Faculty Bibliography

AIMS: Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. METHODS AND RESULTS: The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. CONCLUSION: This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. CLINICAL TRIAL REGISTRATION: NCT00699998.

Introduction: Physical activity (PA) reduces the risk of events in patients with stable coronary heart disease (CHD). Biomarkers reflecting myocardial dysfunction, renal function and inflammatory activity are associated with outcomes in stable CHD. It is poorly known to what extent the benefits of PA may be linked to biomarker levels. Hypothesis: The association between PA and outcomes may be mediated by processes indicated by changes in the levels of prognostic biomarkers. Methods: At baseline, 15,486 patients with stable CHD participating in the global STABILITY trial, completed a baseline lifestyle questionnaire including self-reporting on hours spent each week on mild, moderate and vigorous exercise, corresponding to approximately 2, 4 and 8 METS, respectively. Plasma levels of high-sensitivity (hs) C-reactive protein (hs-CRP), hs-troponin T (hs-TnT), N-terminal pro-B type natriuretic peptide (NT-proBNP), cystatin-C, growth differentiation factor-15 (GDF-15) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were assessed from plasma samples obtained at baseline. Associations between PA and biomarker levels were evaluated after multivariable adjustments (age, gender, traditional clinical cardiovascular risk factors and standard biomarkers including cholesterol levels) with sedentary patients as reference. Results: Associations between levels of PA and hs-CRP, hs-TnT, NT-proBNP, cystatin C, GDF-15 and activity of Lp-PLA2 are shown in the Table, after adjustments for co-variables. PA was independently and inversely associated with all biomarker levels, except for Lp-PLA2. Conclusions: Increasing PA, was independentlyand inversely associated with levels of most clinically important biomarkers, except for Lp-PLA2. The effects of PA on outcomes may partly be explained by disease processes reflected by changes in biomarker levels

Introduction: Clinical practice guidelines have recommended evidence based medicine (EBM) and treatment targets for optimal management of BP, LDL Cholesterol (LDLc) and of HbA1c in diabetic patients with stable coronary heart disease [CHD]. However the importance of achieving these goals is uncertain Hypothesis: In patients with stable CHD achievement of goals for blood pressure, LDLc, and HbA1c in diabetics, and use of EBM are associated with a lower risk of major adverse cardiovascular events [MACE] Methods: In 13,624 patients with stable CHD, who participated in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial, BP, LDLc and HbA1c in diabetes were assessed at baseline, and at 3, 6 and 12 month follow-up visits; BP and medication use were additionally assessed at 1 month. EBM; aspirin, beta blockers, ACE / ARB, and statins, were recommended for patients without contraindications. Standard of care (SOC) targets were BP<140/90 mmHg, LDLc <70mg/dl and <100mg/dl, and HbA1c<7% in 4711 diabetics. Achievement of each of these targets was defined as meeting the target on >4 of 5 visits for BP and EBM, and >3 of 4 biochemical measurements. A landmark analysis assessed the association between achievement of EBM and of each SOC target during the first year of the study and MACE, defined as cardiovascular death, MI, or stroke, during a further 2.7 years follow-up, after adjusting for baseline predictors of MACE in a Cox proportional hazards model Results: See Table Conclusions: High rates of evidence based medicine use were achieved. MACE was related to LDLc. After one year the risk of subsequent MACE was reduced for patients who met target LDLc levels and for diabetic patients who achieved target HbA1c

Introduction: Secondary preventive guidelines recommend patients with stable coronary heart disease (CHD) take at least 30 min of moderate or vigorous physical activity (PA) on at least 5 days/week. Hypothesis: Lower levels of PA may be beneficial for cardiovascular (CV) prognosis. Aim: To evaluate associations between self-reported PA, including mild intensity exercise and outcomes in a global cohort of patients with stable CHD. Methods: A lifestyle questionnaire was completed at baseline by 15,486 (97.8%) STABILITY participants. Total PA was estimated from individual subject self-reports of hours spent each week on mild, moderate and vigorous exercise, 2, 4 and 8 METS respectively. Associations between the total amount of PA and MACE (CV mortality, non-fatal myocardial infarction or non-fatal stroke), CV and non-CV mortality were evaluated using Cox proportional hazard models adjusting for age, gender, treatment allocation, markers of disease severity and CV risk factors during a median follow-up of 3.7 yrs. Results: For all subjects, a greater proportion of MET.hours was spent taking mild (50.4%) compared to moderate (39.7%) and vigorous (10.0%) PA. The mean (+/-SD) PA reported for the 'sedentary' (t1, n=5281), 'mildly active' (t2, n=5055) and 'moderately active' (t3, n=5151) tertiles were t1 12.1+/-7.4, t2 39.6+/-7.4 and t3 104.3+/-45.9 MET.hours/week. Compared to 'sedentary' subjects the 'mild' and 'moderate' PA tertiles had a lower risk of MACE HR 0.96 (95% CI 0.85-1.08) and 0.79 (0.70-0.91), p=0.0019, CV death 0.89 (0.75-1.06) and 0.69 (0.57-0.85), p=0.0019, and non-CV death 0.54 (0.41-0.72) and 0.72 (0.55-0.95), p<.0001. See Figure. Conclusions: In patients with stable CHD there is a strong inverse association between self-reported PA and MACE, CV mortality and non-CV mortality. Even modest amounts of mild intensity exercise are associated with lower mortality

INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

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.