Acute Myocardial Infarction

Empagliflozin after Acute Myocardial Infarction

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Abstract

BACKGROUND

Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown.

METHODS

In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis.

RESULTS

A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups.

CONCLUSIONS

Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.)

After acute myocardial infarction, patients are at increased risk for heart failure and death, particularly if they present with congestion or a decreased left ventricular ejection fraction.1-3 Treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors improves cardiovascular outcomes in high-risk patients with type 2 diabetes, those with chronic kidney disease, and those with heart failure with a reduced or preserved left ventricular ejection fraction.4 In the EMMY trial (Impact of Empagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients with Acute Myocardial Infarction), patients who received empagliflozin after an acute myocardial infarction had a reduced natriuretic peptide concentration, an increased left ventricular ejection fraction, and a decreased cardiac volume; however, this trial was not designed to assess clinical outcomes.5 The DAPA-MI trial (Dapagliflozin Effects on Cardiometabolic Outcomes in Patients with an Acute Heart Attack) was limited by the small number of clinical events during the trial and therefore was unable to assess the effects of SGLT2 inhibitor therapy after myocardial infarction on rates of death or hospitalizations for heart failure.6

Here, we report the results of the EMPACT-MI trial (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction), in which empagliflozin was compared with placebo with respect to the risk of hospitalization for heart failure or death among patients with acute myocardial infarction and either a new reduction in left ventricular ejection fraction or signs or symptoms of congestion (or both).

Methods

TRIAL OVERSIGHT

The EMPACT-MI trial was an international, event-driven, double-blind, randomized, placebo-controlled trial. The trial design has been described previously.7 The trial was approved by the ethics committee at each trial site, and all the patients provided written informed consent. The trial sponsors were Boehringer Ingelheim and Eli Lilly. The trial protocol (available with the full text of this article at NEJM.org) was developed and amended by the executive and steering committees, which included employees of Boehringer Ingelheim (who represented the sponsors) and provided scientific oversight on the development of the statistical analysis plan (available with the protocol), patient recruitment and follow-up, and data analysis. An independent data monitoring committee reviewed the safety data. Statistical analyses were performed by employees of Boehringer Ingelheim with oversight by the executive committee, and key analyses were verified by an independent statistician. The first author prepared the first draft of the submitted manuscript, which was reviewed and edited by all the authors. The first and last authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol and the statistical analysis plan.

PATIENTS

Patients were men and women 18 years of age or older who had been hospitalized with an acute myocardial infarction within 14 days before randomization and had either evidence of a newly developed left ventricular ejection fraction of less than 45% or signs or symptoms of congestion that resulted in treatment during the index hospitalization (or both). Patients needed to have at least one additional enrichment factor (a clinical factor that was known to be associated with hospitalization for heart failure or death from any cause), including an age of 65 years or older; a newly developed ejection fraction of less than 35%; a history of myocardial infarction, atrial fibrillation, or type 2 diabetes; an estimated glomerular filtration rate (GFR) of less than 60 ml per minute per 1.73 m2 of body-surface area; an elevated natriuretic peptide or uric acid level; an elevated pulmonary artery or right ventricular systolic pressure; three-vessel coronary artery disease; peripheral artery disease; or no revascularization for the index myocardial infarction. Patients with a previous diagnosis of heart failure, as well as those who were taking or planning to take SGLT2 inhibitors, were excluded. A full list of eligibility criteria is provided in the Supplementary Appendix (available at NEJM.org) and was published previously.7

TRIAL DESIGN

Patients who met the eligibility criteria were randomly assigned in a 1:1 ratio to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care. Randomization was performed with the use of interactive response technology and was stratified according to type 2 diabetes status and geographic region (North America, Latin America, Europe, or Asia). The EMPACT-MI trial had a streamlined design, with the collection of essential data only, including information about specific safety events, and mainly remote follow-up of patients (by means of a Web-based application or a telephone call) with only a few face-to-face visits; the trial assessed investigator-reported end-point events rather than centrally adjudicated end-point events.

After randomization, patients had a remote visit at 2 weeks, a face-to-face visit at 6 months, and remote visits every 6 months thereafter until the end of the trial, when a final telephone call was performed. During these visits, data on prespecified end points, safety events, and adherence to the trial regimen were collected. Data on all concomitant medications were collected for 6 months after randomization; thereafter, medication data were collected only on open-label initiation of treatment with SGLT2 inhibitors or combined treatment with SGLT1 and SGLT2 inhibitors. Because of the established safety profile of empagliflozin,8-10 we used focused safety reporting, in which the investigators reported only serious adverse events, adverse events that led to discontinuation of the trial regimen for at least 7 consecutive days, and adverse events of special interest. All the patients who underwent randomization were followed for the duration of the trial, regardless of whether they received empagliflozin or placebo.

TRIAL END POINTS

The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. The key secondary end points in the prespecified hierarchical testing strategy were the total number of hospitalizations for heart failure or death from any cause, the total number of nonelective cardiovascular hospitalizations or death from any cause, the total number of nonelective hospitalizations for any cause or death from any cause, and the total number of hospitalizations for myocardial infarction or death from any cause. Additional prespecified end points are described in the Supplementary Appendix. In lieu of central adjudication, end-point events were reviewed and categorized according to prespecified definitions by investigators at the trial sites who were unaware of trial-group assignment and had received training in reviewing end-point events. Investigator-reported end-point events were verified according to the algorithm described in the Supplementary Appendix.

STATISTICAL ANALYSIS

In this event-driven trial, we estimated that 532 patients with a primary end-point event would provide the trial with 85% power to detect a 23% lower risk of an event in the empagliflozin group than in the placebo group, with a two-sided type I error of 0.05. The original protocol planned for the enrollment of 3312 patients, with an option to increase enrollment to 5000 patients if the accrual of events was slower than expected. The sample size was further increased to 6500. These decisions were made on the basis of blinded trial data, with no change to the target number of events or revisions to effect-size projections or power calculations. No interim efficacy analyses were performed.

The analyses of the primary composite end point and its components were performed according to the intention-to-treat principle and included all the patients who underwent randomization. The differences between the empagliflozin and placebo groups in the risk of a primary end-point event were assessed with the use of a Cox proportional-hazards model that included the baseline covariates of age, geographic region, estimated GFR (<45, 45 to <60, 60 to <90, or ≥90 ml per minute per 1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration formula), left ventricular ejection fraction (<35% or ≥35%), type 2 diabetes status, persistent or permanent atrial fibrillation, previous myocardial infarction, peripheral artery disease, and smoking status. Data for patients who did not have a primary end-point event were censored on the last day they were known to have been free of the event, which may have been the last time point before the patient was lost to follow-up (under the assumption of noninformative censoring).

A prespecified hierarchical testing procedure was used, beginning with the primary end point and then proceeding to the set of key secondary end points. A Hochberg step-up procedure was used to assess the first and second key secondary end points at the same level of hierarchy, with the next two key secondary end points subsequently tested in a hierarchical manner.

All key secondary end points were analyzed with the use of a negative binomial regression model that included the same covariates as the primary model and the logarithm of time as an adjustment for observation time. The observation time started on the day of randomization and ended on the last day when information about end-point events was collected for an individual patient, which may have been the last time point before the patient was lost to follow-up. Post hoc sensitivity analyses that accounted for the competing risks of death from any cause and death from cardiovascular causes were performed with the use of Fine and Gray models for time to a first hospitalization for heart failure, time to death from cardiovascular causes, and time to a first hospitalization for heart failure or death from cardiovascular causes. Safety analyses included all the patients who received at least one dose of empagliflozin or placebo. The confidence intervals for the secondary and exploratory end points were not adjusted for multiplicity and should be interpreted as exploratory.

Results

PATIENTS

From December 2020 through March 2023, a total of 6610 patients at 451 sites in 22 countries were screened, of whom 6522 were randomly assigned to receive empagliflozin at a dose of 10 mg daily (3260 patients) or placebo (3262 patients). The median time from admission to randomization was 5 days (interquartile range, 3 to 8). The characteristics of the patients at baseline were similar in the two trial groups (Table 1).11 A total of 78.4% of the patients had a left ventricular ejection fraction of less than 45%, and 57.0% had signs or symptoms of congestion that resulted in treatment during the index hospitalization. Among the patients with signs or symptoms of congestion, 20.6% had a left ventricular ejection fraction of at least 45%. The most common enrichment factors included an age of 65 years or older (in 50.0% of the patients), type 2 diabetes (in 31.9%), and three-vessel coronary artery disease (in 31.0%); 70.5% of the patients had more than one enrichment factor (Table S1 in the Supplementary Appendix). Nearly 75% of the patients who underwent randomization presented with ST-segment elevation myocardial infarction (STEMI), and revascularization for the index myocardial infarction was performed in 89.3%.

TABLE 1

Characteristics of the Patients at Baseline.

The trial regimen was stopped prematurely for reasons other than death in 684 patients (21.2%) in the empagliflozin group and in 716 patients (22.2%) in the placebo group. A total of 436 patients (6.7%) started treatment with an open-label SGLT2 inhibitor during the trial, including 201 (6.2%) in the empagliflozin group and 235 (7.2%) in the placebo group. A total of 6328 patients (97.0%) were followed until the end of the trial for the occurrence of a primary end-point event, and 6467 patients (99.2%) had data on vital status available at the end of the trial (Fig. S1). The median duration of follow-up was 17.9 months, and the median duration of exposure to empagliflozin or placebo was similar in the two trial groups (Table S4). Adherence to the trial regimen is shown in Table S5.

END POINTS

A primary end-point event — a first hospitalization for heart failure or death from any cause — occurred in 267 of 3260 patients (8.2%) in the empagliflozin group and in 298 of 3262 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19) (Table 2 and Figure 1). Results for the primary end point, a first hospitalization for heart failure, and death from any cause were consistent across subgroups (Figure 2 and Figs. S2 and S3). Results for the primary end point were consistent across sensitivity analyses, which included additional categories of hospitalization for heart failure (Fig. S4). Causes of death are shown in Table S6.

FIGURE 1

Kaplan–Meier Estimates and Cumulative Incidence Function for the Composite Primary End Point and Its Components.

FIGURE 2

Composite Primary End Point, According to Prespecified Subgroups.

TABLE 2

Primary, Secondary, and Other End Points.

Results for key secondary end points are shown in Table 2. The rate ratio (empagliflozin vs. placebo) was 0.87 (95% CI, 0.68 to 1.10) for the total number of hospitalizations for heart failure or death from any cause, 0.92 (95% CI, 0.78 to 1.07) for the total number of nonelective cardiovascular hospitalizations or death from any cause, 0.87 (95% CI, 0.77 to 1.0) for the total number of nonelective hospitalizations for any cause or death from any cause, and 1.06 (95% CI, 0.83 to 1.35) for the total number of hospitalizations for myocardial infarction or death from any cause.

With respect to exploratory end points, death from cardiovascular causes occurred in 132 patients (4.0%) in the empagliflozin group and in 131 patients (4.0%) in the placebo group (hazard ratio, 1.03; 95% CI, 0.81 to 1.31). The time to death from cardiovascular causes and the time to a first hospitalization for heart failure or death from cardiovascular causes were similar in the two trial groups (Figs. S5 and S6). The total number of hospitalizations for heart failure was 148 in the empagliflozin group and 207 in the placebo group, with a rate of 2.4 and 3.6 events, respectively, per 100 patient-years (rate ratio, 0.67; 95% CI, 0.51 to 0.89). Results of sensitivity analyses that accounted for the competing risks of death from any cause or death from noncardiovascular causes were consistent with those from Cox regression models (data not shown).

SAFETY

A similar percentage of patients in the two trial groups had a serious adverse event (23.7% in the empagliflozin group and 24.7% in the placebo group) or an adverse event that resulted in permanent discontinuation of the trial regimen (3.8% in each group) (Table 3). Contrast-induced acute kidney injury occurred in 8 patients (0.2%) in the empagliflozin group and in 9 patients (0.3%) in the placebo group.

TABLE 3

Adverse Events in the Safety Population.

Discussion

In the EMPACT-MI trial, empagliflozin treatment did not lead to a significantly lower risk of a composite primary end-point event — a first hospitalization for heart failure or death from any cause — than placebo among patients presenting with an acute myocardial infarction and an increased risk of heart failure. The rates of prespecified key secondary end-point events did not differ substantially in the two trial groups.

Recently, the DAPA-MI trial, which excluded patients with diabetes, did not show a lower risk of death from cardiovascular causes or hospitalization for heart failure with dapagliflozin therapy than with placebo after acute myocardial infarction.6 The prespecified composite primary end point in the DAPA-MI trial was changed to a seven-level win ratio. The actual numbers of heart-failure events or deaths were too few to allow for any meaningful conclusion.12 The data from the EMPACT-MI trial help fill the gap in knowledge about the effect of SGLT2 inhibitors in patients after acute myocardial infarction.

Certain factors may have contributed to the lack of an effect of empagliflozin on the primary composite end point in the EMPACT-MI trial. Deaths from any cause composed 52% of the primary end-point events and occurred in a similar percentage of patients in the two trial groups. By design, we enrolled patients soon after acute myocardial infarction, a time when several mechanisms that may not be amenable to modification with SGLT2 inhibition, which include cardiac causes (e.g., stent thrombosis, recurrent myocardial infarction, mechanical complications, and scar-related ventricular arrhythmias) and noncardiac causes within the first 30 days, contribute to mortality.13

As in our trial, the sample size in the PARADISE-MI trial (Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction) was increased because of low rates of primary end-point events — 6.7 and 7.4 events per 100 patient-years in the valsartan–sacubitril and ramipril groups, respectively.14,15 These rates and the rates in our trial are lower than those observed in previous trials and observational studies.16,17 The reasons for this may be related to multiple factors, including the widespread use of medical therapies, timely access to revascularization after myocardial infarction, and the coronavirus disease 2019 (Covid-19) pandemic, as well as regional wars in the case of the EMPACT-MI trial.18

The number and percentage of heart-failure events that contributed to the primary end point may have been affected by several factors. Our trial was conducted during the Covid-19 pandemic, when the number of hospitalizations for heart failure decreased substantially.19 Patients with less severe symptoms may not have sought care or may have been treated in the outpatient setting. In addition, two of the regions where our trial was conducted were affected by war.20 Heart-failure events other than hospitalization were not included in the primary end point. In some other trials, outpatient heart-failure events have contributed meaningfully to the total burden of heart-failure events. For example, of the 4744 patients randomly assigned to receive dapagliflozin or placebo in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), 549 were hospitalized for heart failure, 33 had a heart-failure event that resulted in the receipt of intravenous diuretic therapy in the outpatient setting, and 604 had a worsening heart-failure event that resulted in the initiation or intensification of oral diuretic therapy in the outpatient setting.21 Whether the inclusion of a broader measure of the burden of heart failure in the primary end point would have affected the results of our trial is unclear.

In our trial, some of the patients with a lower left ventricular ejection fraction or congestion at the time of randomization may have had a stunned myocardium that was reversible; further improvement after revascularization is unlikely in this lower-risk population.3,22,23 This might be the case particularly in patients with STEMI, who composed nearly 75% of the patients in the EMPACT-MI trial, in which approximately 90% of the patients underwent early revascularization.

Previous trials involving patients with established heart failure or with type 2 diabetes and atherosclerotic cardiovascular disease have shown reductions of 29 to 35% in the relative risk of hospitalization for heart failure among patients treated with SGLT2 inhibitors as compared with patients who received placebo.8–10,24,25 The findings of our exploratory analyses of a first hospitalization for heart failure and the total number of hospitalizations for heart failure in the empagliflozin group as compared with the placebo group appear to be consistent with the results of these previous trials, and further study of the effects of SLGT2 inhibitors on heart-failure outcomes in high-risk patients after myocardial infarction may be warranted.

We did not observe evidence of increased rates of serious adverse events, adverse events that resulted in permanent discontinuation of the trial regimen, or adverse events of special interest. The data from EMPACT-MI trial further build on the safety profile of SGLT2 inhibitors in patients across the spectrum of cardiovascular risks and provide evidence for the safety of these agents in hospitalized patients.8,26,27

Our trial has limitations. The end-point events were not centrally adjudicated but were assessed by site investigators according to prespecified definitions. Outpatient heart-failure events were not analyzed as clinical end points. Despite our attempts to improve the representation of women, older adults, and historically underrepresented racial and ethnic minorities in this trial, their representation remained suboptimal. Some patients in these groups are at increased risk for heart failure after myocardial infarction, and further work is needed to improve their representation (Table S3).1,28 Only focused safety data were collected.

In the current trial, empagliflozin did not reduce the risk of the composite primary end-point event — a first hospitalization for heart failure or death from any cause — in patients with acute myocardial infarction who were at increased risk for heart failure.

Stress Ulcer Prophylaxis in Mechanically Ventilated Patients With Acute Myocardial Infarction

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Abstract

Background

Proton pump inhibitors (PPIs) and histamine type 2-receptor blockers (H2Bs) are commonly used for stress ulcer prophylaxis among patients requiring invasive mechanical ventilation (IMV). Recent studies suggest an increased mortality associated with PPIs compared to H2Bs, but these studies poorly represent patients with cardiovascular disease or acute myocardial infarction (AMI).

Objectives

The aim of this study was to compare outcomes related to stress ulcer prophylaxis with PPIs compared to H2Bs in patients with AMI requiring IMV.

Methods

We queried the Vizient Clinical Data Base for adults aged ≥18 years admitted between October 2015 and December 2019 with a primary diagnosis of AMI and requiring IMV. Using multivariable logistic regression, we assessed for the association between stress ulcer prophylaxis and in-hospital mortality.

Results

Including 11,252 patients with AMI requiring IMV, 66.7% (n = 7,504) received PPIs and 33.3% (n = 3,748) received H2Bs. Age, sex, and the proportion of patients presenting with ST-segment elevation myocardial infarction or cardiogenic shock were similar between groups (all, P > 0.05). Compared to PPIs, patients receiving H2Bs had a lower mortality (41.5% vs 43.5%, P = 0.047), which was not statistically significant after multivariate adjustment (odds ratio 0.97; 95% confidence interval: 0.89-1.06, P = 0.49). In unadjusted and adjusted analyses, H2Bs use was associated with fewer ventilator days, less ventilator-associated pneumonia, and lower hospitalization cost but similar Clostridium difficile infections.

Conclusions

Among patients with AMI requiring IMV in this observation cohort study, there was no difference in mortality among patients receiving H2Bs vs PPIs for stress ulcer prophylaxis despite fewer ventilator days and lower ventilator-associated pneumonia in those receiving H2Bs.

Introduction

Stress ulcer prophylaxis is commonly prescribed for critically ill patients to minimize the morbidity related to clinically significant gastrointestinal (GI) bleeding events.1 Current guidelines recommend stress ulcer prophylaxis for those at high risk of GI bleeding, which commonly includes patients requiring invasive mechanical ventilation (IMV), coagulopathy, sepsis, shock, history of previous GI bleeding, and those on antiplatelet therapy.2-5 Proton pump inhibitors (PPIs) and histamine-2 receptor blockers (H2Bs) are the most frequently prescribed agents for acid suppression therapy.6,7 In a meta-analysis of 57 randomized controlled trials, including over 7,000 patients, PPIs were found to be more effective at preventing GI bleeding, but potentially increased the risk of pneumonia compared to H2Bs.8 More recently, the PEPTIC (Proton Pump Inhibitors vs Histamine-2 Receptor Blockers for Ulcer Prophylaxis Treatment in the Intensive Care Unit) trial of over 26,000 mechanically ventilated patients similarly found those receiving PPIs had a lower risk of upper GI bleeding compared to those randomized to H2Bs. However, 90-day mortality was nonsignificantly (P = 0.054) higher in the PPI group and significantly increased in those who underwent cardiac surgery.9

Patients presenting with acute myocardial infarction (AMI) may be especially vulnerable to GI bleeding due to the use of antiplatelet and antithrombotic medications,10,11 especially those who are critically ill requiring IMV.12 In addition, stress ulcer prophylaxis selection may be particularly critical in this group as PPIs generally have more interactions than H2Bs with antiplatelet and antithrombotic therapy.13 A recent scientific statement from the American Heart Association currently recommends PPIs for high-risk patients as “reasonable to administer.”4 However, the evidence for either option in this patient population is limited and must be balanced with known risks, including Clostridium difficile infections (CDIs) and ventilator-associated pneumonia (VAP).14,15 Given these gaps in the literature, we aimed to compare outcomes related to PPI and H2B use for stress ulcer prophylaxis among mechanically ventilated patients with AMI.

Discussion

In this multicenter study of stress ulcer prophylaxis, we report several important findings using a largely understudied population of patients presenting with AMI. First, use of H2B compared to PPIs for stress ulcer prophylaxis did not result in a statistically significant difference in mortality after adjustment for markers of acuity. Second, patients who received stress ulcer prophylaxis with H2Bs experienced fewer days of IMV. Third, the use of H2Bs was associated with less VAP compared to those who received PPIs, but CDI was not different. Finally, patients receiving H2Bs were less likely to require postintubation transfusions and undergo endoscopy. Taken together, despite potentially more complications with PPIs, mortality was similar between groups in this patient population with AMI.

To our knowledge, this is the first study to investigate the use of PPIs vs H2Bs for stress ulcer prophylaxis in critically ill, nonsurgical patients with AMI. Patients with cardiovascular disease represent a minority in most landmark trials exploring the clinical implications of stress ulcer prophylaxis. For example, in the SUP-ICU (Stress Ulcer Prophylaxis in the Intensive Care Unit) trial, only 9% and 6% of patients had a pre-existing history of previous AMI or chronic heart failure, respectively.18 Similarly, in the recent PEPTIC trial, <7% of patients were reported to have a history of chronic cardiovascular disease. In addition, fewer than 10 to 15% of patients were admitted to the ICU with an acute, nonoperative cardiovascular diagnosis, which is not defined further and may represent a heterogenous group with varying management considerations.9 The paucity of evidence guiding stress ulcer prophylaxis strategies among critically ill patients with AMI is a gap in literature that this study addresses.

Our results parallel findings of the PEPTIC trial, which did not find a statistically significant difference in mortality among 26,000 general ICU patients receiving H2Bs compared to PPIs for stress ulcer prophylaxis.9 A higher mortality was reported among patients receiving PPIs in a prespecified subgroup of cardiac surgery patients, though a secondary analysis found mortality was statistically similar between treatment groups after adjusting for patient- and site-specific factors.19 Specific to the AMI population, prior observational studies describe an increased risk of adverse cardiovascular outcomes associated with PPI use, thought to be driven by pharmacologic interactions with dual antiplatelet therapy and endothelial dysfunction.20 However, one of the largest prospective randomized trials, COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial), concluded there was no increase in major adverse cardiovascular events during a 6-month period among nonsurgical acute coronary syndrome patients coprescribed omeprazole and clopidogrel.21 Our findings are consistent with other studies suggesting the pharmacologic interaction between antiplatelet agents and PPIs has limited clinical impact, even in critical illness.

Our study also found that patients receiving PPIs experienced more VAP and days of IMV compared to those receiving H2Bs. PPIs promote bacterial colonization by reducing gastric acidity, which predisposes patients to VAP. By inhibiting H + ATPases, PPIs also impair neutrophil oxidative burst and phagolysosome formation, thereby blunting the immune response.22 Similar to our findings, Bashar et al23 reported a 3-fold increase in VAP among mechanically ventilated patients randomized to receive stress ulcer prophylaxis with PPIs compared to H2B, though duration of IMV was similar between the groups.

Conclusions

We found that stress ulcer prophylaxis with H2Bs compared to PPIs in patients with AMI requiring IMV was associated with fewer ventilator days and VAP; however, there was no difference in mortality between the 2 groups. Our findings suggest that choice of either stress ulcer prophylaxis, despite potentially more complications with PPIs, is associated with a similar in-hospital mortality.

Impact of risk factors related to metabolic syndrome on acute myocardial infarction in younger patients

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Abstract

Despite diagnostic and therapeutic advancements in cardiovascular medicine, myocardial infarction (MI) remains a major cause of adverse outcomes in younger MI patients, i.e., those who are aged 55 years or younger. Traditional cardiovascular risk factors have not often been emphasized in the management of younger MI patients. However, plaque rupture or erosion, which is deeply related to cardiovascular risk factors, remains the most common etiology of MI even in younger patients. The global increase in the prevalence of obesity underscores the clinical importance of metabolic syndrome (MetS), i.e., obesity-associated cardiovascular risk factors, dyslipidemia, diabetes mellitus and particularly hypertension, in younger people. The concept of “lifetime risk” of cardiovascular disease reinforces the need for prevention or treatment of MetS. This review focuses on the risk factors related to MetS and an overall understanding of recent profiles of younger MI patients. We hope that this review will aid in the primary prevention of MetS-related risk factors and the prevention of cardiovascular disease, particularly MI, in younger patients.

Role Of Metoprolol Tartrate In Management Of Acute Myocardial Infarction In The Present Era

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It has long been known that among patients with acute myocardial infarction (MI), beta-blocker therapy is beneficial in reducing infarct size and early mortality. [1] However, there is still an ongoing debate regarding which agent to be used and more importantly when to initiate it? What is the ideal patient population for this therapy and does it make a difference in which route (parenteral or oral) is used? And most importantly –do these agents have a benefit in the current primary percutaneous coronary intervention (PCI) era.

The following review aims to provide evidence-based answers to such questions that are encountered by all physicians and cardiologists involved in caring for cardiac patients.

Why beta-blockers are beneficial in acute MI?

Proposed mechanisms by which these agents benefit MI patients are:

  • Decreasing the oxygen demand due to the reductions in heart rate, blood pressure, and contractility, and the consequent relief of ischemic chest pain. [2]
  • Decreased risk of ventricular fibrillation as suggested by experimental studies demonstrating an increase in the ventricular fibrillation threshold and by clinical trials showing a relative risk reduction in sudden cardiac death. [3],[4]

The first mechanism serves to reduce the ongoing ischemic insult to the myocardium and in principle should limit the infarct size [2]. The latter mechanism is responsible for improving survival [4].

The journey of beta-blockers: “The story of several ups and down”.

Beta-blockers have long been a component of care in patients with acute myocardial infarction because of the mechanisms cited above. Preclinical studies showed reduced infarct size in dogs, particularly when the beta-blockers are administered before coronary artery ligation. [5]

Several clinical studies performed in the pre-reperfusion era have demonstrated beneficial effects of β-blockers in acute myocardial infarction in terms of reduction of infarct size [6] or improved survival. [7]

In the thrombolytic era, randomized studies involving early intravenous administration of beta-blockers showed promising results. In the appropriate post-infarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with reduced myocardial ischemia, risk of re-infarction, and ventricular fibrillation. [8][9]

So, the overall use of beta-blockers in the acute setting in patients with STEMI may be summarized as predominantly beneficial in the pre-reperfusion era.

METOCARD-CNIC trial: “The game-changer” [10]

In 2013, Ibanez et al published the results of the effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) study that aimed to fill the existing gap in the clinical investigation of intravenous β-blockade administered before primary PCI in patients with STEMI.

This multicenter, prospective, randomized study compared early IV metoprolol tartrate (prior to reperfusion) to no metoprolol prior to reperfusion.

Patients were eligible for enrolment if they presented with an anterior STEMI, if their symptom duration was >30 min, and if reperfusion could be performed within 6 h of symptom onset. Exclusion criteria included Killip class III or IV, PR interval >240 ms, type II or III atrioventricular block, systolic blood pressure <120 mmHg, heart rate <60 bpm persistently, history of prior MI, or currently active beta-blocker therapy.

MRI was performed 5–7 days after infarction in all other patients and infarct size was quantified.

Relative to controls, infarct size was significantly lower (25.6 ± 15.3 vs 32.0 ± 22.2 g; p = .012) in patients treated with IV metoprolol. This difference was greatest in patients with TIMI grade 0–1 flow prior to PCI; in this cohort, infarct size was 26.7 ± 15.0 g in patients treated with IV metoprolol, and 34.4 ± 20.0 g in controls (p = .0024). Additionally, there was no difference in adverse cardiac events between groups in the first 24 h.

Of note, 34.9% of the initial myocardial area at risk was salvaged in the metoprolol group compared with 27.7% in the control group.

The authors concluded that in patients with anterior wall STEMI, intravenous metoprolol before PCI reduced infarct size and improved left ventricular function with no excess of adverse events within the first 24 hours after STEMI. (10)

How to use metoprolol tartrate in acute MI setting: [10][11]

The most accepted and widely used dosing regimen is essentially the same as was used in METOCARD-CNIC trial: intravenous metoprolol received up to three 5-mg boluses of metoprolol tartrate 2 minutes apart.

Patients who tolerate this regimen should then receive early oral therapy with Metoprolol Tartrate IR 25-50mg PO BID:

One should start the first dose 15-30 minutes after the last IV dose. The goal is to discharge at HR at approximately 70bpm.

Is one beta-blocker preferable over the other?

Metoprolol is a lipophilic cardioselective beta-1-adrenergic receptor inhibitor that competitively blocks beta1-receptors with minimal or no effects on beta-2 receptors at oral doses of less than 100 mg in adults. [12]Unlike non-selective beta-blockers like propranolol, metoprolol is safer for use in patients with peripheral vascular disease, respiratory conditions, and others. [13]

Cardioprotective benefits of beta-blockers in acute MI settings are not a class effect. While Werf et al, [14] who randomized STEMI patients undergoing thrombolysis to receive pre-thrombolysis atenolol or placebo, did not find any reduction in infarct size by intravenous β-blocker administration; the TEAHAT study found a significant infarct size reduction when using intravenous metoprolol [15].

Clinical takeaways:

  • Infarct size is a major determinant of post-infarction mortality, so limiting the extent of myocardial necrosis in STEMI is a major therapeutic target. [16]
  • Huge resources have been dedicated to exploring novel therapies that might reduce infarct size but so far with little success.
  •  IV Metoprolol tartrate- an inexpensive medication already approved for STEMI treatment can significantly reduce infarct size simply by being administered before reperfusion.
  •  Once the acute phase is over, the American College of Cardiology recommends that patients who have had a MI be treated with a beta-blocker like metoprolol indefinitely.

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock.

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Abstract

Background In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. Methods In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. Results At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. Conclusions Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI.

Effect of Beta-Blocker Dose on Survival After Acute Myocardial Infarction

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Background  Beta-blocker therapy after acute myocardial infarction (MI) improves survival. Beta-blocker doses used in clinical practice are often substantially lower than those used in the randomized trials establishing their efficacy.

Objectives  This study evaluated the association of beta-blocker dose with survival after acute MI, hypothesizing that higher dose beta-blocker therapy will be associated with increased survival.

Methods  A multicenter registry enrolled 7,057 consecutive patients with acute MI. Discharge beta-blocker dose was indexed to the target beta-blocker doses used in randomized clinical trials, grouped as >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target dose. Follow-up vital status was assessed, with the primary endpoint of time-to-death right-censored at 2 years. Multivariable and propensity score analyses were used to account for group differences.

Results  Of 6,682 patients with follow-up (median 2.1 years), 91.5% were discharged on a beta-blocker (mean dose 38.1% of the target dose). Lower mortality was observed with all beta-blocker doses (p < 0.0002) versus no beta-blocker therapy. After multivariable adjustment, hazard ratios for 2-year mortality compared with the >50% dose were 0.862 (95% confidence interval [CI]: 0.677 to 1.098), 0.799 (95% CI: 0.635 to 1.005), and 0.963 (95% CI: 0.765 to 1.213) for the >0% to 12.5%, >12.5% to 25%, and >25% to 50% of target dose groups, respectively. Multivariable analysis with an extended set of covariates and propensity score analysis also demonstrated that higher doses were not associated with better outcome.

Conclusions  These data do not demonstrate increased survival in patients treated with beta-blocker doses approximating those used in previous randomized clinical trials compared with lower doses. These findings provide the rationale to re-engage in research to establish appropriate beta-blocker dosing after MI to derive optimal benefit from this therapy.

APPROACH to Cardiac Troponin Elevations in Patients With Renal Disease

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A 62-year-old male presented to the emergency department with chest pain radiating down his left arm that lasted 40 minutes and awakened him 3 hours prior to arrival. It was associated with shortness of breath, nausea, and diaphoresis. You note a history of hypertension and hypercholesterolemia controlled with hydrochlorothiazide and atorvastatin. In addition, he has chronic renal failure, for which he tells you that his doctor thinks he might soon require dialysis. His father had died of an acute myocardial infarction (AMI) at 70 years of age. Physical examination shows no acute distress. His blood pressure is 149/89 mmHg and heart rate is 86 bpm. On auscultation, both heart sounds are audible and normal, although you do notice a fourth heart sound and bibasilar rales on the chest posteriorly along with bilateral pedal edema to the level of the mid-shins and mild jugular venous distension. A 12-lead ECG suggests left ventricular hypertrophy (LVH) but is otherwise unremarkable, and his chest x-ray is normal. Upon reviewing his blood work you notice that his cardiac troponin (cTn) level drawn on admission was elevated and that his most recent estimated glomerular filtration rate (eGFR) is 23 mL/min. The resident with you concludes the elevated cTn can be explained by the patient’s renal failure and that his kidneys are no longer able to excrete it effectively. He goes on to state that, despite the patient’s highly suggestive report of chest pain and impressive risk factors, in the absence of ECG changes or “new” cTn elevations, this cannot be classified as an AMI. The patient is therefore not at high risk and so is not a candidate for an invasive strategy and can be managed with medical therapy alone.

Our approach

The resident is correct in recalling that the universal definition of AMI requires elevated biochemical markers of myocardial necrosis in addition to either symptoms of cardiac ischemia or ECG changes indicative of ischemia. In addition, he is correct in noting that elevated cTn levels related to cardiac ischemia are associated with an adverse prognosis and that these high-risk patients benefit from an early invasive strategy. However, the resident has made a number of errors as well. The cTn used here is a conventional assay and, with these, cTn is typically only elevated in patients with end-stage renal disease (ESRD). In this setting, raised levels increase progressively as the duration of dialysis increases and are associated with a poor prognosis. This patient may require renal replacement therapy soon, but, for the time being, his eGFR is not low enough to explain the elevated cTn. Even if it was low enough, there is no evidence that cTn is cleared renally. cTn may persist in the blood of patients with ESRD due to alternative cleavages involved in the degradation of the protein. This is also likely to be the reason why there are more elevations of cTnT than of cTnI, although both predict adverse long-term outcomes. Furthermore, concomitant changes such as LVH and other metabolic changes can often be attributed to cTn elevations.

This patient’s cTn may in fact be associated with a coronary event. A more diligent resident may have checked the patient’s chart for previous cTn levels, which, if in the normal range, would help to identify a rising pattern. The universal definition for AMI states that clinicians should look for a rising and/or falling pattern in cTn levels. This may not necessarily be synonymous with an AMI, but certainly indicates an acute event, which, along with a suggestive ECG or clinical history, should help to confirm the diagnosis of an AMI. Patients who present late (12–18 hours) after the onset of symptoms may not demonstrate a rising/falling pattern, so clinical judgment must be used. However, in this situation, the patient presented 3 hours after the onset of symptoms and one would expect a rising pattern associated with an acute coronary event. Thus, serial cTn levels should be drawn at 3 and 6 hours from the point of the patient’s arrival. A documented rising pattern in conjunction with the clinical history will confirm the diagnosis of AMI and trigger the decision for an early invasive approach, but the patient should receive full antiplatelet therapy in the meantime if suspicion of an acute coronary syndrome is high. If such a pattern is not present, alternative diagnoses should be sought. A presumptive diagnosis of AMI should not be made. This is particularly important among patients with ESRD whose cTn is elevated at baseline and who are at higher risk for bleeding as a result of their uremic state, and should not, therefore, be needlessly subjected to invasive procedures. In addition, the use of IV contrast during angiography may lead to worsening of already compromised renal function, further highlighting the need for appropriate case selection. A useful approach for these patients is to have cTn drawn routinely in outpatient settings, which can provide a baseline cTn level with which levels drawn during an acute presentation can be compared to help make a diagnosis.

Marked elevations in cTn tend to occur in only four situations: AMI, myocarditis, renal failure, and, on rare occasions, with an analytical error. Thus, serially drawn levels are still required, and a crucial facet of this problem is defining what degree of change in cTn is required. One such approach may be to define a level of change that exceeds the degree of analytical imprecision associated with a particular assay. This will vary from assay to assay and should be calculated and reported by laboratories. The changes required will be large on a percentage basis when the initial level is low, but, in ESRD where the baseline levels are elevated, lesser changes are required. Some have suggested a change of 50% when values are close to the 99% upper reference limit and 20% when they are above this.

With a high-sensitivity troponin assay, a higher proportion of elevated levels will be appreciated and will often be associated with abnormal renal function, even when it is mild. As with conventional assays, these elevations also predict poor outcomes. These observations clarify to some extent the relationship between renal dysfunction and troponin, but also create the clinical challenge of discriminating elevations related to an acute cardiac event from other pathologies.

Ultimately, an understanding of cTn testing in conjunction with Bayesian principles of diagnostic testing must inform the decision-making process. This patient’s risk factors (including the fact that he has chronic renal failure) and clinical presentation give rise to a high pretest probability of disease. The isolated elevation in cTn determined using a conventional assay is unlikely to be related to his renal failure but cannot be immediately attributed to AMI until a changing pattern is observed, at which point his post-test probability of disease will justify an early invasive approach. When in doubt, clinical judgment must be used. Lastly, but of equal importance, is the fact that the elevation is associated with an adverse prognosis. Thus, our astute resident should investigate whether there is good control of blood pressure, volume, and lipids and institute preventative pharmacotherapy as appropriate.

Copeptin Helps “Copeptin Helps in the Early Detection Of Patients with Acute Myocardial Infarction”: the primary results of the CHOPIN Trial ONLINE FIRST.

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“Copeptin Helps in the Early Detection Of Patients with Acute Myocardial Infarction”: the primary results of the CHOPIN Trial ONLINE FIRST

Objectives  Demonstrate that copeptin level <14 pmol/L allows ruling out AMI when used in combination with cardiac troponin I (cTnI) <99th percentile and a non-diagnostic ECG at the time of presentation to the emergency department (ED).

Background  Copeptin is secreted from the pituitary early in the course of acute myocardial infarction (AMI).

Methods  This was a 16-site study in 1967 chest pain patients presenting to an ED within 6 hours of the onset of chest pain. Baseline demographics and clinical data were collected prospectively. Copeptin and a contemporary sensitive cTnI (99th percentile 40 ng/L; 10% coefficient of variation (CV) 0.03 μg/L) were measured in a core laboratory. Patients were followed for 180 days. The primary outcome was diagnosis of AMI. Final diagnoses were adjudicated by two independent cardiologists blinded to copeptin results.

Results  AMI was the final diagnosis in 156 patients (7.9%). A negative copeptin and cTnI at baseline ruled out AMI for 58% of patients, with a NPV of 99.2% (95% CI 98.5-99.6). AMIs not detected by the initial cTnI alone were picked up with copeptin >14 pmol/L in 23/32 patients (72%). NSTEMIs undetected by cTnI at 0h were detected with Copeptin >14 pmol/L in 10/19 patients (53%). Projected average time-to-decision could be reduced by 43% (from 3.0 hours to 1.8 hours) by the early rule out of 58% of patients. Both abnormal copeptin and cTnI were predictors of death at 180 days (p<0.0001 for both, c index 0.784 and 0.800, respectively). Both were independent of age and each other and provided additional predictive value (all p<0.0001).

Conclusion  Adding copeptin to cTnI allowed safe rule out of AMI with a NPV >99% in patients presenting with suspected ACS. It has the potential to rule out AMI in 58% of patients without serial blood draws.

Source: JACC