comparison of the effects on quality of life and of the efficacy and tolerability of lovastatin...

Comparison of the Effects on Quality of Life and of the Efficacy and Tolerabihty of

LovastalLin Versus Prwvastat;n Matthew R. Weir, MD, Marc L. Berger, MD, Mary L. Weeks, MS, Charles L. Liss, MS,

and Nancy C. Santanello, MD, MS, for the Quality of Life Multicenter Group

This multicenter study compared the effects of lovastatin (40 mg) and pravastatin (40 mg) on quality of life. Men, aged 20 to 65 years old, with primary hypercholesterolemia (types Ila and Ilb) were eligible for enrollment if baseline low-density lipoprotein cholesterol met the first National Cholesterol Education Pro- gram adult treatment enrolled into a 6-wee

uidelines. Eligible patients were & diet baseline period, followed

by a 6-week diet-plus-placebo period. Patients whose low-densi

7 Cholestero lipoprotein cholesterol still met National

Education Program guidelines for drug therapy were randomized into the double-blind, active- treatment period to receive either lovastatin 40 mg or pravastatin 40 mg/day for 12 weeks. Clinic visits were scheduled every 4 weeks and included complete serum

lipid profiles, monitoring of adverse experiences, and patient completion of health-related quality-of-life questionnaires. The primary end point of the study was the change in quali

7 of life, as measured by the Notting-

ham Health Profi e (part 1) after 12 weeks of treatment. Secondary end

r ints included responses to a general

health question rom the National Health and Nutrition Examination Survey, sexual function questions from the Medical Outcomes Study, and stress/life event questions from the National Institutes of Health Post-Coro- nary Artery Bypass Grafting Study. No significant differences between the 2 groups were observed in tolerability, health-related quality-of-life measures, or changes in lipid profiles.

(Am J Cardiol 1996;77:475-479)

C urrently, there are 4 approved inhibitors of hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA)

reductase available in the United States: lovastatin, pravastatin, simvastatin, and fluvastatin. Although all these compounds have similar chemical structures, there are differences in lipophilicity; the clinical significance of this property is disputed.’ In an effort to more care- fully characterize any potential differences between the therapies, we designed a study to evaluate possible effects on health-related quality-of-life measures. Since there is already extensive experience with both drugs in clinical trials2 and with marketed use, our hypothesis in designing the study was that no differences, in health- related quality of life would be expected, and that the tolerability profile of the 2 drugs would be similar.

METHODS Design: This clinical trial was a multicenter, double-

blind, double-dummy, randomized, parallel study to compare the quality of life, efficacy, and tolerability of lovastatin 40 mg and pravastatin 40 mg in adult male patients with primary hypercholesterolemia. After pro- viding a complete medical history, and undergoing a physical examination, electrocardiogram, laboratory tests, and quality-of-life assessment, patients entered a B-week, diet-only period. At the end of this period, health-related measures of quality of life were

From the Division of Nephrolo y and Clinical Research Unit, Depart- ment of Medicine, University o Maryland Hospital, Baltimore, Mary 7 land, and Merck & Co., Inc., West Point, Pennsylvania. Manuscript received August 8, 1995; revised manuscript received October 19, and accepted October 20.

Address for reprints: Matthew R. Weir, MD, University of Mary land Hospital, Division of Nephrology, 22 South Greene Street, Bal- timore, Maryland 2 120 1

reassessed, and lipid and liver function tests were repeat- ed. Patients then entered a 6-week, diet-plus-placebo period. One week before randomization, a qualifying lipid profile was obtained. After a 12-week baseline period, patients whose low-density lipoprotein (LDL) clio- lesterol still met National Cholesterol Education Pro- gram guidelines for drug therapy were randomized to 12 weeks of treatment with either lovastatin 40 mg or pravastatin 40 mg. Randomization was stratified based on the presence or absence of coronary artery disease. Lipid analysis and quality-of-life assessments, as well as spontaneous reports of adverse events, were obtained every 4 weeks during the lZweek, active-treatment period. All lipid and lipoprotein analyses were performed at a central laboratory, SciCor, Inc., which is certified by the Centers for Disease Control National Heart, Lung, and Blood Institute Standardization program. LDL cholesterol was calculated using the Friedewald formula.3 The stress and life-event scale instrument was used at the beginning and end of baseline and at the etid of the lZweek, active-treatment period. Lovastatin or matching placebo was given at each evening meal. Pravastatin or matching placebo was given at bedtime.

Male patients between 20 and 65 years of age with primary hypercholesterolemia (types IIa, IIb) were eligible for entry into the study. A total of 798 patients were screened, and 426 were randomized to 1 of the 2 therapies. Patients with impaired hepatic or renal function, history of myocardial infarction or coronary artery bypass surgery within 6 months, history of cerebrovascular accident associated with permanent sequelae, or peripheral vascular disease that interfered with normal daily function, or who had been treated with any inves- tigational drug or any lipid-lowering medication during the previous 6 weeks (6 months for probucol) were

PREVENTIVE CARDIOLOGY/LOVASTATIN AND PRAVASTATIN 475

TABLE I Demographic Characteristics of Study Population

Lovastatin Pravastatin Total

inN;,2;; I (nN; 2::)

Patients I”/)

inN;Qfl

Characteristics Patients (%) Patients (%)

Age* 49.3 * 9.7 51 .O * 9.2 50.1 f 9.5 Race+

White 176 (83.4) 193 (89.8) 369 (86.6) Black 23 (10.9) 19 (8.8) 42 (9.9) Oriental 3 (1.4) 3 (0.7) Hispanic 9 (4.3) 2 (0.9) 11 (2.6) Native American 1 (0.5) 1 (0.2)

*Values are expressed as number of years * SD. W&es ore expressed as number (%I, .

TABLE II Coronary Heart Disease Risk Status Summary

Lovastatin Pravastatin Total (n = 211)

No. of in{0 2::) inN=,~~fl

Risk Status Patients (%) Patients (%) Patients (%)

Definite CAD 29 (13.7) 30 (14.0) 59 (13.9) CAD risk Factors*

Men 211 (100.0) 215 (100.0) 426 (100.0) Family history of CAD 60 (28.4) 55 (25.6) 115 (27.0) Cigarette smoking 38 (18.0) 39 (18.1) 77 (18.1) Systemic hypertension 78 (37.0) 78 (36.3) 156 (36.3) Low HDL cholesterol 52 (24.6) 48 (22.3) 100 (23.5) Diabetes mellitus 6 (2.8) 6 PI 12 (2.8) Cerebrovascular/peripheral vascular 10 (4.7) 8 (3.7) 18 (4.2)

disease Severe obesity 66 (31.3) 60 (27.9) 126 (29.6) 22 risk factors including definite CAD 178 (84.4) 182 (84.7) 360 (84.5) 22 risk factors excluding definite CAD 151 (71.6) 157 (73.0) 308 (72.3) tow-risk status 27 (14.7) 28 (13.0) 59 (13.9)

*High-risk status patients are those with definite coronary artery and ~2 risk factors for coronary artery disease. tow-risk status patients are those with 51 factor for coronary artery disease.

CAD = coronary artery disease; HDL = highdensity lipoprotein.

Analyses of the mean percent change in the lipid variables (total cholesterol, LDL cholesterol, very low density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol/HDL cholesterol, and LDL cholesterol/HDL cholesterol ratios) were conducted using analysis of vari- ance (ANOVA) models. ANOVA was used to compare

treatments with respect to the change from the randomization-day observa- tion to each subsequent treatment time. Emphasis was placed on the ending time period (after 12 weeks of treatment). The ANOVA model included terms for an overall mean, treatments, investigator, strata (3 groups: presence of coronary artery disease, 22 risk factors for coronary artery disease, <l risk factor) and the interactions of treatments with investigators and strata. The paired t test was used for within- group comparisons of baseline to each time period.

The Nottingham Health Profile was scored without weighting into the 6 quality-of-life domains. A chi-square test was used to compare the 2 treatment groups with respect to the distribution of patients over the categories of the change from baseline response. The chi-square test compares -the 2

excluded. Patients with a history of depression, anxiety, or other psychiatric disorder, a sleep disorder, an irreg- ular or changing work-shift schedule, or use of any psy- chotropic drugs or other centrally acting agents were also excluded. Patients were eligible for study entry, if, at the qualifying visit (after 6 weeks of diet and 6 weeks of diet-plus-placebo treatment), their triglyceride level was ~400 mg/dl, total cholesterol level was between 240 and 340 mg/dl inclusive, and LDL cholesterol level was 2290 mg/dl for patients without coronary artery disease or with <2 other coronary artery disease risk factors, or LDL cholesterol level was 2160 mg/dl for patients with coronary artery disease or the presence of 2 other coronary artery disease risk factors.

Quality-of-life assessments: Four different instruments constitute the health-related, quality-of-life assessment of each patient in this clinical trial: (1) The Nottingham Health Profile (38 items) is a validated generic profile measure that assesses the following domains: energy, pain, emotional reactions, sleep, social isolation, and physical mobility$ (2) the National Health and Nutri- tion Examination Survey General Health Question (1 item)5; (3) a 6-item sexual function questionnaire derived from the Medical Outcomes Study6; and (4) the Stress/Life Events Scale from the National Institutes of

476 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 77

Health Post-Coronary Artery Bypass Grafting study focusing on the frequency and bother of 12 life events7 The questionnaires were self-administered by patients during clinic visits.

Statistical analysis: Comparability of the 2 treatment groups at baseline was assessed by the t test or chi-square test, as appropriate.

treatment groups with regard to the distribution of patients over the 7 possible categories of response (i.e., -3, -2, -LO, 1, 2, and 3). A 7-point distribution of categories was used for each dimension of quality of life. For categories with a larger range than above, the 2 categories on the end of the distribution were collapsed to values c-2 or >2. This was justified by the small amount of data outside the limits for most dimensions.

An all-patients-treated approach was used in the analysis of the quality-of-life data. All patients who received 21 dose of test drug and had at least 1 mea- surement on treatment were included in the analysis. In the event of early withdrawal, a patient’s last value was carried forward to each subsequent time period for analysis. Statistical significance of comparisons of treatment with regard to the primary end point (the 6 domains of the Nottingham Health Profile) was declared at the 0.0083 level (Bonferroni correction: 0.05/6).

All patients were included in the analysis of safety. Incidence of adverse experiences in each treatment group was compared with Fisher’s exact test.

RESULTS Demographic characteristics: A total of 426 patients

were randomized to either lovastatin (n = 211) or

MARCH 1, 1996

TABLE III Changes in Lipid Variables With Lovastatin and Pravastatin in Men With Primary Hypercholesterolemia

Variables Time

Period

Lovastatin (40 mg/d) Pravastatin (40 mg/d) (n = 211) (n = 215)

Mean Mean No. of Percent No. of Percent Potients Mean Change* SD+ Patients Mean Change* SD+ p Value

Total Baseline 211 270 - 33 215 200 35 cholesterol Week 12 210 215 -19.9 11 213 225 -1T.3 11 0.397

LDL(mg/4 Baseline 211 195 - 30 215 202 - 30 cholesterol Week 12 210 139 -27.9 13 213 150 -25.6 14 0.108

H$w/4 Baseline 211 42 - 10 215 42 - 10

cholesterol Week 12 210 45 +8.5 16 213 45 +8.2 16 0.935

Triglycerides

(w/4

Baseline 211 174 - 88 215 183 49

Week 12 210 153 -6.0 38 213 157 -8.6 55 0.720 TC/HDL Baseline 211 6.8 1.5 215 7.0 - 1.8

ratio Week 12 210 5.0 -2y.2 12.6 213 5.3 -24.2 14.0 0.351 LDL/HDL Baseline 211 4.9

-37.6 1.2 215 5.1 - 1.4

ratio Week 12 210 3.3 13.5 213 3.5 -30.4 13.9 0.175

*All changes were statistically significant from boseline within treatment groups except very low density lipoprotein cholesterol for lovastotin at week 12. tSD = standard deviation of meon percent change, except at baseline. HDL = high-density lipoprotein; LDL = lowdensity lipoprotein; TC = total cholesterol.

pravastatin (n = 215), from 1 of 28 centers around the United States. Numbers of patients enrolled among the centers ranged from 1 to 28 patients. The median enrollment was 14.5. Centers with few patients3 were combined for the purpose of analysis. The median age of the study population was 50 years (Table I). The difference between treatment groups was small, but statistically significant. There was also a significantly higher percentage of nonwhite patients in the lovastatin group (17%) than in the pravastatin group (10%). The treatment groups were very similar with respect to the incidence of coronary artery disease risk factors (Table II).

Nineteen of the 426 patients (4.5%) discontinued therapy early during the 1Zweek study period (lovastatin, n = 9; pravastatin, n = 10). The most common rea- son for withdrawal was adverse clinical events (lovastatin, n = 3; pravastatin, n = 4). Other reasons for study withdrawal were either that patients were lost to follow- up (lovastatin, n = 1; pravastatin, n = 4) or that they were noncompliant with study medication (lovastatin, n = 3; pravastatin, n = 0).

Efficacy (Table III): Patients in both groups experienced statistically significant mean percent reductions from baseline to the end of the study for total and LDL cholesterol, as well as for the total cholesterol/HDL cholesterol and LDL/HDL cholesterol ratios at all time peri- ods, both for all patients and within each risk status subgroup. Patients in both groups also had similar mean percent increases in HDL cholesterol. Patients receiving lovastatin had a slightly higher mean percent reduction in LDL cholesterol (-27.9%) than did patients receiving pravastatin (-25.6%), whereas the opposite was true for triglycerides and very low density lipoprotein cholesterol. Results of the mean percent changes for the other lipid variables were nearly identical. There were no statistically significant differences between treatments with regard to the mean percent change from baseline to the

end of the study for any lipid variable, either for all patients or for any subgroup.

The number of patients experiencing either a 10% or 20% reduction in total cholesterol was very similar across risk-status groups and treatments. Approximate- ly 80% of the population had a 210% reduction in total cholesterol, whereas slightly >50% of the population had a 20% reduction. Similar results were noted for the number of patients experiencing either a 10% or 20% reduction in LDL cholesterol. Nearly 90% of the patients in each treatment group had a 210% reduction in LDL cholesterol, whereas approximately 70% of the study population (76% lovastatin, 69% pravastatin, p = 0.103) had a 220% reduction in LDL cholesterol. A significantly higher (p <O.OOl) percentage of patients receiving lovastatin (45%) reached the National Cholesterol Education Program guideline goal for LDL cholesterol than did patients receiving pravastatin (26%).

Quality of life (Table IV): There were no changes in quality-of-life measures between the beginning and the end of the diet-only period, spanning 6 weeks. The percentage of patients with no change in health-related quality-of-life measures from baseline to the end of the study was nearly 80% and above for all 6 domains of the Not- tingham Health Profile for both treatment groups. The percentage of patients with a 51.0 change from baseline in either direction was ~90% for all domains. There were no statistically significant differences found between treatment groups with respect to any of the domains.

Approximately 70% of the population had no change in response to the National Health and Nutrition Exam- ination Survey General Health Question. Nearly all patients in both treatment groups had a 51.0 change on both treatments. Seventy percent of patients in each group had no change in sexual function from baseline to the end of the study, as evaluated with the Medical Out- comes Study sexual function questionnaire. Although this dimension of quality of life had the greatest amount


TABLE IV Quality-of-life Summary Change from Baseline* to Week 12

% of Patients

Possible Actual improvement

No Change Worsening

Dimension Range Range Treatmentt n <-2 -2 -1 0 1 2 >2 p Value*

Nottingham Health Profiles Energy (-3, 3) i-2, 4 1 209 0% 1% 3% 91% 4% 1% 0%

P 210 0% 1% 3% 91% 4% <l% 0% 0.599

Pain l-8, 8) (-8, 7) L 209 cl% 0% 2% 91% 2% 1% 3%

P 210 cl% 1% 8% 82% 4% 1% 3% 0.468

Emotional reactions (-9, 9) (-4, 51 L 209 <l% 3% 6% 82% 5% 2% 1% P 209 2% 4% 11% 77% 3% 1% 2% 0.113

Sleep (-5, 51 (-4, 4) L 209 <l% 1% 8% 79% 10% <l% <l% P 210 <l% 1% 10% 79% 8% 2% 0% 0.933

Social isolation i-5, 51 (-4, 3) L 210 0% 1% 2% 96% 1% 0% 0%

9 210 <1% 0% 2% 95% 2% cl% cl% 0.355

Physical mobility I-8, 8) (-5, 5) L 210 <lo/, 0% 5% 88% 5% 1% 1%

P 209 <l% 1% 5% 88% 4% 1% cl% 0.689

NHANES General Health6 (-4, 4) (-2, 21 L 208 0% 0% 14% 68% 18% cl% 0% P 208 0% <l% 10% 75% 14% cl% 0% 0.929

MOS Sexual function’ (-12, 12) (-12, 12) L 208 3% 2% 7% 70% 8% 3% 7% P 208 3% 3% 6% 70% 6% 4% 8% 0.963

Stress and life events scale* (-50, 50) (-16, 16) L 200 16% 8% 4% 46% 6% 4% 16% P 202 17% 7% 5% 44% 4% 6% 17% 0.847

*With no weighing or resealing tt = lovastatin; P = pravastatin bvastotin versus pravastatin, chi-square test. MOS = Medical Outcome Study; NHANES = National Health and Nutrition Examination Survey.

I

1

of variability and response, the percentage of patients in each category of response was nearly identical for the 2 treatment groups. Slightly ~50% of the study population had no change in response to the Stress and Life Events Scale. The results by category were very similar for the 2 treatment groups.

No statistically significant differences were found between treatment groups with regard to any of the health-related quality-of-life instruments used in this study. In addition, few changes from baseline were observed in any of the quality-of-life domains that were measured.

Adverse experiences: One hundred eighty-six of the 426 patients (44%) entered into the study experienced an adverse event during the 1Zweek study period. The lovastatin (42%) and pravastatin (45%) treatment groups were similar with regard to the overall incidence of adverse experience. The most common adverse events reported ,were upper respiratory infection (ll%), headache (6%), and asthenia/fatigue (3%). Less than one third of all adverse events reported were indicated as drug related. Headache was the most common drug- related adverse event (2.3%). There were no significant differences between the 2 therapies with regard to any of the drug-related adverse experiences.

Four patients had serious adverse events during the course of the study and required hospitalization. Nqne of these adverse events were considered drug related, and none resulted in discontinuation of the patient from the study. Of the 7 patients who were withdrawn from the study due to clinical adverse experiences (lovastatin, n=3; pravastatin, n = 4), 6 reported multiple adverse events. None of the adverse events was considered serious. The following were reported by >l patient: insom-

nia (lovastatin, n = 2; pravastatin, n = 1); fatigue (lovastatin, n = 2; pravastatin, n = 1); and nausea (lovastatin, n = 1; pravastatin, n = 1). Nineteen patients in the lovastatin group (9%) and 12 patients in the pravastatin group (6%), had a laboratory-confirmed adverse experience. Approximately half of these in each group were considered drug related, none were considered serious. The only laboratory-confirmed adverse events to be reported more than once were alanine transaminase increases (4%), aspartate transaminase increases (3%), and hyper- glycemia (0.7%). There were no statistically significant differences between treatments with regard to overall incidence of laboratory-confirmed adverse events.

DISCUSSION The results of this randomized, double-blind, clinical

trial demonstrate that, in a group of male patients with primary hypercholesterolemia, the 4 different instruments used to assess health-related quality-of-life measures in this clinical teal were consistent in demonstrat- ing minimal influence of these therapies on a patient’s perception of health-related quality-of-life measures. Not only were the results of the Nottingham Health Profile not significant at the multiplicity-adjusted a level of 0.0083, but they were also not statistically significant at the conventional level of significance (p ~0.05).

There could be other possible reasons for the non- significant results we observed between the treatment groups other than that there are no true differences between the drugs with regard to health-related quality- of-life measures: (1) The quality-of-life instruments were not sensitive enough to detect differences between treatments; and (2) the study did not have adequate power to detect significant differences even if they existed.

478 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 77 MARCH 1, 1996

The instruments used to assess health-related quality of life have all been previously used in other clinical trials and are accepted measures. However, these instruments are generic, not disease-specific measures; there- fore, they may not assess all relevant domains of health- related quality of life as it applies to hyperlipidemia. This study period was also brief, spanning 12 weeks, which could limit our understanding about long-term effects of these therapies on quality of life. With respect to the domains of sleep and energy levels, which are clearly important in hyperlipidemia, no differences were seen, and as best as we can determine with these generic instruments, there were no overall differences between the 2 HMG-CoA reductase inhibitors.

With regard to the power of the study to detect significant differences if they existed, one can take the number of patients actually measured in this study and the SDS observed for each dimension of quality of life and determine the minimal detectable difference to observe statistical significance with 95% power at both levels of significance (i.e., p co.05 and ~0.0083). For the Not- tingham Health Profile, the minimal detectable difference for the weighted dimensions was ~6 on a scale of 0 to 100, even at the 0.05 level of significance. For the Medical Outcomes Study sexual function questionnaire, the corresponding value was 7.6 on a scale of 0 to 100.

In the current study, lovastatin and pravastatin were equally effective in improving the lipoprotein profile of patients. There were no differences observed in the overall incidence of adverse events. There also were no dif- _ ferences in health-related quality-of-life measures and there was little change from baseline in any of the measures used. The hypothesis that the lipophilicity of HMG-CoA reductase inhibitors may correlate with pen- etration of the central nervous system and perhaps result in adverse events is not substantiated by our findings, or by many previous studies. *-lo Assessment of sleep, energy level, and emotional reactions are probably the most relevant health-related quality-of-life domains with respect to this hypothesis, and no differences were observed in the present study between lovastatin and pravastatin. This study supports the concept that HMG- CoA reductase inhibitors are effective and well tolerat- ed in the management of primary hypercholesterolemia and do not adversely affect health-related quality of life.

Acknowledgment: We wish to thank Karyl Fleck and Rosemaria Jackson for their dedicated and expert secre- tarial assistance.

APPENDIX The Qudiiy of life Muhiceniw group: Steven C. Bowman, MD, Tampa Bay Med- ical Research, Inc., Clearwater, n; L. Michael Breeden, MD, McGuire Clinic, Richmond, VA; Elliott W. Chideckel, MD, West Virginia University, Morgantown, WV; Steven G. Chrysant, MD, PhD, Oklahoma Cardiovascular & Hypertension Center, Oklahoma City, OK: Carlos Hugo Espinel, MD, FACP, FACN, The Blood Pressure Center, Arlington, VA; Jennifer Hamilton, MD, University of Maryland Hospital, Veterans Administration Hospital, Baltimore, MD, Robert L. Haynie, MD, PhD, Mount Sinai Medical Center, Cleveland, OH, Moti L. Kashyap, MD, Veter- ans Administration Medical Center -Long Beach, Long Beach, CA, Neil M. Kass- man, MD, Statesville Medical Gmup, Statesville, NC; James Kern, MD, Williamette Valley Research, Portland, OR; James W. Kintigh, MD, Denbigh Family Practice, Newport News, VA; Jon H. Levine, MD, Clinical Research Associates, Nashville, TN; James John Maciejko, PhD, FACC, Nicholas Z. Kerin, MD, Sinai Hospital Lioid Clinic. Detroit. MI: Thomas C. Marburv. MD. Orlando Cliiical Research C&r, O&do, FL;‘De& C. McCluskey, Jb, Cl&al Resources, Mogadore, OH; William S. Mullican, MD, MediSphere, Inc., Evansville, IN; Kathleen M. Mur- phy, MD, research for Health, Inc., Houston, m, Paul M. Murray, MD, Cardiac Disease Specialists of Atlanta, GA; David T. Nash, MD, Syracuse, NY; Albert Oberman, MD, MPH, University of Alabama at Birmingham; Carl Oshrain, MD, Rochester. NY: David B. Pitts. MD. Cardiovascular Risk Prevention Clinic. Chat- tanooga, ‘%r; J&n M. Stafford, MD, it. Joseph, MI; Phillip D. Toth, MD, FACP, Midwest Institute for Clinical Research, Indianapolis, IN, Brad J. Wallum, MD, Eastside Endocrinology and Diabetes, Bellevue, WA; Marc S. Weinberg, MD, FACP, Hypertension and Nephrology, Inc., The REN Center, Providence, RI; William J. Wickemeyer, MD, Iowa Heart Center Research, Des Moines, IA.

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