Health and cost benefits associated with the use of metoprolol in heart attack patients

Abstract

Heart attack (myocardial infarction) is a highly prevalent entity worldwide. Widespread implementation of reperfusion strategies has dramatically reduced the mortality associated with infarction. Paradoxically, the mortality reduction has significantly increased the incidence of chronic heart failure (HF). Treatment of HF, once present, represents a huge socioeconomic burden on individuals and healthcare systems. The possibility of preventing rather than treating post-infarction HF would be of paramount importance. Given that infarct size is the main determinant of adverse post-infarction outcomes (including chronic HF), therapies able to reduce infarct size are needed. The single administration of intravenous metoprolol before reperfusion has been recently shown to reduce infarct size and reduce the cases of chronic HF in a proof-of-concept trial. If confirmed in larger trials, this low-cost therapy is expected to have a major health and socioeconomic impact.

Keywords::

• β-blocker
• cost–effectiveness
• heart failure
• implantable cardioverter-defibrillator
• infarct size
• left ventricular ejection fraction
• metoprolol
• mortality
• myocardial infarction

Heart attack, mainly presented as ST-segment elevation myocardial infarction (STEMI) due to complete occlusion of an epicardial coronary artery, is a leading cause of mortality and morbidity worldwide [1]. Timely reperfusion and aggressive invasive management (percutaneous coronary interventions [PCI]) have been demonstrated as the most effective therapy to reduce the mortality associated with STEMI. Risk-adjusted in-hospital mortality had decreased from ≈30% in 1985 to ≈5.5% among STEMI patients treated in routine practice in 2008 [2], reaching a plateau thereafter [3]. The latter suggests that additional strategies beyond reperfusion are needed to further reduce mortality in this population.

Paradoxically, the significant reduction in acute mortality during a STEMI, resulting from the universal implementation of timely reperfusion, has significantly increased the incidence of chronic heart failure (HF): patients with poor left ventricular function previously have died in the acute phase, but with the advent of reperfusion now survive the acute episode and continue to live with a significantly damaged heart [2]. Indeed, STEMI is a major cause of chronic HF, with reduced left ventricular ejection fraction (LVEF) post-infarction being one of the single principal causes of chronic HF, both in developed and other low- to middle-income countries [4,5]. Because mortality rates for STEMI patients have declined, attention has shifted toward reducing post-infarction HF because this outcome is thought to reflect the downstream impact of acute therapies for STEMI.

Immense research efforts have led to chronic HF interventions (pharmacological and device-based) that reduce long-term mortality in STEMI survivors with low LVEF [6]. Nonetheless, the implementation of these strategies comes at a high cost, which precludes its universal application [7,8]. Chronic treatment of HF once present represents a huge social and economic burden on individuals and healthcare systems. Moreover, for chronic HF, frequent hospital readmissions are the main contributors to the escalating long-term healthcare costs [9,10]. The possibility of preventing (rather than treating) post-infarction HF would therefore be of significant clinical and socioeconomic importance.

The size of the infarct after a STEMI has been demonstrated as the main determinant of adverse post-infarction outcomes (including chronic HF). Patients with larger infarcts are at the highest risk since they have chronic severely depressed LVEF and associated HF [11]. Therefore, cost–effective therapies able to reduce infarct size are urgently needed since smaller infarctions will result in better heart performance and translate into fewer short- and long-term adverse clinical outcomes, helping to alleviate the huge socioeconomic burden of post-infarction HF.

Early intravenous (iv.) β-blocker initiation during a STEMI was proposed long ago as a therapy to limit infarct, but its real cardioprotective capacity during STEMI has been controversial [12]. Metoprolol tartrate was one of the first β-blockers released for clinical use and second iv. β-blocker agent clinically approved in the USA in 1978 [13]. Metoprolol is a β1-selective blocker. In spite of the availability of other drugs from the same family, metoprolol offers some potential advantages, like short half-life, easy administration in bolus injection and potential pleiotropic effects. These advantages, in addition to the clinical benefits here described, makes metoprolol the leading drug of its class. Surprisingly, in the current era of primary PCI as the treatment of choice for STEMI, no randomized trials assessing the beneficial effects of pre-reperfusion β-blocker administration had been reported until the advent of the METOCARD-CNIC trial [14,15].

In this trial, patients (mean age ≈ 58 years, ≈ 85% males) with anterior STEMI, Killip I or II, revascularized by PCI within 6 h from symptom onset with no obvious contraindication for the administration of β-blockers were randomized to receive up to three 5-mg iv. boluses of metoprolol tartrate [16] or control. In this context, early iv. metoprolol administration before reperfusion reduced infarct size (adjusted treatment effect, –6.5 g; 95% CI, –11.4 to –1.8; p = 0.012) and increased LVEF (adjusted treatment effect 2.7%; 95% CI, 0.1–5.2; p = 0.045) with no increase in adverse events in the acute phase (7.1% in the pre-reperfusion iv. metoprolol group, vs 16 events (12.3%) in the control group; p = 0.21). Patients receiving iv. metoprolol tartrate before reperfusion had a reduced incidence of HF readmissions over a median 2 years follow-up (2.2 vs 7% in iv. metoprolol and control groups, respectively, p = 0.04) [15]. Of note, the occurrence of severely depressed LVEF at 6 months was significantly lower in patients treated with iv. metoprolol (11 and 27% of patients in the iv. metoprolol and control groups, respectively, had an LVEF ≤35%, p = 0.006). Consequently, the proportion of patients fulfilling class-I indications for implantable cardioverter defibrillator (ICD) was significantly lower in the metoprolol group [15,17]. Early β-blockage before reperfusion is not encouraged in clinical guidelines, mainly due to the results of the COMMIT trial, which demonstrated no short-term net clinical benefit of early metoprolol in STEMI patients undergoing thrombolysis [18]. This trial recruited all comers with almost no restriction. Subgroup analyses suggested that patients fitting the inclusion criteria of the METOCARD-CNIC 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 less than 1 month. It is plausible that longer follow-up of the COMMIT trial would show additional benefit of early metoprolol administration in survivors. Thus, an important lesson from the COMMIT trial is that not all STEMI patients benefit from very early β-blockage, a deduction supported by the results observed in the METOCARD-CNIC trial [15], following the personalized medicine principle.

ICD devices are of great value in reducing long-term mortality rates of STEMI patients. However, the enormous economic burden for health services precludes its universal implementation [19]. Even in advanced economies, cost considerations preclude universal implementation of ICD therapy in all patients who fulfill class-I indication [8]. Of note, mean initial implantation costs including procedure and single-chamber ICD device have been estimated to be around €30,000 ($40,000 in the USA or £23,000 in the UK) [20]. This initial estimation does not include post-discharge costs (tests, follow-up exams), potential related complications or device replacement. Some studies addressing cost–effectiveness of ICD therapy for post-infarction primary prevention have suggested unfavorable results for device implantation, even for class-I indication patients [21]. Moreover, there are many intangible impacts on psychological aspects. Fear of death, shock and public embarrassment are commonly experienced by recipients. The possibility of reducing the number of patients fulfilling criteria for primary prevention ICD implant would have an impact in the reduction of costs and also in the increased accessibility of those with a clinical indication. The cost of iv. metoprolol is less than €2 (<$3 in the USA or<£4 in the UK), and thus it appears a highly cost–effective therapy to tackle the huge socioeconomic burden associated with post-infarction HF.

It is important to highlight that the METOCARD-CNIC trial was powered to detect differences in infarct size; therefore, all other promising findings described here should be taken as hypothesis generating. The ‘Impact of pre-reperfusion Metoprolol On clinical eVEnts after myocardial infarctiON’ (MOVE ON!) trial is a European endeavor that will recruit more than 3000 patients in seven countries. The MOVE ON! trial will prospectively test the hypothesis that a single administration of iv. metoprolol in STEMI patients transferred to PCI will reduce the incidence of hard clinical endpoints, including chronic HF and cardiac mortality, and will specifically evaluate the savings to the healthcare systems by this low-cost therapy.

The cost of chronic HF treatment is estimated to represent 2% of the total healthcare budgets across Europe [5]. This represents approximately €48 billion for the European member states. STEMI is the most common cause of chronic HF, accounting for approximately 35% of all chronic HF cases. Thus, the cost of treating STEMI and its consequences is approximately €20 billion/year in Europe. The potential cost savings associated with early metoprolol administration are speculative at this stage, but a plausible scenario can be proposed: assuming that half of the at-risk population might be able to receive the new therapy proposed in this application, the 25% reduction in cases of post-infarction chronic HF might represent a saving of around €5 billion/year across Europe. The MOVE ON! trial will tell whether these projections are real. If positive, it may have a major health and socioeconomic impact on infarcted patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.