Tardif, Jean‐Claude

AbstractRandomized controlled trials (RCTs) remain the gold standard to evaluate clinical interventions, producing the highest level of evidence while minimizing potential bias. Inadequate recruitment is a commonly encountered problem that undermines the completion and generalizability of RCTs—and is even more challenging when enrolling amidst a pandemic. Here, we reflect on our experiences with virtual recruitment of non‐hospitalized patients in the United States for ColCorona, an international, multicenter, randomized, placebo‐controlled coronavirus disease 2019 (COVID‐19) drug trial. Recruitment challenges during a pandemic include constraints created by shelter‐in‐place policies and targeting enrollment according to national and local fluctuations in infection rate. Presenting a study to potential participants who are sick with COVID‐19 and may be frightened, overwhelmed, or mistrusting of clinical research remains a challenge. Strategies previously reported to improve recruitment include transparency, patient and site education, financial incentives, and person‐to‐person outreach. Active measures taken during ColCorona to optimize United States recruitment involved rapid expansion of sites, adjustment of recruitment scripts, assessing telephone calls versus text messages for initial contact with participants, institutional review board‐approved financial compensation, creating an infrastructure to systematically identify potentially eligible patients, partnering with testing sites, appealing to both self‐interest and altruism, and large‐scale media efforts with varying degrees of success.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 ( ADCY9 ) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Objectives To test the relationship between increasing severity of obesity, calculated risk and observed outcomes. Methods Patients with symptoms suggestive of coronary artery disease (CAD) (n=10 003) were stratified according to body mass index (BMI). We compared risk factors, pooled risk scores and physicians’ perception of risk. Cox regression tested the association between BMI and (1) presence of obstructive CAD and (2) composite clinical endpoints (death, cardiovascular death, unstable angina hospitalisation and myocardial infarction). Results BMI was ≥30 kg/m2 in 48% of patients and ≥35 in 20%. Increasingly obese patients were younger, female and non-smoking but with higher prevalence of hypertension, diabetes, black race and sedentary lifestyle. Pooled risk estimates of CAD were highest in those with mid-range BMI. In contrast, physicians’ estimation of the likelihood of significant CAD based on clinical impression increased progressively with BMI. For a 10% increase in the Diamond-Forrester probability of CAD, the adjusted OR for obstructive CAD was 1.5 (95% CI 1.4 to 1.5) in patients with BMI <35, but only 1.2 (95% CI 1.1 to 1.3) in those with BMI ≥35 (interaction p<0.001). Framingham Risk Score increased across increasing BMI categories. However, there was a strong and consistent inverse relationship between degree of obesity and all three composite clinical endpoints over a median 25 months of follow-up. Conclusions Despite perceptions of higher risk and higher risk scores, increasingly obese patients had obstructive CAD less frequently than predicted and had fewer adverse clinical outcomes. There is a need for risk assessment tools and guidelines that account for obesity. Trial registration number NCT01174550.

Background The Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non‐ST‐Segment Elevation Myocardial Infarction ( SELECT ‐ ACS ) trial suggested beneficial effects of inclacumab, a monoclonal antibody directed against P‐selectin, on periprocedural myocardial damage. This study evaluated the effect of inclacumab on myocardial damage according to varying time intervals between study drug infusion and percutaneous coronary intervention ( PCI ). Methods and Results Patients (n=544) enrolled in the SELECT ‐ ACS trial and randomized to receive 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 hours before PCI ) were divided according to the time interval between study drug infusion and PCI . The primary end point was the change in troponin I from baseline at 16 and 24 hours after PCI . In patients receiving inclacumab 20 mg/kg with a short (less than median) time interval between infusion and PCI , placebo‐adjusted geometric mean percent changes in troponin I, creatine kinase–myocardial band, and peak troponin I at 24 hours were −45.6% ( P =0.005), −30.7% ( P =0.01), and −37.3% ( P =0.02), respectively. No significant changes were observed in patients with a long (greater than median) time interval between infusion and PCI . Placebo‐adjusted geometric mean percent changes in troponin I and creatine kinase–myocardial band were −43.5% ( P =0.02) and −26.0% ( P =0.07), respectively, when inclacumab 20 mg/kg was administered between 1 and 3 hours before PCI , whereas the drug had no effect with longer intervals. Conclusions Inclacumab 20 mg/kg significantly reduces myocardial damage after PCI in patients with non– ST ‐segment elevation myocardial infarction, and benefits are larger when the infusion is administered <3 hours before PCI . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01327183.