Double-masked comparison of the quality of life of hypercholesterolemic men treated with simvastatin or pravastatin

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2 I, NO. 10, 1999

Double-Masked Comparison of the Quality of Life of Hypercholesterolemic Men Treated with Simvastatin or Pravastatin Mary Seed,DM FRC Path,’ and Matthew R. Weir, MD: for the International Quality of Life Multicenter Group* ‘Imperial Colleg e School of Medicine, London, United Kingdom, and 2University of Maryland, Baltimore, Maryland

ABSTRACT The efficacy, safety, and impact on quality of life of once-daily treatment with simvastatin 20 mg and pravastatin 40 mg were compared in a multinational, randomized, double-masked trial involving 387 men 21 to 72 years of age with primary mild-to-moderate hypercholesterolemia. The trial consisted of a 12-week baseline period, which included 6 weeks of single-masked placebo administration, and a 12-week double-masked active treatment period. Throughout the trial, patients were maintained on a standard lipidlowering diet. Efficacy variables were plasma lipid levels and a measurement of health-related quality of life evaluated by means of a self-administered questionnaire (the Nottingham Health Profile [ NHP]) and other questionnaires related *Members of the International Quality of Life Multicenter Group are listed in the Acknowledgments. Accepted for publication April 5, 1999. Printed in the USA. Reproduction in whole or part is not permitted.

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to general health, sexual function, and stress/life events. Clinic visits were scheduled at study entry (week -12), at initiation and week 5 of placebo (weeks -6 and -1, respectively); at randomization (week I, day 1); and after 4, 8, and 12 weeks of active treatment. At each visit, blood samples were collected for determination of lipid levels and the NHP, the principal measure of health-related quality of life, was administered. Primary safety measures were adverse events and laboratory test results. All statistical comparisons were two-sided, and significance was defined as P s 0.05 except for the NHP questionnaire, which was P s 0.01. Treatment with simvastatin 20 mg/d for 12 weeks (n = 194) resulted in significantly greater reductions in plasma total cholesterol and low-density lipoprotein cholesterol levels (25.7% and 33.6%, respectively) compared with pravastatin 40 mgid for 12 weeks (n = 193) (19.0% and 26.3%, respectively) (P < 0.00 1). No detrimental effects on health-related quality-of-life measurements were reported with either drug. A small but statistically significant 0149.291 V99/$19.00

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improvement in emotional reaction from baseline (P < 0.001) was observed after 12 weeks of treatment with simvastatin. At least 75% of simvastatin-treated patients indicated no change in response from baseline on NHP domain scores; these findings were similar to those for pravastatin-treated patients. The differences in the changes in lipid profiles between the 2 treatment groups were not associated with any observed differences in tolerability or health-related quality-oflife measures. Key words: HMG-CoA reductase inhibitors, simvastatin, pravastatin, hypercholesterolemia.

INTRODUCTION Evidence accumulated during the past 20 years indicates a pivotal role for plasma cholesterol in the development of atherosclerosis and its principal clinical consequence, coronary heart disease (CHD).’ Prospective observational studies*,” have demonstrated a continuous positive relationship between CHD risk and plasma cholesterol levels. Over the past 12 years, both primary and secondary prevention studies4-7 have shown that the use of lipidlowering medications is associated with a reduced risk of coronary events. The Scandinavian Simvastatin Survival Study8 was the first study to show unequivocally the beneficial effects of lowering cholesterol on total mortality as well as on coronary mortality in hypercholesterolemic patients with documented CHD. In this study, the 35% reduction in low-density lipoprotein cholesterol (LDL-C) over a median 5.4 years of treatment with simvastatin was associated with significant reductions in total mortality (30%), coronary mortality (42%), and major coronary events, including fatal and nonfatal myocardial in-

farction (34%), as well as the need for coronary angioplasty or bypass graft procedures (37%). More recently, a significant reduction (20%) in coronary deaths and nonfatal myocardial infarctions has been demonstrated with long-term therapy with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin, again in patients with documented CHD and an initial LDL-C level between 3 .O and 4.5 mmol/L (115 and 175 mg/dL)? These studies have convinced cardiologists and primary health care practitioners alike of the importance of lowering lipid levels. However, undertreatment persists. The EUROASPIRE study”’ showed that 36% of patients reviewed 6 months after myocardial infarction had total cholesterol levels ~5 5 mmol/L (2 10 mg/dL) and were not receiving lipid-lowering drugs. Approximately 32% of all patients were using lipid-lowering drugs; however, of these, 48% still had a total cholesterol level ~5.5 mmol/L (210 mg/dL), which exceeds the recommended level for secondary prevention.‘” The most effective drugs currently available for the treatment of hypercholesterolemia are the HMG-CoA reductase inhibitors (statins). These agents inhibit the rate-limiting enzyme HMG-CoA in cholesterol synthesis. Cholesterol synthesis is thereby decreased, and receptor-mediated catabolism of LDL is enhanced.” Differences in physicochemical properties and nonhuman, in vitro/in vivo tissue distribution data between simvastatin and pravastatin resulted in early speculation that the 2 drugs had different safety profiles and effects on well-being.i2 However, clinical studies have not demonstrated such differences in safety. For example, when simvastatin and pravastatin 1759

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were compared in a study to evaluate their potential effects on sleep, the qualitative changes in sleep for patients treated with simvastatin were not significantly different from those found with pravastatin or placebo. I3 In addition to safety and efficacy, quality of life is a growing area of interest in medical management of diseases. Therefore, the impact of long-term lipid-lowering therapy on well-being and quality of life should be an important consideration in the management of hypercholesterolemia. Adverse effects on quality of life can diminish compliance, which in turn can undermine the positive effects of lipid lowering on the risk for coronary morbidity and mortality. This trial was designed to compare the effects of once-daily treatment with simvastatin 20 mg and pravastatin 40 mg on health-related quality of life in men with hypercholesterolemia. This was measured using the Nottingham Health Profile (NHP).14 This trial also assessedand compared the lipid-lowering effectiveness, safety, and tolerability of simvastatin and pravastatin.

PATIENTS AND METHODS Patient Selection Male patients aged 21 to 72 years with primary hypercholesterolemia despite compliance with a lipid-lowering diet participated in this randomized, doublemasked, parallel-group trial. The trial was conducted in accordance with the Declaration of Helsinki at 37 clinics in 6 European countries and with US regulations for investigational new drugs. All patients gave written informed consent. On entering the active-treatment period, patients were required to have a plasma 1760

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total cholesterol concentration between 6.2 and 8.8 mmol/L (240 and 340 mg/dL) and a plasma triglyceride level ~4.6 mmol/L (400 mg/dL). In addition, the baseline plasma LDL-C concentration had to be (I) ~4.9 mmol/L (190 mg/dL) for patients without CHD and <2 CHD risk factors; or (2) ~4.1 mmol/L (160 mg/dL) for those with CHD or for those without CHD but with 22 CHD risk factors. Patients with any of the following were excluded from participation: secondary hypercholesterolemia; type 1, III, IV, or V hyperlipidemia; myocardial infarction or coronary bypass surgery within 6 months of trial entry; unstable, intermediate, or vasospastic angina; active liver disease; peripheral vascular disease limiting physical activity; persistent gastrointestinal dysfunction; or prior cerebrovascular accident with permanent sequelae. A history of psychiatric, neuromuscular, or primary sleep disorders disqualified patients from entry. Likewise, patients with a history or current record of drug, alcohol, or other substance abuse, or an irregular or changing work shift schedule were excluded. Patients with diabetes or hypothyroidism were allowed to participate if their disease was adequately controlled. Concurrent use of immunosuppressant agents, erythromycin or structurally related compounds, psychotropic or centrally acting drugs, or drugs with a significant effect on serum lipids was not permitted during the trial and represented a criterion for exclusion from the study.

Trial Design The trial consisted of a 12-week baseline run-in period followed by randomization to 12 weeks of double-masked active treatment. Six weeks before initiation

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of the baseline period, all lipid-lowering medication was discontinued and patients were placed on or continued with the American Heart Association Step 1 diet, a standard lipid-lowering diet that restricts daily intake to 55% carbohydrates, 15% protein, 30% fat (polyunsaturated/monounsaturated/saturated fatty-acid ratio of l/l il) and 300 mg cholesterol. Patients continued this diet throughout the trial. After the first 6 weeks of the dietary run-in period, patients meeting the lipid inclusion criteria and having none of the exclusion criteria were given 2 placebo tablets matching simvastatin 10 mg and 2 placebo tablets matching pravastatin 20 mg, administered once daily in the evening for the next 6 weeks. Patients meeting the lipid inclusion criteria and having none of the exclusion criteria after the 12-week baseline period were randomly assigned to receive 12 weeks of daily treatment with either simvastatin 20 mg/d and placebo tablets matching pravastatin 40 mg/d or pravastatin 40 mgid and placebo tablets matching simvastatin 20 mg/d. Placebo tablets matching simvastatin and pravastatin were manufactured by Merck & Co., Inc., Whitehouse Station, New Jersey. Commercially available simvastatin 20-mg tablets and pravastatin 40mg tablets were used. The total daily doses of simvastatin and pravastatin were chosen on the basis of equivalent cholesterollowering potency.t5%t6

Efficacy Variables Clinic visits were scheduled at entry to the baseline period (week -12), at initiation of placebo (week -6), after 11 weeks of the baseline period (week -I), on randomization to active treatment (week 1, day 1), and after 4,8. and 12 weeks of ac-

tive therapy (weeks 4,8, and 12). The primary measure of health-related quality of life, the NHP,i4 was administered at each visit except week -1. The NHP is a selfadministered questionnaire requesting “yes” or “no” responses to 38 statements. This well-validated tool for measuring health-related quality of life was translated into the language of each of the participating countries and its interpretation was culturally validated. Questionnaires concerning other domains not included in the NHP-stress and life events, sexual function, and general health-were also administered.t4 The questionnaires on sexual function and general health were administered at each visit except week -1, and the questionnaire on stress/life events was administered on entry to the baseline (week -12) and active-treatment (week 1, day 1) periods and at the conclusion of the activetreatment period (week 12). At each visit, a 12-hour fasting blood sample was collected for determination of plasma concentrations of total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C); each was measured enzymatically. LDL-C concentrations were calculated using the Friedewald equationI

Safety Assessments Safety and tolerability were evaluated throughout the trial by adverse event reporting and vital sign (eg, pulse, blood pressure, body weight) measurement by the site medical team at each visit. In addition, laboratory safety was monitored by obtaining a blood sample at each visit (except on the first day of active therapy) for the assessment of liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phos1761

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phatase, and total bilirubin). In addition, blood samples collected on entry to the baseline and active-treatment periods and at the conclusion of the trial were analyzed for hematologic variables (hemoglobin, hematocrit, white blood cell count, and differential) and clinical chemistry variables (blood urea nitrogen, creatinine, glucose, serum electrolytes, and creatine kinase [CK]). At these visits, a urine sample was also collected and analyzed for specific gravity, protein, and cells, and a physical examination was performed that included measurement of vital signs. A I2-lead electrocardiogram was obtained 12 weeks before beginning the trial (unless done within 3 months of study entry) and again at its completion, if clinically indicated. The relationship of adverse events to study drug was determined based on the investigator’s assessment of responses to questions about observed and reported events recorded on an adverse events form. Statistical Efficacy and Analyses The comparability of the 2 treatment groups at baseline was assessedwith respect to patient characteristics, mean quality-oflife questionnaire scores, and lipid values using the Fisher exact test for dichotomous variables, the Wilcoxon rank sum test for ordered categoric variables, and a two-sample t-test or Wilcoxon rank sum test for continuous variables. All patients for whom data were recorded at baseline and in 2 1 active-treatment period were included in the efficacy analyses (intent-to-treat analysis). The baseline value was defined as the last measurement during the placebo baseline period. The last double-masked measurements of patients who were withdrawn 1762

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from the study were carried forward to subsequent time points. Questionnuires Health-related quality-of-life responses on the NHP were scored using the requirements established by Hunt et al.14 The 3X statements in the questionnaire were grouped into 6 areas: emotional reactions, energy, pain, physical mobility, sleep, and social isolation. For each patient, the number of “yes” responses in each domain was calculated and the score was resealed on a scale from 0 to 100, with the maximum score of 100 indicating all statements in that section were answered affirmatively. The higher the score, the greater the perceived health problems in that domain. Analysis of the results of the NHP questionnaire was based on the change from baseline in the mean sum of unweighted scores for each of the 6 domains of health. A nonparametric approach was used since most of the patients had no change in most scores from baseline to the end of the study. For each of the 6 health domains, changes from baseline after 12 weeks of active treatment were compared between treatment groups using an analysis of variance (ANOVA) with treatment and investigator as model effects. ANOVA was performed on the ranks of values across treatment groups and investigators because of the nonparametric nature of these data. Withingroup comparisons were carried out using the Wilcoxon signed-rank test. Additionally, the Wilcoxon rank sum test was used to compare the distribution of patients within categories of change from baseline responses in the 2 treatment groups. This analysis included only patients who answered all questions in a domain. Changes in quality of life, as assessedby the general health questionnaire, sexual

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function questionnaire, and stress/life events questionnaire, were analyzed using the same method used for the NHP questionnaire. Lipids ANOVA models were used to compare treatment groups with respect to percentage of change from baseline in lipid variables. The models included terms for treatment and investigator. Parametric results (ANOVA on the actual values) were reported for all lipid variables except triglycerides. Because of the lack of normality in the distribution of the percentage of change from baseline, the analysis of total triglycerides was nonparametric (ANOVA on the ranks of values across treatment groups and investigators). Within-group comparisons were carried out using the Wilcoxon signed-rank test for triglycerides and the paired t test for all other lipid variables. Sufely Profile The treatment groups were compared with respect to the incidence of clinical and laboratory adverse events using the Fisher exact test. Changes in clinical safety measurements from baseline to week 12 were analyzed using ANOVA on actual values, with treatment and investigator as factors, and changes within each treatment group were assessedusing the paired t test. Changes in laboratory safety measurements from baseline to week 12 were analyzed using ANOVA on ranked values, with treatment and investigator as factors, and changes within each treatment group were assessedusing the Wilcoxon signedrank test. All statistical comparisons were twosided. Statistical significance was set at P s 0.05, except for the NHP questionnaire. Multiple comparison procedures

were used to control the overall type I rate for the comparison of treatments with regard to the different NHP components. A difference between treatments was declared significant if the corresponding P value was ~0.01. The treatment-by-investigator interactions were tested at a significance level of 0.10. RESULTS

Patient Disposition and Baseline Characteristics A total of 387 men were randomly assigned to treatment with simvastatin 20 mg/d (n = 194) or pravastatin 40 mg/d (n = 193). The 2 treatment groups had similar CHD risk status and lipid concentrations at baseline. A slightly greater number of older patients was randomly assigned to the pravastatin group (P = 0.04); the mean ages in the pravastatin and simvastatin groups were 52 and 50 years, respectively. Similar numbers of patients in the simvastatin and pravastatin groups had CHD (49 [25%] and 5 1 [26%], respectively). A total of 177 patients (9 1%) in the simvastatin group and I80 (93%) in the pravastatin group completed 12 weeks of double-masked therapy. Seven patients in each treatment group discontinued treatment because of clinical adverse experiences. The adverse experiences were not considered serious and affected the body as a whole, with no prominent event or body system reported.

Reduction in Plasma Lipids The mean baseline and follow-up values and the mean percentage of change from baseline in plasma lipid concentrations (me1763

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dian percentage of change for triglycerides) after 12 weeks of treatment with simvastatin 20 mg/d or pravastatin 40 mg/d are shown in Table I. Once-daily administration of either drug resulted in statistically significant improvements fi-om baseline in plasma levels of total cholesterol, LDL-C, triglycerides, and HDL-C (P < 0.001). The mean percentages of reduction in total and LDL-C levels with simvastatin 20 mg/d were greater than those seen with pravastatin 40 mg/d after 12 weeks of treatment (25.7% vs 19.0% and 33.6% vs 26.3%, respectively) (P < 0.001). Increases in HDL-C levels were similar in the 2 treatment groups. Guidelines from the National Cholesterol Education Program (NCEP)‘* for the treatment of patients with primary hypercholesterolemia recommend lowering LDL-C to

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~4.1 mmol/L ( 160 mg/dL) for those without CHD and with <2 CHD risk factors, to 53.4 mmol/L (130 mg/dL) for those without CHD but with ~2 CHD risk factors, and to ~2.6 mmol/L (100 mg/dL) for those with CHD. Overall, 48% of patients treated with simvastatin 20 mg/d achieved these target goals after 12 weeks of treatment, compared with 26% of those receiving pravastatin 40 mgid (P < 0.00 1). Notably, target goals for patients with CHD were achieved by 20% of simvastatin-treated patients, compared with 2% of pravastatin-treated patients (P = 0.005) (Figure I). Changes in Health-Related Quality of Life Table 11 summarizes mean baseline scores and mean changes in scores from

Table I. Mean* plasma lipid concentrations and percentage of change from baseline (BL) to week 12. Simvastatin 20 mg/d Lipid Total cholesterol (mmol/L) (mg/dL) Triglycerides (mmol/L) (mg/dL) LDL-C (mmol/L) (mg/dL.) HDL-C (mmolil,) (mg/dL)

Pravastatin 40 mg/d

No. of Patients

BL

Week 12

% Change

No. of Patients

BL

Week 12

% Change

192 290

7.51 21s

5.54 285

-2s.7+$ 230

191

7.40

5.98

-19.0’

192 170

I .95 130

1.47 180

-2 I .s+ 14s

191

2.02

1.64

-1523+

187 210

5.38 13.5

3.52 205

-33.6+* 1.50

186

5.31

3.88

-26.3+

192

I.15 45

I .22 so

12.2’

189

1.14 4.5

I .22 so

LDLC = low-density lipoprotein cholesterol: HDL-C = high-density lipoprotein cholesterol. *Median values are given for triglycerides. ‘P < 0.001, change from baseline to week 12. iP < 0.001, between-groupdifference (simvastatin vs pravastatin).

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I 1..5+

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80

H Simvastatin 20 mg/d q Pravastatin 40 mg/d

No CHD, c2 RF (54.1 mmol/L; 160 mg/dL)

’

No CHD, r2 RF (53.4 mmol/L; 130 mg/dL)

’

CHD (~2.6 mmol/L;

100 mg/dL)

Figure 1. Percentage of patients achieving National Cholesterol Education Program’s target levels, by coronary heart disease (CHD) risk-factor (RF) status. *P = 0.00 1; 'P = 0.05. Table II. Mean scores at baseline (BL) and mean change from BL to week 12 as assessed using the Nottingham Health Profile (NHP).12* NHP Domain Emotional reaction Simvastatin* Pravastatin’ Energy Simvastatin Pravastatin Pain Simvastatin Pravastatin Physical mobility Simvastatin Pravastatin Sleep Simvastatin Pravastatin Social isolation Simvastatin Pravastatin

No. of Patients

Mean B L Score

Mean Change from BL to Week 121’

187 189

7.5 6.1

-2.5" -1.4

185

8.6 9.5

a.4

1x9

-1.8

187 IX8

6.1

6.2

0.3 0.6

189 190

5.8 5.8

-0.4 0.9

IX8

13.0 13.7

-1.4 4.3

1.4 1.9

-0.2 4.5

190 18X

190

*Simvastatin dose, 20 mgid: pravastatin dose, 40 mg/d. +Range,O-100. with 0 representingbest and 100 representingworst quality of life ‘Negative change score reflects a perceived improvement in quality of life, SF’ = 0.001, change from baseline to week 12.

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Improvement Emotional Reaction Energy Pain Physical Mobility Sleep Social Isolation 20

I 15

I 10

I 5

Percentage

I I 0

I 5

I 10

I 15

1 20

of Patients

Figure 2. Distribution of patients, by change from baseline to week 12 in the Nottingham Health Profile questionnaire.14 baseline to week 12 on each of the 6 domains of the NHP in patients treated with simvastatin 20 mgid or pravastatin 40 mgld. A negative change score reflects a perceived improvement in quality of life. At baseline, the 2 groups perceived themselves to have similar health problems within the 6 NHP domains. Mean baseline scores for each domain were all ~14 on a scale from 0 to 100. where 100 represented the worst quality of life. Within each treatment group >95% of patients completed each of the 6 domains of the NHP at baseline and end of treatment. For the emotional reaction domain, there was a small but statistically significant improvement from baseline after 12 weeks of treatment with simvastatin (P = 0.001) but not with pravastatin. None of the changes from baseline to week I2 in the areas of energy, pain, physical mobility, sleep, and social isolation were statistically significant for either group. It is evident from Table 11that the mean changes from baseline on all the healthrelated quality-of-life domains were small; 1766

this is largely a result of the high percentage of patients who indicated no change in quality-of-life status from baseline while receiving the trial medication. The percentage of patients in either treatment group who indicated no change in quality of life from baseline to study end was nearly 75% for the emotional reaction and sleep domains; nearly 85% for the energy, pain, and physical mobility domains; and ~95% for the social isolation domain. Figure 2 presents the percentage of patients in the simvastatin and pravastatin groups who indicated that they had an improved or worsened quality of life at week 12 on each of the 6 NHP domains. Once-daily treatment with either simvastatin 20 mg or pravastatin 40 mg did not result in statistically significant changes in any of the other 3 quality-oflife measures, nor were there any significant between-group differences in the change from baseline in these variables. On the sexual function questionnaire, -80% of patients in both groups indicated that they were sexually active both at base-

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line and at week 12. At the end of the trial, >60% of all patients in both treatment groups indicated no change in sexual function; of the remainder, the number of patients who said that their sexual function had deteriorated was similar to the number who indicated an improvement. Tolerability and Safety The tolerability and safety of once-daily treatment with simvastatin 20 mg and pravastatin 40 mg were comparable, with 35% (68/l 94) of patients in the simvastatin group and 29% (561193) in the pravastatin group reporting any clinical adverse experience during the study. Drug-related adverse events reported by >l % of patients in either group were asthenialfatigue, abdominal distention, abdominal pain, diarrhea, insomnia, nervousness, and impotence. The only serious clinical adverse experience reported in this trial was a malignant neoplasm of the salivary gland in a simvastatin-treated man with a history of parotid cancer. None of the laboratory adverse experiences reported at week 12 in the study were serious or necessitated discontinuation of treatment. Moreover, no patient in either group had increases in ALT or AST of >3 times the upper limit of normal or in CK levels ranging from >5 to 10 times the upper limit of normal. There were no clinically meaningful or statistically significant changes from baseline to week 12 in heart rate, diastolic or systolic blood pressure, or body weight in either treatment group. DISCUSSION Treating men having primary hypercholesterolemia with simvastatin 20 mgid or pra-

vastatin 40 mg/d for 12 weeks had no clinically meaningful effect on patients’ responses to a widely used quality-of-life questionnaire. At least 75% of patients in both treatment groups reported no change in perceived health-related quality of life from baseline to the end of the study on the 6 areas of well-being and social and cognitive functioning assessedby the NHP. The men in this study (mean age, 51 years) perceived sleep to be the least satisfactory domain, judging from NHP scores that were noticeably higher than those in other domains. However, there was no significant change in patients’ perception of sleep with either drug during the 12-week study. The baseline quality of life of this group of patients was considered by the investigators to be good (ie, initial NHP scores were low). Therefore, our findings may not necessarily extend to patients having a significantly poorer quality of life at baseline (ie, those with high initial scores on the NHP). In this respect, the patients with high scores initially showed a greater change in NHP scores during the study than did patients with lower scores. Although this study examined quality of life over a relatively brief period (I 2 weeks), and patients require long-term lipid-lowering therapy, the perception of alterations in quality of life tends to occur initially and not thereafter. Studies of longerterm therapy ‘,‘,I9 should show whether a 12-week assessmentsuch as ours will tend to have different results than a l- or 5-year study. Our results are similar to previously reported results showing that treatment with the HMG-CoA-reductase inhibitors lovastatin, simvastatin, and pravastatin does not adversely affect quality of life in patients with primary hypercholesterolemia,2g23 1767

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Although simvastatin and pravastatin had generally similar, negligible effects on measures of health-related quality of life in this trial, simvastatin 20 mg/d was significantly more effective than pravastatin 40 mg/d (the maximum recommended dose) in reducing levels of total and LDL-C. Consequently, more patients in the simvastatin group than in the pravastatin group (P = 0.005) achieved the target LDL-C levels recommended in the NCEP guidelines I8 by the end of the 12week trial. However, among the patients in our study, whose mean LDL-C level was 5.3 mmol/L (205 mg/dL), only 20% of patients with CHD who were treated with simvastatin 20 mg and 2% of those taking the full 40-mg dose of pravastatin achieved LDL-C levels 52.6 mmol/L ( 100 mg/dL). This reflects the current practice of undertreating patients at risk, of whom only a small proportion achieve NCEP goals. The superior cholesterol-lowering effectiveness of simvastatin compared with pravastatin observed in this trial is similar to findings from other controlled comparative studiestsTi6 in which the dose of simvastatin was either equivalent to or lower than that of pravastatin. CONCLUSIONS The results of this 12-week trial showed no distinctions in safety and tolerability profiles or impact on health-related qualityof-life variables between simvastatin and pravastatin. Similarly, there is no negative effect associatedwith the greater cholesterollowering power of simvastatin. It is encouraging that therapy with simvastatin or pravastatin, which is required for longterm treatment of patients with CHD or with multiple risk factors for CHD, is not associated with any detrimental effects on 1768

health-related quality of life. Based on its greater ability to lower cholesterol, simvastatin may be the preferred agent in the treatment of hypercholesterolemia. ACKNOWLEDGMENTS The trial was supported by a grant from Merck & Co., Inc., Whitehouse Station, New Jersey. The International Quality of Life Multicenter Group consisted of the following clinical investigators. Belgium: Dr C. Brohet, Cliniques Universitaires St. Luc; Dr F. Defoer, Hopital Militaire, Brussels; Frunce: Prof Bernard Bauduceau, Hopital Begin, Saint Mande; Dr Michel Chelly, Laboratoire d’Analyses de Biologic Medicale, Ablon; Dr Philippe Douste-Blazy, Hopital Purpan, Toulouse; Dr Jean-Pierre Hespel, Hopital Sud, Rennes; Dr JeanMichel Lecerf, Laboratoire d’Analyses de Biologie Medicale, Lompert; Germany: Dr Helmut Heddaeus, Wiirselen; Dr Dirk Heinz, Krankenhaus Wermelskirchen; Dr Gerhard Jakobs, Aachen; Dr Frank Merfort, Moenchengladbach; Prof Dr Jiirgen Schneider, University of Marburg Med Zentr F Innere Medizin, Marburg; Italy: Prof Aldo Bigalli, Ospedale S. Chiara, Pisa; Dr Pierugo Carbonin, lnst Clin Med Gen E Ter Med University Catt, Rome; Prof Luigi Cattin, lnst di Clinica Medica Ospedale di Cattinara, Trieste; Prof Renato Fellin, lnst Pat Me Univer Ferrara; Prof Pier Agostino Gioffre, Div Cardiochimrgia, 11Univ European Hospital, Rome; Prof Pierluigi Mattioli, Dip Med Sperimentale, Catanzaro; Prof Albert0 Notarbartolo, I! Patologia Medica, Palermo; Sweden: Dr Stig Eriksson, Familjelakarenheten, Sodra Sala; Dr Dag Gilstring, Sysslomangata 15 V, Uppsala; Dr Margareta Goransson, DL Lanna, Lannaholm; Dr Peter Hallman, Ovakohal-

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san Siidra Porten, Hofors; Dr Jan Holmgren, Jordbro VC, Haninge; Dr Tina Holmqvist, VC Norresta Silvergkd, Landskrona; Dr Ann Marie Hiirnqvist-Bunell, Wkersberga VC, hersberga; Dr Leif Johansson, VC Nykiipings Lasarett, Nykoping; Dr Ingrid Karlstrom, Viks5ngs DSL, Vasteras; Dr Peter Montnemery, KockumhHlsan, Malmo; Dr Mats Persson, Ersboda Health Center, Umea; United Kingdom: Dr R. Cramb, Queen Elizabeth Hospital, Birmingham; Prof J. Feely, St. James Hospital, Dublin; Dr D. Johnston, Queen’s University Hospital, Belfast; Dr Marc MacMahon, Chiltem International, Slough, Berkshire; Dr Michael Ryan, Ninewells Hospital, Dundee; Dr Mary Seed, Charing Cross Hospital, London; United States: Dr Matthew R. Weir, IJniversity of Maryland, Baltimore. Address correspondence to: Mary Seed, DM FRC Path, Imperial College School of Medicine, Charing Cross Hospital, 5th Floor, North Wing, Fulham Palace Road, London W6 8RF, UK. REFERENCES Thompson GR. Pathophysiology of blood lipids. In: Julian DG, CammAJ. Fox KM, et al, eds. Diseases of the Heart. 2nd ed. Philadelphia: W.B. Saunders;1996:77-87. StamlerJ, 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 screeneesof the Multiple Risk Factor Intervention Trial (MRFIT). ./AMA. 1986;256:2823-2828. 3. Pooling Project Research Group. Relationship of blood pressure,serum cholesterol, smoking habit, relative weight and ECG

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