Nonstatin therapy to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality, with low-density lipoprotein (LDL) cholesterol being a causative risk factor. Though statins have a decades-long track record of efficacy and safety, nonstatin agents may be used to reduce LDL cholesterol as an adjunct or alternative to statin therapy. Several new nonstatin medications have been approved in recent years, with robust data from clinical trials supporting their use in atherosclerotic disease. This review addresses the indications, evidence, and important prescribing considerations for using nonstatin lipid-lowering therapy and proposes a practical approach for determining when to initiate nonstatin therapy.

Contemporary Management of Obesity: A Comparison of Bariatric Metabolic Surgery and Novel Incretin Mimetic Drugs.

The global prevalence of obesity has risen sharply during the past half-century, reaching pandemic proportions and creating a public health crisis. Obesity is a recognized risk factor for the development of diabetes, atherosclerosis, hypertension, hepatic steatosis, and many other cardiometabolic disorders with significant resultant morbidity and mortality. Though treatment of obesity can prevent or slow the progression of the aforementioned illnesses, efforts to help patients achieve reliable and sustainable weight loss have had limited success. Improving nutrition and increasing physical activity results in a host of health benefits; however, the weight loss achieved with lifestyle interventions alone is modest and difficult to sustain. Early attempts at medical and surgical treatment of obesity were plagued with adverse effects and complications. Moreover, these approaches failed to demonstrate long-term health benefits, even when weight loss was achieved. Recently, novel incretin-based therapies targeting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors have gained popularity because of their effectiveness in achieving substantial weight loss in patients both with and without diabetes. Following many successful clinical trials, there are now multiple GLP-1 receptor agonists and one dual GLP-1-GIP receptor agonist approved by the Food and Drug Administration for chronic weight management. Advancements in laparoscopic surgical technique and refinements in procedure selection have similarly improved the safety and efficacy of bariatric metabolic surgery for patients with obesity. In this review, we discuss the advantages and disadvantages of contemporary pharmacologic and surgical weight management strategies. We review the data regarding expected weight loss, glycemic control, cardiometabolic benefits, and potential adverse effects of various treatment approaches. As obesity rates continue to rise worldwide, it is imperative that clinicians keep these considerations in mind in order to better care for patients.

Impact of the COVID-19 Pandemic on Conduct and Results of CLEAR Outcomes Trial.

INTRODUCTION: The COVID-19 pandemic disrupted clinical research. CLEAR Outcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%. CLEAR Outcomes began before and continued for 2.7 years after the start of the pandemic. METHODS: The impact of the COVID-19 pandemic on patient disposition, adverse events, and major adverse CV events (MACE) in CLEAR Outcomes was assessed. RESULTS: Rates of severe infection, hospitalization, or first MACE associated with a positive COVID-19 test were low and balanced between treatment groups. Rates of all-cause death, non-CV death, and undetermined death increased in the pandemic period compared with the pre-pandemic period, while rates of CV death with a known etiology remained stable. A sensitivity analysis excluding undetermined deaths occurring after the onset of the pandemic from the CV death designation yielded hazard ratios of 0.84 (95% CI, 0.76-0.93) for the primary endpoint and 0.94 (95% CI, 0.76-1.16) for the secondary endpoint of CV death, compared with 0.87 (95% CI, 0.79-0.96) and 1.04 (95% CI, 0.88-1.24), respectively, in the original analysis. CONCLUSION: The CLEAR Outcomes trial continued uninterrupted throughout the COVID-19 pandemic. Certain trial endpoints may have been impacted by the pandemic. Specifically, the classification of undetermined deaths as CV deaths may have attenuated the effect of BA on key efficacy endpoints.

Cangrelor in cardiogenic shock and after cardiopulmonary resuscitation: A global, multicenter, matched pair analysis with oral P2Y12 inhibition from the IABP-SHOCK II trial.

AIMS: Cangrelor has a potentially favorable pharmacodynamic profile in cardiogenic shock (CS). We aimed to evaluate the clinical course of CS patients undergoing percutaneous coronary intervention (PCI) treated with cangrelor. METHODS AND RESULTS: We retrospectively identified 136 CS patients treated with cangrelor. Patients were 1:1 matched to CS patients from the IABP-SHOCK II trial not receiving cangrelor by age, sex, cardiac arrest, type of myocardial infarction, culprit lesion, glycoprotein IIb/IIIa inhibitor, and oral P2Y12-receptor inhibitor and followed-up for 12 months. The study cohort consisted of 88 matched pairs. Thirty-day and 12-month mortality was 29.5% and 34.1% in cangrelor-treated patients and 36.4% and 47.1% in control group (P = 0.34 and P = 0.08, respectively). The rate of definite acute stent thrombosis was 2.3% in both groups. Moderate and severe bleeding events occurred in 21.6% in the cangrelor and 19.3% in the control group (P = 0.71). Patients treated with cangrelor more frequently experienced ≥1 TIMI flow grade improvement during PCI (92.9% vs. 81.2%, P = 0.02). CONCLUSION: Cangrelor treatment was associated with similar bleeding risk and significantly better TIMI flow improvement compared with oral P2Y12 inhibitors in CS patients undergoing PCI. The use of cangrelor in CS offers a potentially safe and effective antiplatelet option and should be evaluated in randomized trials.

The Current Landscape of Atrial Fibrillation and Atrial Flutter Clinical Trials: A Report of 348 Studies Registered With ClinicalTrials.gov.

OBJECTIVES: This analysis sought to systematically characterize trial-level patterns in atrial fibrillation/atrial flutter (AF/AFL) by using the ClinicalTrials.gov database. BACKGROUND: Despite an abundance of clinical trials in this field, there is a lack of high-level evidence guiding management of AF/AFL. METHODS: We queried all closed, phase II to IV interventional trials registered in the ClinicalTrials.gov database through October 2016 that enrolled patients known to have AF/AFL. Published trials were evaluated for methodological quality, using the 3-item Jadad scale (range: 0 to 5, where 5 = highest quality). RESULTS: The initial search yielded 465 uniquely registered studies, of which 348 directly studied AF/AFL. Of those studies, 173 (50%) were published, enrolling a median of 190 patients from a median of 15 sites. The volume of published trials increased over time (7% prior to 2008 vs. 41% from 2014 to 2016; p < 0.001 for trend). Of the completed trials, 29% remain unpublished. Industry sources accounted for most funding (54%). Recurrence of AF/AFL was the most common endpoint (45%), whereas rates of primary clinical endpoints were low (13%). The mean Jadad score of published trials of pharmacological approaches (n = 112) was 4.0 ± 1.4. Of the 61 AF/AFL trials involving ablation or device therapies, 69% were randomized, 28% were single-arm studies, and patient, proceduralist, and event-ascertainment blinding was used in 16%, 4%, and 44%, respectively. CONCLUSIONS: Contemporary trials of AF/AFL are often multicenter and modest in size. The primary study endpoint is commonly recurrence of arrhythmia, even in high-quality and late-phase trials. Although methodological quality is high in trials of pharmacologic approaches, trials of AF/AFL ablation and device therapies variably employ randomization and blinding.

Molecular determinants of metaplastic and neoplastic transformation in the esophageal epithelium.

A metaplastic change where normal squamous mucosa of the esophagus is replaced by columnar mucosa is considered an adaptive process to withstand the chronic gastroesophageal reflux injury. However, this phenotypic switch in the esophageal mucosa is associated with an increased propensity to undergo neoplastic transformation. In this chapter, we review the molecular alterations that are relevant to metaplastic and neoplastic transformations in the esophagus and also discuss the mechanisms that could potentially contribute to this transformation.