Yuyin Liu

Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography

Background: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. Methods: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. Results: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46–2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01–4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36–3.43; P=0.001). Conclusions: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.

Circulating Proneurotensin Concentrations and Cardiovascular Disease Events in the Community: The Framingham Heart Study.

Objective—Neurotensin is a peptide whose receptor (sortilin receptor 1) is linked to cardiovascular disease (CVD) development. We hypothesized concentrations of proneurotensin (stable profragment of neurotensin) would predict incident cardiovascular events in community-based subjects. Approach and Results—Blood samples from 3439 participants in the Framingham Heart Study (FHS) Offspring cohort (mean age 59.2 years, 47.1% male) were tested for proneurotensin. Primary outcome of interest was incident hard CVD (myocardial infarction, stroke, and cardiovascular death); interaction between proneurotensin concentration with sex, low-density lipoprotein concentrations, and sortilin receptor 1 single-nucleotide polymorphisms was sought. At baseline, those in the highest log-proneurotensin quartile were younger and heavier (P<0.001); across proneurotensin quartiles, more prevalent hard CVD (from 3% to 7%; P<0.001) and diabetes mellitus (from 6% to 14%; P<0.001) were present. In age- and sex-adjusted models, log-proneurotensin concentrations predicted incident hard CVD (hazard ratio [HR], 1.24 per SD change in log-proneurotensin; 95% confidence intervals [CIs], 1.11–1.39; P<0.001), a finding that remained on adjustment for standard CVD risk factors (HR, 1.13; 95% CI, 1.01–1.27; P=0.03). Elevated log-proneurotensin concentrations were associated with shorter time to first event (P=0.02). We found no effect modification by sex, low-density lipoprotein concentration, or sortilin receptor 1 single-nucleotide polymorphisms. Concentrations of proneurotensin were modestly associated with left ventricular mass and coronary artery calcium in these subjects. Conclusions—Higher concentrations of proneurotensin are associated with a greater risk of incident cardiovascular events in the community. This association did not vary according to sex, baseline low-density lipoprotein, or sortilin receptor 1 genotype.

The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial

Dual anti‐platelet therapy with clopidogrel and low‐dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti‐platelet therapy. Whether or not omeprazole improves patient‐reported outcomes is undetermined.

Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial

To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).

Baseline adiponectin concentration and clinical outcomes among patients with diabetes and recent acute coronary syndrome in the EXAMINE trial

To investigate adiponectin levels and cardiovascular (CV) outcomes in patients with diabetes and recent acute coronary syndrome (ACS).

Ischemic cardiac outcomes and hospitalizations according to prior macrovascular disease status in patients with type 2 diabetes and recent acute coronary syndrome from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care trial

BACKGROUND Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post-acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE. METHODS Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline. RESULTS There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease. CONCLUSIONS EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry

Background It is poorly understood whether insurance type may be a major contributor to the underuse of oral anticoagulation (OAC) among patients with atrial fibrillation (AF), particularly for novel oral anticoagulants (NOACs). Methods We performed a retrospective cohort registry study of patients with insurance, AF, CHA2DS2‐VASc ≥2, and at least one outpatient encounter recorded in the ACC NCDRs PINNACLE Registry between January 1, 2011 and December 31, 2014. We used hierarchical regression, adjusting for patient characteristics and clustering by physician, to evaluate the association of insurance type (Private, Military, Medicare, Medicaid, Other) with receipt of OAC (any OAC, warfarin, or NOAC). Results In 363,309 patients (age 75 ± 10; 48% female), we found a significant difference in proportions of OAC and NOAC prescription across insurance types (OAC: Military 53%, Private 53%, Medicare 52%, Other 41%, Medicaid 41%, P < .001; NOAC: Military 24%, Private 19%, Medicare 17%, Other 17%, Medicaid 8%, P < .001). After adjustment for patient characteristics and facility, private, Medicaid, and other insurance were independently associated with a lower odds of OAC prescription relative to Medicare, but military insured patients were not significantly different. After adjustment, military and private insurance were independently associated with a higher odds of NOAC prescription relative to Medicare, while Medicaid and other insurance were associated with a lower odds of NOAC prescription. Conclusions In a contemporary US AF population, there was significant variation of OAC prescription across insurance plans, with the highest among private and Medicare insured patients. These differences may indicate that insurance plan, and its associated pharmacy benefits, affect the pace of diffusion of new therapies.

PROTON-PUMP INHIBITORS REDUCE RISK OF GASTROINTESTINAL EVENTS REGARDLESS OF ASPIRIN DOSE IN PATIENTS REQUIRING DUAL ANTIPLATELET THERAPY: INSIGHTS FROM THE COGENT TRIAL

The COGENT trial showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. Randomized

Addressing High Placebo Response in Neuroscience Clinical Trials

In pharmacological research of Major Depressive Disorder (MDD), 38–50% of all short-term, acute, Phase 3 clinical studies failed to distinguish active drug from placebo, even for approved antidepressants (Gispen-de Wied et al. 2012; Khin et al. 2011), while 15% of the studies were considered negative (Chen et al. 2014). Although not all of these failed trials represent false negatives, meta-analyses of antidepressant studies suggest that high variability in the placebo response, independent of drug response, explains the majority of the variability in trial outcome (Alkermes announces advances 2014; Gispen-de Wied et al. 2012; Khin et al. 2011). The net result of this is an increasing number of failed clinical trials in depression, resulting in medications with potential clinical value not reaching patients in need. As summarized in a recent review by Rutherford et al. (2014), “High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market”, and by Gispen-de Wied et al. (2012), “All efforts should be made to optimize the clinical development of drugs in the psychiatric domain, in order to improve the intrinsic quality of studies and reduce the burden to both pharmaceutical companies and society of too many trials needed to complete the dossier”.

Early and Chronic Dipeptidyl‐Peptidase‐IV Inhibition and Cardiovascular Events in Patients With Type 2 Diabetes Mellitus After an Acute Coronary Syndrome: A Landmark Analysis of the EXAMINE Trial

Background Antihyperglycemic therapies may increase the risk of cardiovascular events including hospitalization for heart failure. There is a paucity of data evaluating the cardiovascular safety of antihyperglycemic therapies in the high‐risk period following an acute coronary syndrome (ACS). Methods and Results The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial randomized 5380 patients who were 15 to 90 days post ACS to the dipeptidyl dipeptidase‐IV (DPP‐IV) inhibitor alogliptin versus placebo; mean follow‐up was 18 months. Using a landmark analysis, we assessed the (1) burden of cardiovascular events from randomization to 6 months (early period) and from 6 months to the end of follow‐up (late period) and (2) the risk of cardiovascular events associated with early (up to 6 months) and chronic (6 months to end of follow‐up) DPP‐IV inhibition with alogliptin. Patients with early versus late events had similar baseline demographic profiles. Overall, 42.1% of the composite of cardiovascular death/myocardial infarction/stroke and 47.5% of hospitalization for heart failure occurred in the early period. Early DPP‐IV inhibition did not increase the risk of early cardiovascular death/myocardial infarction/stroke (hazard ratio 0.96, 95% confidence interval, 0.76–1.21) or hospitalization for heart failure (1.23, 95% confidence interval, 0.84–1.82). Similarly, chronic DPP‐IV inhibition did not increase the risk of late cardiovascular death/myocardial infarction/stroke (hazard ratio 1.03, 95% confidence interval, 0.89–1.26) or hospitalization for heart failure (hazard ratio 1.02, 95% confidence interval, 0.85–1.22). Conclusions Early after an ACS, patients with type 2 diabetes mellitus experience a significant burden of HF events and recurrent ACS. DPP‐IV inhibition with alogliptin appears to be safe even in the high‐risk period following an ACS.