Projected coronary heart disease risk benefit with ezetimibe

Atherosclerosis 179 (2005) 375–378

Projected coronary heart disease risk benefit with ezetimibe Glenn M. Daviesa,∗ , John R. Cooka , John Erbeyb , Evo Alemaoc , Enrico P. Veltrid a

Merck Research Laboratories, Merck and Co., Inc.-BL2-3, 10 Sentry Parkway, Blue Bell, West Point, PA 19422, USA b Schering-Plough Pharmaceuticals, Kenilworth, NJ, USA c Merck and Co. Inc., Whitehouse Station, NJ, USA d Schering-Plough Research Institute, Kenilworth, NJ, USA

Received 29 March 2004; received in revised form 16 September 2004; accepted 19 October 2004 Available online 15 December 2004

Abstract Low density lipoprotein (LDL) cholesterol and total cholesterol (TC) are the primary clinical parameters of interest for any cholesterol intervention. Clinicians are interested in how the reduction of these lipid parameters as well as increases in high density lipoprotein (HDL) relate to changes in coronary heart disease (CHD) risk. The objective of this analysis was to estimate the additional CHD risk reduction that could potentially be provided by co-administration of ezetimibe with statin therapy. Data from four double-blind placebo controlled clinical trials were used to predict the level of CHD risk reduction that might be achieved by co-administration of ezetimibe with statin therapy when compared to those receiving statin as monotherapy. Patients without a previous history of CHD were included in the analysis. Projected CHD risk reduction was calculated as percent change in projected CHD risk from baseline to 12 weeks based on observed lipid levels at those time points. For all the studies combined greater reductions in percent change in 5-year CHD risk were observed for patients receiving ezetimibe and statin as co-therapy, 53.4%, when compared to those receiving statin alone, 39.7%. Co-administration of ezetimibe with statin therapy provides an additional 13.7% reduction in predicted 5-year CHD risk when compared to statin monotherapy. Reductions in 5-year CHD risk for each of the statin studies ranged from 16.1% for lovastatin to 9.8% for atorvastatin. Co-administration of ezetimibe with statins could significantly reduce CHD events in patients with primary hypercholesterolemia. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Risk appraisal function; Co-administration; Statin

1. Introduction Numerous epidemiologic studies [1–5] and clinical trials [6–11] have confirmed that improvements in lipid parameters (i.e., reductions in LDL and total cholesterol and increases in HDL cholesterol) result in reduced CHD risk. In a metaanalysis of eight randomized clinical trials of statins, Gould et al. [12] demonstrated that every 10% points of cholesterol lowering reduces CHD mortality risk by 15% and total mortality risk by 11%. These authors concluded that the effect of statins on CHD and total mortality risk can be explained by their lipid lowering ability and appears to be directly propor∗

Corresponding author. Tel.: +1 484 344 7027; fax: +1 484 344 3855. E-mail address: glenn [email protected] (G.M. Davies).

0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.10.030

tional to the degree to which they lower lipids. Consequently, the ultimate goal of any lipid lowering intervention is to reduce CHD risk. Ezetimibe is a new chemical entity that inhibits the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat-soluble vitamins. Ezetimibe complements the lipid-altering effects of other therapies such as statins. Clinical studies have shown that co-administration of ezetimibe with statins could provide as much as an additional 12–14% reduction in LDL cholesterol, an additional 10–12% reduction in total cholesterol and an additional 2–5% increase in HDL cholesterol [13–16] in patients with primary hypercholesterolemia. These studies also indicate that co-administration of ezetimibe with the lowest dose of statin could provide similar reductions in LDL cholesterol when

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G.M. Davies et al. / Atherosclerosis 179 (2005) 375–378

compared to monotherapy with the highest dose of statin [13–16]. Given the improved lipid profile that ezetimibe provides when co-administered with statins, it is of interest to evaluate how this improvement may translate into reduced CHD risk. CHD risk appraisal functions based on the Framingham Heart Study have been developed to be able to predict an individual’s risk of a future CHD event [17–19]. The objective of this evaluation is to use CHD risk appraisal functions to see how the additional lipid-altering effects of ezetimibe translate into projected CHD risk reductions.

2. Methods Data from four randomized clinical trials that evaluated the effect of co-administration of statin therapy with ezetimibe in a population of patients with primary hypercholesterolemia were used to estimate the percent change in projected 5 and 10-year CHD risk from baseline to 12 weeks [13–16]. After completing dietary stabilization, a 2–12 weeks washout period and a 4 weeks run-in-period, patients with baseline LDL cholesterol between 145 and 250 mg/dl and triglycerides ≤350 mg/dl were randomized to receive placebo, ezetimibe 10 mg, statin monotherapy with doses of 10, 20, 40 or 80 mg, or ezetimibe 10 mg co-administered with one of the doses of statin therapy. Detailed illustrations of the basic study designs are given in the primary publications [13–16]. Separate studies were conducted for lovastatin (10, 20, 40 mg) [15], pravastatin (10, 20, 40 mg) [16], simvastatin (10, 20, 40, 80 mg) [14] and atorvastatin (10, 20, 40, 80 mg) [13]. Lipid parameters were monitored for a 12-week period. Five and 10-year projected CHD risk were estimated using a risk appraisal function developed by Andersen et al. [17–18] from data collected by the Framingham Heart Study. The risk equation is based on an accelerated failure time model that can estimate primary CHD risk for a period of 4–12 years. Separate equations were developed for males and females. Variables in the models include age, current smoking, diabetes, diastolic or systolic blood pressure, presence of leftventricular hypertrophy and ratio of total cholesterol to HDL cholesterol. For each patient in the four randomized clinical trials, the 5- and 10-year CHD risk estimates were calculated at baseline and at 12 weeks. For the 12-week calculation all model parameters except the total cholesterol to HDL cholesterol ratio were held at their baseline values. Patients with missing model parameters at baseline or 12 weeks were excluded from the analysis. In addition, patients with a history of CHD were excluded because the risk equations are relevant only for patients who are CHD-free. Percent change in CHD risk was summarized in each study for patients receiving ezetimibe plus statins and for those receiving statin monotherapy by pooling across statin dose groups. Pooled estimates of CHD risk were also computed

across all four studies. Patients receiving placebo or ezetimibe monotherapy were excluded from the analysis. The difference in mean percent change in CHD risk between the statin + ezetimibe and statin monotherapy groups and its corresponding 95% confidence interval was calculated for each study and the pooled studies.

3. Results A total of 1861 patients across the four clinical studies received either statin monotherapy, or statin plus ezetimibe 10 mg. Of the 1861 patients, 152 patients were excluded because they had a previous history of CHD and 18 patients were excluded because of missing endpoint data or for missing data for one or more of the model parameters. Consequently, 1691 patients (n = 840, ezetimibe + statin, n = 851 statin monotherapy) were included in the analysis of projected CHD risk. Baseline demographics and lipid parameters are summarized in Table 1. The summary of the pooled baseline demographics and lipid parameters suggested that there were no differences between those receiving ezetimibe and those who did not. Patients receiving ezetimibe experienced an additional 9–12% reduction in their baseline TC:HDL cholesterol ratio compared to those receiving statin monotherapy (Table 2). Mean baseline CHD risk ranged from 4.0 to 5.3% for 5 years and 10.3 to 12.0% for 10 years across the four studies (Table 3). The percent reduction in baseline primary CHD risk for patients receiving statin and ezetimibe was significantly greater than for those receiving statin monotherapy (Table 3). This result was consistent across the four statin studies. Patients treated with lovastatin and ezetimibe were projected Table 1 Baseline lipid profile and other demographics pooled across studies Baseline lipid profile

Ezetimibe + statin, n = 840

Statin Monotherapy, n = 851

Total cholesterol (mg/dl) HDL Cholesterol (mg/dl) LDL Cholesterol (mg/dl) calculated Ratio TC:HDL cholesterol

264.4 (25.1) 51.3 (12.4) 178.5 (20.8)

265.3 (25.4) 51.5 (11.7) 179.6 (21.3)

5.4 (1.2)

5.4 (1.2)

Other baseline characteristics Age 57.0 (S.D. = 11.6) Gender – male (%) 41.1 SBP (mmHg) 128.9 (16.1) DBP (mmHg) 80.5 (9.2) Diabetes (%) 4.9 ECG-LVH (%) 0.4 Smoking (%) 10.8 Statin therapies Lovastatin (%) Simvastatin (%) Pravastatin (%) Atorvastatin (%)

21.1 29.4 22.3 27.3

55.5 (S.D. = 12.1) 39.7 128.7 (16.2) 79.5 (9.0) 4.9 0.4 13.4 23.0 28.8 22.0 26.2

G.M. Davies et al. / Atherosclerosis 179 (2005) 375–378

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Table 2 Percent change in TC/HDL cholesterol ratio from baseline to 12 weeks post-randomization Statin therapy

Lovastatin Simvastatin Pravastatin Atorvastatin Pooled

Ezetimibe + statin mean (S.D.)

Statin monotherapy mean (S.D.)

Baseline ratio

12-Week ratio

Percent reduction

Baseline ratio

12-Week ratio

Percent reduction

5.4 (1.2) 5.4 (1.1) 5.3 (1.2) 5.5 (1.3) 5.4 (1.2)

3.6 (0.9) 3.1 (0.8) 3.6 (0.9) 3.0 (1.0) 3.3 (0.9)

33.5 (13.3) 40.8 (14.4) 32.0 (11.6) 43.8 (15.5) 38.1 (14.7)

5.5 (1.2) 5.4 (1.1) 5.5 (1.2) 5.2 (1.3) 5.4 (1.2)

4.3 (1.1) 3.8 (1.0) 4.3 (1.0) 3.4 (1.0) 3.9 (1.1)

21.0 (11.4) 29.7 (13.9) 21.6 (11.3) 34.6 (14.0) 27.2 (14.0)

Table 3 Percent change in 5- and 10-year primary CHD risk predictions based on lipid profile at baseline and at 12 weeks post-randomization Statin therapy

Year risk

Ezetimibe + statin

Statin monotherapy

Baseline CHD risk

12-Week CHD risk

Percent change

Baseline CHD risk

12-Week CHD risk

Percent change

Absolute percent difference (95% CI)a

Lovastatin

5 10

5.1 11.1

2.7 6.4

−47.0 −42.7

4.9 10.5

3.4 7.8

−30.9 −27.6

−16.1 (−19.8,−12.4) −15.0 (−18.4,−11.6)

Simvastatin

5 10

4.4 12.0

2.0 6.1

−57.5 −51.6

4.0 11.2

2.4 7.1

−43.5 −38.3

−14.0 (−17.5,−10.5) −13.1 (−16.5,−10.0)

Pravastatin

5 10

4.7 10.3

2.6 6.1

−46.5 −42.2

4.9 10.7

3.5 7.9

−31.8 −28.5

−14.7 (−18.1,−11.3) −13.7 (−16.9,−10.6)

Atorvastatin

5 10

5.3 11.6

2.2 5.4

−59.5 −54.9

4.9 10.6

2.6 6.1

−49.7 −45.4

−9.8 (−13.6,−6.0) −9.5 (−13.1,−5.9)

Pooled

5 10

4.9 11.3

2.3 6.0

−53.4 −48.5

4.6 10.8

2.9 7.2

−39.7 −35.6

−13.7 (−15.7,−11.8) −13.0 (−14.8,−11.2)

a

Difference in mean percent change ±1.96 * standard error.

to receive an additional 16.1% reduction in their 5-year predicted CHD risk and an additional 15% reduction (42.7% versus 27.6%) in their 10-year risk when compared with patients treated with lovastatin monotherapy. Patients treated with simvastatin and pravastatin received an additional 14.0 and 14.7% reduction, respectively in their 5-year risk and, 13.1 and 13.7% reduction, respectively in their 10-year risk. Patients treated with atorvastatin and ezetimibe received an additional 10% reduction in 5- and 10-year risk when compared to those treated with atorvastatin monotherapy (Table 2). Percent reduction in CHD risk ranged from 42 to 60% for those who received statin and ezetimibe compared to 28–50% for those treated with statin monotherapy. For all four studies combined, patients treated with statin and ezetimibe received an additional 13.7 and 13.0% reduction in 5- and 10-year CHD risk, respectively when compared to those treated with statin monotherapy.

4. Discussion Studies have shown that ezetimibe provides significant reductions in LDL cholesterol and total cholesterol when coadministered with a patient’s current statin therapy [13–16]. The results of this analysis suggest that the improvements in TC/HDL ratio may translate into substantial reductions in actual CHD risk. For this analysis, we chose Anderson’s risk function to estimate CHD risk. A recent comprehensive

review of CHD risk appraisal functions suggested that Anderson’s equation may provide the best predictive validity [19] of CHD events compared to other CHD risk appraisal functions that exist in the literature [20,21]. Most of these equations were based on data from the Framingham Heart Study and the equations were developed to estimate projected CHD risk for either a short period of time (≤4 years) or for a fixed time interval. Anderson’s risk equation can calculate risk for any time horizon between 4 and 12 years. Wilson’s risk equation for primary CHD can calculate risk for a fixed 10-year period [20]. When we applied Wilson’s equation to the patients in the four randomized clinical trials, 10-year CHD risk estimates were higher than those obtained with Anderson’s equation. However, the differences in percent change between those receiving ezetimibe co-administration compared to those who received statin monotherapy were similar with the two risk equations. We also investigated the percent reduction in 5 and 10-year CHD risk using Anderson’s point scoring algorithm. This algorithm assigns points for total cholesterol and HDL separately. The algorithm provided slightly higher estimates of 5 and 10-year CHD risk for both treatment groups and ezetimibe co-administered with statin provided an additional 13.2 and 12.3% reduction in 5 and 10-year CHD risk when compared to statin monotherapy. These results are consistent with those obtained from Anderson’s risk appraisal function. This analysis focuses on patients without a history of CHD. Clinical studies such as AFCAPS have shown that re-

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ductions in LDL cholesterol and TC are related to decreased risk of coronary events [8] in patients with primary hypercholesterolemia. Patients receiving lovastatin in AFCAPS experienced a 25.0% reduction in LDL cholesterol and an 18.4% reduction in TC over the course of 1 year. The 5year cumulative incidence of myocardial infarction (fatal or non-fatal), unstable angina, or sudden cardiac death for patients receiving lovastatin was 3.5%. Based on Anderson’s equation, the projected risk at 5 years for patients receiving lovastatin was 9.1% at baseline and 6.7% after 1 year of treatment suggesting that this equation may over estimate the risk of CHD. However, the estimated 5-year relative risk reduction for CHD events in AFCAPS was 37%, which is greater than the projected relative risk reduction of 26% based on Anderson’s equation. Co-administration of ezetimibe with statin therapy could provide additional reductions in risk of CHD events compared to patients receiving statin monotherapy. It has been shown in several statin clinical studies that altering the lipid profile of patients translates into reduced risk of cardiovascular events. Consequently, the beneficial lipid altering effects of co-administration of ezetimibe with statin should reduce risk of cardiovascular events. The projected CHD risk reductions that were estimated in this study are based on changes in lipid profiles over a 12-week period and would only be maintained over the patient’s life time by continuing on therapy. Long-term studies are needed to confirm the projected results of this analysis. Acknowledgments Funding for this research was provided by Merck & Co. Inc., West Point, PA and Schering-Plough Inc. Kenilworth, NJ. References [1] Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97(18 (May 12)):1837–47. [2] Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256(20 (November 28)):2823–8. [3] McGill Jr HC, Strong JP. The geographic pathology of atherosclerosis. Ann N Y Acad Sci 1968;149(2 (November 21)):923–7. [4] Keys A, Karvonen MJ, Punsar S, et al. Serum cholesterol and 24-year mortality of men in Finland. Int J Epidemiol 1984;13(4 (December)):428–35.

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