Introduction. agents that have, until recently, been the only ones readily available in NZ. A Medline search from January

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1 A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP) Peter W. Beggs, 1 David W.J. Clark, 2 Sheila M. Williams, 3 & David M. Coulter 4 1 Dunedin School of Medicine; 2 Department of Pharmacology, School of Medical Sciences; 3 Department of Preventive and Social Medicine, School of Medicine and 4 IMMP, National Toxicology Group, School of Medicine, University of Otago, Dunedin, New Zealand Aims Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use. Methods A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme s (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy. Results 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs. Conclusions In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin. Keywords: treatment outcomes, normal clinical practice, postmarketing surveillance, gemfibrozil, bezafibrate, simvastatin, antihyperlipidaemic agents Introduction In an investigation of lipid lowering agents, Andrade and colleagues [1] observed that findings from clinical trials may not be applicable in non-trial settings. Because of current interest in treating dyslipidaemia as a means of reducing the risk of ischaemic heart disease and the lack of data outside of controlled clinical trials, we have used data from the New Zealand (NZ) Intensive Medicines Monitoring Programme (IMMP) to compare, in normal clinical practice, the use of the three newer lipid lowering Correspondence: Dr D. M. Coulter, Director IMMP, National Toxicology Group, Dunedin School of Medicine, University of Otago, Box 913, Dunedin, New Zealand. Received 8 June 1998, accepted 13 July agents that have, until recently, been the only ones readily available in NZ. A Medline search from January 1987 to May 1997 including the terms primary care, general practice, or clinical practice and lipid lowering for all three drugs individually failed to find any further relevant studies. The lipid lowering agents bezafibrate, gemfibrozil and simvastatin, were intensively monitored for adverse events in the NZ IMMP for 5 years ( January 1989 until February 1994). This is a scheme of early post marketing surveillance designed to detect new adverse reactions to medicines [2]. In brief, a near complete record is obtained of all NZ patients. Prescription records are received from dispensing pharmacists in community and hospital pharmacies over the whole country. Details include the names and addresses of 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47,

2 P. W. Beggs et al. patients who have been prescribed the drugs currently rate, a follow-up letter and second questionnaire was sent being monitored, together with prescription details and the to doctors from whom no reply was received after prescribers names and addresses. In regions comprising 25% approximately 2 months. of the country this is done by using duplicate prescriptions Collation and analysis of data were performed using for IMMP drugs with pharmacists sending the duplicates to SAS. Chi squared tests were used to compare the the adverse reactions centre in Dunedin: the remainder categorical variables. Body mass index (BMI) was calcu- send computer generated lists. Adverse events are reported lated from weight and height. by a combination of prescription follow-up questionnaires The lipid values were logarithmically transformed and spontaneous reporting. before analysis. Analysis of variance was used to derive If further information is required on use or adverse the mean of the ratio of the before and after measures event profiles or if a cluster of events signals a possible for each treatment. These are presented with their 95% reaction to a drug, additional questionnaires may be sent confidence intervals (CI). Regression analysis adjusting to prescribers and, in some cases, directly to patients. The for the initial value for each measure was used to examine scheme has resulted in the early detection or confirmation the ratio of the changes in bezafibrate and simvastatin of several adverse drug reactions [3 5] and has also compared with gemfibrozil. The ratios of the differences demonstrated that some drug-event associations are and their 95% CI are shown. unlikely to be adverse reactions [6]. Nationwide ethical approval from the NZ Regional The data for this study were taken from a trial run of Health Authority Human Ethics Committees was granted a study to assess a signal of an adverse reaction (increased for this study. rate of angina with bezafibrate, unpublished). The results of the pilot indicated confounding by indication as the reason for the excess of angina with bezafibrate. Results Of the 597 questionnaires sent 476 (79.7%) were Methods returned. Three hundred and ninety-four (66% of the total sent) contained information that was sufficiently Patients prescribed bezafibrate, gemfibrozil or simvastatin complete to allow analysis: bezafibrate 130; gemfibrozil were randomly selected from the complete IMMP cohorts 139; simvastatin 125). numbering , 4541 and 7588 respectively and the prescribers were identified to enable a survey using written questionnaires. Where possible, the prescribers Demographic features selected were the general practitioners responsible for the continuing care of the patients. As expected, more males were prescribed lipid lowering Six hundred patients (200 on each lipid lowering drug) drugs and this was consistent for the three drug groups were selected for this investigation. Clerical error reduced (bezafibrate 54%; gemfibrozil 58%; simvastatin 57% the simvastatin cohort to 197 with the target 200 males). There were no significant differences in the mean questionnaires being sent for bezafibrate and gemfibrozil. ages of patients in each group (bezafibrate=57.5 years; Patients prescribed bezafibrate were randomly selected gemfibrozil=59.6 years; simvastatin=56.3 years). The from each region of NZ in proportion to total prescribing regional distribution of the valid responses was similar for nationally and then patients for gemfibrozil and simvastatin all three drugs. The mean duration of therapy with were matched with these for region and gender. Patients bezafibrate was longer than that with gemfibrozil and were matched for region to allow for differences in simvastatin; bezafibrate 1.5 years (s.d.=1.44); gemfibrozil prescribing patterns, ethnicity and monitoring methods. 1.0 year (s.d.=1.08) and simvastatin 1.0 year (s.d.=1.03). There were insufficient with known age to use this in matching. A questionnaire was posted to each patient s doctor. It Reasons for using lipid lowering drugs was designed to elicit information on and allow compari- Indications for use are shown in Table 1. An open ended sons of: indication; lipid values; dose; duration of therapy; question requested a specific diagnosis. There were 325 any concomitant drug therapy used; risk factors for (82.5%) responses to this question. Many doctors were ischaemic heart disease. This included a request for uncertain of the specific diagnosis but did indicate the patient data on age, gender, weight and height, smoking, most obvious reason for drug use. Data from a separate diabetes mellitus, hypertension and hypothyroidism. question about pre-existing angina showed no statistically Outcome measurements were changes in serum lipid significant difference in prevalence among groups values and withdrawals from therapy. The reasons for (bezafibrate 54, 43%; gemfibrozil 52, 45%; simvastatin withdrawal were requested. To improve the response 63, 53%) Blackwell Science Ltd Br J Clin Pharmacol, 47,

3 Lipid lowering agents in normal practice Table 1 Specific diagnosis or reason for use of bezafibrate, gemfibrozil or simvastatin. Figures are numbers of responses to this question (%). Bezafibrate Gemfibrozil Simvastatin Total Stated indication (n=103) (n=116) (n=106) (n=325) Familial 18 (17.5) 19 (16.4) 33 (31.1) 70 (21.6) hypercholesterolaemia Hypercholesterolaemia 11 (10.7) 17 (14.7) 20 (18.9) 48 (14.8) Ischaemic heart disease 8 (7.8) 8 (6.9) 13 (12.3) 29 (9.0) Combined hyperlipidaemia 8 (7.8) 14 (12.1) 3 (2.8) 25 (7.7) Hyperlipoproteinaemia 6 (5.8) 5 (4.3) 7 (6.6) 18 (5.6) Diabetes 7 (6.8) 4 (2.6) 4 (2.8) 15 (4.6) Type II hyperlipidaemia 6 (5.8) 3 (2.6) 3 (2.8) 12 (3.7) Low HDL 4 (3.9) 5 (4.3) 0 9 (2.8) Other 4 (3.9) 6 (5.2) 3 (2.8) 13 (4.0) Uncertain 44 (42.7) 53 (45.7) 35 (33.0) 132 (40.7) Risk factors for ischaemic heart disease Statistically significant differences were observed in two risk factors (Table 2). Bezafibrate was prescribed for 30 (25.2%) patients with diabetes mellitus compared with gemfibrozil 8 (7.2%) and simvastatin 8 (7.4%) with answers to this question totalling 119, 111 and 108 respectively. There were also more hypertensive patients in the bezafibrate group (72, 59.5%) compared with gemfibrozil (53, 46.9%) and simvastatin (45, 40.5%, totals were 121, 113 and 111 respectively). There were no statistically significant differences for cigarette smoking, hypothyroidism or mean BMI for males or females. patients), aspirin (34), and nitrates (32). The distribution of concomitant medications between the three lipid lowering agents was similar and there were no differences that might confound the interpretation of changes in lipid levels. Effects of lipid lowering drugs on lipid levels The ratios of the changes and their 95% CI of gemfibrozil to simvastatin and bezafibrate are presented in Table 3. Regression analysis adjusting for the initial values showed that decreases in total cholesterol for patients taking gemfibrozil were significantly less than for those using either bezafibrate or simvastatin. Although the ratio of Concomitant medications change was greatest for bezafibrate, the relative ratio of the change was less because of differences in the initial There were 62 different drugs recorded as used in value. The reduction in low density lipoproteins (LDL) combination with the lipid lowering agents. The most for those on simvastatin was significantly greater than common types were b-adrenoceptor blockers (54 that for gemfibrozil. Bezafibrate increased high-density lipoprotein (HDL) Table 2 Differences in risk factors for ischaemic heart disease. levels significantly more than either gemfibrozil or simvastatin. The reduction in serum triglycerides was Patients Number 95% confidence significantly less for simvastatin than for either of the (%) Odds ratio interval other two agents. Diabetes mellitus Bezafibrate (25.2) Reasons for stopping treatment with lipid lowering drugs Gemfibrozil * There were significant differences between the three (7.2) drugs for cessation of therapy (Table 4). The greatest Simvastatin * difference was for inadequate response where 22 (15.8%) (7.4) patients stopped gemfibrozil compared with seven (5.4%) Hypertension for bezafibrate (OR=4.02; 95% CI= ) and Bezafibrate two (1.6%) for simvastatin (OR=11.56; CI= (59.5) ). Gemfibrozil * Gemfibrozil treatment was also stopped more fre- (46.9) quently (n=17, 12.2%) due to a possible adverse reaction Simvastatin * (40.5) compared with bezafibrate (7, 5.4%) and simvastatin (6, 4.8%). Approximately half of the adverse reactions leading *Bezafibrate vs gemfibrozil or simvastatin. to withdrawal of gemfibrozil were gastrointestinal Blackwell Science Ltd Br J Clin Pharmacol, 47,

4 P. W. Beggs et al. Table 3 Comparison of changes in serum lipid values: gemfibrozil vs bezafibrate and simvastatin. Mean ratio Relative ratios* after/before 95% Confidence of mean changes 95% Confidence Number treatment interval with treatment interval Total cholesterol Gemfibrozil Bezafibrate Simvastatin LDL Gemfibrozil Bezafibrate Simvastatin HDL Gemfibrozil Bezafibrate Simvastatin Triglycerides Gemfibrozil Bezafibrate Simvastatin *Ratio of differences between bezafibrate and gemfibrozil, and simvastatin and gemfibrozil after adjusting for initial value of variable of interest. Table 4 Main reasons for cessation of therapy with lipid lowering drugs. Gemfibrozil Bezafibrate* Simvastatin* Odds Odds n % n % ratio (95% CI) n % ratio (95% CI) Total patients Total off treatment ( ) ( ) Inadequate ( ) ( ) response Adverse reaction ( ) ( ) *Compared with gemfibrozil. CI=confidence intervals. Overall, the total cessation rate for gemfibrozil was disease, diagnosis and severity of lipid disorder and some significantly greater than bezafibrate (OR=2.65; 95% outcomes of therapy. Therefore, although the study was CI= ) and simvastatin (OR=3.50; CI= not specifically designed to compare efficacy of treatment, ). the methodology is appropriate. The results are likely to reflect outcomes in most other Discussion and conclusions developed countries and are consistent where comparisons are possible, with a study in non-trial settings in the USA This retrospective study on randomised and matched by Andrade et al. [1]. Because of its short duration and low samples of the IMMP cohorts for bezafibrate, gemfibrozil numbers, our NZ study cannot address the clinical outcomes and simvastatin should provide a reliable indication of the of lipid related mortality and rates of myocardial infarction short term outcome of treatment in terms of efficacy in and this was not one of the objectives. However, analyses normalising abnormal lipid values and their tolerability in of randomised trials of cholesterol lowering have consistently normal clinical practice in NZ. It was designed to shown that for every 10% relative reduction in blood evaluate a signal of an adverse reaction with bezafibrate cholesterol there is an approximate 15 20% relative and the design included comparison of indications for reduction in coronary heart disease mortality and morbidity treatment, the presence of risk factors for ischaemic heart after about 5 years of treatment [7, 8] and a study on the Blackwell Science Ltd Br J Clin Pharmacol, 47,

5 Lipid lowering agents in normal practice effects of the drugs on lipid values is therefore a useful dence as to the comparative effects of bezafibrate and surrogate for clinical outcome. gemfibrozil on glucose tolerance and insulin resistance, but For reasons of differences in patient selection and the it seems to weigh in favour of bezafibrate [9, 10] and the many confounding variables in community practice that preferred use of bezafibrate in the presence of diabetes are often controlled for in clinical trials, results may differ mellitus by NZ doctors reflects this opinion. The higher between the two. This study and that of Andrade in the rate of hypertension in patients prescribed bezafibrate may United States is therefore helpful in understanding what result from the greater prevalence of diabetes. The significant is happening in non-trial settings, which is the important excess of new or worsening angina reported during end issue. Andrade s study examined discontinuation rates monitoring which stimulated this study, was probably due of antihyperlipidaemic drugs in primary care compared to the confounding influence of these two risk factors for with those of randomised clinical trials. The drugs ischaemic heart disease. included bile acid sequestrants, niacin, gemfibrozil and In this comparison of the three lipid lowering agents, lovastatin. For all except lovastatin the risk of discontinu- the recognisable biases would favour gemfibrozil. The ation was substantially higher in primary care than in the presence of more diabetes mellitus in the bezafibrate trials. The comparable rate of drug discontinuation of group would tend to produce a more unfavourable 28% for gemfibrozil was similar to our IMMP study with outcome. The mean duration of therapy for patients on a rate of 32% and the rates for withdrawals because of bezafibrate was also 50% greater than gemfibrozil and inefficacy were 14.8% and 15.8%, and for adverse simvastatin. In addition, the indications for use of reactions were 9.5% and 12.2%, respectively. Lovastatin, simvastatin in NZ were restricted to patients with more the representative of the HMG CoA reductase inhibitors severe lipid related disease and those who had not in the American study, had similar gross rates of responded satisfactorily to the fibrates. These biases make discontinuation for lack of efficacy to that of simvastatin the observed differences of reduced efficacy and higher in the IMMP (2.4% and 1.6% respectively) and also for rate of withdrawals and adverse reactions with gemfibrozil adverse effects (6.5% and 4.8% respectively). even more significant. In the IMMP study it was expected that the two The fibrates still have a significant place in the fibrates would perform similarly. However, while treatment of dysplipidaemia in modern clinical practice bezafibrate and gemfibrozil reduced LDL and triglycerides and this is reflected in drug usage figures. Although the to a similar extent, bezafibrate was significantly better use of the HMG CoA reductase inhibitors has increased than gemfibrozil at reducing total cholesterol and increas- markedly, the use of the fibrates has not declined in ing HDL. Patients on gemfibrozil had more withdrawals England. Figures from the Prescription Pricing Authority because of inefficacy and this was consistent with the (PPA) of national trends in the usage of fibrates show a differences observed in changes of lipid values. Results steady increase to December 1996 with a levelling off are variable in trials comparing their efficacy [9, 10, 11]. until the latest available figures at September 1997 For gemfibrozil it is often not possible to predict those (Ferguson JJ, personal communication, 1998). As referred patients who will respond well and the response has been to above, they are a logical choice in treating the high noted to be variable [11]. One study, a randomised trial serum triglyceride and low HDL in diabetes mellitus [13]. of 59 non-diabetic patients with type II hyperlipoprotei- High levels of plasma fibrinogen are being increasingly naemia, showed that bezafibrate had significantly fewer recognised as an important cardiovascular risk factor and adverse reactions compared with gemfibrozil as well as fibrates have been reported to be the most effective drugs better efficacy at lowering serum total cholesterol, LDL in lowering fibrinogen [14]. Should active lowering of and blood glucose [12]. The IMMP study showed that elevated fibrinogen become established in clinical practice, withdrawal of therapy overall was a significantly greater the use of fibrates may increase in future. Because problem with gemfibrozil compared with bezafibrate and bezafibrate is currently regarded as the most effective simvastatin and this included significantly more withdrawals fibrate in lowering fibrinogen, it is likely that this drug because of adverse reactions. As expected, will become the drug of choice for this indication. simvastatin compared favourably with the fibrates in However, other fibrates (such as gemfibrozil) are also lowering total cholesterol and LDL. It also had the lowest effective and may also be used in future for this purpose. withdrawal rate because of adverse reactions. Statin-fibrate combined treatment is also an option in The significantly greater prevalence of diabetes mellitus difficult to manage dyslipidaemias. Earlier this was amongst patients prescribed bezafibrate has not been discouraged because of the perceived increased risk of previously demonstrated in practice. The use of fibrates in myositis or rhabdomyolysis [15], However, a review of diabetic patients reflects a logical choice as they frequently 21 clinical trials of statin-fibrate combined treatment have high serum triglyceride and low HDL levels as well as involving a total of 486 patients concluded that the elevated total cholesterol levels. There is conflicting evi- combinations were proven to be effective and safe [16] Blackwell Science Ltd Br J Clin Pharmacol, 47,

6 P. W. Beggs et al. Type II hyperlipidaemia was the most common indi- Monitoring Programme. Pharmacoepidemiology and Drug Safety cation. Another reason for current use of fibrates is 1998; 7: control of pharmaceutical expenditure. The fibrates are 3 Coulter DM, Edwards IR. Mianserin and agranulocytosis in New Zealand. Lancet 1990; 336: cheaper and in NZ the use of statins is restricted because 4 Coulter DM, Edwards IR. Cough associated with captopril of this. and enalapril. Br Med J 1987; 294: The data from the PPA show that the fibrate most 5 Coulter DM, Edwards IR, Savage RL. Survey of neurological commonly used in England is bezafibrate with gemfibrozil problems with amiodarone in the New Zealand Intensive maintaining a small, but fairly constant share which is Medicines Monitoring Programme. NZ Med J 1990; 103: however exceeded by ciprofibrate and fenofibrate. These latter two are not available in NZ where IMMP data 6 Coulter DM. Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a showed that gemfibrozil usage was approximately half method of postmarketing surveillance. Br Med J 1988; 296: that of bezafibrate. Bezafibrate is not approved for marketing in Australia where gemfibrozil is the most 7 Scandinavian Simvastatin Survival Study Group. Randomised commonly used fibrate (Boyd I, personal communication, trial of cholesterol lowering in 4444 patients with coronary 1998). Neither is bezafibrate used in the United States, heart disease: the Scandinavian Simvastatin Survival (4S) but gemfibrozil is available and widely used (Chen M, Study. Lancet 1994; 344: personal communication, 1998). In the Helsinki Heart 8 Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with Study, a randomised double-blind trial, gemfibrozil hypercholesterolaemia. N Engl J Med 1995; 333: mg twice daily reduced the incidence of coronary 9 Goa KL, Barradell LB, Plosker GL. Bezafibrate: An update of heart disease after 5 years by 34% compared with placebo- its pharmacology and use in the management of treated patients [17]. There is less evidence of cardiovas- dyslipidaemia. Drugs 1996; 52: cular benefit to support the use of bezafibrate, but in a 10 Spencer CM, Barradell LB. Gemfibrozil: A reappraisal of its study of 92 young male survivors of myocardial infarction, pharmacological properties and place in the management of the Bezafibrate Coronary Atherosclerosis Intervention dyslipidaemia. Drugs 1996; 51: Todd PA, Ward A. Gemfibrozil: A review of its Trial, bezafibrate reduced the rate of progression of pharmacodynamic and pharmacokinetic properties and atherosclerotic lesions and the rate of coronary events therapeutic use in dyslipidaemia. Drugs 1998; 11: [18]. Another much larger study, the Bezafibrate 12 Kremer P, Marowsky C, Jones C, Acacia E. Therapeutic Infarction Prevention trial in 300 men is not yet effects of bezafibrate and gemfibrozil in hyperlipoproteinaemia reported [19]. Type IIa and IIb. Cur Med Res Opin 1989; 11: As described, the indications are that the fibrates will 13 Oki JC. Dyslipidaemias in patients with diabetes mellitus: continue to be used extensively for specific indications in classification and risks and benefits of therapy. Pharmacotherapy the foreseeable future and it is clear that bezafibrate and 1995; 15: Fowkes FGR. Fibrinogen and cardiovascular disease in clinical gemfibrozil are still widely used in spite of a marked practice. Eur Heart J 1995; 16 Suppl A: increase in the use of statins. This IMMP study in a non- 15 Pierce R, Wysowsky DK, Gross TP. Myopathy and trial setting, which showed gemfibrozil was less effective rhabdomyolysis associated with lovastatin-gemfibrozil than bezafibrate in raising serum levels of HDL- combination therapy. J Am Med Ass 1990; 264: cholesterol and lowering total cholesterol and resulted in 16 Shviro I, Leitersdorf E. The patient at risk: who should we be more withdrawals for adverse reactions, raises the question treating? Br J Clin Pract Symposium Supplement 1996; 77A: of the suitability of gemfibrozil as a first choice fibrate Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men We thank the doctors who assisted with follow up of their patients with dyslipidaemia. Safety of treatment, changes in risk and our Data Manager Mrs Janelle Ashton. The study was financed factors, and incidence of coronary heart disease. N Engl J Med from research funds of the Department of Pharmacology. Mrs 1987; 317: Williams is supported by the Health Research Council of 18 Ericsson C-G, Hamsten A, Nilsson J, Grip L, Svane B, de New Zealand. Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male References postinfarction patients. Lancet 1996; 346: Goldbourt U, Behar S, Reicher-Reiss H, et al. Rationale and 1 Andrade SE, Walker AM, Gottlieb LK, et al. Discontinuation design of a secondary prevention trial of increasing serum of antihyperlipidemic drugs: do rates reported in clinical trials high-density lipoprotein cholesterol and reducing triglycerides reflect rates in primary care settings? N Engl J Med 1995; 332: in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial). Am J Cardiol 2 Coulter DM. The New Zealand Intensive Medicines 1993; 71: Blackwell Science Ltd Br J Clin Pharmacol, 47,