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Differences Between Statins on Clinical Endpoints: a Population- Based Cohort Study

Posted on: Saturday, 15 October 2005, 03:00 CDT

By Dieleman, Jeanne P; van Wyk, Jacobus T; van Wijk, Marc A M; Et al

ABSTRACT

Objective: Many studies have shown differences between statins based on surrogate endpoints, but few have studied differences in reaching clinical endpoints.

This study compares the risk of cardiovascular and cerebrovascular events between atorvastatin users and other statin users in daily general practice.

Research design and methods: A cohort study was performed in the Integrated Primary Care Information project database, a longitudinal general practice research database with electronic patient records of more than 500000 individuals in the Netherlands. All new statin users in the period 1st September 1999 to 31st December 2002 were included. Multivariate Cox-regression analysis was used to compare the occurrence of the primary endpoint between atorvastatin users and other statin users.

Main outcome measures: The primary endpoint was the composite outcome of fatal or non-fatal myocardial infarction, admission for unstable angina pectoris, fatal or non-fatal cerebrovascular accidents, or transient ischaemic events.

Results: 3499 new statin users were identified, including 797 patients with a history of cardiovascular disease. 1341 persons started with simvastatin (38.3%), 1154 with atorvastatin (33.0%), 811 with pravastatin (23.2%) and 193 with other statins (5.5%). The median follow-up was 1.9 years. Two hundred and thirty three patients (6.7%) experienced a primary endpoint. Atorvastatin users had a significantly lower risk of cardiovascular and cerebrovascular events than users of other statins (relative risk [RR]: 0.70, 95% confidence interval [CI]: 0.55-0.96). The relative risks of atorvastatin users compared to simvastatin and pravastatin users individually were 0.70 (95% CI: 0.48-1.02) and 0.78 (95% CI: 0.52- 1.16), respectively. The protective effect of atorvastatin was more pronounced in persons without a history of cardiovascular or cerebrovascular events.

Conclusion: Atorvastatin showed a more favourable effect on fatal and non-fatal cardiovascular and cerebrovascular events in the general population than other statins.

Introduction

Cardiovascular disease (CVD) due to atherosclerosis is a leading cause of death in western countries. Treatment with 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors (statins) has been widely accepted and implemented in most guidelines for patients with CVD and for primary prevention in patients at increased risk of CVD1,2. Statins exert their action by lowering the concentration of low-density lipoprotein cholesterol (LDL-C), an important modifiable risk factor for CVD3-8. In addition statins have a beneficial effect on the inflammatory process believed to be involved in atherosclerotic plaque formation5,9-11. Large scale randomized clinical trials have shown clinical benefit of statins in the treatment and prevention of CVD12-19. Recently an observational study in the Untied Kingdom showed that the beneficial effect of statins can be extended to all patients with coronary heart disease20.

Although all available statins have demonstrated efficacy, differences between individual statins exist. Rosuvastatin has been reported as being more efficacious than other statins in improving lipid profiles21. The antiinflammatory effects of atorvastatin have been reported as more potent than that of other statins22'24. In addition, the anti-oxidant properties of atorvastatin have been studied, and benefits attributed to the existence of active metabolites10. Whereas achieving lipid-lowering goals by different statins has been studied well23"27, the ability of different statins to actually reduce the CVD risk in daily practice has not been addressed to date. In the present study we compared atorvastatin with other statins on clinical endpoints in a primary care setting.

Patients and methods

Setting

The study was conducted in the Integrated Primary Care Information (IPCI) project database, a longitudinal general practice research database in the Netherlands. All residents in the Netherlands are registered with a general practitioner (GP) independent of their health status. The GP deals with 90% of the health problems and acts as the gatekeeper for access to specialized care28. The IPCI project was started by the Department of Medical Informatics of the Erasmus MC, University Medical Centre Rotterdam in the Netherlands. The database contains longitudinal data from computerbased patient records of more than 150 GPs throughout the Netherlands. Presently the database comprises data on more than 500000 subjects (3% of the Dutch population), with an age and gender distribution similar to the Dutch population.

Available data include anonymous eligibility and demographic information (age, sex, patient identification and GP registration information), symptoms, diagnoses, specialist findings, hospital admissions, prescriptions, indications for therapy, physical findings and laboratory findings. The International Classification of Primary Care (ICPC) is the coding system used to register patient complaints and diagnoses, although diagnoses and complaints can also be entered as free text. Prescription data include product name, quantity dispensed, dosage regimens, strength and indication. The National Database of drugs, maintained by the Royal Dutch Association for the Advancement of Pharmacy (KNMP), enables the coding of prescriptions according to the Anatomical Therapeutic Chemical (ATC) classification scheme recommended by the World Health Organization (WHO). The IPCI database system complies with European Union guidelines on the use of medical data for medical research and has been proven valid for pharmaco-epidemiological research29.

Study population

The source population for this study comprised all subjects of 18 years and older with at least one year of valid database history. A valid database history means that the patient is registered with the GP and that the GP participates in the IPCI project. The study population consisted of all subjects from the source population who started their first statin treatment during the study period (i.e. new users only). The study period for patient inclusion started on 1st September 1999, when the cholesterol guideline from the Dutch GP- society (NHG) was issued, and ended on 31st December 2002. Follow- up lasted from the first statin prescription until the occurrence of a study endpoint, 31st December 2003 or last IPCI data deliverance by the GP; whichever came first.

Statin treatment

Statin use was identified from the prescription files, which contain information on GP prescriptions and repeat prescriptions from specialists. It was classified as secondary prevention if a history of cardiovascular or cerebrovascular disease was present at baseline and as primary prevention if there was no history of cardiovascular or cerebrovascular disease. The analysis included atorvastatin, simvastatin, fluvastatin and pravastatin. Cerivastatin was included, but was withdrawn from the market during the study period. We were unable to include rosuvastatin, since there were insufficient users at the time of analysis.

Duration of treatment was calculated for each prescription as the number of prescribed units divided by the prescribed daily units. We also calculated the starting dosage of statin by multiplying the prescribed daily units by the prescribed unit strength of the first prescription. The starting dose was expressed in defined daily dosage (DDD) equivalents according to the WHO criteria (ATC index with DDDs 2003, WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway) in order to allow for comparisons between statins. Since equivalence as assumed by the WHO does not necessarily indicate equal potency, we additionally categorized the starting dose according to a recently published potency conversion table30 adapted from Maron et al. (2000)31, and Illingworth and Tobert (1994)32, based on the cholesterol lowering properties of different statins given at a certain dose. For example, this table considers 10mg atorvastatin, 20 mg simvastatin, 40 mg pravastatin, 80 mg fluvastatin and 0.4mg cerivastatin as equipotent at a high potency (27% reduction in total cholesterol).

In order to take account of the potential influence of differences in the course of treatment, we assessed treatment discontinuation and switching behaviour. Discontinuation of statin treatment was defined as the absence of a new prescription for at least 6 months after the end of the last prescription. Switching was defined as the prescription of another type of statin within 6 months of the end of the last prescription. We estimated adherence to statin treatment per individual statin as the number of days in a year that statins were prescribed for, divided by the number of days of follow-up in that year, censored for treatment discontinuation and switching.

Study endpoints

As primary outcome of our study we considered a composite of cardiovascular and cerebrovascular outcomes comprising fatal and non- fatal myocardial infarction, acute hospital admission for angina pectoris, fatal and non-fatal cerebrovascular accidents and transient ischaemic attack. As a secondary outcome measure we looked at cardiovascular events only, thereby ignoring cerebrovascular accidents. All diagnoses occurring in the database, either as free text or as I\CPC code, were considered and reviewed in the patient records by two medically qualified investigators who were blinded for relevant exposure.

In addition, we described the cholesterol lowering effect of statins as the maximal reduction in cholesterol/ high-density lipoprotein (HDL) ratio within 6 months after starting statin treatment for patients with an elevated ratio at baseline (i.e. cholesterol/HDL > 5).

Co-variates

Apart from statin use we considered other potential risk factors for cardiovascular and cerebrovascular events, such as age, gender, health care insurance, history of cardiovascular and cerebrovascular disease, presence of diabetes mellitus, hypertension or antihypertensive treatment, cholesterol/HDL ratio, smoking and Framingham risk score33. Where missing in subjects treated for primary prevention, we imputed average population values of the cholesterol/HDL ratio for calculation of the Framingham risk score34.

Analysis

Baseline differences between statin users were tested by using a Pearson's Chi-square for categorical variables, f-test for continuous normally distributed variables and Mann-Whitney U for continuous skewed variables. The difference in risk of cardiovascular and cerebrovascular events between statins was analyzed by using univariate and multivariate Cox-regression analysis. Since the median follow-up time was 1.9 years, we censored the analysis at 2 years. In the analysis we compared atorvastatin, being the statin with the highest LDL-C reducing potency, to other statins individually and as one reference group. Multivariate or adjusted analysis included all co-variates that were associated with the primary endpoint at a p-value of 0.1 and all other known risk factors for the study outcome. Since total cholesterol and HDL measurements are rarely performed in daily practice, we used missing indicators for missing cholesterol/HDL ratios in the analyses. In the Cox-model, exposure to statin treatment was principally considered as intention-to-treat, thereby ignoring treatment discontinuations and switches. To evaluate the influence of treatment discontinuation and switching we also performed an as- treated-analysis in which follow-up was additionally censored upon discontinuation or switching. In an exploratory analysis we also compared the effect of statins between persons treated for primary prevention and persons treated for secondary prevention and performed a sensitivity analysis with cardiovascular events as the only study endpoint.

Statistical significance was accepted at a two-sided p-value of < 0.05. All statistical analyses were performed in SPSS version 10.0.

Results

Patient population

Between September 1999 and December 2002, 3499 persons started treatment with a statin, 1341 on simvastatin (38.3%), 1154 on atorvastatin (33.0%), 811 on pravastatin (23.2%) and 193 on other statins (5.5%). Patient characteristics are summarized in Table 1. In brief, 43% were female, the mean age was 60.6 (SD 11.6) years and 22.8% had a prior history of cardiovascular or cerebrovascular events. Cholesterol/ HDL ratios were available for 569 (16.3%) patients. The median ratio was 5.0 (inter quartile range [IQR]: 3.9- 6.3) and accordingly 280 (49.2%) patients had a ratio above 5.0. With respect to relevant patient characteristics the following differences were found between users of various statins. There were more females among fluvastatin users and more males among cerivastatin users than among atorvastatin users. Pravastatin users were slightly older, more often had a history of cardiovascular or cerebrovascular disease and more often had cholesterol/HDL levels above 5. There were more smokers among simvastatin users. Fluvastatin and cerivastatin were given at relatively lower dosages. Overall, the potency of the prescribed atorvastatin regimens was higher than that of other statins (Table 1).

Patients contributed a total of 6862 years of followup with a median duration of 1.9 years (IQR: 1.2-2.7).

Table 1. Baseline characteristics of patients starting statin treatment according to type of statin

Statin treatment

The total number of treatment days on statins during the first year of follow-up accumulated to 1469 years with a median of 160 days per patient (IQR: 90-215). Forty-six per cent of patients did not persist with the initial treatment during the study period, mainly due to discontinuation (82.5%). The rate of non-persistence with atorvastatin was lower than with fluvastatin (p = 0.001) and cerivastatin (p < 0.001) but similar to simvastatin and pravastatin. It should however be noted that cerivastatin was withdrawn from the market during the study period.

Overall adherence with statin use was low but was similar for all statins. The median adherence was 55.7% (IQR: 35.3-72.9), which means that patients had statins available for 55.7% of the follow- up time based on prescription refills issued until treatment discontinuation, switch or the end of follow-up. The median daily dosage used at treatment initiation was 10mg for atorvastatin, 20 mg for simvastatin and 40 mg for pravastatin, corresponding to more than one DDD of simvastatin and pravastatin (Table 1).

Study endpoints

During follow-up, 233 patients experienced a cardiovascular or cerebrovascular event, 102 (43.8%) following a history of cardiovascular or cerebrovascular disease. Events comprised non- fatal myocardial infarction (n = 75), fatal myocardial infarction (n = 20), hospital admission for instable angina pectoris (n = 56), non- fatal cerebrovascular accident (n = 35), fatal cerebrovascular accident (n = 3) and transient ischaemic attack (n = 44). Atorvastatin users had the lowest one-year risk of cardiovascular and cerebrovascular events (hazard rate 3.10 per 100 persons, 95% confidence interval [CI]: 2.08-4.12) and fluvastatin users had the highest risk (Figure 1). The two-year risks were 5.24 (95% CI: 3.82- 6.65) for atorvastatin, 6.69 (95% CI: 5.22-8.16) for simvastatin, 7.59 (95% CI: 4.26-10.92) for pravastatin, 10.35 (95% CI: 4.25- 16.45) for fluvastatin and 10.54 (95% CI: 3.54-17.54) for cerivastatin.

Risk factors for cardiovascular and cerebrovascular events in our study population included age, gender, history of cardiovascular disease and cholesterol/ HDL ratio above 5 (Table 2). Including these in the multivariate analysis together with other known risk factors (smoking, diabetes, hypertension and number of defined daily doses) resulted in an adjusted RR of 0.70 (95% CI: 0.55-0.96) for atorvastatin compared to other statins together (Table 3). Comparing atorvastatin to each individual statin separately showed a statistically non-significant lower risk of cardiovascular and cerebrovascular events than pravastatin (RR: 0.78, 95% CI: 0.52- 1.16) and simvastatin (RR: 0.70, 95% CI: 0.48-1.02) and a statistically significant lower risk than fluvastatin (RR: 0.38, 95% CI: 0.19-0.76) and cerivastatin (RR: 0.41, 95% CI: 0.20-0.88).

Figure 1. Kaplan Meier diagram of survival until fatal or non- fatal cardiovascular or cerebrovascular events within two years after starting statin treatment. A = atorvastatin; S = simvastatin; P = pravastatin; C = cerivastatin; F = fluvastatin

In the as-treated analysis, in which we additionally censored upon treatment switch or discontinuation, the protective effect of atorvastatin relative to other statins remained the same (RR: 0.70, 95% CI: 0.50-0.97). Stratification for primary or secondary prevention showed a more favourable effect of atorvastatin in the group treated for primary prevention (RR: 0.61, 95% CI: 0.39-0.97; n = 2702) than in those treated for secondary prevention (RR: 0.82, 95% CI: 0.51-1.30; n = 797) but the effect-modification was not statistically significant. Restricting the outcome to cardiovascular events lowered the RR estimate slightly (atorvastatin versus other statins adjusted RR: 0.65, 95% CI: 0.43-0.97).

Out of 280 patients with a baseline cholesterol/HDL ratio above 5, only 78 (28%) had a repeat measurement within 6 months. Cholesterol/HDL ratio reduction to below 5 was achieved in 54% of atorvastatin users, 55% of simvastatin users, 46% of pravastatin users, 40% of fluvastatin users and 33% of cerivastatin users (p = 0.904).

Discussion

The results of this observational population based cohort study suggest that atorvastatin is associated with a lower risk of cardiovascular and cerebrovascular events than other statins under uncontrolled everyday circumstances of a primary care setting. This finding was not influenced by known risk factors for cardiovascular and cerebrovascular disease such as age, gender, diabetes, smoking and a prior history of cardiovascular or cerebrovascular disease and remained in an as-treated analysis. The difference seemed most pronounced in subjects who were treated for primary prevention and was greatest compared to fluvastatin. A 30% statistically non- significant risk lower risk was observed with atorvastatin compared to simvastatin and pravastatin. Restriction of the outcome to cardiovascular events increased the observed differences.

In contrast to the controlled conditions and well defined populations in the clinical trial setting, which repeatedly demonstrated the beneficial effects of statins, our data were derived from a primary care setting under every day circumstances. Only one earlier study reported the effect of statins in such a setting20. They concluded that the beneficial effect observed in clinical trials is also observed in the primary care setting. Our data further suggest a difference between individual statins.

Table 2. Risk factors for cardiovascular and cerebrovascular events

The short-term preventive effect of atorvastatin appears to be substantial as shown in our study and is in keeping with other studies35-38. It is unknown whether the reported anti-oxidant and anti-inflammatory properties of atorvastatin10,22-24 can explain the observed early reduction in cardiovascu\lar events. It would support the dynamic model of atheroma plaque formation and ruptures, which suggests that antiinflammatory treatment can produce immediate vascular wall protection39,40. On the other hand, differences in cholesterol lowering properties between statins may account for the observed differences in clinical effect. Our data showed acceptable cholesterol/HDL ratio reductions in approximately half the population with elevated ratios at baseline. There were no significant differences between statins. However, we cannot draw any firm conclusions from this observation since cholesterol measurements were very infrequent and our study was not powered to examine small differences.

Table 3. Association between statin use and the risk of cardiovascular and cerebrovascular events

This observational cohort study using data from a primary care setting may have important limitations. Although there is no reason to believe from current data that statins are prescribed differentially between persons with different cardiovascular risk profiles, we cannot completely exclude the presence of confounding by indication. However, the distribution of baseline characteristics and known risk factors did not point at a consistently different patient type among the statins. Nevertheless, since atorvastatin is supposed to have unique cardiovascular benefits in addition to its LDL lowering potency it could theoretically be prescribed to persons with a higher risk. Hence confounding by indication, if any, would work in the opposite direction of our findings. Misclassification of exposure and of exposure duration is of no major concern in the intention-to-treat analysis. Misclassification of outcome may have occurred in terms of omitting events in the GP record. Such misclassification is unlikely to be differential between different statins, since review of potential cases was blinded for the exposure under study and the research question, and data in the IPCI database are collected for health care purposes independently of any research question studied in the database.

Finally, it may seem odd that some known risk factors for cardiovascular and cerebrovascular events, such as diabetes and hypertension, did not appear as a risk factor in our analysis. It should however be noted that we investigated a sample from the general population already treated with statins by the GP. The risk profile of such a population is not comparable with the risk profile of an untreated population. All our patients have risk factors for cardiovascular disease for which reason they received statin treatment.

Conclusions

In conclusion, this study suggested a favourable effect of atorvastatin compared to other statins in the prevention of fatal and non-fatal cardiovascular and cerebrovascular events in the general population. The risk reduction was observed across all statins, but only reached statistical significance if compared to all statins together and to fluvastatin and cerivastatin individually. The observed effect was most pronounced in primary prevention and mostly driven by the prevention of cardiovascular events.

Acknowledgement

Declaration of interest: This study was supported by a grant from Pfizer BV, Capelle a/d IJssel, The Netherlands. The sponsor had no influence on the data collection, analysis and reporting.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3099_4, Accepted for publication: 26 July 2005

Published Online: 24 August 2005

doi:10.1185/030079905X61866

Jeanne P. Dieleman(a), Jacobus T. van Wyk(a), Marc A. M. van Wijk(a), G van Herpen(a), Sabine M. J. M. Straus(abc), Hans Dunselman(a) and Miriam C. J. M. Sturkenboom(a,b)

a Department of Medical Informatics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands

b Department of Epidemiology and Biostatistics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands

c Medicines Evaluation Board, The Hague, The Netherlands

Address for correspondence: J. P. Dieleman, Department of Medical Informatics, Erasmus MC, University Medical Centre Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands, email: j.dieleman@erasmusmc.nl

Key words: Cardiovascular diseases - Cerebrovascular disorders - Cohort studies - Statins - Treatment outcome

Copyright Librapharm Sep 2005

Source: Current Medical Research and Opinion

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