October 2009 | Vol 6 | N.º 10 | CNIC-13 [ PDF (328 KB)]

Future Perspectives for Myocardial Salvage
Role of β-blockers in Cardioprotection: A new look at an old drug.

Borja Ibanez, Valentin Fuster, Jesús Jiménez-Borreguero, Ginés Sanz, Carlos Macaya, Juan Badimon
Correspondence:
Borja Ibanez. Imaging in Experimental Cardiology Laboratory, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC). Melchor Fernández Almagro, 3. 28029, Madrid, Spain. Phone: (+34) +34 91 453.13.40. Fax: (+34) 91 453 12 45.
Email bibanez@cnic.es

Abstract
Acute myocardial infarction (AMI) is a leading cause of mortality worldwide. Intense research over the past several decades has shown that infarct size is a major predictor of future cardiovascular events. Consequently, limitation of necrosis size during an AMI (myocardial salvage) is a matter of intense research. Beyond the implementation of social programs that can shorten the time from onset of symptoms to reperfusion, there is still a need for the development of coadjutant treatments that can increase cardioprotection.
Beta-adrenergic antagonists (β-blockers) are among the most widely studied drugs in the AMI setting. The salutary effects of β-blockers in this setting are indisputable; however, their optimal timing and route of initiation are still matters of debate. Indirect clinical evidence suggests that early intravenous initiation of β-blockers may result in a clinical benefit vastly exceeding that of later oral initiation. In addition, preliminary data from our laboratory have shown that the extensive cardioprotective effect associated with pre-reperfusion initiation of the selective β1-blocker metoprolol is abrogated when it is initiated orally after reperfusion. Because current clinical guidelines support the latter regimen of β-blockade, the demonstration of the clinical superiority of the early intravenous initiation will have important clinical implications. We are investigating cardioprotection by studying the effects of previously approved drugs. This cost-effective clinical research refinement could have immediate clinical implications.

Scope of the Problem.
Acute myocardial infarction (AMI) is a major public health problem in industrialised countries and is becoming an increasingly significant problem in emergent countries as well. It is estimated that ~15% of deaths worldwide are due to ischaemic heart disease, the leading cause of death in developed countries. Beyond the high mortality rate (~50%) of AMI patients before first contact with the emergency medical system, the mortality rate remains high during hospitalization (~5%) and within six months after discharge from hospital (~5%). The human and economic costs associated with AMI events are therefore of monumental magnitude. The final size of the necrosis resulting from an AMI is a major predictor of mortality and morbidity and thus a key factor in the economic burden of this disease.¹

Cardioprotection in acute myocardial infarction (AMI). Role of Reperfusion.
The preservation of healthy myocardium during a heart attack has been considered the holy grail of contemporary cardiology.² After the recognition of the temporal progression of myocardial necrosis during an AMI, it was proven that infarct size could be limited by an early coronary reperfusion.³ It is an accepted dogma that time to reperfusion is the most effective cardioprotective intervention. Early reperfusion is able to vastly limit MI size and, consequently, limit morbidity and mortality. In recent years, programs aimed at shortening the time from AMI diagnosis to coronary reperfusion have been widely developed. Despite early reperfusion, the final necrotic area following an AMI is still large in most cases, with a subsequent high incidence of repetitive cardiovascular events, heart failure and chronic disability. Hence, cardioprotective interventions that are able to increase myocardial salvage beyond reperfusion are a subject of intense research efforts.⁴

Ischaemia/Reperfusion Injury in AMI.
It is very clear that reperfusion is the strongest cardioprotective intervention. Paradoxically, however, the process of restoring blood flow to the ischaemic area can induce additional damage to the myocardium (so-called (lethal) perfusion injury),⁵ reducing the beneficial effects of reperfusion. This form of myocardial injury, which by itself can induce cardiomyocyte death and increase infarct size, may partially explain why, despite optimal coronary reperfusion, the rates of death and cardiac failure after AMI are still high.⁶ Widely available preclinical and clinical evidence has shown that interventions performed at the time of reperfusion can increase myocardial salvage,⁷ proving the existence of reperfusion injury.

β-blockers in AMI.
The β-blocker family of drugs has been extensively studied in the context of AMI. β-blockers are first line of treatment in secondary prevention after an AMI. In clinical practice, β-blockers have been unquestionably demonstrated to be beneficial, resulting in reduced mortality when administered after an AMI.⁸ As a result, current practice guidelines recommend β-blockade within the first 24 hours of AMI,1 with no emphasis on its initiation before reperfusion. β-blockers decrease the incidence of life-threatening arrhythmias, reinfarction, and recurrent ischaemia, preventing LV remodelling as well.⁹ β-blockers were proposed as cardioprotective agents long ago,¹⁰ but their genuine ability to limit infarct size is still an unanswered question. Several human clinical studies, most performed in or before the thrombolytic era, showed opposite results.¹¹-¹⁵ In the age of percutaneous angioplasty for coronary revascularization, the effect of β-blockade has been analyzed in a limited and nonrandomised fashion. Several retrospective investigations have suggested that administration of β-blockers immediately before or during reperfusion results in lower mortality when compared to placebo.¹⁶ In these studies, the effects of therapies on MI size were not documented. Finally, Dr. Fuster’s group reported that AMI patients undergoing percutaneous angioplasty who are already on β-blockers have significantly smaller MIs than those who did not receive β-blockers before AMI.¹⁷A common limitation in clinical studies testing the cardioprotective abilities of β-blockers is that MI size has usually been quantified by indirect surrogates, such as creatine kinase-MB fraction levels or ECG changes. With the advent of delayed-enhancement (DE) MRI, it is now possible to accurately quantify the extent of myocardial necrosis in vivo.¹⁸

Very recently, we studied the cardioprotective effects of the β1-selective blocker metoprolol in a swine model of AMI. In this examination, necrotic size was assessed in vivo by MRI few days after AMI, as it is performed in humans. This examination represented the first assessment on the effect of β-blockers using state-of-the-art human non-invasive imaging technology, providing additional translatability to this study (Figure 1). It was demonstrated that the administration of metoprolol during ongoing ischaemia was extremely cardioprotective compared to placebo.¹⁹ In a successive animal study, we observed that when metoprolol is initiated orally a few hours after reperfusion (as current clinical guidelines encourage), the cardioprotective effects of metoprolol are abrogated (Ibanez et al., submitted). This pre-clinical study, the first to compare these two regimens of β-blockade in AMI (pre- vs. post-reperfusion), suggested that the timing of β-blocker initiation may have a significant impact on the final size of MI, which is a strong predictor of cardiovascular events.

A critical drawback when analyzing β-blocker studies is the heterogeneity in the initiation of administration. It is unknown how many patients in each trial received the β-blocker agent before, during or soon after reperfusion. After unravelling the critical role of reperfusion itself on the final MI size, this question becomes even more important. Indeed, in a recent pre-clinical study, we observed that metoprolol administration during ongoing ischaemia could reduce ischaemia/reperfusion injury (Ibanez et al., submitted). If this hypothesis is accurate, then the cardioprotective activities of metoprolol would be restricted to its administration before coronary reperfusion, a consideration that could have immediate clinical implications.

It is important to note that no clinical study has prospectively compared the pre- versus post-reperfusion initiation of β-blockade. One of the few pieces of information in this regard is a post-hoc retrospective analysis of the CADILLAC trial.¹⁶ Despite the fact that there was no assessment of MI size, 30-day mortality was significantly lower in the group of patients receiving intravenous β-blockers before reperfusion compared to those receiving oral β-blockers at later times (Figure 2).¹⁶ In addition, LV motion recovery at 7 months was significantly improved in the pre-reperfusion intravenous β-blocker patients.

After scrutinizing the results of the CADILLAC sub-analysis¹⁶ and placing them in context with our pre-clinical findings explained above,¹⁹ it is arguable that a prospective study comparing the cardioprotective effects of pre-reperfusion β-blockade in comparison with its initiation orally in the subacute phase (as clinical guidelines recommend) might answer an important clinical debate. In close collaboration with researchers and institutions doing cutting-edge work in Spain, at the CNIC, we are going to begin a multicenter clinical trial comparing the two strategies of metoprolol initiation explained above. The results from this trial may have important clinical implications. If our hypothesis is corroborated, β-blockade should be intravenously initiated as soon as possible after AMI diagnosis in order to increase myocardial salvage in patients with no contraindications for β-blockade.

COMMIT trial and early β-blockade warning
One of the main reasons that recent clinical guidelines discourage early intravenous β-blockade in AMI1 is the report of the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT). The results of this trial have discredited the value of early intravenous metoprolol administration in AMI.²⁰ In this megatrial, more than 20,000 AMI patients undergoing thrombolysis were randomised to very early intravenous metoprolol followed by oral metoprolol or matching placebo. There is no information on the effect of therapies on MI size. Despite the fact that there were significant reductions in reinfarction and ventricular fibrillation rates in the metoprolol group, there were no differences in mortality. This was due mainly to an excess in cardiogenic shock in the β-blocker arm.²⁰ When analyzing these results, it should be noted that the inclusion criteria in this trial differed greatly from current standards. First, patients were randomised within 24 hours of AMI onset, undergoing fibrinolysis 10.3 ±6.3 hours after symptom onset. Ten hours after a coronary occlusion, the percentage of myocardium at risk that can be rescued by any intervention, including revascularization itself, is limited. It is also noteworthy that while mortality was reduced in the metoprolol arm by 5% and 2.5% in Killip class I and II AMI patients, respectively, it was 19% higher in Killip class III patients receiving metoprolol. In addition, patients with systolic blood pressure <120 mmHg had an increased mortality rate when receiving metoprolol. These results reinforce the contraindication of β-blocker therapy in patients with overt heart failure. These kinds of patients have been systematically excluded from all other β-blocker studies. Hence, the results of the COMMIT should be interpreted with caution, because it is possible that metoprolol would have resulted in a positive result if the inclusion criteria were more coherent. Indeed, the COMMIT researchers performed a meta-analysis of the effects of early intravenous β-blocker therapy including more than 50,000 AMI patients from different trials. When excluding the “high-risk” COMMIT patients (patients with contraindications for intravenous β-blockade), the effects on death, reinfarction, and cardiac arrest during the scheduled treatment periods are significantly lower for early intravenous β-blockade (Figure 3).

Role of Non-invasive Imaging in AMI Trials.
The performance of large-scale human trials with clinical endpoints represents the best means of proving the clinical benefits of novel strategies. However, such clinical trials are performed at huge personal and economic costs. Therefore, in the era of research refinement, surrogate markers that are known to predict clinical events are increasingly used as primary endpoints in proof-of-concept clinical trials.

After an AMI, the incidence of cardiovascular events is determined largely by the structural and functional abnormalities resulting from myocardial necrosis.²¹ Both left ventricular ejection fraction (LVEF) and LV end-systolic volume have consistently been revealed as major predictors of adverse cardiovascular events (including all-cause mortality) after AMI.²² These parameters are therefore widely used as surrogate markers for clinical endpoints in clinical trials. However, quantification of LVEF and LV volumes early (<1 month) after an AMI is not a specific tool for evaluating the extension of irreversible myocardial injury. The development of novel imaging technologies allows precise quantification of the necrotic area post-AMI.¹⁸ Late gadolinium enhancement (LGE)-MRI is a technique that can accurately assess myocardial infarct size,¹⁹,²³ with very high reproducibility for necrotic size quantification.24 While single-photon emission computed tomography (SPECT) is an established method, the higher spatial resolution of LGE-MRI allows increased sensitivity for infarct detection.²⁵ In addition, LGE-MRI has higher reproducibility than SPECT for MI size quantification, allowing a reduction in the sample sizes of trials²⁶. Importantly, a prospective study recently demonstrated that the necrotic extent quantified by LGE-MRI is a stronger predictor of cardiovascular events than LVEF or end-systolic LV volume.²⁷

Finally, LGE-MRI has been proposed as an effective tool for substantiating the existence and quantifying the extent of ischaemia/reperfusion injury and verifying persistent therapeutic benefits.²⁸ In fact, T2-weighted MRI can reliably identify the area at risk by delineating the infarct-related myocardial edema,²⁹ making it possible to normalise MI size to the area at risk (Figure 1).¹⁹

Because of its non-invasive, harmless nature and its high accuracy, MRI is an attractive tool that is increasingly used in modern AMI clinical trials.²⁸,³⁰
The clinical trial that we are going to perform will use state-of-the-art MRI technology to quantify the primary endpoint of the study: extent of myocardial salvage.

Conclusions
Coronary reperfusion is the best strategy for limiting necrosis size during an AMI. Given that MI size is a strong predictor of cardiovascular events, the development of novel strategies that can enhance myocardial salvage is a subject of intense research efforts. We have taken the approach of revisiting the effects of drugs already approved for clinical use (β-blockers), a consideration that may have immediate clinical implications. After performing encouraging pre-clinical examinations, we hypothesized that metoprolol can exert powerful cardioprotective abilities when it is initiated before reperfusion. This hypothesis is being tested in a multicenter clinical trial involving researchers and clinical institutions in Spain. ³¹,³²