medical therapeutic strategies, and, in particular, with other cardiovascular interventions, the treatment of hypertensive patients and individuals with hypercholesterolemia is acceptably cost-effective. When the treatment is aimed at high-risk patients, such as elderly hypertensives or patients with established CHD, then blood-pressure lowering and lipid-lowering regimes become even more cost-effective. Thus, in the primary prevention setting and when considering individuals with multiple-risk factors, there is no convincing economic argument against treating these individuals to the best of our abilities. REFERENCES 1. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in incidence of coronary heart disease. JAMA 1984;251: Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P: Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;260: Carlson LA, Rosenhamer G: Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223: Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344: Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ for the West of Scotland Coronary Prevention Study Group: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333: Sacks FM, Pfeffer MA, Moyé LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E for the Cholesterol and Recurrent Events Trial Investigators: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335: The Long-Term Intervention with Pravastatin in Ischaemic 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 Med 1998;339: Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr for the AFCAPS/TexCAPS Research Group: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998;279: The Post Coronary Artery Bypass Graft Trial Investigators: The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronaryartery bypass grafts. N Engl J Med 1997;336: Pedersen TR, Kjekshus J, Berg K, Olsson AG, Wilhelm-

6 104S MCMURRAY AJH OCTOBER 1999 VOL. 12, NO. 10, PART 2 sen L, Wedel H, Pyorala K, Miettinen T, Haghfelt T, Faergeman O, Thorgeirsson G, Jönsson B, Schwartz JS for the Scandinavian Simvastatin Survival Study Group: Cholesterol lowering and the use of healthcare resources. Results of the Scandinavian Simvastatin Survival Study. Circulation 1996;93: Jönsson B, Johannesson M, Kjekshus J, Olsson AG, Pedersen TR, Wedel H: Cost-effectiveness of cholesterol lowering. Results from the Scandinavian Simvastatin Survival Study (4S). Eur Heart J 1996;17: Caro J, Klittich W, McGuire A, Ford I, Pettitt D, Norrie J, Shepherd J for the WOSCOPS Economic Analysis Committee: International economic analysis of primary prevention of cardiovascular disease with pravastatin in WOSCOPS. Eur Heart J 1999;20: Caro J, Klittich W, McGuire A, Ford I, Norrie J, Pettitt D, McMurray J, Shepherd J: West of Scotland Coronary Prevention Study: economic benefit of analysis of primary prevention with pravastatin. Br Med J 1997;315: Wood D, DeBacker G, Faergeman O, Graham I, Mancia G, Pyörälä K: Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Eur Heart J 1998;19: Dahlof B, Hansson L, Lindholm L, Rastam L, Schersten B, Wester PO: Swedish trial in old patients with hypertension. A prospective multicentre study in Swedish primary health care. Scand J Prim Health Care 1986;4: Hulley SB, Furberg CD, Gurland B, McDonald R, Perry HM, Schnaper HW, Schoenberger JA, Smith WM, Vogt TM: Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985;56: Johannesson M, Dahlof B, Lindholm LH, Ekbom T, Hansson L, Oden A, Schersten B, Wester PO, Jönsson B: The cost-effectiveness of treating hypertension in elderly people an analysis of the Swedish Trial in Old Patients with Hypertension (STOP Hypertension). J Intern Med 1993;234: Johannesson M: The cost-effectiveness of hypertension treatment in Sweden: an analysis of the criteria for intervention and the choice of drug treatment. J Hum Hypertens 1996;10:S23 S26.