2 Minute Medicine Rewind October 29, 2018

Intravenous Iron in Patients Undergoing Maintenance Hemodialysis

Patients undergoing hemodialysis typically receive intravenous iron, despite a lack of established clinical efficacy. In this randomized controlled trial, investigators randomized 2141 patients undergoing hemodialysis to either high-dose iron sucrose, administrated proactively, or low-dose iron-sucrose, administered reactively to compare the safety and efficacy of these regimens in patients undergoing hemodialysis. The primary outcome examined was a composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death. Researchers found that the high-dose group required a lower median monthly dose of erythropoiesis-stimulating agent (median difference -7539 IU, 95% CI -9485 IU to -5582 IU), and that more rapid increases in hemoglobin level were observed over time for the high-dose group. The composite end point occurred in 30.5% of the high-dose group compared to 32.7% of the low-dose group (HR 0.88, 95% CI 0.76 to 1.03, p<0.001 for noninferiority, p=0.11 for superiority). In terms of individual outcomes, the rate of death was 22.5% in the high-dose group compared to 25.7% in the low-dose group (HR 0.84, 95% CI 0.71 to 1.00). The rate of hospitalization for heart failure was significantly lower in the high-dose group (HR 0.66, 95% CI 0.47 to 0.93). Rates of serious adverse events and infection were similar between the two groups. Taken together, the results from this study indicate that high-dose proactive intravenous iron regimens are non-inferior to low-dose reactive intravenous iron regimens, with some improved outcomes and reduced need for erythropoiesis-stimulating agents. This study was limited in that it was open-label and did not examine quality of-life data. The safety of the high-dose regimen also needs to be studied long term.

Phase Ib/II Study of Pembrolizumab and Pegylated Interferon Alfa-2b in Advanced Melanoma

Programmed death-1 (PD-1) inhibitors have shown efficacy in the treatment of melanoma. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature has been shown to correlate with response to PD-1 blockade. As such, the receipt of combination therapy with interferon (IFN) may enhance anti-tumor effects. In this open-label phase Ib/II trial, investigators treated 43 patients with stage IV PD-1-naïve melanoma with escalating doses of pegylated (PEG)-IFN combined with pembrolizumab (2mg/kg every 3 weeks, intravenously) until disease progression, in order to study the safety and objective response rate of the combination therapy. The phase II portion of the study examined the recommended phase II dose, and included a subset of 31 patients. Researchers found that no dose-limiting toxicity was found for any of the three PEG-IFN dose cohorts (1 µg/kg, 2 µg/kg, and 3 µg/kg). As such, 3 µg/kg of PEG-IFN was combined with 2 mg/kg of pembrolizumab for the phase II portion of the trial. Two patients with the highest PEG-IFN dose experienced grade 4 events and discontinued treatment, but still showed ongoing responses. In terms of efficacy, investigators assessed the objective response rate to be 60.5%, with 46.5% of patients exhibiting an ongoing response. Median time to response was 12 weeks, and median progression-free survival was 11 months (95% CI 6 months to not reached) in all patients. Progression-free survival rates at 6, 12, and 24 months were 64%, 46%, and 46%, respectively, in all patients. In non-responders, progression-free survival was 6 months (95% CI 2 months to 8 months). Results from this trial therefore suggest that the combination of pembrolizumab and PEG-IFN exhibits important clinical activity for PD-1 naïve melanoma, as the objective response rate of 60.5% was higher than the current disease control rate of 48.8%. It is important to note, however, that this study did not have a control group, and that this study had findings in contrast to another phase IB study testing pembrolizumab and PEG-IFN I melanoma. As such, further studies are needed to evaluate the safety and efficacy of this combination treatment.

Association of Secondary Preventive Cardiovascular Treatment After Myocardial Infarction With Mortality Among Patients With Schizophrenia

Patients with schizophrenia have a shortened life expectancy of 15-20 years compared with the general population, with excess cardiac mortality contributing to this difference. Interestingly, no studies have evaluated the impact of cardioprotective medications after myocardial infarction (MI) in this patient population. In this nationwide cohort study, investigators examined 105,018 patients with MI, including 684 patients with schizophrenia, in order to examine whether exposure to cardioprotective medication reduces all-cause mortality after MI among patients with schizophrenia compared with the general population. Investigators found that patients with schizophrenia had a higher prevalence of diabetes (32.5% vs. 23.8%, p<0.001), COPD (45.9% vs. 37.5%, p<0.001), and substance abuse (25.0% vs. 4.6%, p<0.001), and were less likely to be treated with antiplatelets, vitamin K antagonists, beta-blockers, ACEIs, and statins than the general population (p<0.001 for all comparisons). In terms of mortality, 44.9% of patients with schizophrenia included in this study died compared to 26.6% of the general population. Patients with schizophrenia and no cardioprotective treatment had the highest mortality rate in comparison to the general population (HR 8.78, 95% CI 4.37 to 17.65), while patients with schizophrenia and cardioprotective treatment also had a higher mortality rate than the general population (HR 1.97, 95% CI 1.25 to 3.10). Taken together, results from this study support improving exposure to cardioprotective medications in patients with schizophrenia. This study was limited in that treatment exposure was measured by whether patients obtained prescriptions, with no information on medication adherence. The data analyzed from this study also lacked information on important lifestyle factors and confounders, including smoking and diet.

Association of Weather With Day-to-Day Incidence of Myocardial Infarction

The influence of certain weather trends on the incidence of myocardial infarction (MI) has not been well established. In this prospective population-based study, investigators obtained daily weather data from the Swedish Meteorological and Hydrological Institute for 274,029 MIs in order to determine whether an association exists between weather and the rate of MI. Investigators found that minimum air temperature was negatively associated with MI, as a 1-standard deviation (7.4 degrees Celsius) increase in minimum air temperature was associated with a 2.8% reduction in MI (unadjusted IRR, 0.972, 95% CI 0.967 to 0.977, p <0.001). This association was consistent after stratifying for non-ST elevation MI (NSTEMI) and ST-elevation MI (STEMI) as well as other weather parameters. Sunshine duration was negatively associated with overall MI but not for STEMIs. The only weather parameters associated with higher rates of MI were wind velocity (unadjusted IRR 1.077, 95% CI 1.055 to 1.098, p<0.001) and snow precipitation, although the latter did not reach statistical significance. Overall, results from this study suggest that cold weather is associated with higher rates of MI, which has implications for resource allocation and preparation during certain seasons. It is important to note, however, that the effect estimates were modest, and that the averaging of daily nationwide weather could have affected results.

Relationship of Left Ventricular Thrombus Formation and Adverse Outcomes in Acute Anterior Myocardial Infarction in Patients Treated with Primary Percutaneous Coronary Intervention

Anterior acute ST-segment elevation myocardial infarctions (ant-AMIs) are often complicated by left ventricular thrombosis (LVT). While the use of percutaneous coronary intervention (PCI) can greatly reduce the infarct area and therefore the formation of LVT, this complication still occurs in an estimated 4-15% of patients. How LVTs affect the outcomes of patients with ant-AMIs that have undergone primary percutaneous coronary intervention (PCI) has not been well characterized. In this retrospective cohort study, investigators analyzed data from 1533 consecutive patients with ant-AMI who received primary PCI in order to examine the effect of LVTs on one-year major adverse cardio-cerebrovascular events (MACCE). Investigators found that 7.1% of the patients included in this study developed an LVT. During the first 24 hours after onset of ant-AMIs, patients with LVT had lower left ventricular ejection fraction, longer ischemia time, higher myocardial enzyme peaks, and higher Killip classification (p<0.001 for all comparisons). Investigators also found that 21.7% of patients with LVT experienced at least one MACCE event compared to 10.3% of patients without LVT (p<0.001); in terms of individual components of MACCE, the only statistically significant difference was in the incidence of heart failure (OR 2.41, 95% CI 1.29 to 4.58, p=0.001). In addition, after adjustment for cofactors, investigators found LVT as a significant independent predictor of MACCE within one year (HR 2.28, 95% CI 1.12 to 6.38, p=0.02). Investigators also examined the differences in LVT and MACCE for patients who had INR of 2 or greater compared to those with INR <2, and found that the risk of MACCE was lower for patients with a higher INR (13.5% vs. 29.6%, p=0.049). Taken together, the results from this study indicate that there is a non-trivial incidence of LVTs for patients with ant-AMIs and that LVTs remain an independent predictor for heart failure, which is important for risk stratification. Results also suggest that oral coagulation and maintenance of target INRs can be beneficial. This study was limited in that it diagnosed LVT with transthoracic echocardiograms rather than cardiac magnetic resonance imaging, which might have a higher sensitivity and specificity. It is also important to note that more studies are needed to investigate causality, as this study did not show whether LVTs cause heart failure or vice versa.

Image: PD

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