Patients With STEMI Undergoing Remote Ischaemic Conditioning
Patients With STEMI Undergoing Remote Ischaemic Conditioning
We found that remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction seemed to improve long-term clinical outcomes.
This is the first trial to evaluate the effect of remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention on long-term clinical outcomes in patients with myocardial infarction. A recent meta-analysis including 23 randomized trials investigating the effect of remote ischaemic conditioning on clinical outcomes showed a reduction in cardiac biomarker release and peri-procedural myocardial infarction, but did not demonstrate an effect on major adverse cardiovascular events or mortality. However, the meta-analysis was mainly based on trials in low-risk patients undergoing elective cardiac procedures and only investigated short-term clinical outcomes, i.e. up to 6 months after the index event. Only one trial besides our parent trial was conducted in high-risk patients with ST-elevation myocardial infarction and this trial did not evaluate clinical outcomes, but only the effect of remote ischaemic conditioning on the release of biochemical myocardial necrosis markers and ST-segment resolution.
More recently, results from the CRISP stent trial in patients undergoing elective percutaneous coronary intervention have demonstrated a lower MACCE rate in the remote ischaemic preconditioning group compared with the control group after 6 years of follow-up [23 vs. 36, HR = 0.58 (95% CI: 0.35–0.97), P = 0.039]. Additionally, a trial in patients undergoing elective CABG randomized to remote ischaemic preconditioning or standard therapy has showed a reduction in MACCE [13.9 vs. 18.9%, HR = 0.32 (95% CI: 0.14–0.71), P = 0.05] and all-cause mortality [1.9 vs. 6.9%, HR = 0.27 (95% CI: 0.08–0.98), P = 0.046] after a mean follow-up duration of 1.54 years. While these two trials reported an effect of remote ischaemic conditioning on long-term clinical outcomes in a priori low-risk patients undergoing elective cardiac procedures, our results demonstrate an effect of remote ischaemic conditioning on long-term clinical outcomes in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction.
We have presented per-protocol as well as intention-to-treat data. Although intention-to-treat data increase sample size and hence statistical power, we focused on the per-protocol analysis in accordance with the conclusion in our parent trial that was based on an improvement in myocardial salvage index per-protocol.
The reduction in our primary endpoint MACCE was mainly driven by a reduction in all-cause mortality. Evaluating specific death causes, the point estimates suggested a reduction in both cardiac and non-cardiac mortality. The reduction in cardiac mortality was expected from the parent trial results. The reduction in non-cardiac mortality was not and most likely arose by chance. Importantly, the results for MACCE when excluding non-cardiac mortality supported our conclusion. We note that the previously demonstrated improvement in myocardial salvage index and left ventricular function may translate into a reduction in the post-infarction heart failure rate driven by fewer device implantations due to chronic heart failure. However, the overall number of post-infarction heart failure diagnoses was too low to draw firm conclusions.
In the parent trial a subgroup analysis of myocardial salvage index stratified by vessel patency and infarct location showed that the effect of remote ischaemic conditioning was most pronounced in patients with an occluded vessel on admission and in patients with LAD infarcts. Although our subgroup analyses did not allow firm conclusions, our results do not reject the assumption that a beneficial effect is predominantly achieved in patients with an occluded vessel on admission consistent with the hypothesis that the effect of remote ischaemic conditioning is mainly associated with an attenuation of reperfusion injury. On the other hand, the clinical effect of remote ischaemic conditioning was independent on infarct location, indicating that all patients with ST-elevation myocardial infarction may benefit from this low-risk treatment.
The present trial has limitations. The power calculation in the parent trial was based on the myocardial salvage index. Here, we report long-term clinical outcomes. Importantly, despite wide CIs due to the sample size, all point estimates supported a beneficial effect. We defined heart failure as readmission for heart failure. We may have underestimated the rate of heart failure, because outpatient diagnoses were not included. However, this potential misclassification would bias the estimates towards null and thus cannot explain the reduced HR for heart failure. Substantial confounding is less likely owing to the randomized design and because the intention-to-treat analysis supported the results from the per-protocol analysis. Also, adjustment for the difference in hypertension frequency among the groups at baseline did not change the results.
The outcome of this first trial to evaluate the effect of remote ischaemic conditioning on long-term clinical outcomes in patients with ST-elevation myocardial infarction is encouraging. A simple, cost-effective intervention, which can easily be applied in the pre-hospital setting in patients with acute cardiac events, may in fact have the potential to reduce morbidity and mortality. However, our results need to be confirmed in a larger multicentre trial before remote ischaemic conditioning can be implemented in guidelines as an adjunct to primary percutaneous coronary intervention.
Discussion
We found that remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction seemed to improve long-term clinical outcomes.
This is the first trial to evaluate the effect of remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention on long-term clinical outcomes in patients with myocardial infarction. A recent meta-analysis including 23 randomized trials investigating the effect of remote ischaemic conditioning on clinical outcomes showed a reduction in cardiac biomarker release and peri-procedural myocardial infarction, but did not demonstrate an effect on major adverse cardiovascular events or mortality. However, the meta-analysis was mainly based on trials in low-risk patients undergoing elective cardiac procedures and only investigated short-term clinical outcomes, i.e. up to 6 months after the index event. Only one trial besides our parent trial was conducted in high-risk patients with ST-elevation myocardial infarction and this trial did not evaluate clinical outcomes, but only the effect of remote ischaemic conditioning on the release of biochemical myocardial necrosis markers and ST-segment resolution.
More recently, results from the CRISP stent trial in patients undergoing elective percutaneous coronary intervention have demonstrated a lower MACCE rate in the remote ischaemic preconditioning group compared with the control group after 6 years of follow-up [23 vs. 36, HR = 0.58 (95% CI: 0.35–0.97), P = 0.039]. Additionally, a trial in patients undergoing elective CABG randomized to remote ischaemic preconditioning or standard therapy has showed a reduction in MACCE [13.9 vs. 18.9%, HR = 0.32 (95% CI: 0.14–0.71), P = 0.05] and all-cause mortality [1.9 vs. 6.9%, HR = 0.27 (95% CI: 0.08–0.98), P = 0.046] after a mean follow-up duration of 1.54 years. While these two trials reported an effect of remote ischaemic conditioning on long-term clinical outcomes in a priori low-risk patients undergoing elective cardiac procedures, our results demonstrate an effect of remote ischaemic conditioning on long-term clinical outcomes in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction.
We have presented per-protocol as well as intention-to-treat data. Although intention-to-treat data increase sample size and hence statistical power, we focused on the per-protocol analysis in accordance with the conclusion in our parent trial that was based on an improvement in myocardial salvage index per-protocol.
The reduction in our primary endpoint MACCE was mainly driven by a reduction in all-cause mortality. Evaluating specific death causes, the point estimates suggested a reduction in both cardiac and non-cardiac mortality. The reduction in cardiac mortality was expected from the parent trial results. The reduction in non-cardiac mortality was not and most likely arose by chance. Importantly, the results for MACCE when excluding non-cardiac mortality supported our conclusion. We note that the previously demonstrated improvement in myocardial salvage index and left ventricular function may translate into a reduction in the post-infarction heart failure rate driven by fewer device implantations due to chronic heart failure. However, the overall number of post-infarction heart failure diagnoses was too low to draw firm conclusions.
In the parent trial a subgroup analysis of myocardial salvage index stratified by vessel patency and infarct location showed that the effect of remote ischaemic conditioning was most pronounced in patients with an occluded vessel on admission and in patients with LAD infarcts. Although our subgroup analyses did not allow firm conclusions, our results do not reject the assumption that a beneficial effect is predominantly achieved in patients with an occluded vessel on admission consistent with the hypothesis that the effect of remote ischaemic conditioning is mainly associated with an attenuation of reperfusion injury. On the other hand, the clinical effect of remote ischaemic conditioning was independent on infarct location, indicating that all patients with ST-elevation myocardial infarction may benefit from this low-risk treatment.
The present trial has limitations. The power calculation in the parent trial was based on the myocardial salvage index. Here, we report long-term clinical outcomes. Importantly, despite wide CIs due to the sample size, all point estimates supported a beneficial effect. We defined heart failure as readmission for heart failure. We may have underestimated the rate of heart failure, because outpatient diagnoses were not included. However, this potential misclassification would bias the estimates towards null and thus cannot explain the reduced HR for heart failure. Substantial confounding is less likely owing to the randomized design and because the intention-to-treat analysis supported the results from the per-protocol analysis. Also, adjustment for the difference in hypertension frequency among the groups at baseline did not change the results.
The outcome of this first trial to evaluate the effect of remote ischaemic conditioning on long-term clinical outcomes in patients with ST-elevation myocardial infarction is encouraging. A simple, cost-effective intervention, which can easily be applied in the pre-hospital setting in patients with acute cardiac events, may in fact have the potential to reduce morbidity and mortality. However, our results need to be confirmed in a larger multicentre trial before remote ischaemic conditioning can be implemented in guidelines as an adjunct to primary percutaneous coronary intervention.