October 2014 FAQs

What is the new evidence behind the effectiveness of β-blocker therapy for outcomes post-myocardial infarction?

Introduction

Myocardial infarction (MI) affects many people in the United States; over 515,000 MIs occur and 205,000 MIs recur over the course of a year.1 The American Heart Association (AHA) calculates an MI will occur every 44 seconds in the United States, and over 150,000 deaths occurred in connection with an MI in 2010. Myocardial infarction, along with unstable angina (UA), belongs to an overarching disease state called acute coronary syndrome (ACS), which occurs when myocardial oxygen demand and supply are imbalanced.2 Most ACS cases are due to the presence of an unstable atherosclerotic plaque in the coronary arteries. Acute coronary syndrome is divided into 2 categories—ST-elevation MI (STEMI) or non-ST-elevation MI/unstable angina (NSTEMI/UA)—based on the presence or absence of changes on the patient’s electrocardiogram. Unstable angina is distinct from NSTEMI in that the ischemia does not produce significant insult for the myocardium to release biomarkers such as troponins T or I. Non-ST elevation MI tends to be less severe and extensive in comparison to STEMI. The ability of β-blockers to decrease the heart rate should result in increased diastolic coronary filling time and decreased myocardial oxygen demand.3,4 Thus, use of β-blockers in the setting of ACS appears to be logical and well supported by physiological evidence.

Background

The 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for UA/NSTEMI briefly mentions the evidence discrepancy and resultant controversy in the early use of intravenous (IV) β-blockers; in an attempt to balance all the available evidence, the guideline recommends the use of oral β-blockers within 24 hours when no contraindications exist for management of the patients around the time of the MI, although the exact contraindications are not outlined.5 For long-term management, the same guideline states that β-blockers are an option for all UA/NSTEMI patients. If the patient was not acutely started on a β-blocker at the time of admission, the medication should be initiated quickly after the event, ideally within a few days. In the 2013 ACCF/AHA guidelines for STEMI, the recommendations given are similar for oral β-blocker initiation, except for provision of specific contraindications for oral β-blocker therapy such as patients with “…signs of heart failure, evidence of a low output state, increased risk for cardiogenic shock…” along with an additional recommendation to continue the therapy during and after the hospital stay.6

The 2011 AHA/ACCF secondary prevention guideline for coronary vascular disease recommends all patients with reduced ejection fraction with heart failure or MI who do not have contraindications to therapy should be given a β-blocker (Class I recommendation, level of evidence: A).7 Additionally, all patients with normal left ventricular function with a history of MI or ACS should begin and stay on β-blocker therapy for 3 years according to the same guideline (Class I recommendation, level of evidence: B). The guideline authors emphasize that the best evidence for β-blocker use is in patients with an MI in the past 3 years with or without reduced ejection fraction. The following recommendations are stated to be supported by less evidence and can be considered “optional” per the authors; continuation of β-blocker therapy beyond 3 years in all patients with normal left ventricular function is reasonable, as is β-blocker therapy in patients with reduction ejection fraction (<40%) but do not have heart failure or prior MI. Finally, for all other patients with coronary or other vascular disease, β-blockers could be considered as chronic therapy.

Although the evidence appears to be strong for β-blocker use, much of the evidence to support the guidelines was produced before reperfusion therapies became readily used.5,7-9 Reperfusion therapies include methods such as fibrinolytic therapy (eg, alteplase, tenecteplase) and percutaneous intervention (PCI).2,6,10,11 The reperfusion era refers to the time after these interventions became more commonplace as a part of MI treatment. The use of early reperfusion therapy leads to significantly less myocardial damage, and additional non-reperfusion therapies such as statins and antiplatelet agents contribute to fewer complications and decreased mortality in patients post-MI, possibly making the older evidence irrelevant in the contemporary treatment setting.11 The length of β-blocker therapy is subject to a similar debate, with most supportive evidence for guidelines’ recommendations (ranging from a few years to indefinite therapy) produced over 2 decades ago. In general, since the initiation of the reperfusion era, little evidence has been produced in support of the guidelines.9

The COMMIT/CCS-2 trial is an important example of β-blocker trials in the reperfusion era; it was conducted in over 45,000 patients from 1999 to 2005, some of which had undergone fibrinolytic therapy.12 The co-primary endpoints of all-cause mortality and a composite of death, reinfarction and cardiac arrest were not statistically significantly improved in patients randomized to metoprolol compared to placebo.2,6,12 The metoprolol group had more cardiogenic shock within 1 day of the MI, along with some reduction in re-infarction and ventricular fibrillation, albeit later in therapy; thus, the results of COMMIT/CCS-2 suggest that patients may be at risk for cardiogenic shock before the benefit from decreased re-infarction and ventricular fibrillation manifests. Patients appear to be at particular risk for such complications if they are older (age >70), exhibit signs of acute heart failure or are hypotensive (systolic blood pressure <120 mm Hg).2,6 Taking into account the newer methods of managing the patient presenting with MI and the new evidence that contradicts the old evidence, a robust analysis of all available evidence was needed to help guide clinician decisions.9

Recent meta-analysis

A recently published meta-analysis conducted by Bangalore et al attempted to consolidate the available, robust evidence from randomized controlled trials. 9 The meta-analysis’ objectives were to evaluate the current literature to assess how the reperfusion era has affected β-blockers outcomes in patients who experienced an MI, the effect of early IV β-blocker therapy, and the optimal duration of β-blocker use. Published trials that were published up to the first week of February 2013 and compared β-blockers with controls (ie, placebo, no treatment, or other active treatment) in 100 or more patients with MI were included. Trials were excluded if β-blockers were studied in patients post-MI with left ventricular systolic dysfunction or heart failure because the benefit of β-blocker therapy is well established in these patients. If the trial compared 2 different β-blockers, it was also excluded.

The analyzed trials were first divided into acute- (randomized patients within 48 hours of symptom onset) and post-MI trials.9 Additionally, if more than 50% of the patients were given aspirin or a statin, reperfused, and/or revascularized (ie, coronary artery bypass graft), the trial was classified as having taken place in the reperfusion era. If less than 50% of the patients were treated with the aforementioned therapies, the trial was labeled as having taken place in the pre-reperfusion era. The eras were also referred to as strata. The acute-MI pre-reperfusion era trials were compared to the acute-MI reperfusion era trials, and a similar comparison was completed for the post-MI trials. Incident rate ratios (IRR) of outcomes per 100 person-months were calculated for comparison in the intent-to-treat population. The authors captured a primary outcome of all-cause mortality, with secondary outcomes of cardiovascular mortality, sudden death, recurrent MI, angina pectoris, heart failure, cardiogenic shock, stroke, and drug discontinuation.

A pre-specified test for interaction was done to compare the primary outcome between the 2 eras with pinteraction<0.10 considered statistically significant for the existence of a treatment effect difference; if the primary outcome was found to be significantly different between the 2 eras, all other secondary outcomes would be interpreted separately.9 The authors also preplanned sensitivity analyses to test the robustness of the calculated primary and secondary outcomes. To do so, the parameters of the input data were varied in the following ways: combining data from both acute- and post-MI trials, including only the data from trials with at least 400 patients or which compared β-blockers to placebo, excluding the COMMIT/CCS-2 trial, etc. A meta-regression analysis was also completed to test if a relationship existed between the percentages of patients who underwent reperfusion in a trial to the outcome of the trial.

After completion of the systematic literature search, the authors identified 60 trials for a total of 102,003 enrolled patients.9 These patients were followed for a mean of 10 months with follow-up time ranging from the patient’s hospital stay to 4 years post-MI. About one-fifth of the patients (20,418 patients) were followed for over a year. Twenty of the trials were considered post-MI and 40 were considered acute-MI. Most patients (48,806 patients) were in the 12 trials from the reperfusion era whereas 31,479 patients were from the pre-reperfusion era trials.

Acute-MI trials

In the primary outcome of all-cause mortality, β-blocker use appeared to be associated with a reduction in overall mortality in the pre-reperfusion era but not in the reperfusion era, and the effect difference is statistically significant (pinteraction=0.02).9 Thus, all secondary outcomes were interpreted separately as predetermined. In the examination of cardiovascular mortality, β-blocker use in the pre-reperfusion era was associated with its reduction, but β-blocker use in the reperfusion era was neutral for cardiovascular mortality. No pinteraction value was provided. The use of β-blockers in both eras was associated with a decrease in repeat MI and angina. Neither era of β-blocker use showed a relationship of benefit or harm with sudden death and stroke as endpoints.9 The treatment effects did not differ significantly between strata for MI, angina, sudden death, and stroke.

Use of β-blockers was not seen to increase the risk of cardiogenic shock during the pre-reperfusion era but was associated with increased risk during the reperfusion era; the effect difference was statistically significant (pinteraction=0.03).9 Finally, a greater risk of drug discontinuation was seen with their use in the more recent era as compared to the pre-reperfusion era; the difference was statistically significant (p interaction<0.0001). These results are summarized in Table 1.

Table 1. Outcomes from analysis of acute-myocardial infarction trials

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

Post-MI trials

Unlike the acute-MI trials, the effect of β-blocker therapy on the primary endpoint of all-cause mortality was not statistically different between the pre-reperfusion and reperfusion strata for the post-MI trials (pinteraction=0.23); β-blocker use was associated with reduced all-cause mortality in the pre-reperfusion era whereas no change was seen in the reperfusion era.9 The same trend existed for MI, including a non-significant p interaction value. The risk of heart failure and drug discontinuation was increased for β-blocker use both in the pre-reperfusion era, but the IRR point estimates suggested greater risk for these endpoints in the reperfusion era. The difference trended toward significance for drug discontinuation (pinteraction=0.14) but was overtly significant for heart failure (pinteraction=0.008). Because the primary outcome was not statistically significant, the significance of this secondary outcome is highly susceptible to type II error; the reader should interpret with caution. These results are summarized in Table 2.

Table 2. Outcomes from analysis of post-myocardial infarction trials

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

Another particular point of contention in clinical practice is the length of β-blocker therapy as previously mentioned.11 The meta-analysis attempted to delineate the appropriate length of therapy.9 At 30 days of therapy in the pre-reperfusion era, β-blockers were found to provide benefit for all-cause mortality, cardiovascular mortality, and angina. At the same time point, during the reperfusion era, β-blocker use showed a benefit for MI and angina but also an increase in heart failure, cardiogenic shock and drug discontinuation. Between 30 days and 1 year of therapy, β-blocker use in the pre-reperfusion era was associated with a benefit in all-cause mortality, cardiovascular mortality, sudden death and MI. During this same time point in the reperfusion era, β-blocker use was associated with a significant increase in heart failure and drug discontinuation. β-blocker use more than 1 year after the MI still showed a benefit for all-cause mortality and sudden death in the pre-reperfusion era; data from the reperfusion era were not reported.

This study analyzed the timing of β-blocker administration as well.9 For pre-reperfusion era trials, all-cause mortality was decreased with the use of early initial IV β-blocker use (IRR=0.83, 95% confidence interval [CI] 0.75-0.92) whereas oral use was not associated with the same trend (IRR=0.99, 95% CI 0.83-1.19).9 The difference is statistically significant (pinteraction=0.09) so that the benefit is driven by the results of IV β-blocker trials and not oral β-blocker trials. In these same trials, early IV β-blocker use was associated with a benefit in cardiovascular mortality, MI, and angina pectoris but did not provide an impact in heart failure and cardiogenic shock. In reperfusion era trials, early IV β-blocker use was associated with decreased risk of MI and angina pectoris but increased risk of heart failure and cardiogenic shock. In the same trials, early IV β-blocker use was not associated with any benefit on mortality, cardiovascular mortality, sudden death, and stroke. These results are summarized in Table 3.

Table 3 Outcomes of early intravenous β-blocker use

a Numerical values were not provided, but authors stated no impact on these outcomes

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

The authors did not specifically provide the results of the sensitivity analyses but simply stated that the results of those analyses did not deviate significantly from the other published results. Importantly, even though COMMIT/CCS-2 was the main driver of the results in the reperfusion era, the authors noted that even after censoring those results, β-blocker use in the era did not show a benefit towards all-cause mortality (IRR 0.76; 95% CI 0.48, 1.21; p=0.25). Additionally, although β-blockers were shown to be beneficial for all-cause mortality in the pre-reperfusion era acute-MI trials, the result was mainly due to data from high-risk for bias trials; in only analyzing trials with low-risk for bias, no such benefit was found. Finally, although the trend was not statistically significant (p=0.056), the all-cause mortality benefits of β-blocker therapy decreased with increasing percentage of patients who had undergone reperfusion therapy.

In conclusion, the Bangalore et al meta-analysis found a significant interaction on the era of reperfusion on the outcomes of β-blockers for use in patients who experienced an MI; β-blockers were found to be beneficial in the era of pre-reperfusion but not in the current era of reperfusion.9 If a patient is begun on 30 days of β-blocker therapy post reperfusion, they may benefit from decreased risk of re-infarction and angina, but be placed at increased risk of heart failure, cardiogenic shock without any mortality benefit. The guidelines should review this newly available evidence, particularly in patients managed using current medical and surgical therapies.

Other new evidence

In the past few years, information about β-blocker use in recent, real-world settings has also been published, mostly in the setting of registry information and with widely varied results reported.13-18 Two Korean studies found β-blocker use to be associated with a lower risk of all-cause death and cardiac death.13,14 An American study also found β-blocker therapy to be beneficial in patients with a recent MI.15 Two Japanese studies, however, both found no benefit toward all-cause death with β-blocker use; one study even found an increased risk of all-cause death. 16,17 Finally, in another study which evaluated the timing and route of β-blocker administration, deaths while in the hospital were associated most with IV early β-blocker use and least with delayed β-blocker use.9, 18

Critique and Conclusion

From the results of the Bangalore meta-analysis, the benefit of β-blockers in the reperfusion era appears unclear.9 The meta-analysis itself was well designed and attempted to address several relevant clinical questions about β-blockers’ current place in therapy. The input data for the analyses were fairly robust although many trials were at high risk for bias, especially in the pre-reperfusion era acute-MI trials. The outcomes examined were also clinically important. The combination of these factors made this meta-analysis an important addition to the available data on this subject. The authors appear to have arbitrarily chosen a separation point (50%) by using each trial’s percent of reperfusion, revascularization and/or use of statins and aspirin in its patients as a variable to distinguish between the two eras; it is unclear whether this value was chosen based on clinical practice or previous data. Another limitation was the inability of the meta-analysis to separate the effects of reperfusion strategies from other medical management strategies, but this is an inherent weakness of meta-analyses of clinical trials and unfortunately unresolvable.

Even with its flaws, the study found that the use of β-blockers in settings similar to contemporary management of MIs is not associated with benefit in all-cause mortality and actually shows signs of harm in heart failure and cardiogenic shock.9 β-blocker therapy did seem to be beneficial in the pre-reperfusion era, but the large proportion of high risk for bias trials calls into question the validity of results. The reduction in mortality for β-blockers in the pre-reperfusion era does not necessarily indicate the same result for when a patient with an MI is medically managed without reperfusion strategies; this speculation has been shown to be false in COMMIT/CCS-2. An argument may be made that since COMMIT/CCS-2 was the main driver of the results, the emphasis on evidence from one trial is overly strong; however, even after removal of those data, there was no mortality benefit in the reperfusion era acute-MI trials. This may be secondary to the important role of other medical management options such as statins and antiplatelet therapy. 9,11

Because no benefit was shown for β-blocker therapy in the reperfusion era, the reader may question the power of the analysis to detect a difference. 9 The analysis of acute-MI trials was adequately powered to detect a difference had a true difference existed; it was powered at 99% to detect hazard ratios of 0.95 for benefit and 1.05 for harm. The power was low, however, in post-MI trials, as there were only 2 reperfusion era trials in this analysis. Thus, even though no difference was found in treatment effect in post-MI trials, the analysis may have been underpowered. The meta-analysis’ attempt to draw well-evidenced conclusions from randomized clinical trials did yield some interesting results, but the results of the observation trials remain conflicting to both each other and the meta-analysis; even though the observational trials do provide inherently weaker evidence due to the trial design, the information provided is still of concern and should be considered in clinical decision making.13-18

The authors speculate that the lack of medical and reperfusion therapies in the past may have caused widespread scarring of the myocardium, leading to increased ventricular arrhythmias and subsequently death.9 In this situation, β-blocker therapy likely prevented many deaths by inhibiting sudden death. With the advancement of MI management, less scarring may potentially occur, and the β-blockers’ benefit of sudden death prevention may be outweighed by the increased risk of cardiogenic shock and heart failure. In consideration of all the available data, trialing a β-blocker for 30 days in patients who present with a large infarct or who do not present in a timely manner may be rational; these patients somewhat emulate the clinical picture of MIs in the pre-reperfusion era, and β-blockers have the potential to be of value. However, the lack of mortality benefit, increased risk of other detrimental health conditions, and possible benefit for re-infarction and angina must be carefully weighed against each other for the most appropriate clinical decision.

References:

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28-e292.

2. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey LAcute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811456. Accessed July 28, 2014

3. Poirier L, Tobe SW. Contemporary use of beta-blockers: clinical relevance of subclassification. Can J Cardiol. 2014;30(5 Suppl):S9-S15.

4. Shacham Y, Leshem-Rubinow E, Roth A. Is long-term beta-blocker therapy for myocardial infarction survivors still relevant in the era of primary percutaneous coronary intervention? Isr Med Assoc. 2013;15(12):770-774.

5. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(23):e179-e347.

6. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.

7. Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432-2446.

8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.

9. Bangalore S, Makani H, Radford M, et al. Clinical Outcomes with beta-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials. [published online ahead of print Jun 10 2014]. Am J Med. doi:10.1016/j.amjmed.2014.05.032.

10. Revascularization and reperfusion therapy. In: Bavry A, Bhatt D, eds. Acute Coronary Syndromes in Clinical Practice. London, UK: Springer London; 2009:69-77.

11. Thompson PL. Should beta-blockers still be routine after myocardial infarction? Curr Opinion Cardiol. 2013;28(4):399-404.

12. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1622-1632.

13. Yang JH, Hahn JY, Song YB, et al. Association of Beta-Blocker Therapy at Discharge With Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. JACC. Cardiovasc Interv. 2014;7(6):592-601.

14. Choo EH, Chang K, Ahn Y, et al. Benefit of beta-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention. Heart. 2014;100(6):492-499.

15. Andersson C, Shilane D, Go AS, et al. Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J Am Coll Cardiol. 2014;64(3):247-252.

16. Bao B, Ozasa N, Morimoto T, et al. Beta-Blocker therapy and cardiovascular outcomes in patients who have undergone percutaneous coronary intervention after ST-elevation myocardial infarction. Cardiovasc Interv Thera. 2013;28(2):139-147.

17. Nakatani D, Sakata Y, Suna S, et al. Impact of beta blockade therapy on long-term mortality after ST-segment elevation acute myocardial infarction in the percutaneous coronary intervention era. Am J Cardiol. 2013;111(4):457-464.

18. Park KL, Goldberg RJ, Anderson FA, et al. Beta-blocker use in ST-segment elevation myocardial infarction in the reperfusion era (GRACE). Am J Med. 2014;127(6):503-511.

Prepared by:

Ruixuan Jiang

Doctor of Pharmacy Candidate, 2015

College of Pharmacy

University of Illinois at Chicago

October 2014

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What are the findings of the HEAT-PPCI trial?

Introduction

Primary percutaneous coronary intervention (PPCI) is the preferred method of reperfusion for patients presenting with ST-segment elevation myocardial infarction (STEMI) within 12 hours of symptom onset.1-4 Patients undergoing PPCI require antithrombotic therapy with both antiplatelet and anticoagulant medications. The most recent American and European guidelines on PPCI for STEMI recommend the use of oral dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor in addition to an intravenous (IV) anticoagulant (unfractionated heparin [UFH] or bivalirudin).1,2 Recommendations regarding additional IV antiplatelet therapy with glycoprotein IIb/IIIa inhibitors (GPIs) are dependent upon the choice of anticoagulant. 1-4 Glycoprotein IIb/IIIa inhibitors can be used with both bivalirudin and UFH in the “bailout” setting such as the occurrence of a large thrombus, slow or no re-flow, or in the event of other thrombotic complications and can be routinely used in patients receiving UFH.4 While the American and European guidelines do not clearly state a preference for one anticoagulant regimen over another, both note an increased risk of bleeding with UFH and GPI use compared to bivalirudin alone.1-4

The HORIZONS-AMI trial was an open-label, randomized, multicenter trial that compared the difference in clinical outcomes with bivalirudin versus UFH in PPCI.5 Patients receiving PPCI for STEMI reperfusion were randomized to either bivalirudin alone with bailout use of GPIs or UFH with routine use of GPIs. Bivalirudin improved event-free survival at 30 days, reduced the risk of major bleeding, and decreased both cardiac and all-cause mortality. The authors noted a statistically significant increase in stent thrombosis with bivalirudin during the first 24 hours following PPCI; however, the initial increase was balanced by a decrease in stent thrombosis with bivalirudin compared to UFH 24 hours to 30 days after PPCI.

The EUROMAX trial investigated the use of bivalirudin in the pre-hospital/transport setting for PPCI compared to UFH with selective use of GPIs. 6 In this open-label, randomized, international study, GPIs were used in 69.1% of the UFH-treated patients versus 11.5% of bivalirudin-treated patients. As was shown in the HORIZONS-AMI trial, bivalirudin significantly decreased the composite outcome of death and major bleeding at 30 days and increased the risk of stent thrombosis within the first 24 hours following PPCI.5,6 However, unlike HORIZONS-AMI, the EUROMAX trial showed that bivalirudin did not significantly decrease the risk of death alone at 30 days when compared to UFH.

Bivalirudin decreased major bleeding in both trials, but had conflicting results in reducing mortality.5,6 Due to these conflicting results and the differential use of GPIs in previous trials, the HEAT-PPCI (How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention) trial was designed to assess whether bivalirudin alone or UFH alone (with only bailout use of GPIs in both groups) was superior in preventing major adverse cardiac events (MACE) and major bleeding at 28 days post-PPCI for STEMI.7 This article summarizes the HEAT-PPCI trial and addresses the recent controversies surrounding its results, clinical applicability, and ethics.

Literature Review

The HEAT-PPCI trial was an open-label, randomized, single-center trial.7 All patients presenting to the PPCI service at Liverpool Heart and Chest Hospital in the United Kingdom were screened for enrollment. Patients were enrolled in the trial if they were over the age of 18 and had no active bleeding, no preclusion to oral DAPT, and no previous enrollment in the trial. Patients were then randomized 1:1, stratified by age over or under 75 years, and presence or absence of cardiogenic shock, to either UFH or bivalirudin with bailout use of the GPI abciximab. The investigators employed delayed consent in which they made no attempt to seek patient consent prior to randomization. Patients or their representatives were approached after the procedure to acquire formal consent.

All randomized patients received standard of care treatment with oral DAPT.7 Upon entry to the catheterization lab the patient received the study drug(s) (doses shown in Table 1). Follow-up to determine the occurrence of primary and secondary outcomes occurred at 28 days post-randomization. The primary efficacy outcome was a composite of MACE, and the primary safety outcome was the occurrence of major bleeding. Both primary and secondary outcomes are shown in Table 2. The investigators were not blinded at follow-up, but a blinded clinical events committee adjudicated all outcomes.

Table 1. Dosing of study drugs used in the HEAT-PPCI trial.7

Between February 2012 and November 2013 the investigators enrolled and randomized 1829 patients, an unprecedented 97% of all patients who presented for PPCI and underwent angiography.7 Treatment groups were well matched in baseline characteristics and non-anticoagulant periprocedural pharmacotherapy. Thirty percent of patients were female, 96% were white, and the mean age was 63 years. About 90% of patients received the higher potency P2Y12 inhibitors, ticagrelor and prasugrel, compared to 10% who received clopidogrel. Most notably, only 13% of patients in the bivalirudin group and 15% of patients in the UFH group received a GPI. Radial arterial access as opposed to femoral arterial access was used in about 80% of the patients in both groups.

As shown in Table 2, UFH significantly decreased the composite outcome of MACE and the individual secondary outcomes of new MI/reinfarction and additional unplanned revascularization compared to bivalirudin.7 Stent thrombosis was more common with bivalirudin at 28 days, which the authors point to as the primary driver of the significant decrease seen in the composite outcome. In terms of safety outcomes, there were no significant differences in bleeding.

Table 2. Primary and secondary safety outcomes at 28 days in the intent-to-treat population.7

Overall, the HEAT-PPCI investigators concluded that UFH is superior to bivalirudin in preventing MACE, particularly reinfarction and the need for revascularization, while showing no difference in bleeding.7

Controversies

The HEAT-PPCI trial has drawn a lot of “heat” regarding the difference in results with prior trials, the validity of the trial itself, and the ethics of delayed consent.8

Why are the results of HEAT-PPCI different than prior trials?

An editorial published in Lancet by Peter Berger and James Blankenship identified 4 main differences between the HEAT-PPCI trial and previous trials that may explain the variances in results seen.9 First, HEAT-PPCI allowed GPI use only in the bailout setting. Second, UFH was dosed at 70 units/kg, which is lower than the doses used in previous trials such as EUROMAX (100 units/kg) when UFH was given alone.6,7 Third, radial access was used in 80% of patients, which is known to reduce bleeding as compared to the alternative of femoral access. Finally, 90% of patients were receiving higher potency P2Y12 inhibitors (prasugrel and ticagrelor).9 It is argued that these differences make direct comparisons with previous trials invalid.7-9

Are the results of the HEAT-PPCI trial valid?

The HEAT-PPCI investigators received tough criticism about trial design at the American College of Cardiology 2014 Scientific Session in April 2014. 8 Panel members at the session criticized the bivalirudin dosing, arguing that a more prolonged bivalirudin infusion would have given bivalirudin a fairer chance. The HEAT-PPCI investigators conceded that a longer infusion may have closed the gap between UFH and bivalirudin, but added that it makes little sense to increase doses of bivalirudin to achieve equivalent effects with lower-priced UFH.8,9 Panel members also critiqued the adjudication of reinfarction occurrences, suggesting that these events may have been misclassified.8 HEAT-PPCI investigators responded that even if events were misclassified within the composite MACE outcome, the primary efficacy outcome results would not have changed. The investigators also noted that the lack of blinding at follow-up could have affected results, but previous trials were not blinded either.7

Was the HEAT-PPCI trial ethical?

The HEAT-PPCI trial received full ethics approval to use a delayed consent process, in which all patients were randomized and treated prior to providing consent.7 Patient approval was obtained after the procedure and 4 patients denied consent or withdrew from the study. In an editorial written by David Shaw, the ethical considerations of the delayed consent process in this trial are discussed.10 Both trial medications are labeled for anticoagulation with PPCI, and there is no clear recommendation to use one versus the other. Patients present for PPCI every day and a physician makes a decision without first consulting the patient. In addition, attempting to obtain full informed consent prior to randomization would have potentially delayed time-to-procedure, resulted in “uninformed” consent, or decreased enrollment in the trial. Thus, Shaw argues that it would have been unethical to not use a delayed consent process.

Conclusion

The HEAT-PPCI trial provides evidence in favor of UFH over bivalirudin in the setting of PPCI for STEMI reperfusion. The single-center design and controversies regarding the ethics of delayed consent limit the clinical applicability of the results of this trial. However, with few inclusion and exclusion criteria and an impressive 97% enrollment of all candidates presenting for PPCI, it has been argued that the results of this trial are more applicable to clinical practice than previous trials showing the superiority of bivalirudin. It is reasonable to expect that future PPCI guidelines will address the HEAT-PPCI trial and its potential effect on clinical practice.

References

1. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122.

2. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31(20):2501-2555.

3. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140.

4. Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569-2619.

5. Stone GW, Witzenbichler B, Guagliumi G, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358(21):2218-2230.

6. Steg PG, van't Hof A, Hamm CW, et al; EUROMAX Trial Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med . 2013;369(23):2207-2217.

7. Shahzad A, Kemp I, Mars C, et al; HEAT-PPCI Trial Investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial [published online ahead of print July 5, 2014]. Lancet. doi:10.1016/S0140-6736(14)60924-7.

8. Wood S. HEAT-PPCI: heparin bests bivalirudin in STEMI, amid heated debate. Medscape website. http://www.medscape.com/viewarticle/822927. Published April 1, 2014. Accessed July 18, 2014.

9. Berger PB, Blankenship JC. Is the heat on HEAT-PPCI appropriate [comment][published online ahead of print July 5, 2014]. Lancet. doi:10.1016/S0140-6736(14)61041-2.

10. Shaw D. Heat-PPCI sheds light on consent in pragmatic trials [comment][published ahead of print July 5, 2014]. Lancet. doi:10.1016/S0140-6736(14)61040-0.

Prepared by:

Jody Mallicoat

Doctor of Pharmacy Candidate, 2015

College of Pharmacy

University of Illinois at Chicago

October 2014

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What is the role of thrombolysis in submassive pulmonary embolism?

Introduction

Myocardial infarction (MI) affects many people in the United States; over 515,000 MIs occur and 205,000 MIs recur over the course of a year.1 The American Heart Association (AHA) calculates an MI will occur every 44 seconds in the United States, and over 150,000 deaths occurred in connection with an MI in 2010. Myocardial infarction, along with unstable angina (UA), belongs to an overarching disease state called acute coronary syndrome (ACS), which occurs when myocardial oxygen demand and supply are imbalanced.2 Most ACS cases are due to the presence of an unstable atherosclerotic plaque in the coronary arteries. Acute coronary syndrome is divided into 2 categories—ST-elevation MI (STEMI) or non-ST-elevation MI/unstable angina (NSTEMI/UA)—based on the presence or absence of changes on the patient’s electrocardiogram. Unstable angina is distinct from NSTEMI in that the ischemia does not produce significant insult for the myocardium to release biomarkers such as troponins T or I. Non-ST elevation MI tends to be less severe and extensive in comparison to STEMI. The ability of β-blockers to decrease the heart rate should result in increased diastolic coronary filling time and decreased myocardial oxygen demand.3,4 Thus, use of β-blockers in the setting of ACS appears to be logical and well supported by physiological evidence.

Background

The 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for UA/NSTEMI briefly mentions the evidence discrepancy and resultant controversy in the early use of intravenous (IV) β-blockers; in an attempt to balance all the available evidence, the guideline recommends the use of oral β-blockers within 24 hours when no contraindications exist for management of the patients around the time of the MI, although the exact contraindications are not outlined.5 For long-term management, the same guideline states that β-blockers are an option for all UA/NSTEMI patients. If the patient was not acutely started on a β-blocker at the time of admission, the medication should be initiated quickly after the event, ideally within a few days. In the 2013 ACCF/AHA guidelines for STEMI, the recommendations given are similar for oral β-blocker initiation, except for provision of specific contraindications for oral β-blocker therapy such as patients with “…signs of heart failure, evidence of a low output state, increased risk for cardiogenic shock…” along with an additional recommendation to continue the therapy during and after the hospital stay.6

The 2011 AHA/ACCF secondary prevention guideline for coronary vascular disease recommends all patients with reduced ejection fraction with heart failure or MI who do not have contraindications to therapy should be given a β-blocker (Class I recommendation, level of evidence: A).7 Additionally, all patients with normal left ventricular function with a history of MI or ACS should begin and stay on β-blocker therapy for 3 years according to the same guideline (Class I recommendation, level of evidence: B). The guideline authors emphasize that the best evidence for β-blocker use is in patients with an MI in the past 3 years with or without reduced ejection fraction. The following recommendations are stated to be supported by less evidence and can be considered “optional” per the authors; continuation of β-blocker therapy beyond 3 years in all patients with normal left ventricular function is reasonable, as is β-blocker therapy in patients with reduction ejection fraction (<40%) but do not have heart failure or prior MI. Finally, for all other patients with coronary or other vascular disease, β-blockers could be considered as chronic therapy.

Although the evidence appears to be strong for β-blocker use, much of the evidence to support the guidelines was produced before reperfusion therapies became readily used.5,7-9 Reperfusion therapies include methods such as fibrinolytic therapy (eg, alteplase, tenecteplase) and percutaneous intervention (PCI).2,6,10,11 The reperfusion era refers to the time after these interventions became more commonplace as a part of MI treatment. The use of early reperfusion therapy leads to significantly less myocardial damage, and additional non-reperfusion therapies such as statins and antiplatelet agents contribute to fewer complications and decreased mortality in patients post-MI, possibly making the older evidence irrelevant in the contemporary treatment setting.11 The length of β-blocker therapy is subject to a similar debate, with most supportive evidence for guidelines’ recommendations (ranging from a few years to indefinite therapy) produced over 2 decades ago. In general, since the initiation of the reperfusion era, little evidence has been produced in support of the guidelines.9

The COMMIT/CCS-2 trial is an important example of β-blocker trials in the reperfusion era; it was conducted in over 45,000 patients from 1999 to 2005, some of which had undergone fibrinolytic therapy.12 The co-primary endpoints of all-cause mortality and a composite of death, reinfarction and cardiac arrest were not statistically significantly improved in patients randomized to metoprolol compared to placebo.2,6,12 The metoprolol group had more cardiogenic shock within 1 day of the MI, along with some reduction in re-infarction and ventricular fibrillation, albeit later in therapy; thus, the results of COMMIT/CCS-2 suggest that patients may be at risk for cardiogenic shock before the benefit from decreased re-infarction and ventricular fibrillation manifests. Patients appear to be at particular risk for such complications if they are older (age >70), exhibit signs of acute heart failure or are hypotensive (systolic blood pressure <120 mm Hg).2,6 Taking into account the newer methods of managing the patient presenting with MI and the new evidence that contradicts the old evidence, a robust analysis of all available evidence was needed to help guide clinician decisions.9

Recent meta-analysis

A recently published meta-analysis conducted by Bangalore et al attempted to consolidate the available, robust evidence from randomized controlled trials. 9 The meta-analysis’ objectives were to evaluate the current literature to assess how the reperfusion era has affected β-blockers outcomes in patients who experienced an MI, the effect of early IV β-blocker therapy, and the optimal duration of β-blocker use. Published trials that were published up to the first week of February 2013 and compared β-blockers with controls (ie, placebo, no treatment, or other active treatment) in 100 or more patients with MI were included. Trials were excluded if β-blockers were studied in patients post-MI with left ventricular systolic dysfunction or heart failure because the benefit of β-blocker therapy is well established in these patients. If the trial compared 2 different β-blockers, it was also excluded.

The analyzed trials were first divided into acute- (randomized patients within 48 hours of symptom onset) and post-MI trials.9 Additionally, if more than 50% of the patients were given aspirin or a statin, reperfused, and/or revascularized (ie, coronary artery bypass graft), the trial was classified as having taken place in the reperfusion era. If less than 50% of the patients were treated with the aforementioned therapies, the trial was labeled as having taken place in the pre-reperfusion era. The eras were also referred to as strata. The acute-MI pre-reperfusion era trials were compared to the acute-MI reperfusion era trials, and a similar comparison was completed for the post-MI trials. Incident rate ratios (IRR) of outcomes per 100 person-months were calculated for comparison in the intent-to-treat population. The authors captured a primary outcome of all-cause mortality, with secondary outcomes of cardiovascular mortality, sudden death, recurrent MI, angina pectoris, heart failure, cardiogenic shock, stroke, and drug discontinuation.

A pre-specified test for interaction was done to compare the primary outcome between the 2 eras with pinteraction<0.10 considered statistically significant for the existence of a treatment effect difference; if the primary outcome was found to be significantly different between the 2 eras, all other secondary outcomes would be interpreted separately.9 The authors also preplanned sensitivity analyses to test the robustness of the calculated primary and secondary outcomes. To do so, the parameters of the input data were varied in the following ways: combining data from both acute- and post-MI trials, including only the data from trials with at least 400 patients or which compared β-blockers to placebo, excluding the COMMIT/CCS-2 trial, etc. A meta-regression analysis was also completed to test if a relationship existed between the percentages of patients who underwent reperfusion in a trial to the outcome of the trial.

After completion of the systematic literature search, the authors identified 60 trials for a total of 102,003 enrolled patients.9 These patients were followed for a mean of 10 months with follow-up time ranging from the patient’s hospital stay to 4 years post-MI. About one-fifth of the patients (20,418 patients) were followed for over a year. Twenty of the trials were considered post-MI and 40 were considered acute-MI. Most patients (48,806 patients) were in the 12 trials from the reperfusion era whereas 31,479 patients were from the pre-reperfusion era trials.

Acute-MI trials

In the primary outcome of all-cause mortality, β-blocker use appeared to be associated with a reduction in overall mortality in the pre-reperfusion era but not in the reperfusion era, and the effect difference is statistically significant (pinteraction=0.02).9 Thus, all secondary outcomes were interpreted separately as predetermined. In the examination of cardiovascular mortality, β-blocker use in the pre-reperfusion era was associated with its reduction, but β-blocker use in the reperfusion era was neutral for cardiovascular mortality. No pinteraction value was provided. The use of β-blockers in both eras was associated with a decrease in repeat MI and angina. Neither era of β-blocker use showed a relationship of benefit or harm with sudden death and stroke as endpoints.9 The treatment effects did not differ significantly between strata for MI, angina, sudden death, and stroke.

Use of β-blockers was not seen to increase the risk of cardiogenic shock during the pre-reperfusion era but was associated with increased risk during the reperfusion era; the effect difference was statistically significant (pinteraction=0.03).9 Finally, a greater risk of drug discontinuation was seen with their use in the more recent era as compared to the pre-reperfusion era; the difference was statistically significant (p interaction<0.0001). These results are summarized in Table 1.

Table 1. Outcomes from analysis of acute-myocardial infarction trials

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

Post-MI trials

Unlike the acute-MI trials, the effect of β-blocker therapy on the primary endpoint of all-cause mortality was not statistically different between the pre-reperfusion and reperfusion strata for the post-MI trials (pinteraction=0.23); β-blocker use was associated with reduced all-cause mortality in the pre-reperfusion era whereas no change was seen in the reperfusion era.9 The same trend existed for MI, including a non-significant p interaction value. The risk of heart failure and drug discontinuation was increased for β-blocker use both in the pre-reperfusion era, but the IRR point estimates suggested greater risk for these endpoints in the reperfusion era. The difference trended toward significance for drug discontinuation (pinteraction=0.14) but was overtly significant for heart failure (pinteraction=0.008). Because the primary outcome was not statistically significant, the significance of this secondary outcome is highly susceptible to type II error; the reader should interpret with caution. These results are summarized in Table 2.

Table 2. Outcomes from analysis of post-myocardial infarction trials

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

Another particular point of contention in clinical practice is the length of β-blocker therapy as previously mentioned.11 The meta-analysis attempted to delineate the appropriate length of therapy.9 At 30 days of therapy in the pre-reperfusion era, β-blockers were found to provide benefit for all-cause mortality, cardiovascular mortality, and angina. At the same time point, during the reperfusion era, β-blocker use showed a benefit for MI and angina but also an increase in heart failure, cardiogenic shock and drug discontinuation. Between 30 days and 1 year of therapy, β-blocker use in the pre-reperfusion era was associated with a benefit in all-cause mortality, cardiovascular mortality, sudden death and MI. During this same time point in the reperfusion era, β-blocker use was associated with a significant increase in heart failure and drug discontinuation. β-blocker use more than 1 year after the MI still showed a benefit for all-cause mortality and sudden death in the pre-reperfusion era; data from the reperfusion era were not reported.

This study analyzed the timing of β-blocker administration as well.9 For pre-reperfusion era trials, all-cause mortality was decreased with the use of early initial IV β-blocker use (IRR=0.83, 95% confidence interval [CI] 0.75-0.92) whereas oral use was not associated with the same trend (IRR=0.99, 95% CI 0.83-1.19).9 The difference is statistically significant (pinteraction=0.09) so that the benefit is driven by the results of IV β-blocker trials and not oral β-blocker trials. In these same trials, early IV β-blocker use was associated with a benefit in cardiovascular mortality, MI, and angina pectoris but did not provide an impact in heart failure and cardiogenic shock. In reperfusion era trials, early IV β-blocker use was associated with decreased risk of MI and angina pectoris but increased risk of heart failure and cardiogenic shock. In the same trials, early IV β-blocker use was not associated with any benefit on mortality, cardiovascular mortality, sudden death, and stroke. These results are summarized in Table 3.

Table 3 Outcomes of early intravenous β-blocker use

a Numerical values were not provided, but authors stated no impact on these outcomes

Abbreviations: CI, confidence interval; IRR, incident rate ratio.

The authors did not specifically provide the results of the sensitivity analyses but simply stated that the results of those analyses did not deviate significantly from the other published results. Importantly, even though COMMIT/CCS-2 was the main driver of the results in the reperfusion era, the authors noted that even after censoring those results, β-blocker use in the era did not show a benefit towards all-cause mortality (IRR 0.76; 95% CI 0.48, 1.21; p=0.25). Additionally, although β-blockers were shown to be beneficial for all-cause mortality in the pre-reperfusion era acute-MI trials, the result was mainly due to data from high-risk for bias trials; in only analyzing trials with low-risk for bias, no such benefit was found. Finally, although the trend was not statistically significant (p=0.056), the all-cause mortality benefits of β-blocker therapy decreased with increasing percentage of patients who had undergone reperfusion therapy.

In conclusion, the Bangalore et al meta-analysis found a significant interaction on the era of reperfusion on the outcomes of β-blockers for use in patients who experienced an MI; β-blockers were found to be beneficial in the era of pre-reperfusion but not in the current era of reperfusion.9 If a patient is begun on 30 days of β-blocker therapy post reperfusion, they may benefit from decreased risk of re-infarction and angina, but be placed at increased risk of heart failure, cardiogenic shock without any mortality benefit. The guidelines should review this newly available evidence, particularly in patients managed using current medical and surgical therapies.

Other new evidence

In the past few years, information about β-blocker use in recent, real-world settings has also been published, mostly in the setting of registry information and with widely varied results reported.13-18 Two Korean studies found β-blocker use to be associated with a lower risk of all-cause death and cardiac death.13,14 An American study also found β-blocker therapy to be beneficial in patients with a recent MI.15 Two Japanese studies, however, both found no benefit toward all-cause death with β-blocker use; one study even found an increased risk of all-cause death. 16,17 Finally, in another study which evaluated the timing and route of β-blocker administration, deaths while in the hospital were associated most with IV early β-blocker use and least with delayed β-blocker use.9, 18

Critique and Conclusion

From the results of the Bangalore meta-analysis, the benefit of β-blockers in the reperfusion era appears unclear.9 The meta-analysis itself was well designed and attempted to address several relevant clinical questions about β-blockers’ current place in therapy. The input data for the analyses were fairly robust although many trials were at high risk for bias, especially in the pre-reperfusion era acute-MI trials. The outcomes examined were also clinically important. The combination of these factors made this meta-analysis an important addition to the available data on this subject. The authors appear to have arbitrarily chosen a separation point (50%) by using each trial’s percent of reperfusion, revascularization and/or use of statins and aspirin in its patients as a variable to distinguish between the two eras; it is unclear whether this value was chosen based on clinical practice or previous data. Another limitation was the inability of the meta-analysis to separate the effects of reperfusion strategies from other medical management strategies, but this is an inherent weakness of meta-analyses of clinical trials and unfortunately unresolvable.

Even with its flaws, the study found that the use of β-blockers in settings similar to contemporary management of MIs is not associated with benefit in all-cause mortality and actually shows signs of harm in heart failure and cardiogenic shock.9 β-blocker therapy did seem to be beneficial in the pre-reperfusion era, but the large proportion of high risk for bias trials calls into question the validity of results. The reduction in mortality for β-blockers in the pre-reperfusion era does not necessarily indicate the same result for when a patient with an MI is medically managed without reperfusion strategies; this speculation has been shown to be false in COMMIT/CCS-2. An argument may be made that since COMMIT/CCS-2 was the main driver of the results, the emphasis on evidence from one trial is overly strong; however, even after removal of those data, there was no mortality benefit in the reperfusion era acute-MI trials. This may be secondary to the important role of other medical management options such as statins and antiplatelet therapy. 9,11

Because no benefit was shown for β-blocker therapy in the reperfusion era, the reader may question the power of the analysis to detect a difference. 9 The analysis of acute-MI trials was adequately powered to detect a difference had a true difference existed; it was powered at 99% to detect hazard ratios of 0.95 for benefit and 1.05 for harm. The power was low, however, in post-MI trials, as there were only 2 reperfusion era trials in this analysis. Thus, even though no difference was found in treatment effect in post-MI trials, the analysis may have been underpowered. The meta-analysis’ attempt to draw well-evidenced conclusions from randomized clinical trials did yield some interesting results, but the results of the observation trials remain conflicting to both each other and the meta-analysis; even though the observational trials do provide inherently weaker evidence due to the trial design, the information provided is still of concern and should be considered in clinical decision making.13-18

The authors speculate that the lack of medical and reperfusion therapies in the past may have caused widespread scarring of the myocardium, leading to increased ventricular arrhythmias and subsequently death.9 In this situation, β-blocker therapy likely prevented many deaths by inhibiting sudden death. With the advancement of MI management, less scarring may potentially occur, and the β-blockers’ benefit of sudden death prevention may be outweighed by the increased risk of cardiogenic shock and heart failure. In consideration of all the available data, trialing a β-blocker for 30 days in patients who present with a large infarct or who do not present in a timely manner may be rational; these patients somewhat emulate the clinical picture of MIs in the pre-reperfusion era, and β-blockers have the potential to be of value. However, the lack of mortality benefit, increased risk of other detrimental health conditions, and possible benefit for re-infarction and angina must be carefully weighed against each other for the most appropriate clinical decision.

References:

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28-e292.

2. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey LAcute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811456. Accessed July 28, 2014

3. Poirier L, Tobe SW. Contemporary use of beta-blockers: clinical relevance of subclassification. Can J Cardiol. 2014;30(5 Suppl):S9-S15.

4. Shacham Y, Leshem-Rubinow E, Roth A. Is long-term beta-blocker therapy for myocardial infarction survivors still relevant in the era of primary percutaneous coronary intervention? Isr Med Assoc. 2013;15(12):770-774.

5. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(23):e179-e347.

6. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.

7. Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432-2446.

8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.

9. Bangalore S, Makani H, Radford M, et al. Clinical Outcomes with beta-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials. [published online ahead of print Jun 10 2014]. Am J Med. doi:10.1016/j.amjmed.2014.05.032.

10. Revascularization and reperfusion therapy. In: Bavry A, Bhatt D, eds. Acute Coronary Syndromes in Clinical Practice. London, UK: Springer London; 2009:69-77.

11. Thompson PL. Should beta-blockers still be routine after myocardial infarction? Curr Opinion Cardiol. 2013;28(4):399-404.

12. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1622-1632.

13. Yang JH, Hahn JY, Song YB, et al. Association of Beta-Blocker Therapy at Discharge With Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. JACC. Cardiovasc Interv. 2014;7(6):592-601.

14. Choo EH, Chang K, Ahn Y, et al. Benefit of beta-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention. Heart. 2014;100(6):492-499.

15. Andersson C, Shilane D, Go AS, et al. Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J Am Coll Cardiol. 2014;64(3):247-252.

16. Bao B, Ozasa N, Morimoto T, et al. Beta-Blocker therapy and cardiovascular outcomes in patients who have undergone percutaneous coronary intervention after ST-elevation myocardial infarction. Cardiovasc Interv Thera. 2013;28(2):139-147.

17. Nakatani D, Sakata Y, Suna S, et al. Impact of beta blockade therapy on long-term mortality after ST-segment elevation acute myocardial infarction in the percutaneous coronary intervention era. Am J Cardiol. 2013;111(4):457-464.

18. Park KL, Goldberg RJ, Anderson FA, et al. Beta-blocker use in ST-segment elevation myocardial infarction in the reperfusion era (GRACE). Am J Med. 2014;127(6):503-511.

Prepared by:

Ruixuan Jiang

Doctor of Pharmacy Candidate, 2015

College of Pharmacy

University of Illinois at Chicago

October 2014

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