BACKGROUND Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. METHODS In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y 12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. RESULTS Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. CONCLUSIONS In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y 12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.

clinicaltrials.gov Identifier: NCT02298088.

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SummaryAimsConcomitant renin–angiotensin–aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF.MethodsThis was an open‐label, noncontrolled single‐sequence study. After a 24‐h run‐in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II–IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin‐converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]).ResultsOn Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio‐to‐baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT‐proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin‐1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100‐ and 200‐mg doses, the Cmax and AUC 0–12 h for sacubitril and LBQ657 were approximately dose‐proportional while that of valsartan was less than dose‐proportional.ConclusionsTreatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

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Clinical guidelines for the treatment of patients with non‐ST‐segment elevation myocardial infarction (NSTEMI) recommend an invasive strategy with cardiac catheterization, revascularization when clinically appropriate, and initiation of dual antiplatelet therapy regardless of whether the patient receives revascularization. However, although patients with NSTEMI have a higher long‐term mortality risk than patients with ST‐segment elevation myocardial infarction (STEMI), they are often treated less aggressively; with those who have the highest ischemic risk often receiving the least aggressive treatment (the “treatment‐risk paradox”). Here, using evidence gathered from across the world, we examine some reasons behind the suboptimal treatment of patients with NSTEMI, and recommend approaches to address this issue in order to improve the standard of healthcare for this group of patients. The challenges for the treatment of patients with NSTEMI can be categorized into four “P” factors that contribute to poor clinical outcomes: patient characteristics being heterogeneous; physicians underestimating the high ischemic risk compared with bleeding risk; procedure availability; and policy within the healthcare system. To address these challenges, potential approaches include: developing guidelines and protocols that incorporate rigorous definitions of NSTEMI; risk assessment and integrated quality assessment measures; providing education to physicians on the management of long‐term cardiovascular risk in patients with NSTEMI; and making stents and antiplatelet therapies more accessible to patients.

Background: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment–elevation myocardial infarction. Methods: REAL-TIMI 63B (A Randomized, Placebo‑controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment–elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. Results: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103–221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6–24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3–13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79–16.38; placebo: 10.48%, [IQR, 4.92–16.61], 1-sided P =0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA–1.10], 1-sided P =0.30). There was no significant difference in treatment emergent serious adverse events. Conclusions: Administration of MEDI6012 in patients with acute ST-segment–elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03578809.

Primary percutaneous coronary intervention (PCI) is the preferred reperfusion method in patients with ST-segment elevation myocardial infarction (STEMI). In patients with STEMI who cannot undergo timely primary PCI, pharmacoinvasive treatment is recommended, comprising immediate fibrinolytic therapy with subsequent coronary angiography and rescue PCI if needed. Improving clinical outcomes following fibrinolysis remains of great importance for the many patients globally for whom rapid treatment with primary PCI is not possible. For patients with acute coronary syndrome who underwent primary PCI, the PLATO trial demonstrated superior efficacy of ticagrelor relative to clopidogrel. Results in the predefined subgroup of patients with STEMI were consistent with the overall PLATO trial. Patients who received fibrinolytic therapy in the 24 hours before randomization were excluded from PLATO, and there is thus a lack of data on the safety of using ticagrelor in conjunction with fibrinolytic therapy in the first 24 hours after STEMI. The TREAT study addresses this knowledge gap; patients with STEMI who had symptom onset within the previous 24 hours and had received fibrinolytic therapy (of whom 89.4% had also received clopidogrel) were randomized to treatment with ticagrelor or clopidogrel (median time between fibrinolysis and randomization: 11.5 hours). At 30 days, ticagrelor was found to be non-inferior to clopidogrel for the primary safety outcome of Thrombolysis in Myocardial Infarction (TIMI)-defined first major bleeding. Considering together the results of the PLATO and TREAT studies, initiating or switching to treatment with ticagrelor within the first 24 hours after STEMI in patients receiving fibrinolysis is reasonable.