Faculty Bibliography

Senior housestaff and junior faculty are often expected to perform clinical research, yet may not always have the requisite knowledge and skills to do so successfully. Formal degree programs provide such knowledge, but require a significant commitment of time and money. Short-term training programs (days to weeks) provide alternative ways to accrue essential information and acquire fundamental methodological skills. Unfortunately, published information about short-term programs is sparse. To encourage discussion and exchange of ideas regarding such programs, we here share our experience developing and implementing INtensive Training in Research Statistics, Ethics, and Protocol Informatics and Design (INTREPID), a 24-day immersion training program in clinical research methodologies. Designing, planning, and offering INTREPID was feasible, and required significant faculty commitment, support personnel and infrastructure, as well as committed trainees. Clin Trans Sci 2014; Volume #: 1-7.

IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.

BACKGROUND: The Occluded Artery Trial (OAT) randomized stable patients (n=2201) >24h (calendar days 3-28) after myocardial infarction (MI) with totally occluded infarct-related arteries (IRA), to percutaneous coronary intervention (PCI) with optimal medical therapy, or optimal medical therapy alone (MED). PCI had no impact on the composite of death, reinfarction, or class IV heart failure over extended follow-up of up to 9years. We evaluated the impact of early and late reinfarction and definition of MI on subsequent mortality. METHODS AND RESULTS: Reinfarction was adjudicated according to an adaptation of the 2007 universal definition of MI and the OAT definition (>/=2 of the following - symptoms, EKG and biomarkers). Cox regression models were used to analyze the effect of post-randomization reinfarction and baseline variables on time to death. After adjustment for baseline characteristics the 169 (PCI: n=95; MED: n=74) patients who developed reinfarction by the universal definition had a 4.15-fold (95% CI 3.03-5.69, p<0.001) increased risk of death compared to patients without reinfarction. This risk was similar for both treatment groups (interaction p=0.26) and when MI was defined by the stricter OAT criteria. Reinfarctions occurring within 6months of randomization had similar impact on mortality as reinfarctions occurring later, and the impact of reinfarction due to the same IRA and a different epicardial vessel was similar. CONCLUSIONS: For stable post-MI patients with totally occluded infarct arteries, reinfarction significantly independently increased the risk of death regardless of the initial management strategy (PCI vs. MED), reinfarction definition, location and early or late occurrence.

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with >/=10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that >/=10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, >/=3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by >/=4 of 32 stress perfusion defects or >/=3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions.

BACKGROUND: Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. METHODS: In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). RESULTS: During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). CONCLUSIONS: In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

BACKGROUND: In a prospective study, we previously identified plaque disruption (PD: plaque rupture or ulceration) in 38% of women with myocardial infarction (MI) without angiographically obstructive coronary artery disease (CAD), using intravascular ultrasound (IVUS). Underlying plaque morphology has not been described in these patients and may provide insight into the mechanisms of MI without obstructive CAD. METHODS: Forty-two women with MI and <50% angiographic stenosis underwent IVUS (n = 114 vessels). Analyses were performed by a blinded core laboratory. Sixteen patients had PD (14 ruptures and 5 ulcerations in 18 vessels). Plaque area, % plaque burden, lumen area stenosis, eccentricity, and remodeling index were calculated for disrupted plaques and largest plaque by area in each vessel. RESULTS: Disrupted plaques had lower % plaque burden than the largest plaque in the same vessel (31.9% vs 49.8%, P = .005) and were rarely located at the site of largest plaque (1/19). Disrupted plaques were typically fibrous and were not more eccentric or remodeled than the largest plaque in the same vessel. CONCLUSIONS: Plaque disruption was often identifiable on IVUS in women with MI without obstructive CAD. Plaque disruption in this patient population occurred in fibrous or fibrofatty plaques and, contrary to expectations based on prior studies of plaque vulnerability, did not typically occur in eccentric, outwardly remodeled, or soft plaque in these patients. Plaque disruption rarely occurred at the site of the largest plaque in the vessel. These findings suggest that the pathophysiology of PD in women with MI without angiographically obstructive CAD may be different from MI with obstructive disease and requires further investigation.

Background: Patients with moderate or severe ischemia have a heightened risk for myocardial infarction and cardiovascular death. Geographic variation in the proportion of stress myocardial perfusion imaging (MPI) and echocardiography (echo) with at least moderate ischemia is unknown. Methods: De-identified monthly MPI and stress echo screening logs from sites participating in the NHLBI-funded ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trial were reviewed for site-specific number of studies with site-interpreted moderate or severe ischemia. Data are reported as site-weighted medians (interquartile range [IQR]). Results: 97 sites contributed 448 months totaling 46,530 studies. Of 34,463 MPI and 12,067 stress echo studies, 1,308 (3.9% [IQR: 1.2, 8.0]) and 466 (3.2% [IQR: 0.0, 10.0]), respectively, had at least moderate ischemia (P=0.74). Median age was 66 years (IQR: 59, 73); 29.5% were female. Regional variation in study proportion with at least moderate ischemia was observed for both MPI and stress echo (P<0.001 for both, Table) and age (P<0.001), but not for sex (P=0.22). Compared to outside-US, US studies were less likely to have at least moderate ischemia (P<0.001). Conclusions: Regional variations exist in the proportion of stress imaging studies with moderate or severe ischemia. Moderate or severe ischemia was lowest among US studies, suggesting inter-country variability in the clinical assessment of ischemia. (Figure Presented)

Background: The Third Universal Definition of Myocardial Infarction (MI) designates an increase in cardiac troponin concentration (cTn) > 99th percentile of a normal reference population as the decision level for MI diagnosis. The variability among hospitals in the lab-determined cTn level to diagnose MI [cTn decision level] relative to the assay manufacturer determined 99th percentile has not been well characterized. Methods: We surveyed 93 sites from 15 countries participating in the NHLBI ISCHEMIA trial to ascertain the cTn assay used at their hospital labs, its 99th percentile, as well as the cTn MI decision level. The ratio of cTn MI decision level to cTn 99th percentile was calculated for each lab. Results: Laboratories employed 32 unique cTn assays from 7 manufacturers; 77% used cTnI assays and 23% used cTnT assays. Highly sensitive assays were used in 18 labs (19.4%). The ratio of cTn MI decision level to cTn 99th percentile was <1 at 7 labs (7.5%), equal to 1 at 29 labs (31.2%) and >10 at 18 labs (19.4%) (Figure). Substantial variability was observed in cTn MI decision level even among labs using the same assay. Conclusion: Significant variability exists in the cTn MI decision level used by hospital laboratories relative to the assay cTn 99th percentile. Only one-third of labs follow the Third Universal Definition of MI. These data have important implications for the diagnosis of MI in clinical practice and adjudicating MI endpoints in clinical trials. (Figure Presented)

AIMS/OBJECTIVE:Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD. METHODS AND RESULTS/RESULTS:We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (OR(adj) 0.15; 95% CI, 0.11-0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (OR(adj) 0.19 (0.14-0.25) and 0.37 (0.28-0.49), respectively). CONCLUSION/CONCLUSIONS:Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.