Omega-3 Meds Not Effective After MI, EMA Panel Concludes


The European Medicine Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has concluded that omega-3 fatty acid medicines are not effective for secondary prevention after myocardial infarction (MI).

Omega-3 fatty acid medicines at a dose of 1 g per day have been authorized in several European Union countries since 2000 for preventing heart disease or stroke after MI and for lowering high triglycerides.

When they were authorized, the available data showed “some benefits in reducing serious problems with the heart and blood vessels, although the benefits were considered modest,” the EMA said in a news release. “Further data that have become available since then have not confirmed the beneficial effects of these medicines for this use.”

The CHMP’s conclusion, released at their December meeting, means that these medicines will no longer be authorized for such use.

Their review included results of the open-label GISSI Prevenzione study from 1999, which supported the initial authorization of these products, as well as retrospective cohort studies, more recent randomized controlled trials, and results of meta-analyses.

“The review concluded that, while a small relative risk reduction was seen in the original open label GISSI Prevenzione study, such beneficial effects were not confirmed in more recent randomized controlled trials,” the EMA said. The review found no new safety concerns.

The Committee’s decision does not affect the authorization of omega-3 fatty acid medicines for the treatment of hypertriglyceridemia.

The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Support for the CHMP decision comes from results of the large VITAL trial, which found little benefit from omega-3 supplements (or vitamin D supplementation) for the prevention of cardiovascular disease, as reported by Medscape Medical News.

In the ASCEND trial, a 1 g dose of omega-3 fatty acids had no effect on serious vascular events (or cancer or mortality) when used for primary prevention in patients with diabetes.

However, in the REDUCE-IT trial, a high-dose purified form of the omega-3 oil, eicosapentaenoic acid (EPA), in patients with elevated triglycerides who had cardiovascular disease or diabetes and one additional risk factor did show significant benefit, with a 25% relative risk reduction in major adverse

Omega-3 Meds Not Effective After MI, EMA Panel Concludes


The European Medicine Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has concluded that omega-3 fatty acid medicines are not effective for secondary prevention after myocardial infarction (MI).

Omega-3 fatty acid medicines at a dose of 1 g per day have been authorized in several European Union countries since 2000 for preventing heart disease or stroke after MI and for lowering high triglycerides.

When they were authorized, the available data showed “some benefits in reducing serious problems with the heart and blood vessels, although the benefits were considered modest,” the EMA said in a news release. “Further data that have become available since then have not confirmed the beneficial effects of these medicines for this use.”

The CHMP’s conclusion, released at their December meeting, means that these medicines will no longer be authorized for such use.

Their review included results of the open-label GISSI Prevenzione study from 1999, which supported the initial authorization of these products, as well as retrospective cohort studies, more recent randomized controlled trials, and results of meta-analyses.

“The review concluded that, while a small relative risk reduction was seen in the original open label GISSI Prevenzione study, such beneficial effects were not confirmed in more recent randomized controlled trials,” the EMA said. The review found no new safety concerns.

The Committee’s decision does not affect the authorization of omega-3 fatty acid medicines for the treatment of hypertriglyceridemia.

The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Support for the CHMP decision comes from results of the large VITAL trial, which found little benefit from omega-3 supplements (or vitamin D supplementation) for the prevention of cardiovascular disease, as reported by Medscape Medical News.

In the ASCEND trial, a 1 g dose of omega-3 fatty acids had no effect on serious vascular events (or cancer or mortality) when used for primary prevention in patients with diabetes.

However, in the REDUCE-IT trial, a high-dose purified form of the omega-3 oil, eicosapentaenoic acid (EPA), in patients with elevated triglycerides who had cardiovascular disease or diabetes and one additional risk factor did show significant benefit, with a 25% relative risk reduction in major adverse cardiovascular events.

Omega-3 Meds Not Effective After MI, EMA Panel Concludes


The European Medicine Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has concluded that omega-3 fatty acid medicines are not effective for secondary prevention after myocardial infarction (MI).

Omega-3 fatty acid medicines at a dose of 1 g per day have been authorized in several European Union countries since 2000 for preventing heart disease or stroke after MI and for lowering high triglycerides.

When they were authorized, the available data showed “some benefits in reducing serious problems with the heart and blood vessels, although the benefits were considered modest,” the EMA said in a news release. “Further data that have become available since then have not confirmed the beneficial effects of these medicines for this use.”

The CHMP’s conclusion, released at their December meeting, means that these medicines will no longer be authorized for such use.

Their review included results of the open-label GISSI Prevenzione study from 1999, which supported the initial authorization of these products, as well as retrospective cohort studies, more recent randomized controlled trials, and results of meta-analyses.

“The review concluded that, while a small relative risk reduction was seen in the original open label GISSI Prevenzione study, such beneficial effects were not confirmed in more recent randomized controlled trials,” the EMA said. The review found no new safety concerns.

The Committee’s decision does not affect the authorization of omega-3 fatty acid medicines for the treatment of hypertriglyceridemia.

The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Support for the CHMP decision comes from results of the large VITAL trial, which found little benefit from omega-3 supplements (or vitamin D supplementation) for the prevention of cardiovascular disease, as reported by Medscape Medical News.

In the ASCEND trial, a 1 g dose of omega-3 fatty acids had no effect on serious vascular events (or cancer or mortality) when used for primary prevention in patients with diabetes.

However, in the REDUCE-IT trial, a high-dose purified form of the omega-3 oil, eicosapentaenoic acid (EPA), in patients with elevated triglycerides who had cardiovascular disease or diabetes and one additional risk factor did show significant benefit, with a 25% relative risk reduction in major adverse cardiovascular events.

Is There an Increased Risk of Dementia After Surviving a Myocardial Infarction?


To survive a myocardial infarction but then face the potential for the development of dementia is unsettling to say the least. In a study in this issue of Circulation, Sundbøll and colleagues[1] test this association in a Danish nationwide patient registry. Administrative records are used to track incident dementia over ≤35 years of follow-up for 314 911 one-year survivors of myocardial infarction (MI) and 1 573 193 controls without MI. Although all-cause dementia did not differ between the groups over the follow-up period, vascular dementia was more frequent in individuals with an MI, particularly in those with a stroke during follow-up or who required coronary artery bypass grafting (CABG) surgery.

When interpreting what these results mean for the survivor of an MI, however, it is important to consider how these conditions were defined and what the likely explanation might be for the observed associations. In this study, individuals with MI and without MI were clearly 2 different groups of individuals: although matched to the MI cases for sex, birth year, and calendar year, it is not surprising that those people without an MI had lower vascular risk with higher levels of educational attainment and socioeconomic status than did their counterparts who did experience an MI. Although attempts were made to adjust for these observed differences, it is likely that these groups remain substantively different.

As a result of these differences, it remains unclear whether the increased risk is because of the MI or the underlying risk that led to the MI in the first place. This question has been addressed in individuals undergoing CABG surgery: although cognitive decline was noted to be high in earlier studies among individuals undergoing CABG surgery, with 42% reportedly experiencing cognitive decline at 5 years,[2] studies that included a control group of individuals with similar coronary artery disease but who did not undergo CABG found that decline did not differ at 6 years between the CABG group and their nonsurgical coronary artery disease counterparts.[3] Cognitive decline was steeper, however, in both of these coronary artery disease groups than in the group without vascular disease.[4] Thus, if one could study patients with identical vascular risk factors, with similar coronary artery disease, but with some experiencing MI and others not, it is likely that cognitive decline and dementia rates might be similar in these groups. Evaluation of these risk factors in population-based studies supports this finding, with higher rates of dementia in individuals with many of the same vascular risk factors that are known to be important for MI risk: hypertension, diabetes mellitus, smoking, and high cholesterol.[5,6] A recent systematic review considered 24 cohort studies and found an elevated risk of cognitive impairment or dementia (odds ratio, 1.45) in individuals with coronary heart disease, including but not limited to MI.[7]

Another consideration in the interpretation of these results involves the determination of the dementia diagnoses: because dementia diagnoses were obtained from medical records, it is likely that clinicians making these diagnoses were biased based on knowledge of that individual’s vascular (and MI) history. Thus, an individual with new-onset cognitive decline and a history of MI is much more likely to be labeled as having vascular dementia than would someone without these risk factors but with similar decline. In fact, having no vascular history but having new dementia symptoms would probably make it more likely that someone would be diagnosed with Alzheimer’s disease (AD). This might explain the finding in this study that AD is actually less common in this study in individuals with prior MI, with vascular dementia more common in the survivors of an MI.

The association in question is challenging to study, given these clear differences in the types of people who do and do not get MIs and the previously described possibility of bias in identifying and defining dementia cases. Yet there is an important message here: patients who experience MI are diagnosed with vascular dementia at a higher rate than the general population. Furthermore, in real clinical practice, patients with MI are different than those without MI, just as seen in this study, and patients with MI are more likely to be labeled as having vascular dementia than are individuals without an MI. Therefore, this message and its implications need to be understood by clinicians caring for patients recovering from MI. Screening for cognitive impairment may be especially important in individuals with advanced enough coronary artery disease to experience an MI, and certainly risk factor management will be critical.

In this study,[1] individuals experiencing stroke during follow-up had an especially strong association between MI and vascular dementia, with an odds ratio of 4.48, compared with 1.30 for MI in individuals without stroke. This could still reflect differences in the extent of vascular risk, with those individuals with both MI and stroke likely having the greatest extent of underlying vascular risk, thus increasing the risk for vascular dementia, or could reflect ascertainment bias with a further increased likelihood of being given a label of vascular dementia with that history. This is especially likely because cerebrovascular disease, particularly with a clear temporal relation to the onset of dementia, is part of the NINDS-AIREN (National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences) diagnostic criteria for vascular dementia[8] and is a specific exclusionary criterion for AD.[9] Despite these concerns, however, this emphasizes an important aspect of care after an MI and suggests that it may be especially important to prevent stroke in this high-risk population. At 1 year after an MI, stroke is estimated to occur in 21.4 individuals per 1000 MIs and is predicted by individual characteristics (diabetes mellitus, hypertension, age, nonwhite race) as well as characteristics of the MI (anterior location and prior MI or atrial fibrillation),[10] with similar risk factors and rates found in other studies.[11] Although stroke may not be the direct cause of the increased risk of vascular dementia in all survivors of an MI, there is evidence that cognition declines more steeply after a stroke,[12] and thus it is especially important in a vulnerable individual to avoid this complication after an MI.

Vascular dementia is rarely a pure entity, with increasing evidence for overlap between vascular and AD etiologies of dementia. Dementia risk is increased in individuals with elevated vascular risk, and this study adds important data demonstrating potentially higher risk in individuals with MI, particularly those who experience a stroke or require CABG surgery during follow-up after an MI. Treatment after MI that focuses on control and prevention of vascular risk factors is likely to decrease chances of stroke and may even decrease chances of dementia. Survival after MI has improved over the last few decades,[13] which means there is a larger, older portion of the population with elevated vascular risk. Because age is a major risk factor for AD as well, and there is increasing evidence for clinical and even mechanistic overlap between these 2 pathologies (AD and vascular disease),[14,15] it is likely that risk for dementia in this population of survivors of an MI may increase in the coming years. This study reminds us of the importance of vascular risk factor treatment, prevention, and monitoring for cognitive decline in an especially vulnerable portion of the population.

Predictors, Trends, and Outcomes (Among Older Patients ≥65 Years of Age) Associated With Beta-Blocker Use in Patients With Stable Angina Undergoing Elective Percutaneous Coronary Intervention


Objectives  This study sought to examine predictors, trends, and outcomes associated with β-blocker prescriptions at discharge in patients with stable angina without prior history of myocardial infarction (MI) or systolic heart failure (HF) undergoing elective percutaneous coronary intervention (PCI).

Background  The benefits of β-blockers in patients with MI and/or systolic HF are well established. However, whether β-blockers affect outcomes in patients with stable angina, especially after PCI, remains uncertain.

Methods  We included patients with stable angina without prior history of MI, left ventricular systolic dysfunction (left ventricular ejection fraction <40%) or systolic HF undergoing elective PCI between January 2005 and March 2013 from the hospitals enrolled in the National Cardiovascular Data Registry (NCDR) CathPCI registry. These patients were retrospectively analyzed for predictors and trends of β-blocker prescriptions at discharge. All-cause mortality (primary endpoint), revascularization, or hospitalization related to MI, HF, or stroke at 30-day and 3-year follow-up were analyzed among patients ≥65 years of age.

Results  A total of 755,215 patients from 1,443 sites were studied, and 71.4% population of our cohort was discharged on β-blockers. At 3-year follow-up among patients ≥65 years of age with CMS data linkage (16.3% of the studied population), there was no difference in adjusted mortality rate (14.0% vs. 13.3%; adjusted hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.96 to 1.03; p = 0.84), MI (4.2% vs. 3.9%; adjusted HR: 1.00; 95% CI: 0.93 to 1.07; p = 0.92), stroke (2.3% vs. 2.0%; adjusted HR: 1.08; 95% CI: 0.98 to 1.18; p = 0.14) or revascularization (18.2% vs. 17.8%; adjusted HR: 0.97; 95% CI: 0.94 to 1.01; p = 0.10) with β-blocker prescription. However, discharge on β-blockers was associated with more HF readmissions at 3-year follow-up (8.0% vs. 6.1%; adjusted HR: 1.18; 95% CI: 1.12 to 1.25; p < 0.001). Results at 30-day follow-up were broadly consistent as well. During the period between 2005 and 2013, there was a gradual increase in prescription of β-blockers at the index discharge in our cohort (p < 0.001).

Conclusions  Among patients ≥65 years of age with history of stable angina without prior MI, systolic HF or left ventricular ejection fraction <40% undergoing elective PCI, β-blocker use at discharge was not associated with any reduction in cardiovascular morbidity or mortality at 30-day and at 3-year follow-up. Over time, β-blockers use at discharge in this population has continued to increase.

Perspectives

WHAT IS KNOWN? β-blockers have consistently been shown to improve outcomes in a variety of cardiovascular settings and therefore remain widely used.

WHAT IS NEW? This nonrandomized, observational study reports that β-blocker use at discharge among patients ≥65 years of age with stable angina without prior MI, LV systolic dysfunction (LVEF <40%), or systolic HF undergoing elective PCI in routine clinical practice was associated with no difference in post-discharge mortality, revascularization, or rehospitalization related to MI or stroke at 30-day and at 3-year follow-up. Their prescriptions at discharge continue to trend upward with time.

WHAT IS NEXT? The use of β-blockers in this population should be tailored based on other concomitant cardiovascular conditions and completeness of revascularization.

Worse MI Outcomes for the Poor?


More adverse events after discharge in dual Medicare-Medicaid eligibles.

After being hospitalized for a myocardial infarction (MI), patients with dual Medicare-Medicaid eligibility fared worse than their Medicare-only peers following discharge, investigators found.

Adherence to medication after MI was low in both groups, though patients eligible for Medicare and Medicaid — and therefore of lower socioeconomic class by definition — hadbetter adherence to their medications at 1 year (36.4% versus 30.0% for patients only on Medicare, HR 1.55, 95% CI 1.39-1.74), according to Jacob A. Doll, MD, of Duke University School of Medicine in Durham, N.C., and colleagues in their analysis of Medicare data published online in JAMA Cardiology.

Their dual eligibility, however, was also linked to greater risks:
Readmission at 30 days (HR 1.16, 95% CI 1.06-1.26)
Death at 1 year (HR 1.24, 95% CI 1.14-1.36), and
Major adverse cardiac events at 1 year (HR 1.21, 95% CI 1.12-1.31)
These patients “had worse short- and long-term outcomes after MI despite the additional financial support provided by Medicaid,” the investigators wrote. “While prior studies have shown a similar association between low socioeconomic status and worse outcomes, the present study is novel in demonstrating higher rates of postdischarge medication adherence among patients with dual eligibility, presumably owing to the lower copayment burden in this population.”
What’s more, according to the authors, treatment of the dual-eligibles appeared to be of poorer quality, at least according to objective metrics. Examples include “lower rates of reperfusion for ST-segment elevation myocardial infarction, revascularization for non-ST-segment elevation myocardial infarction, drug-eluting stent (DES) use, and prescription of evidence-based medications at discharge,” they wrote.
“[T]here may be a perception among clinicians that dual-eligible patients are less likely to adhere to medications owing to cost. This may contribute to lower usage rates of revascularization and DES, owing to concerns about discontinuation of dual-antiplatelet therapy,” Doll and colleagues wrote.
“Our analysis indicates that these concerns should not be limited to the dual-eligible population. Nonadherence is common for all patients, and interventions to improve adherence should be applied uniformly.”

“Most notably, the findings counter the stereotype that patients of lower financial means are less adherent to their medications,” according to Ian M. Kronish, MD, MPH, of Columbia University Medical Center/New York-Presbyterian Hospital, who was not involved in Doll’s study.
“So long as generous prescription cost subsidies are in place, low income status was not a risk factor for nonadherence. That said, medication nonadherence was common across all income levels, and remains an important target for post-MI quality improvement efforts,” Kronish told MedPage Today.
Doll and colleagues’ retrospective analysis included 17,419 Medicare patients, 27% of whom were dual eligible.
This subgroup was more likely to be female, nonwhite, and have a higher prevalence of comorbidities. Patients in this cohort were also more likely to present with non-ST-segment elevation myocardial infarction. The hazard ratios reported in the study reflected adjustments for these factors and for in-hospital treatment differences.
Doll’s group acknowledged that the investigation was hindered by its retrospective nature and its inherent caveats, among them unmeasured confounders and missing key information — such as pill counts and specific level of financial assistance given to each patient — that would have provided more precise data on medication adherence and socioeconomic status.
Even so, their study “highlights the fact that failure to prescribe optimal medical therapy for dual eligible patients may partially underlie disparities in post-MI outcomes, and that interventions to reduce disparities in post-MI treatment are in order for dual-eligible patients,” Kronish said.
“Prior studies have clearly shown that physicians are terrible at guessing which of their patients is nonadherent to treatment.”
“Future studies should assess the extent to which conscious and unconscious biases based on income status influence physician estimations of their patients’ adherence status, and whether these biases, in turn, adversely influence physician management of post-MI patients,” he suggested.

Can a Single Negative High-Sensitivity Troponin T Level Rule Out Myocardial Infarction?


Negative troponin testing combined with nonischemic electrocardiogram results and non–high-risk clinical presentation conferred a negative predictive value of 99.7%.

Prior studies have suggested that negative and nonincreasing high-sensitivity cardiac troponin (hsTn) levels measured at emergency department (ED) presentation and 1 hour later can rule out acute myocardial infarction (MI) in low-risk patients with nonischemic electrocardiogram (ECG) results (NEJM JW Emerg Med Feb 2016 and Ann Emerg Med 2016 Jan 12; [e-pub]; NEJM JW Emerg Med Jul 2016and JAMA Cardiol 2016 Jun 1; [e-pub]). In the current study, investigators evaluated whether a single hsTnT level can rule out 30-day major adverse cardiac events (acute MI, unstable angina, cardiogenic shock, ventricular arrhythmia, atrioventricular block, cardiac arrest, or death of cardiac or unknown cause).

The prospective observational study included 1138 patients with chest pain who presented to an ED in Sweden. Using a questionnaire designed by the researchers, physicians assessed clinical risk for acute coronary syndrome based on patient history and ECG results. Patients with a nonischemic ECG result and non-high clinical risk (29% of patients) were eligible for evaluation by a single hsTnT measurement. At a cutoff of 5 ng/L, the test had a negative predictive value of 99.7% for 30-day major adverse cardiac events in this group

COMMENT

The authors caution that patients presenting within 2 hours of symptom onset and patients aged >65 years were underrepresented in this study, and therefore it is unclear whether these results are applicable to them. Another limitation is that generalizing the investigators’ method of designating a patient as “non-high risk” may not be straightforward. Nevertheless, I think this study’s results are practice changing, and once hsTn tests become available in the U.S., patients aged <65 years presenting after 2 hours from symptom onset can be spared further testing if an hsTnT level is <5 ng/L.

Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention


Abstract

Background  The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established.

Objectives  This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population.

Methods  STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock.

Results  A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups.

Conclusions  In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19)

Perspectives

COMPETENCY IN PATIENT CARE: In patients with acute STEMI symptoms of <12 h duration given intravenous metoprolol before primary angioplasty, infarct size measured by CMR was not significantly different than in those given a placebo.

Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm


ABSTRACT

Importance  Rapid and accurate diagnosis of acute myocardial infarction (AMI) currently constitutes an unmet need.

Objective  To test a 1-hour diagnostic algorithm to diagnose AMI using a high-sensitivity troponin I assay with a new cutoff level of 6 ng/L.

Design, Setting, and Participants  The Biomarkers in Acute Cardiac Care study is a prospective study that investigated the application of the troponin I assay for the diagnosis of AMI in 1040 patients presenting to the emergency department with acute chest pain from July 19, 2013, to December 31, 2014. Results were validated in 2 independent cohorts of 4009 patients. Final follow-up was completed on July 1, 2015, and data were assessed from July 2 to December 15, 2015.

Exposure  Acute chest pain suggestive of AMI.

Main Outcomes and Measures  Accurate diagnosis or exclusion of AMI and 12-month mortality in patients with acute chest pain.

Results  Of the 1040 patients included from the study cohort, 673 (64.7%) were male and had a median age of 65 (interquartile range, 52-75) years. With application of a low troponin I cutoff value of 6 ng/L, the rule-out algorithm showed a high negative predictive value of 99.8% (95% CI, 98.6%-100.0%) after 1 hour for non–ST-segment elevation MI type 1. The 1-hour approach was comparable to a 3-hour approach. Similarly, a rule-in algorithm based on troponin I levels provided a high positive predictive value with 82.8% (95% CI, 73.2%-90.0%). Moreover, application of the cutoff of 6 ng/L resulted in lower follow-up mortality (1.0%) compared with the routinely used 99th percentile (3.7%) for this assay. Two independent cohorts further validated the performance of this algorithm with high negative and positive predictive values.

Conclusions and Relevance  Patients with possible AMI can be triaged within 1 hour after admission with no loss of safety compared with a 3-hour approach, when a low and sensitive cutoff is applied. This concept enables safe discharge or rapid treatment initiation after 1 hour.

DISCUSSION

Diagnosing AMI

Patients presenting with acute chest pain at the emergency department make heavy use of limited medical resources. Therefore, the need for fast but safe decision making is urgent. A rapid discharge might result from a single high-sensitivity troponin I assay finding.18– 20 As recently shown by Shah et al,19 this single-measurement approach enables a safe exclusion of AMI with only 0.4% false-negative findings. In that study, however, the median time from admission until blood sampling was 54 minutes, which might explain why patients with a very early presentation were still detected. To prevent a premature discharge of patients at high risk for future ischemic episodes, especially when patients with recent onset of chest pain (within 2 hours) are taken into account, consecutive measurements might be crucial.21 An approach using 2 consecutive measurements increases sensitivity and specificity, although prolonging the time until the final diagnosis can be made. Herein we show that the accuracy of the 1-hour approach was comparable to the 3-hour approach. Both approaches were superior to a single on-admission determination. The 1-hour approach does not yet integrate any clinical measurement such as electrocardiography, which will further increase the safety of this rule-out strategy.

The rule-in algorithm identified patients with a high accuracy after 1 hour, comparable to a 3-hour approach with preserved specificity. This approach prevents inappropriate cost-intensive management, which includes possibly harmful coronary angiographies. The algorithm performed evenly well in clinically important subgroups, whereas only atrial fibrillation had an effect on the PPV.

The validation of our algorithm in other cohorts (ADAPT and APACE) demonstrated similar high performance by integrating all available cohorts with shorter than the guideline-recommended rule-out window with this specific troponin I assay. Results of this validation testing strengthen the concept of a rapid rule out after 1 hour only, which is now recommended by the NSTEMI European Society of Cardiology guidelines as an alternative to the standard 3-hour approach.8

Cutoff Definition

Guideline-based cutoff values to rule out AMI were derived from the 99th percentile of a specific troponin assay measured in the healthy population. These assays were characterized as sensitive assays, defined by a coefficient of variation near the 99th percentile. Imprecision was relatively high with values below the coefficient of variation. The current high-sensitivity assays, in which precision is high at low cutoff values, are different.

To determine a valid algorithm, we calculated different cutoff values to identify the best-performing one. These calculations resulted in a troponin I cutoff level of 6 ng/L. This cutoff value was higher than that for the 10% coefficient of variation as a marker of imprecision of this specific troponin assay. For comparison we used a cutoff based on the 99th percentile of the troponin I assay. Many patients with the final diagnosis of AMI were not identified by the 99th percentile cutoff and would have been discharged without the correct diagnosis in our study.

Secondary Events During Follow-up

The 1- and 3-hour algorithms using a cutoff value of 6 ng/L resulted in lower mortality than the 99th percentile cutoff, and mortality using the 1-hour algorithm was identical to that of the 3-hour algorithm. Patients diagnosed as having NSTEMI by our algorithm had a significantly higher mortality. Highest mortality was observed in the gray-zone group. This group of patients with continuously elevated but stable troponin levels, which are not necessarily related to coronary disease, requires thorough monitoring and reevaluation.

Strengths and Limitations

An important strength of this study is the application of 2 contemporary high-sensitivity troponin assays. The troponin T assay was used for the final diagnosis with other available and recommended tools, such as electrocardiography, cardiac imaging, and coronary angiography, as well as clinical judgement. In contrast, only the troponin I assay was used for the rule-out and rule-in algorithms. Furthermore, the algorithm was extensively validated using 4009 patients from different geographical regions in other diseases cohorts. Nevertheless, the values presented herein are assay specific and cannot be applied to other assays without additional studies.

CONCLUSIONS

The application of a 1-hour algorithm with a troponin I cutoff level of 6 ng/L in patients with suspected AMI allows for accurate and rapid exclusion and identification of AMI. The 1- and 3-hour approaches yielded results that were not statistically different, whereas the 1-hour approach would allow faster diagnosis or discharge. A low cutoff performed significantly better than the 99th percentile as cutoff in view of follow-up mortality.

Association Between Takotsubo Cardiomyopathy and Axitinib: Case Report and Review of the Literature


Introduction

Axitinib, a small molecule tyrosine kinase inhibitor (TKI), has been approved as a second-line novel therapeutic agent in the treatment of advanced renal cell carcinoma (RCC). Axitinib blocks tumor angiogenesis by focusing specifically on the vascular endothelial growth factor receptor (VEGFR) pathway.1 Clinical trials have demonstrated improved progression-free and overall survival compared with other VEGF inhibitors and TKIs that are currently used as standard therapy. Commonly encountered cardiovascular adverse effects include hypertension, hypertensive crisis, and arterial-venous thrombotic events.15 Stress-induced cardiomyopathy, also known as takotsubo cardiomyopathy (TCM), has previously been reported in association with fluorouracil (FU), bevacizumab, and sunitinib,610 but to our knowledge, this relationship has never been described in patients undergoing chemotherapy with axitinib.

TCM is a rare disorder that is characterized by acute transient left ventricular dysfunction without evidence of obstructive coronary artery disease.6 The clinical presentation of TCM cannot be distinguished from the symptoms of an acute myocardial infarction.79 We here describe a 71-year-old woman who developed TCM in the context of receiving adjuvant therapy with the recently US Food and Drug Administration–approved chemotherapeutic agent axitinib for RCC.

Case Report

A 71-year-old woman without known preexisting cardiovascular risk factors began receiving axitinib therapy for progressive metastatic RCC at the recommended dose of 5 mg orally twice per day. Within 24 hours of administration, the patient developed midsternal and lower chest discomfort with radiation to her left shoulder and arm, shortness of breath, diaphoresis, and tachycardia. She was transferred to the emergency department for further evaluation with a presumptive diagnosis of pneumothorax from a recent therapeutic thoracentesis. A chest x-ray demonstrated a large left pleural effusion without evidence of pneumothorax. An electrocardiogram was suggestive of an anterolateral ST elevation myocardial infarction (Fig 1) in association with elevated cardiac enzyme values, including a troponin I level of 6.95 μg/L, creatine kinase–myocardial band of 26.3 U/L, total creatine kinase of 179 U/L, and brain natriuretic peptide of 496 pg/mL. The patient was given 0.4 mg of sublingual nitroglycerin without improvement and consequently was admitted to the coronary care unit. A computed tomography scan of the chest confirmed the pleural effusion, and a chest tube was placed. Given the atypical presentation, persistent chest pain, and presence of elevated cardiac enzymes, a transthoracic echocardiogram (TTE) was performed, followed by cardiac angiography.

A TTE in a four-chamber view mode (Figs 2 A and 2B) demonstrated severe global hypokinesis of the left ventricle with anterior apical ballooning and evidence of a mildly dilated left ventricular chamber, with an estimated left ventricular ejection fraction of 20% to 25%. Angiographic studies were negative for any occlusive pattern. Right anterior oblique projection of end systolic frame (Fig 3A) compared with end diastolic frame (Fig 3B) showed a large anteroapical and inferoapical akinetic segment with inferobasal and anterobasal hyperkinesis, consistent with the diagnosis of TCM.

The patient was managed medically with administration of carvedilol, lisinopril, aspirin, and termination of axitinib therapy. She remained in the intensive care unit for 1 week because of hypotension and was later transferred to the medical-oncology floor on normalization of her hemodynamic instability; she was subsequently discharged in stable condition. A TTE performed 3 weeks after her initial presentation demonstrated partial recovery with an ejection fraction of 50% to 55% and moderate left ventricular and septal hypertrophy. The patient has remained asymptomatic and continues to have normal left ventricular ejection fraction as of her last follow-up, which was 6 months after her initial presentation.

Discussion

TCM was first encountered and described in 1991 by Dote et al9a in Japan.6 The syndrome is named after the Japanese tako-tsubo, a pod-shaped trap used to catch octopus; the shape of the tako-tsubo is descriptive of the ballooning of the left ventricle during systole in a TCM event.9,11 It is presumed that TCM is caused by an excessive release of catecholamines, specifically adrenaline/epinephrine, which overstimulates the adrenergic receptors on the surface of cardiomyocytes and consequently impairs the response of the cardiac tissue to further adrenergic stimuli.6,8,9,11

It is known that 2.1% to 21% of all adverse chemotherapy events are cardiotoxic in nature; ischemia, vasospasm, arrhythmia, hypertension, QT interval prolongation, and acute cardiomyopathy are the most frequently presumed pathogenetic mechanisms.3It has been proposed that global reversible endothelial injury is the underlying pathogenetic mechanism in TCM.79

TCM most commonly affects postmenopausal women between age 58 and 77 years.69,11 The female predominance is not entirely understood, although some studies hypothesize that women and men have different adrenergic innervations, and that men may have higher adrenergic receptors in the membranes of cardiomyocytes.1113

TCM presents with symptoms of myocardial ischemia and specific features in electrocardiographic, echocardiographic, and cardiac angiographic examinations. As in the case of our postmenopausal patient, an electrocardiogram commonly shows ST segment elevation followed by T-wave inversion in precordial leads, which is suggestive of myocardial infarction. Cardiac enzymes are typically elevated and echocardiography demonstrates left ventricular apical hypokinesis with a compensatory basal hyperkinesis. Coronary angiographic examinations demonstrate the absence of an obstructive coronary artery pattern that distinguishes itself from the typical obstructive findings that are associated with myocardial infarction.6,8,9,11 QT prolongations as in torsade de pointes have also been observed.8,14 Cardiac magnetic resonance imaging is reported to be extremely useful in the diagnosis of TCM, and can contribute not only to judgment of the severity of the disease, but also to the differential diagnosis of TCM and acute myocardial infarction.15 In the case of our patient, cardiac magnetic resonance imaging was not performed, given that cardiac catheterization did not show evidence of coronary artery obstruction.

TCM has previously been associated with the administration of FU, bevacizumab, and sunitinib,710,1620 but a direct association between TCM and the novel VEGF inhibitor axitinib has never been reported. Because of its very recent introduction into oncology treatment options, only limited experience is currently available that would identify the precise mechanisms by which this VEGFR inhibitor induces cardiotoxicity and would assist in establishing a link with TCM.

It is presumed that the method of chemotherapy delivery affects the incidence of cardiotoxicity. It has been found that a continuous infusion is more likely to cause a cardiac adverse effect compared with a bolus or an oral route.8,21 In most of the previously described cases of cardiomyopathy that have occurred with the administration of FU, the symptom onset ensued soon after the first administration of the drug; other occurrences have been observed after serial exposures.8 In the two previously described cases of cardiomyopathy associated with bevacizumab, one of the patients developed symptom onset 48 hours after chemotherapy initiation, and the other patient 3 weeks later.9 In the case of our patient, the symptom onset 24 hours after oral initiation of axitinib is not surprising; despite the oral administration, this agent is rapidly absorbed and reaches peak concentrations within 2 to 6 hours.22

The management of TCM is supportive, and as with our patient, most patients are expected to undergo spontaneous and complete left ventricular dysfunction recovery within 3 to 4 weeks.8 Only 1.5% to 4% of lethal complications, such as cardiogenic shock or ventricular arrhythmias, have been reported in TCM, and recurrence has been observed in less than 10% of all patients.11

Our patient had no preexisting cardiovascular risk factors before the initiation of axitinib, and she was not taking any other chemotherapeutic agents. Her only other possible risk factor was her age, given that TCM is more common in postmenopausal women than in men, and estrogen deficiency may be a risk factor for this pathology, as in myocardial infarction.13 The presumed association between the initiation of axitinib therapy and TCM as described in this case report deserves further prospective clinical observation, but for many reasons, we believe strongly in a causal relationship between the administration of axitinib and the development of TCM in this patient.

Two previous cases of TCM in patients receiving bevacizumab, a monoclonal antibody that inhibits VEGF, have been reported.9 Although axitinib is a TKI, it selectively inhibits VEGFR1, VEGFR2, and VEGFR3, and shares a common pathway with bevacizumab.13,5,9

Our patient’s cardiomyopathy resolved with supportive management and discontinuation of the medication. The absence of a convincing alternative explanation for our patient’s clinical signs and symptoms supports the assumption that axitinib was the responsible agent.

Because of the widespread use of axitinib in the management of RCC and other malignancies,24 it is important for physicians to be aware of, recognize, and promptly treat this condition. The case presented here is, to our knowledge, the first observation of TCM that developed immediately after initiation of the second-generation VEGFR inhibitor axitinib.

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