Long Term Benefit of Early Metoprolol in AMI
This pre-specified follow-up of the METOCARD-CNIC trial shows that patients receiving pre-reperfusion IV metoprolol have a significantly higher long-term mean LVEF compared with control groups and are protected against long-term LVEF depression. These effects were accompanied by a trend towards reduced hard clinical endpoints. To the best of our knowledge, this is the first demonstration of a pharmacological cardioprotective strategy used in conjunction with pPCI resulting in sustained benefits on overall LVEF and in a significant reduction of cases of chronic severe LV systolic dysfunction.
The design of the METOCARD-CNIC trial included a 6 months MRI study for the evaluation of the effect of the therapy on long-term validated prognostic parameters. MRI is the gold standard for the evaluation of heart anatomy and function. In the 6 months MRI, we found that besides a higher LVEF, patients in the IV metoprolol group had significantly smaller LV end-systolic volumes, another well-established post-infarction prognostic parameter. We previously reported a significantly higher LVEF in the IV metoprolol group in the 1-week post-infarction MRI study. As presented, the LVEF values from the 1-week study correlated tightly with the follow-up values in both groups of treatment, supporting the conclusion that the long-term benefits of pre-reperfusion IV metoprolol are a consequence of the short-term beneficial effects detected at 1 week post-infarction. In order to determine whether the attrition of patients between the 1-week and 6-month MRI studies could have biased the results reported here, we evaluated the 1-week MRI LVEF in those patients who underwent the first scan, but not the 6-month follow-up (n = 18): median (first and third quartile) LVEF values were 53.0% (45.5% to 59.0%) in the IV metoprolol group versus 52.5% (46.8% to 62.0%) in the control group, excluding the possibility of selection bias introduced by patient attrition between 1-week and follow-up MRIs.
The long-term beneficial effects of pre-reperfusion IV metoprolol on LVEF were associated with a nonsignificant trend toward reduced hard clinical endpoints. The main limitation for the interpretation of this finding is that our trial was not powered to detect differences in clinical events. Other small trials testing the effect of cardioprotective strategies in STEMI have reported a significant reduction in long-term events despite being underpowered. In the CONDI (Remote Ischemic Conditioning in Primary PCI) trial, Sloth et al. found that remote ischemic conditioning in STEMI seemed to improve long-term clinical outcomes. Their minimum follow-up was 3 years, whereas ours was 12 months. In fact, the survival curves in the CONDI trial showed a clear divergence after 2 years of follow-up. In a different study, Stone et al. found that intracoronary abciximab in anterior STEMI resulted in a significant events reduction in the non–pre-specified time range (30 days to 12 months) post-infarction. Given the strong trend towards events reduction found in our trial, it is plausible that longer follow-up will reveal statistically significant differences. Similarly, non–pre-specified analyses of our study showed statistical significance (heart failure admission HR: 0.32; p = 0.046). However, we feel that these non-powered or non–pre-specified analyses are of limited value even when statistical significance is shown. We believe that our data form a sufficient basis for a larger STEMI clinical trial of early IV metoprolol powered for clinical events reduction.
The implementation of reperfusion strategies over the past decades has significantly reduced the acute mortality associated with STEMI. However, a high proportion of survivors remain at high risk of future cardiovascular events throughout life, including sudden death and repetitive episodes of heart failure. Long-term post-infarction LV systolic function is a major predictor of these clinical events; indeed, LVEF remains the principal objective parameter used for the indication for post-infarction heart failure therapies. Extensive clinical research has led to chronic heart failure interventions (pharmacological and device-based) that reduce long-term mortality in STEMI survivors with low LVEF. Nonetheless, the implementation of these strategies comes at a high socioeconomic cost. The enormous economic burden for health services is the main factor preventing universal implementation of these new heart failure therapies, and most countries in development cannot afford them, despite having implemented reperfusion strategies for STEMI. Even in advanced economies, economic considerations prevent universal use of the most expensive therapies (ICD and cardiac resynchronization devices). The present trial demonstrates that administration of a low-cost therapy (<2€ in Spain, <$3 in the United States) results in higher long-term LVEF. Although the observed 3.7-point absolute difference in mean LVEF could be judged as small, the much lower number of patients with severely depressed LVEF in the treatment group is more clinically relevant, and would translate into a greater socioeconomic impact. Furthermore, the number of patients with a formal indication for ICD implantation according to clinical guidelines was two-thirds less among the IV metoprolol patients. Overall, the rate of actual ICD implantation among cases with a formal indication was 33% (9 of 27, Table 2 ). This rate of ICD implantation is in agreement with other dedicated studies (rate between 30% and 35%), and above what is seen in the general population (around 13%).
In the first report on the METOCARD-CNIC trial, we documented an average 20% smaller infarct size in patients randomized to IV metoprolol, as evaluated by MRI 1 week after infarction. At 6 months, total infarct size difference between groups had been attenuated (15.6 g in the IV metoprolol group vs. 18.6 g in the control group, p = 0.07). Thus, despite the infarct size still being ≈17% smaller in the active treatment group, the natural shrinkage of scar tissue narrowed the absolute difference. It is also important to consider that this trial was powered to detect differences in infarct size in the acute phase (1 week after STEMI).
Beta-blockers have been shown to reduce mortality when used as secondary prevention after infarction, and are an established part of the pharmacological armamentarium, with a Class I indication in clinical guidelines. However, very early IV administration before reperfusion is not encouraged, mainly because of the results of the COMMIT (Efficacy and Safety of Adding Clopidogrel to Aspirin or Use of Metoprolol in Myocardial Infarction) trial, which showed no short-term net clinical benefit of early metoprolol in STEMI patients undergoing thrombolysis. The COMMIT trial recruited all comers with almost no restriction. By contrast, the METOCARD-CNIC trial recruited Killip class ≤II patients presenting with systolic blood pressure ≥120 mm Hg, heart rate ≥60 beats/min, and reperfused by pPCI within 6 h of infarct onset. Subgroup analyses of the COMMIT trial suggested that patients fitting the inclusion criteria of the METOCARD-CNIC trial benefited from early IV metoprolol in terms of mortality reduction. In addition, the clinical benefits associated with infarct size reduction (and post-infarction LVEF improvement) are expected to occur late (months to years) after STEMI. In the COMMIT trial, clinical follow-up was <1 month. It is plausible that longer follow-up of the COMMIT trial would show additional benefit of early IV metoprolol in survivors. Thus, an important lesson from the COMMIT trial is that not all STEMI patients benefit from very early IV metoprolol, a deduction supported by the results reported here.
This trial was not powered to detect differences in hard clinical endpoints, and thus, the results on this outcome should be taken with caution.
Discussion
This pre-specified follow-up of the METOCARD-CNIC trial shows that patients receiving pre-reperfusion IV metoprolol have a significantly higher long-term mean LVEF compared with control groups and are protected against long-term LVEF depression. These effects were accompanied by a trend towards reduced hard clinical endpoints. To the best of our knowledge, this is the first demonstration of a pharmacological cardioprotective strategy used in conjunction with pPCI resulting in sustained benefits on overall LVEF and in a significant reduction of cases of chronic severe LV systolic dysfunction.
The design of the METOCARD-CNIC trial included a 6 months MRI study for the evaluation of the effect of the therapy on long-term validated prognostic parameters. MRI is the gold standard for the evaluation of heart anatomy and function. In the 6 months MRI, we found that besides a higher LVEF, patients in the IV metoprolol group had significantly smaller LV end-systolic volumes, another well-established post-infarction prognostic parameter. We previously reported a significantly higher LVEF in the IV metoprolol group in the 1-week post-infarction MRI study. As presented, the LVEF values from the 1-week study correlated tightly with the follow-up values in both groups of treatment, supporting the conclusion that the long-term benefits of pre-reperfusion IV metoprolol are a consequence of the short-term beneficial effects detected at 1 week post-infarction. In order to determine whether the attrition of patients between the 1-week and 6-month MRI studies could have biased the results reported here, we evaluated the 1-week MRI LVEF in those patients who underwent the first scan, but not the 6-month follow-up (n = 18): median (first and third quartile) LVEF values were 53.0% (45.5% to 59.0%) in the IV metoprolol group versus 52.5% (46.8% to 62.0%) in the control group, excluding the possibility of selection bias introduced by patient attrition between 1-week and follow-up MRIs.
The long-term beneficial effects of pre-reperfusion IV metoprolol on LVEF were associated with a nonsignificant trend toward reduced hard clinical endpoints. The main limitation for the interpretation of this finding is that our trial was not powered to detect differences in clinical events. Other small trials testing the effect of cardioprotective strategies in STEMI have reported a significant reduction in long-term events despite being underpowered. In the CONDI (Remote Ischemic Conditioning in Primary PCI) trial, Sloth et al. found that remote ischemic conditioning in STEMI seemed to improve long-term clinical outcomes. Their minimum follow-up was 3 years, whereas ours was 12 months. In fact, the survival curves in the CONDI trial showed a clear divergence after 2 years of follow-up. In a different study, Stone et al. found that intracoronary abciximab in anterior STEMI resulted in a significant events reduction in the non–pre-specified time range (30 days to 12 months) post-infarction. Given the strong trend towards events reduction found in our trial, it is plausible that longer follow-up will reveal statistically significant differences. Similarly, non–pre-specified analyses of our study showed statistical significance (heart failure admission HR: 0.32; p = 0.046). However, we feel that these non-powered or non–pre-specified analyses are of limited value even when statistical significance is shown. We believe that our data form a sufficient basis for a larger STEMI clinical trial of early IV metoprolol powered for clinical events reduction.
The implementation of reperfusion strategies over the past decades has significantly reduced the acute mortality associated with STEMI. However, a high proportion of survivors remain at high risk of future cardiovascular events throughout life, including sudden death and repetitive episodes of heart failure. Long-term post-infarction LV systolic function is a major predictor of these clinical events; indeed, LVEF remains the principal objective parameter used for the indication for post-infarction heart failure therapies. Extensive clinical research has led to chronic heart failure interventions (pharmacological and device-based) that reduce long-term mortality in STEMI survivors with low LVEF. Nonetheless, the implementation of these strategies comes at a high socioeconomic cost. The enormous economic burden for health services is the main factor preventing universal implementation of these new heart failure therapies, and most countries in development cannot afford them, despite having implemented reperfusion strategies for STEMI. Even in advanced economies, economic considerations prevent universal use of the most expensive therapies (ICD and cardiac resynchronization devices). The present trial demonstrates that administration of a low-cost therapy (<2€ in Spain, <$3 in the United States) results in higher long-term LVEF. Although the observed 3.7-point absolute difference in mean LVEF could be judged as small, the much lower number of patients with severely depressed LVEF in the treatment group is more clinically relevant, and would translate into a greater socioeconomic impact. Furthermore, the number of patients with a formal indication for ICD implantation according to clinical guidelines was two-thirds less among the IV metoprolol patients. Overall, the rate of actual ICD implantation among cases with a formal indication was 33% (9 of 27, Table 2 ). This rate of ICD implantation is in agreement with other dedicated studies (rate between 30% and 35%), and above what is seen in the general population (around 13%).
In the first report on the METOCARD-CNIC trial, we documented an average 20% smaller infarct size in patients randomized to IV metoprolol, as evaluated by MRI 1 week after infarction. At 6 months, total infarct size difference between groups had been attenuated (15.6 g in the IV metoprolol group vs. 18.6 g in the control group, p = 0.07). Thus, despite the infarct size still being ≈17% smaller in the active treatment group, the natural shrinkage of scar tissue narrowed the absolute difference. It is also important to consider that this trial was powered to detect differences in infarct size in the acute phase (1 week after STEMI).
Beta-blockers have been shown to reduce mortality when used as secondary prevention after infarction, and are an established part of the pharmacological armamentarium, with a Class I indication in clinical guidelines. However, very early IV administration before reperfusion is not encouraged, mainly because of the results of the COMMIT (Efficacy and Safety of Adding Clopidogrel to Aspirin or Use of Metoprolol in Myocardial Infarction) trial, which showed no short-term net clinical benefit of early metoprolol in STEMI patients undergoing thrombolysis. The COMMIT trial recruited all comers with almost no restriction. By contrast, the METOCARD-CNIC trial recruited Killip class ≤II patients presenting with systolic blood pressure ≥120 mm Hg, heart rate ≥60 beats/min, and reperfused by pPCI within 6 h of infarct onset. Subgroup analyses of the COMMIT trial suggested that patients fitting the inclusion criteria of the METOCARD-CNIC trial benefited from early IV metoprolol in terms of mortality reduction. In addition, the clinical benefits associated with infarct size reduction (and post-infarction LVEF improvement) are expected to occur late (months to years) after STEMI. In the COMMIT trial, clinical follow-up was <1 month. It is plausible that longer follow-up of the COMMIT trial would show additional benefit of early IV metoprolol in survivors. Thus, an important lesson from the COMMIT trial is that not all STEMI patients benefit from very early IV metoprolol, a deduction supported by the results reported here.
Study Limitations
This trial was not powered to detect differences in hard clinical endpoints, and thus, the results on this outcome should be taken with caution.