Multiple drug treatment decreases admissions for recurrent MI in patients with a history of MI. Regardless of drug class, an additional drug known to prevent recurrent MI leads to an additional risk reduction.
The results from our study support the treatment strategies as applied in daily practice. Although randomised clinical trials established the benefits of individual drugs, evidence for the additive effects of different drug classes has been absent up to the present.7
Besides new evidence for multiple drug treatment, our study supplies data on patients who were seldom included in randomised clinical trials as we included elderly, patients with comorbidities or recent MI. Furthermore, we included more women than were studied in randomised clinical trials.
The study does have some limitations. First, case–control studies are susceptible to confounding by indication. Although we adjusted for several potential confounders, we could not adjust for other potential confounders such as the severity of the original MI, hypertension, dyslipidaemia, smoking status, body mass index and socioeconomic background. Further residual confounding due to unmeasured variables might be present. However, there is no indication that these confounders will be disproportionately distributed among cases and controls. This is an observational study and therefore provides less evidence than results from randomised clinical trials. However, given the lack of data from randomised clinical trials on the combined effect of different drugs on recurrent MI, results from observational studies may be very useful.
Second, in case–control studies odds ratios (ORs) may be misleading when interpreted as relative risks. However, the overstatement of the effect size when using ORs can be calculated.26,27
Given the incidence of recurrent MI in the non‐exposed, and the OR of 0.59 we reported for the use of three drugs with PDC >70%, the corresponding relative risk would be 0.64. Therefore we can state that the odds reductions we found closely approximate the risk ratios. Moreover the odds reduction in this study of adding one drug (16%; 95% CI 4 to 26%) is of the same magnitude as the risk reduction established in randomised clinical trials (30% for antiplatelet agents, 25% for β blockers, 10–25% for ACE inhibitors and 10–40% for statins).7
Third, we assumed that the preventive effects of the different drug classes are similar, both for the duration of treatment and the effect size. However, the different drug classes have very different pharmacodynamic effects. The platelet inhibitory effects of antiplatelet agents, for example, persist for 4–6 days, whereas the lipid‐lowering effects and antiatherogenic action of statins take weeks to months. Therefore one might state that current treatment is suitable for use of antiplatelet agents, but the duration of exposure matters for statins. Nonetheless, randomised clinical trials showed benefits after treatment periods that ranged from 2 to 5 years and risk reductions of antiplatelet agents, β blockers, ACE inhibitors and statins seemed to be comparable. Therefore we think it is appropriate to use one definition of exposure for different drug classes and to incorporate the duration of exposure in its definition. Furthermore, subdivision into 15 different combinations from the four earlier mentioned drug classes (antiplatelet agents, β blockers, ACE inhibitors and statins) and incorporation of the degree of medication adherence led to the frequency distribution shown in table 2. As the number of observations for numerous combinations is low, results would be difficult to interpret, assuming that statistical significance could be reached at all.
Both outcome and exposure were not subject to recall bias, as the diagnosis of the hospital admission is recorded at discharge and exposure was derived from prescriptions dispensed in the pharmacy. Although pharmacy dispensing does not imply that the patient always took the drug, there is no reason to suspect systematic bias between cases and controls in adherence to medication. Misclassification of exposure to β blockers, ACE inhibitors and statins seems to be unlikely too as drug‐dispensing records on a patient are virtually complete owing to a strong patient–pharmacy liaison in the Netherlands, and these drugs are not available over the counter. Although antiplatelet agents are available over the counter, we can rule out the possibility that non‐prescription antiplatelet agents have biased our results, for two reasons. First, in the Netherlands a prescription is required for these agents. Second, use of non‐prescription acetylsalicylic acid of higher doses is negligibly low, as over the counter acetylsalicylic acid is not reimbursed by health insurance, whereas prescription antiplatelet agents are fully reimbursed. In the Netherlands, 98.6% of all inhabitants have a health insurance policy covering the costs for prescription drugs.3
In summary, this study shows that multiple drug treatment lowers the number of admissions for recurrent MI in patients with a history of MI. Furthermore, the magnitude of the risk reduction increases as the number of drugs used concomitantly increases. As only 13% of patients admitted to hospital for MI received at least three drugs and were adequately compliant, there seems to be a potential for the improvement of secondary prevention of ischaemic heart disease.