Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomised trials

Study population and patients

The study population was composed of all residents of Tayside who were registered with a general practitioner between 1993 and 2001 inclusive (the “study window”), or from 1 January 1993 until their date of death if they died before the end of the study window.

The study patients were composed of those people in the study population who were discharged from Tayside hospitals during the study window with an incident myocardial infarction. We divided patients into two groups after their hospital episode: statin users and non-statin users.

Outcomes

The study outcomes were all cause mortality and cardiovascular events, defined as a new non-fatal myocardial infarction or cardiovascular mortality during the follow-up period. We defined all cause mortality from mortality data from the General Register Office and cardiovascular mortality as ICD-9 codes 390-459 and ICD-10 codes I00-I99.

Statistical analysis

We summarised data as means with standard deviations for continuous variables and as numbers (percentages) of subjects for categorical variables. We used χ² and t tests to determine significant differences. We also used Cochran-Armitage trend tests if there were more than two categorical variables. In the analyses of the outcomes we calculated adjusted hazard ratios with 95% confidence intervals in Cox regression models with a time dependent variable for statin use. The other covariates in the models were age, sex, Carstairs deprivation category,10 and the different types of cardiovascular co-medication during the follow-up period: β blockers, angiotensin converting enzyme (ACE) inhibitors, other antihypertensive drugs, antiplatelet drugs, nitrates, warfarin, calcium channel blockers, hormone replacement therapy, oral contraceptives, steroids, non-steroidal anti-inflammatory drugs, disease modifying antirheumatic drugs, previous disease histories of angina, stroke, heart failure, peripheral vascular disease, diabetes mellitus, obstructive airway disease, cancer, renal failure, and rheumatoid arthritis. We used SAS, version 8.0 (SAS Institute, Cary, North Carolina, USA) for all statistical analyses.

Observational studies versus randomised trials

In drug treatment research, observational studies can have advantages over randomised controlled trials as they often have large sample sizes and can be more representative of the general population.11 Although randomised controlled trials are the gold standard for judging efficacy, well designed observational studies can examine the findings from randomised controlled trials and assess the effectiveness of drug treatment in routine clinical practice. However, it is important to be aware of “confounding by indication” in making comparisons between patients prescribed and not prescribed specific treatments.12 This phenomenon arises because the risk of bad outcomes is intrinsically higher in patients selected for treatment and because most treatments reduce, but do not remove, risk. Thus, comparisons of treated patients with not treated patients may spuriously imply that drug treatments are actually harmful. Although our study sought to minimise this effect by studying only patients who had had a myocardial infarction, all of whom had a strong indication to receive a statin,13 only half were treated, which implies that some form of selection was involved. The untreated patients were older, more likely to be women, and to have more comorbidity but fewer concurrent cardiovascular drugs (table 1).

Trial versus “real world” population differences

We compared the sociodemographic profile and clinical outcomes between community based patients and patients from randomised controlled trials. We found that older patients and women made up a bigger proportion of the population treated in routine practice than randomised controlled trials, which focused mainly on younger and male patients.

Efficacy versus effectiveness

Compared with the efficacy findings of clinical trials, the effectiveness of drugs in observational analysis of clinical practice is expected to be reduced. This arises because of inaccurate diagnosis, lack of drug dose titration, confounding by indication, less than perfect adherence to treatment by patients and to guidelines by prescribers.14 Despite these potential influences, we found that the benefits of statins observed in our community patients were similar to those observed in randomised controlled trials (0.69, 95% confidence interval 0.59 to 0.80 v 0.79, 0.73 to 0.85). The numbers needed to treat for statin treatment in the community were also similar to those reported in clinical trials.1^–3

Concurrent drug use

In our study, use of β blockers, antiplatelet drugs, and angiotensin converting enzyme inhibitors was independently associated with lower risk of mortality and cardiovascular outcomes, as others have found.15 16 These findings support the notion that some of the different treatments available for secondary prevention do have independent effects and that their combined use may result in synergistic reductions in clinical outcomes.17 Interestingly, patients taking warfarin did not experience any independent reduction in risk of recurrence or death, perhaps owing to confounding or small numbers. Our analysis of the combined effects of cardiovascular drugs shows that patients who took one or two additional drugs had lower risks of death and recurrent myocardial infarction, which indicates that additional treatments are synergistic. However, the risks of death and recurrent myocardial infarction among patients who received a statin and more than two other cardiovascular drugs were similar to the risks in patients after a myocardial infarction who did not receive any drugs. This probably reflects confounding by disease severity in those patients who took three or more drugs, resulting in any synergistic effects of drug treatments being obscured by the intrinsically higher risk of patients treated with more than two additional drugs.

Prescribing of statins has clearly become more common in Tayside in recent years. From 2000, more than 60% of patients after a myocardial infarction in Tayside were prescribed statins. This is a similar proportion to that seen in the second European action on secondary prevention by intervention to reduce events (EUROASPIRE II) study18 across nine European countries. Two large clinical trials (the heart protection study19 and the prospective study of pravastatin in the elderly at risk (PROSPER) study20) were published in 2002, which were outside the timeframe of our study. These trials were relatively inclusive in respect of women and older patients. However, the results were broadly in accord with those observed in our study cohorts.

Limitations of the study

Our study has some limitations. Firstly, we assumed that if a prescription was filled then patients would comply with treatment, but we had no way of knowing whether patients actually took their treatment. We found that men had higher risk of cardiovascular events than women. This may be partly explained by compliance differences between the sexes.21 Secondly, we were limited by the number of covariates on which we had data. Consequently we were not able to adjust for smoking, obesity, and exercise. However, we used the Carstairs socioeconomic deprivation score as a surrogate, which provides adjustment for at least some of these factors.22

Strength of the study

A strength of our study is the population based cohort design, with complete follow-up over the study period. This approach allows a real population to be studied that represents all socioeconomic groups in a universal healthcare coverage scheme.23

Conclusion

About half of patients were taking statins during the study period. Statin use increased from 3.1% for 1993 to 62.9% for 2001. Statin users tended to be younger than non-users and tended to be prescribed more cardiovascular co-medication. Although co-medication provided benefits, statins were independently effective, reducing the likelihood of both the combined cardiovascular outcome and all cause mortality. Older patients and women, who were not well represented in trials, had similar benefit to other people.