Myocardial infarction

Worse MI Outcomes for the Poor?

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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?

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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

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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

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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

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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.1–5 Stress-induced cardiomyopathy, also known as takotsubo cardiomyopathy (TCM), has previously been reported in association with fluorouracil (FU), bevacizumab, and sunitinib,6–10 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.7–9 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.

Fig 1.

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Fig 1.

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.

Fig 2.

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Fig 2.

Fig 3.

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Fig 3.

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.7–9

TCM most commonly affects postmenopausal women between age 58 and 77 years.6–9,11 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.11–13

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,7–10,16–20 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.1–3,5,9

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,2–4 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.

AVOID Oxygen? Evidence of Harm in MI

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Results of a new trial suggest supplemental oxygen therapy in patients with ST-elevation MI (STEMI) may actually be harmful for patients who are not hypoxic[1].

The Air Versus Oxygen in ST-Elevation Myocardial Infarction(AVOID) trial compared supplemental oxygen vs no oxygen unless O2 fell below 94%.

“The AVOID study found that in patients with ST-elevation myocardial infarction who were not hypoxic, there was this suggestion that, potentially, oxygen is increasing myocardial injury, recurrent myocardial infarction, and major cardiac arrhythmia and may be associated with greater infarct size at 6 months,” lead author Dr Dion Stub (St Paul’s Hospital, Vancouver, BC, and the Baker IDI Heart and Diabetes Institute, Melbourne, Australia) concluded.

“These findings certainly need to be confirmed in larger randomized trials that are powered for hard clinical end points, but the AVOID study investigators would really question the current practice of giving oxygen to all patients and certainly to those who have normal oxygen levels to begin with,” he concluded.

The results were presented here at the American Heart Association (AHA) 2014 Scientific Sessions.

Effects on Infarct

Following the first report in 1900 of supplemental oxygen relieving angina, pre- and in-hospital oxygen “has really been a fundamental component of first-aid management of patients with suspected acute myocardial infarction, and this is done the world over,” Stub said. International guidelines differ on who should be given oxygen, he noted, “but all guidelines recognize that this fundamental of practice has very limited evidence behind it in a randomized clinical-trial fashion.”

However, recent physiologic data suggest that even as little as 15 minutes of oxygen can cause hyperoxia, leading to a reduction in coronary blood flow, increased coronary vascular resistance, increased oxygen free radicals, and disturbed microcirculation, he said, “and this all may contribute to increased reperfusion injury, myocardial injury during acute coronary syndromes.”

AVOID was an investigator-initiated randomized, controlled, multicenter trial with the aim of comparing supplemental oxygen therapy with no oxygen in STEMI patients with oxygen saturation in the normal range.

It was a “pragmatic” trial coordinated by the research division of Ambulance Victoria, in conjunction with nine tertiary-care centers in Melbourne, Australia. “A key component of the trial is that all patients were randomized by the paramedics prehospital,” he noted.

Patients were included if they had symptoms suspicious of MI for less than 12 hours, normal oxygen levels, defined as O2sat>94% measured by pulse oximeter, and a diagnostic prehospital ECG with ST-elevation on two or more contiguous leads. Patients were excluded if oxygen saturation was below 94%, they were in an altered conscious state, they received oxygen prior to randomization, or there was planned transport to a nonstudy hospital.

Patients with confirmed STEMI randomized to the oxygen arm (n=218) received 8 L/min of O2 given prehospital right through to admission to the coronary cath lab for primary angioplasty and until they were stable on the ward. Patients in the no-oxygen arm (n=223) were given no oxygen unless they became hypoxic (O2sat<94%).

The co–primary end point was myocardial infarct size based on cardiac enzymes and other markers (mean peak creatinine kinase, mean peak troponin I, area under the curve of creatinine kinase and troponin I).

Patient characteristics in the groups were well-matched. The oxygen was appropriately administered, with 99.5% receiving oxygen via face mask in the prehospital and in-hospital setting, he said. In the no-oxygen group, 4.5% received oxygen prehospital for low oxygen saturations, 7.7% were treated during the procedure in the cath lab, and over 20% while on the ward.

This resulted in significant differences in oxygen saturation throughout the study, Stub noted. Cardiac arrest andcardiogenic shock occurred similarly between groups. Time from paramedic arrival on the scene to hospital arrival was approximately 55 minutes in both groups. Interestingly, they found no indication of symptomatic benefits of oxygen, with pain scores and administration of analgesics also similar in both groups, he pointed out. Details of the procedures were also not different between the study arms.

On the primary end point, they found a significant 25% increase in creatine kinase (CK)—”so the suggestion of increased myocardial injury in those delivered oxygen,” Stub noted.

For the troponin I co–primary end point, the curves were similar, but with wider confidence intervals. “We had one site that had issues early in the trial with regard to ascertaining the standardized troponin assay, so the confidence intervals were a little wider, and this was a nonsignificant result,” Stub said. “So on the one hand, you had a highly significant CK result, with a nonsignificant troponin.”

AVOID Primary End Point: Infarct Size on Cardiac Enzymes

Measure Oxygen No oxygen Ratio of means (oxygen/no oxygen) P
Creatinine kinase (U/L)
Geometric mean peak (95% CI) 1948 (1721–2205) 1543 (1341–1776) 1.26 (1.05–1.52) 0.01
Median peak (IQR) 2073 (1065, 3753) 1727 (737, 3598) — 0.04
Troponin I (µg/L)
Median peak (IQR) 65.7 (30.1, 145.1) 62.1 (19.2, 144.0) — 0.17
Geometric mean peak (95% CI ) 57.4 (48.0–68.6) 48.0 (39.6–58.1) 1.20 (0.92–1.55) 0.18
IQR=interquartile range

A secondary end point was cardiac MRI (CMR), “the gold standard of final infarct size,” which was done in a subgroup of 135 patients at 6 months, he said.

The suggestion of increased infarct size and myocardial injury was again seen. “When we looked at late gadolinium enhancement, there was a significant difference between the oxygen and the no-oxygen group. When this was normalized for left ventricular mass, it was just a nonsignificant trend,” Stub added, but it still suggests the potential for increased myocardial injury.

AVOID: Infarct Size on CMR

Infarct Size Oxygen No Oxygen Ratio of means (oxygen/no oxygen P
Median (IQR, g) 20.3 (9.6, 29.6) 13.1 (5.2, 23.6) 0.04
Geometric mean (95% CI), g 14.6 (11.3–18.8) 10.2 (7.7–13.4) 1.43 (0.99–2.07) 0.06
Median (IQR) proportion of LV mass 12.6 (6.7, 19.2) 9.0 (4.1, 16.3) 0.08
Geometric mean (95% CI) proportion of LV mass 10.0 (8.1–12.5) 7.3 (5.7–9.3) 1.38 (0.99–1.92) 0.06
IQR=interquartile range

The study wasn’t powered to look at major adverse cardiac events, he noted. Mortality was similar between the groups, but significant increases were seen in recurrent MI and in significant arrhythmias in the oxygen group. No significant differences were seen at 6 months on the clinical end points, Stub said.

AVOID: Clinical End Points

End point Oxygen (%) No oxygen (%) p
Hospital discharge
Mortality 1.8 4.5 0.11
Recurrent MI 5.5 0.9 <.01
Stroke 1.4 0.4 0.30
Major bleeding 4.1 2.7 0.41
Significant arrhythmia 40.4 31.4 0.05
6 mo
Mortality 3.8 5.9 0.32
Recurrent MI 7.6 3.6 0.07
Stroke 2.4 1.4 0.43
Repeat revascularization 11.0 7.2 0.17

“Hypothesis-generating” subgroup analysis showed that females, those with the longest symptom-to-intervention times (>180 minutes) and preintervention TIMI 2 or 3 blood flow all favored no oxygen therapy.

During discussion of the trial at a press conference, Stub stressed that these patients were normoxic. “We certainly are not proposing that all patients should not be given oxygen,” he said. “Clearly if you’re having an acute coronary syndrome or any condition in which you’re hypoxic, then oxygen clearly is a lifesaving drug.”

Stub noted that this issue is being further studied by researchers with the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), a national registry of consecutive patients from 29 hospitals in Sweden where angiography and PCIs are performed. The registry was established in 1989 and is independent of funding from industry.

“I think this will be a fantastic study,” Stub told heartwire , and at about 5000 patients, it will have the power to look at clinical end points like mortality. Results are expected to be available in a couple of years.

Dr Robert Harrington (Stanford University, CA), chair of the program committee for this year’s AHA Scientific Sessions, who moderated the press conference, pointed out the SCAAR group conducted the recent TASTE trial of thrombectomy in MI.

“They’re now doing a series of trials, and one of them is a randomized trial of oxygen and mortality as the primary outcome, so kudos,” he said. “They have a system where they can do this very readily.”

Breaking Up With MONA?

The invited discussant for this trial was Dr Karl B Kern (University of Arizona, Tucson), who pointed out that all cardiologists are familiar with MONA, which stands for morphine, oxygen therapy, nitrates, and aspirin.

“We were all taught that MONA is our friend anytime we met a cardiac patient with ischemic chest pain,” Kern said. “But this may be, with the AVOID trial, the beginning of her demise.”

Every good trial has to start with the pneumonic, he said wryly, “and I congratulate the AVOID trial. Should we avoid oxygen after the AVOID trial? Maybe so.”

Results of a Cochrane review on oxygen therapy released last year[2] combined the small studies that have been done to date, he said, “and when combined, the data were clearly inconclusive. It actually suggested harm but was underpowered, so no real conclusion could be made.”

The current study took on that question, and in the prehospital setting, which makes it “even more remarkable,” Kern said. “They found, as they prespecified, that their primary end point of infarct size was significantly less without oxygen. That’s an astounding finding, and really one that I think will cause many cardiologists and physicians to take note and perhaps step back.”

That’s an astounding finding, and really one that I think will cause many cardiologists and physicians to take note and perhaps step back.”

He cautioned, though, that infarct size using biomarkers is still a surrogate end point, not hard clinical outcomes, and the use of biomarkers, “although admirable, is perhaps not today the most accurate.” What is accurate, on the other hand, is the use of CMR, “and the data held up at 6 months as well—with oxygen therapy there was a larger infarct.”

He raised a few issues, though, with the study. One is that they used 6 to 8 L/min of oxygen, while in the hospital phase “we would use less,” 2 to 4 L/min, particularly for this population of patients who were not hypoxic, Kern noted. “The effect of that extra oxygen is not known.”

Although the curves for oxygen saturation clearly separated in the trial, he said he would be interested to see blood gas measures, but these were not available since it was done out of hospital.

Finally, while they were secondary end points, there was an increase in significant arrhythmias and recurrent infarction in those given oxygen. “Certainly the arrhythmias could be explained by microvascular damage and ongoing ischemia, but perhaps not quite so with the recurrent infarctions, which are more typically plaque rupture during the hospital course before discharge,” he said.

“But I really congratulate the authors on this very provocative, if not in fact definitive, trial,” Kern said, and it will be of interest to see if there will ultimately be a mortality difference.

“So back to MONA,” he concluded. “Should we divorce her, or as Neil Sedaka said, at least break up? I guess I’m not quite ready to do that, but I’m certainly willing to date her less often.”

The study was funded by Alfred Hospital Foundation, FALCK Foundation, and Paramedics Australia. Stub reports research grants from the Royal Australian College of Physicians and Cardiac Society of Australia and other research support from St Jude Medical. The coauthors report no relevant financial relationships.

ATLANTIC: In-Ambulance vs. In-Cath Lab Administration of Ticagrelor in STEMI Patients Transferred For Primary PCI

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Pre-hospital administration of ticagrelor in patients with acute ST-segment elevation myocardial infarction (STEMI) does not improve pre-percutaneous coronary intervention (PCI) coronary reperfusion, but it does appear safe and may prevent post-procedural acute stent thrombosis, according to results from the ATLANTIC trial presented Sept. 1 as part of ESC Congress 2014 and simultaneously published in the New England Journal of Medicine. External Link

The international, multi-center trial was based on 1,862 patients with ongoing STEMI of less than six hours duration who received ticagrelor treatment either in the ambulance or in the catheterization lab. Overall, the median time from randomization to angiography was 48 minutes and the median time difference between the two treatment strategies was 31 minutes. According to study investigators, the proportion of patients who did not have a 70 percent or greater resolution of ST-segment elevation before PCI and who did not have thrombolysis in myocardial infarction flow grade 3 in the infarct-related artery at initial angiography did not vary significantly between the two groups. The rates of major adverse cardiovascular events and of major bleeding also did not vary significantly.

However, the rates of definite stent thrombosis were lower in the pre-hospital group than the in-hospital group. “The observed preventive benefit is consistent with pharmacodynamics and ECG findings suggesting that the maximal effort of pre-hospital administration of ticagrelor occurs after the end of the procedure,” the investigators said.

Investigators did note limitations to the study based on the small sample size and the short intervals between administration of ticagrelor and reperfusion. “The time to PCI in our study was extremely short in both groups indicating excellent practice,” they said, “but this may have blunted the drug effect and may not reflect clinical practice.”

Some cardiac MRI findings predict future heart events.

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Certain MRI findings can independently predict future cardiovascular events in patients with coronary artery disease or those who recently had a heart attack, but you have to be careful which ones you choose, according to a study published online January 29 in the Journal of the American College of Cardiology.

In a meta-analysis of 56 previous studies, Dutch researchers found that some cardiac MRI findings are predictive for some types of patients, while there aren’t enough data to support the prognostic power of other results.

“An important finding is that different cardiac MR features are associated with events depending on the patient population under consideration,” wrote lead author Dr. Hamza El Aidi, from the department of cardiology at University Medical Center Utrecht, and colleagues (JACC, January 29, 2014).

Benefits of cardiac MRI

As the authors noted in their study, cardiac MRI has advantages over other imaging modalities because of its high spatial and temporal resolution, its ability to visualize ischemic heart disease in one scan, and its lack of ionizing radiation. Cardiac MRI is also considered the current reference standard for evaluating ventricular function and myocardial fibrosis using late gadolinium enhancement.

“However, data on prognosis from individual studies is limited, most often due to small sample sizes and/or a low number of events in these studies,” they wrote. “Furthermore, the relative prognostic value of the available cardiac MR imaging findings is unclear.”

The researchers decided to assess cardiac MRI’s predictive power based on the following imaging features:

  • Left ventricular ejection fraction (LVEF)
  • Wall motion abnormalities
  • Abnormal myocardial perfusion
  • Microvascular obstruction
  • Late gadolinium enhancement
  • Presence of edema
  • Presence of intramyocardial hemorrhage

Patients were divided into two groups: The first group consisted of those who had experienced a recent myocardial infarction, while the second included patients with suspected or known coronary artery disease (CAD).

The imaging findings were then correlated with “hard events” — all-cause mortality, cardiac death, cardiac transplantation, and myocardial infarction — or major adverse cardiovascular events (MACE), which included hard or other events as defined by authors of the evaluated papers. For each finding, a hazard ratio was calculated to show the association between that factor and future cardiac events in each of the two patient groups.

Paper chase

Cardiac MRI papers published before February 2013 were drawn from Medline and Embase. A total of 56 papers were found to meet the study’s criteria, representing a total population of 25,497 patients.

There wasn’t enough evidence to link cardiac MRI findings with hard events in the patients with recent myocardial infarction, according to the authors. However, findings that did demonstrate prognostic value included the following:

  • In patients with a recent myocardial infarction, LVEF was an independent predictor of MACE in more than 50% of the studies, with a change in hazard ratio (HR) of 1.03 to 1.05 per 1% decrease in LVEF.
  • In patients with suspected or known CAD, the following cardiac MRI findings were predictors of hard events:
    • Wall motion abnormalities (HR range of 1.87-2.99)
    • Perfusion defects (HR range of 3.02-7.77)
    • LVEF (HR range of 0.72-0.82 per 10% increase in LVEF)
    • Infarction (HR range of 2.82-9.43)
  • In patients with suspected or known CAD, perfusion defects were associated with MACE (HR range of 1.76-3.21).

Important predictors

According to the authors, their study is one of the first comprehensive systematic reviews investigating the predictive abilities of different cardiac MRI findings for future cardiovascular events.

“Among patients with suspected or known coronary artery disease, inducible wall motion abnormalities and inducible perfusion defects were the most important independent predictors of hard events,” they wrote. “Other independent predictors were LVEF and infarct size.”

To better assess cardiac MRI, the authors advocated the development of reporting guidelines for prognostic studies in cardiovascular imaging.

They cited the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK), which are used for oncology, and the Prognosis Research Strategy (PROGRESS) recommendations as examples.

“In conclusion, cardiac MRI is capable of providing independent prognostic information that allows for risk stratification after myocardial infarction as well as in patients with suspected or known coronary artery disease,” they wrote.

Bivalirudin Started during Emergency Transport for Primary PCI.

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BACKGROUND

Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown.

METHODS

We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding.

RESULTS

Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients.

CONCLUSIONS

Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis.

Source: NEJM

 

Ibuprofen Kills Thousands Each Year, So What Is The Alternative?

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A recent Reuters’ article opened with the following stunning sentence:

“Long-term high-dose use of painkillers such as ibuprofen or diclofenac is ‘equally hazardous’ in terms of heart attack risk as use of the drug Vioxx, which was withdrawn due to its potential dangers, researchers said.”  

The 2004 Vioxx recall, as you may remember, was spurred by the nearly 30,000 excess cases of heart attacks and sudden cardiac deaths caused by the drug between 1999-2003. Despite the fact that scientific research had accumulated as early as 2000 linking Vioxx to increased heart attacks and strokes, the drug’s manufacturer Merck, and the FDA, remained silent as the death toll steadily increased.

Ibuprofen Kills Thousands Each Year, So What Is The Alternative?

The Reuters report focused on new research published in Lancet indicating the risk of heart attack increases as much as a third and the risk of heart failure doubles among heavier users of NSAID drugs.

INFLAMED: Our Default Bodily State

Why are so many folks taking NSAID drugs like ibuprofen anyway?

Pain and unhealthy levels of inflammation are fast becoming default bodily states in the industrialized world. While in most cases we can adjust the underlying pro-inflammatory conditions by altering our diet, and reducing stress and environmental chemical exposures, these approaches take time, discipline and energy, and sometimes we just want the pain to stop now. In those often compulsive moments we find ourselves popping an over-the-counter pill to kill the pain.

The problem with this approach is that, if we do it often enough, we may kill ourselves along with the pain…

Ibuprofen really is a perfect example of this. As mentioned above, this petrochemical-derivative has been linked to significantly increased risk of heart attack and increased cardiacand all-cause mortality (when combined with aspirin), with over two dozen serious adverse health effects, including:

  1. Anemia[1]
  2. DNA Damage[2]
  3. Hearing Loss[3]
  4. Hypertension[4]
  5. Influenza Mortality[5]
  6. Miscarriage[6]

Ibuprofen is, in fact, not unique in elevating cardiovascular disease risk and/or mortality. The entire category of non-steroidal anti-inflammatory drugs (NSAIDs) appears to have this under-recognized dark side; cardiovascular disease and cardiac mortality score highest on the list of over 100 unintended adverse health effects associated with their use. See also our analysis of the rarely acknowledged dark side to aspirin: The Evidence Against Aspirin And For Natural Alternatives.

So, what does one do? Pain is pain. Whether it happens to you, or you witness it in another (which can be worse), finding relief is a top priority.

Ibuprofen Kills More Than Pain, So What Is The Alternative?

Research on Natural Alternatives To Ibuprofen

Here is some evidence-based research on alternatives to ibuprofen, sourced from the National Library of Medicine:

  1. Ginger – A 2009 study found that ginger capsules (250 mg, four times daily) were as effective as the drugs mefenamic acid and ibuprofen for relieving pain in women associated with their menstrual cycle (primary dysmenorrhea). [7]
  2. Topical Arnica – A 2007 human study found that topical treatment with arnica was as effective as ibuprofen for hand osteoarthritis, but with lower incidence of side effects.[8]
  3. Combination: Astaxanthin, Ginkgo biloba and Vitamin C – A 2011 animal study found this combination to be equal to or better than ibuprofen for reducing asthma-associated respiratory inflammation.[9]
  4. Chinese Skullcap (baicalin) – A 2003 animal study found that a compound in Chinese skullcap known as baicalin was equipotent to ibuprofen in reducing pain.[10]
  5. Omega-3 fatty acids: A 2006 human study found that omega-3 fatty acids (between 1200-2400 mg daily) were as effective as ibuprofen in reducing arthritis pain, but with the added benefit of having less side effects.[11]
  6. Panax Ginseng – A 2008 animal study found that panax ginseng had analgesic and anti-inflammatory activity similar to ibuprofen, indicating its possible anti-rheumatoid arthritis properties.[12]
  7. St. John’s Wort – A 2004 animal study found that St. John’s wort was twice as effective as ibuprofen as a pain-killer.[13]
  8. Anthrocyanins from Sweet Cherries & Raspberries – A 2001 study cell study found that anthrocyanins extracted from raspberries and sweet cherries were as effective as ibuprofen and naproxen at suppressing the inflammation-associated enzyme known as cyclooxygenase-1 and 2.[14]
  9. Holy Basil – A 2000 study found that holy basil contains compounds with anti-inflammatory activity comparable to ibuprofen, naproxen and aspirin.[15]
  10. Olive Oil (oleocanthal) – a compound found within olive oil known as oleocanthal has been shown to have anti-inflammatory properties similar to ibuprofen.[16]
  11. There are, of course, hundreds of additional substances which have been studied for their pain-killing and/or anti-inflammatory effects, and there are also aromatherapeutic approachesthat do not require the ingestion of anything at all, but there is also a danger here. When we think of taking an alternative pain-killer to ibuprofen, we are still thinking within the palliative, allopathic medical model: suppress the symptom, and go on about our business. It would behoove us to look deeper into what is causing our pain. And when possible, remove the cause(s). And that often requires a dramatic dietary shift away from pro-inflammatory foods, many of which most Westerners still consider absolutely delightful, e.g. wheat, dairy,nighshade vegetables and even wheat-free grains, etc.

    [1] Direct cytotoxicity of non-steroidal anti-inflammatory drugs in acidic media: model study on human erythrocytes with DIDS-inhibited anion exchanger. Pharmazie. 2002 Dec;57(12):848-51. PMID: 12561250

    [2] Genotoxicity of ibuprofen in mouse bone marrow cells in vivo. Drug Chem Toxicol. 2012 Jan 27. Epub 2012 Jan 27. PMID: 22283434

    [3] Analgesic use and the risk of hearing loss in men. Am J Med. 2010 Mar;123(3):231-7. PMID: 20193831

    [4] Effect on blood pressure of lumiracoxib versus ibuprofen in patients with osteoarthritis and controlled hypertension: a randomized trial. J Hypertens. 2008 Aug;26(8):1695-702. PMID: 18622250

    [5] The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med. 2010 Oct;103(10):403-11. PMID: 20929891

    [6]  Taking non-aspirin NSAIDs in early pregnancy doubles risk of miscarriage, study shows. BMJ. 2011 ;343:d5769. Epub 2011 Sep 9. PMID: 21908536

    [7] Comparison of effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea. J Altern Complement Med. 2009 Feb 13. PMID: 19216660

    [8] Choosing between NSAID and arnica for topical treatment of hand osteoarthritis in a randomised, double-blind study. Rheumatol Int. 2007 Apr;27(6):585-91. Epub 2007 Feb 22. PMID: 17318618

    [9] Summative interaction between astaxanthin, Ginkgo biloba extract (EGb761) and vitamin C in suppression of respiratory inflammation: a comparison with ibuprofen. Phytother Res. 2011 Jan;25(1):128-36. PMID: 20632299

    [10] The antiinflammatory and analgesic effects of baicalin in carrageenan-evoked thermal hyperalgesia. Anesth Analg. 2003 Dec;97(6):1724-9. PMID: 14633550

    [11] Omega-3 fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surg Neurol. 2006 Apr;65(4):326-31. PMID:16531187

    [12] Potential analgesic and anti-inflammatory activities of Panax ginseng head butanolic fraction in animals. Food Chem Toxicol. 2008 Dec;46(12):3749-52. Epub 2008 Oct 1. PMID:18930781

    [13] Antinociceptive activity of methanolic extracts of St. John’s Wort (Hypericum perforatum) preparation. Pak J Pharm Sci. 2004 Jul;17(2):13-9. PMID: 16414593

    [14] Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedicine. 2001 Sep;8(5):362-9. PMID: 11695879

    [15] Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine. 2000 Mar;7(1):7-13. PMID: 10782484

    [16] Molecular mechanisms of inflammation. Anti-inflammatory benefits of virgin olive oil and the phenolic compound oleocanthal. Curr Pharm Des. 2011 ;17(8):754-68. PMID:21443487