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This randomized trial involving patients with osteoarthritis or rheumatoid arthritis who were at increased cardiovascular risk showed the noninferiority of celecoxib to naproxen or ibuprofen with respect to cardiovascular safety. Nonsteroidal antiinflammatory drugs (NSAIDs) were introduced in the 1960s and became the most widely prescribed class of drugs in the world, with more than 100 million prescriptions issued annually in the United States alone. 1 NSAIDs inhibit cyclooxygenase (COX), which reduces pain and inflammation through the inhibition of prostaglandins. However, the COX enzyme is also present in gastric mucosa, where it stimulates gastroprotective prostaglandins. The identification of two isoforms, COX-1 and COX-2, and the recognition that antiinflammatory and analgesic effects are mediated through COX-2 inhibition — whereas the gastrointestinal toxic effects are linked to COX-1 inhibition — resulted in the development . . .

The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide ( n  = 8,803) versus placebo ( n  = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min −1  1.73 m − 2 , persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P  = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min −1  1.73 m − 2 (95% CI 0.43, 1.06; P  < 0.001) overall and 2.19 ml min −1  1.73 m − 2 (95% CI 1.00, 3.38; P  < 0.001) in patients with baseline eGFR <60 ml min −1  1.73 m − 2 . These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes. ClinicalTrials.gov identifier: NCT03574597 . In a pre-specified secondary analysis of the SELECT trial, once-weekly subcutaneous semaglutide 2.4 mg in patients with obesity was associated with a 22% reduction in the main 5-component kidney composite endpoint compared to patients on placebo.

In a randomized trial involving patients with high-risk vascular disease, the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers but was not associated with a lower rate of cardiovascular events than placebo. Pharmacologic reduction of the low-density lipoprotein (LDL) cholesterol level with statins substantially decreases the risks of death and complications from cardiovascular causes. 1 , 2 Considerable interest has focused on the identification of approaches that might further reduce cardiovascular-event rates among high-risk patients. 3 Epidemiologic studies have shown inverse associations between high-density lipoprotein (HDL) cholesterol levels and cardiovascular outcomes, 4 – 6 a correlation that persists despite treatment with statins. 7 Nevertheless, therapeutic interventions that raise the HDL cholesterol level have not been shown to reduce cardiovascular risk. Cholesteryl ester transfer protein (CETP) modulates the transfer of esterified cholesterol from HDL to apolipoprotein B–containing lipoproteins. 8 Two . . .

The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk. Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597. Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE—an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94–0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93–0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94–0·99]; p=0·007), but not bodyweight (0·99 [0·97–1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77–0·97] after adjustment for time-varying changes in waist circumference). The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction. Novo Nordisk.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

•4-step STEMI protocol improved care in patients with nonsystem delays.•Protocol reduced door-to-balloon time from 132 to 101 minutes.•Rates of bleeding, shock, and AKI significantly declined postimplementation.•Discharge to home improved without increase in in-hospital mortality.•Findings challenge view that nonsystem delays are unmodifiable in STEMI. Hospital-wide strategies improve outcomes in STEMI, yet their impact on patients with nonsystem delays (NSD) to primary PCI remains unknown. This study evaluated the effect of a 4-step comprehensive STEMI protocol (CSP) on outcomes in this high-risk population. This observational cohort analysis included STEMI patients with NSD as defined by the ACC National Cardiovascular Data Registry CathPCI Registry v5.0 criteria, which included difficult vascular access, difficulty crossing the culprit lesion, cardiac arrest and/or need for intubation before PCI, patient delays in providing consent for PCI, emergent placement of left-ventricular support device before PCI, and other reasons. Process and outcome metrics were compared before (January, 2011–July, 2014; n = 163) and after (July, 2014–July, 2019; n = 196) CSP implementation. The CSP comprised: (1) emergency department catheterization-laboratory activation; (2) STEMI Safe Handoff Checklist; (3) immediate transfer to an available laboratory; and (4) radial-first PCI. Among 359 patients with NSD, CSP implementation increased pre-PCI guideline-directed medical therapy (57.1%–79.6%, p <0.001) and radial access (16.6%–55.6%, p <0.001), and reduced median door-to-balloon time (132–101 minutes, p = 0.001). Post-CSP patients experienced lower rates of bleeding (22.7%–10.2%, p = 0.002), cardiac arrest (36.2%–23.5%, p = 0.01), circulatory shock (39.9%–24.5%, p = 0.003), and acute kidney injury (30.7%–19.9%, p = 0.03), with more frequent discharge to home (65.0%–78.6%, p = 0.006). In-hospital mortality was similar (14.1% vs 9.2%, p = 0.20). In conclusion, a 4-step CSP improved process metrics and clinical outcomes among STEMI patients with NSD, challenging the notion that outcomes of NSD cohort are unmodifiable and underscoring the importance of system-based interventions in this high-risk cohort.

ObjectiveLipoprotein(a) (Lp(a)) is an important genetically determined risk factor for atherosclerotic vascular disease (ASCVD). With the development of Lp(a)-lowering therapies, this study sought to characterise patterns of Lp(a) levels in a global ASCVD population and identify racial, ethnic, regional and gender differences.MethodsA multicentre cross-sectional epidemiological study to estimate the prevalence of elevated Lp(a) in patients with a history of myocardial infarction, ischaemic stroke or peripheral artery disease conducted at 949 sites in 48 countries in North America, Europe, Asia, South America, South Africa and Australia between April 2019 and July 2021. Low-density lipoprotein cholesterol (LDL-C) and Lp(a) levels were measured either as mass (mg/dL) or molar concentration (nmol/L).ResultsOf 48 135 enrolled patients, 13.9% had prior measurements of Lp(a). Mean age was 62.6 (SD 10.1) years and 25.9% were female. Median Lp(a) was 18.0 mg/dL (IQR 7.9–57.1) or 42.0 nmol/L (IQR 15.0–155.4). Median LDL-C was 77 mg/dL (IQR 58.4–101.0). Lp(a) in women was higher, 22.8 (IQR 9.0–73.0) mg/dL, than in men, 17.0 (IQR 7.1–52.2) mg/dL, p<0.001. Black patients had Lp(a) levels approximately threefold higher than white, Hispanic or Asian patients. Younger patients also had higher levels. 27.9% of patients had Lp(a) levels >50 mg/dL, 20.7% had levels >70 mg/dL, 12.9% were >90 mg/dL and 26.0% of patients exceeded 150 nmol/L.ConclusionsGlobally, Lp(a) is measured in a small minority of patients with ASCVD and is highest in black, younger and female patients. More than 25% of patients had levels exceeding the established threshold for increased cardiovascular risk, approximately 50 mg/dL or 125 nmol/L.Trial registration number

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. The CLEAR Outcomes trial was conducted uninterrupted during the COVID‐19 pandemic due to key changes in study procedures. The definitions of the trial endpoints were not altered for the pandemic, raising the possibility that outcomes related to cardiovascular mortality may have been impacted.

There are limited data on the impact of anemia on clinical outcomes in unstable angina and non–ST-segment elevation myocardial infarction treated with an early invasive strategy. We sought to determine the short- and long-term clinical events among patients with and without anemia enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Anemia was defined as baseline hemoglobin of <13 g/dl for men and <12 g/dl for women. The primary end points were composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) and major bleeding assessed in-hospital, at 1 month, and at 1 year. Among the 13,819 patients in the ACUITY trial, information regarding anemia was available in 13,032 (94.3%), 2,199 of whom (16.9%) had anemia. Patients with anemia compared with those without anemia had significantly increased adverse event rates in-hospital (composite ischemia 6.6% vs 4.8%, p = 0.0004; major bleeding 7.3% vs 3.3%, p <0.0001), at 1 month (composite ischemia 10% vs 7.2%, p <0.0001, major bleeding 8.8% vs 3.9%, p <0.0001), and 1 year (composite ischemia 21.7% vs 15.3%, p <0.0001). Anemia was an independent predictor of death at 1 year (hazard ratio 1.77, 95% confidence interval [CI] 1.29 to 2.44, p = 0.0005). Composite ischemia was significantly more common among patients who developed in-hospital non–coronary artery bypass surgery major bleeding compared with those who did not (anemic patients 1-year relative risk 2.19, 95% CI 1.67 to 2.88, p <0.0001; nonanemic patients relative risk 2.16, 95% CI 1.76 to 2.65, p <0.0001). In conclusion, in the ACUITY trial, baseline anemia was strongly associated with adverse early and late clinical events, especially in those who developed major bleeding.

Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-α and PPAR-γ agonist aleglitazar. In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with ≤two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4–5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks' treatment with aleglitazar at once-daily doses of 50 μg, 150 μg, 300 μg, or 600 μg, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA 1c) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA 1c measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov, number NCT00388518. The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 μg, 150 μg, and 600 μg aleglitazar groups; and n=2 in 300 μg aleglitazar group). Aleglitazar significantly reduced baseline HbA 1c versus placebo in a dose-dependent manner, from −0·36% (95% CI 0·00 to −0·70, p=0·048) with 50 μg to −1·35% (−0·99 to −1·70, p<0·0001) with 600 μg. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA 1c concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 μg, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 μg, two at 150 μg, and three with placebo) and less than with pioglitazone (four cases), and bodyweight gain was less than with pioglitazone (0·52 kg at 150 μg vs 1·06 kg). The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. F Hoffmann-La Roche AG (Switzerland).