Discussion
In the present pooled analysis, we confirmed what was documented in the individual SMILE studies, namely, that treatment of patients with AMI, with or without left ventricular dysfunction, with zofenopril, effectively reduces the risk of the combined end point of CV death or hospitalisation for CV causes with respect to placebo.11–15 Interestingly, most of the beneficial effects of active drug treatment with zofenopril in our study were already evident in the first weeks following initiation of treatment, and were well maintained over time. As a matter of fact, in zofenopril-treated patients, 70% of the risk reduction was achieved in the first 6 weeks, while an additional 30% was reached at the end of the follow-up. These results are in agreement with previous data showing that treatment with ACEIs begun days to weeks after AMI improves clinical outcomes.17 ,18 Given the peculiar pharmacological characteristics of zofenopril, we may suggest that most of the benefit is achieved with this drug through a primary vasculoprotective and cardioprotective effect, as shown in preclinical studies in animals19 ,20 and in clinical studies in humans,21 ,22 as well as through the prompt blockade of the deleterious effects of neurohumoral activation.23
Our study also compared the effects of zofenopril with those of two other ACEIs (lisinopril and ramipril): treatment with zofenopril reduced the chance of occurrence of the combined end point slightly more than did lisinopril or ramipril, at least in the long term. The only other available large trial assessing the efficacy of different ACEIs after AMI is a non-randomised, observational study by Hansen et al.24 In this study, no differences were observed in the risk of mortality and reinfarction among trandolapril, ramipril, enalapril, captopril, perindopril and other ACEIs, suggesting a class effect rather than a specific activity of the single ACEI. Our results are in contrast with those of the study by Hansen et al, and do not support a class effect but, rather, support differences in the efficacy between different ACEIs. Although our data are quite consistent, being collected through double-blind, randomised, parallel-group, prospective studies with similar designs, we cannot exclude the fact that the superiority of zofenopril might simply be related to a larger number of participants included in this group and to some heterogeneity across the studies. Future direct comparative studies should explore this aspect in detail.
Safety results confirmed that when treatment with zofenopril is initiated at low dose within the first days or weeks of onset of symptoms and signs of AMI, and up-titrated to optimal dose within a week, its tolerability is good, comparable to that observed with the reference drugs, lisinopril and ramipril, and consistent with previous clinical observations in the same field.25
Study limitations
Although the design of the four SMILE studies was very similar, there were some differences in the inclusion criteria, and treatment duration and follow-up, which might have biased the study results, particularly when direct comparisons between different active drug treatments were attempted. For instance, the SMILE-1 study included only those patients who were non-thrombolysed, the SMILE-2 and SMILE-3 included only thrombolysed patients, and the SMILE-4 study included both types of patients. The SMILE-3 study excluded patients with a LVEF <40%, while patients with left ventricular dysfunction were included in the SMILE-4 study. In the SMILE-1 study, active treatments lasted 6 weeks, while observation continued for the subsequent 12 months. In the other SMILE studies, treatment duration and observation coincided, but the time interval differed. In assessments of the differences between treatments, resulting variations in baseline characteristics might have tended to decrease the sensitivity of such analyses to show interaction. However, such differences are inherent to all pooled analysis and the bias introduced into ascertainment of the average effects among the patients is usually limited in size. This is particularly true in our case, because we adjusted comparisons for confounding variables and we used individual patients’ data instead of averages.
Another important study limitation concerns the interpretation of the results of the safety analysis. As a matter of fact, in the SMILE-2 study, the primary end point was a safety factor: the incidence of drug-related severe hypotension. This might explain why the proportion of patients with an adverse event was particularly high in the group of patients receiving lisinopril. Since the rate of adverse events was low in ramipril-treated patients of the SMILE-4 study, when data of these two different ACEIs were pooled together, differences were counterbalanced and thus elided.
Conclusions
The results of the pooled data analysis of the SMILE studies confirm the favourable effects of zofenopril treatment in patients with CHD. The reduction in mortality and morbidity observed in zofenopril-treated patients in comparison to placebo supports the fact that the ACE inhibition and specific pharmacological profile both contribute to the unbeaten efficacy of ACEIs in CHD. These results also strongly support the strategy of starting ACEIs early after AMI, in order to maximise their potential benefits. However, since the clinical benefits persisted during long-term treatment, this also suggests that ACEIs should not be withheld.