Discussion
The main findings of this study were as follows. (1) RASI therapy was associated with a lower incidence of adverse cardiac events in patients with IMR after AMI. (2) There were no significant differences in the incidence of cardiac events according to the use of RASI in patients without IMR.
It has been widely recognised that patients with IMR after AMI have poorer prognosis than those without IMR. IMR occurs as a consequence of global or regional LV remodelling despite a structurally normal valve, which cause the leaflet tethering by displacement of papillary muscles.24–26 Accordingly, the therapeutic approaches should be aimed at the underlying LV dysfunction. Medical therapy including β-blockers and RASI for LV dysfunction and chronic HF is the essential therapy for patients with IMR. Cardiac resynchronisation therapy and coronary revascularisation are also considered in patients with an appropriate indication. Since mitral valve surgery can correct MR severity and improve symptoms of HF, surgical repair of IMR combined with coronary revascularisation has been thought to be a reasonable option. However, it is unclear whether it could improve long-term survival in patients with IMR who do not require CABG.27 28 Considering the uncertain survival benefit and operative risk in patients with IMR, medical therapy may currently be the only reasonable first-line strategy for the patients with IMR after AMI.
Previous studies reported that ACEI was efficacious in reducing IMR in patients with HF and LV dysfunction9 10; however, these studies did not assess the effect of ACEI on cardiovascular events. In a study that investigated the long-term prognosis of medically treated patients with functional MR and LV dysfunction receiving current standard pharmacological therapy, medical therapies including ACEI and β-blocker were not independent predictors of mortality.6 However, a more recent study demonstrated that the use of RASIs was associated with better long-term prognosis in patients with MI and significant (>moderate) IMR.29 Our present study is consistent with those results.
Although ACEIs (or ARB when an ACEI was not tolerated) are recommended in all patients after AMI, a considerable portion of patients after AMI do not receive RASIs in the real-world clinical practice mainly because of intolerance to RASI therapy such as hypotension, renal insufficiency and hyperkalemia. The prescription rate of RASIs at discharge after AMI was approximately 60% in 1998 and 80% in 2010 in a post-MI registry in Japan.30 According to a Japanese registry study that included patients who underwent PCI or CABG, about 70% of patients with history of MI received RASI therapy at discharge, which means almost 30% of patients did not receive RASI therapy.31 Our results suggest that introduction at a low dose and uptitration of RASI should always be considered even in patients with IMR who seem to be intolerant to RASI therapy.
This study did not find a significant association between RASI therapy and reduced cardiac events in patients who did not have IMR after AMI. A possible explanation for these results may be the different patient characteristics in this study compared with previous studies. Many of the non-IMR patients who did not receive RASI therapy had non-dilated LV with preserved EF; in addition, most of the patients in this study were revascularised by primary PCI or emergent CABG during acute phase of MI. In the PREAMI study,19 which investigated whether ACEIs show beneficial effects in elderly postinfarction patients with preserved LVEF, ACEI therapy was associated with reduced LV remodelling, but not with better clinical outcomes. Because non-IMR patients in this study seemed to have a lower risk of cardiovascular events compared with patients in previous trials of ACEIs who had reduced LVEF or chronic HF, this might lead to a failure to find the benefit of RASI therapy in cardiovascular prevention in this patient population. Our results suggest that patients with IMR might receive clinical benefit from RASI therapy after AMI regardless of MR severity and LV dysfunction in the reperfusion setting.
Our study has several limitations. First, since our study was based on a retrospective analysis, initiation of ACEI therapy depended on the physician’s discretion. Although we performed adjustment with the inverse probability treatment weighting to minimise the selection bias, unmeasured confounding factors might be present. Second, we evaluated the long-term effect of RASI based on the medications at discharge. However, the dose and class of RASI, and discontinuation after discharge were not assessed. Thus, patients with and without RASI therapy were compared in an intention-to-treat fashion based on the initial treatment assignment. Duration of RASI therapy may have a significant impact on clinical outcomes in patients with IMR. Third, the peak CK levels may be less accurate than sigma CK levels to evaluate the infarct size. However, since there were wide varieties in the timing and frequency of the assessments of CK levels, we could not calculate the sigma CK levels in all patients. Finally, we assessed IMR semiquantitatively and did not evaluate it quantitatively. The use of colour Doppler for determining MR severity might not be very accurate because of technical and haemodynamic limitations,32 but is part of the routine echocardiographic examination. In addition, although we defined IMR with rigorous echocardiographic criteria, we could not completely exclude patients with pre-existing MR.