Research Goes Red: Early Experience With a Participant-Centric Registry.

RATIONALE: Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention. OBJECTIVE: To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women. METHODS AND RESULTS: The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants' areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women. CONCLUSIONS: RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women's heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women's health.

Clinical and Echocardiographic Diversity Associated With Physical Fitness in the Project Baseline Health Study: Implications for Heart Failure Staging.

BACKGROUND: Clinical and echocardiographic features may carry diverse information about the development of heart failure (HF). Therefore, we determined heterogeneity in clinical and echocardiographic phenotypes and its association with exercise capacity. METHODS: In 2036 community-dwelling individuals, we defined echocardiographic profiles of left and right heart remodeling and dysfunction. We subdivided the cohort based on presence (+) or absence (-) of HF risk factors (RFs) and echocardiographic abnormalities (RF-/Echo-, RF-/Echo+, RF+/Echo-, RF+/Echo+). Multivariable-adjusted associations between subgroups and physical performance metrics from 6-minute walk and treadmill exercise testing were assessed. RESULTS: The prevalence was 35.3% for RF-/Echo-, 4.7% for RF-/Echo+, 39.3% for RF+/Echo-, and 20.6% for RF+/Echo+. We observed large diversity in echocardiographic profiles in the Echo+ group. Participants with RF-/Echo+ (18.6% of Echo+) had predominantly echocardiographic abnormalities other than left ventricular (LV) diastolic dysfunction, hypertrophy and reduced ejection fraction, whereas their physical performance was similar to RF-/Echo-. In contrast, participants with RF+/Echo+ presented primarily with LV hypertrophy or dysfunction, features that related to lower 6-minute walking distance and lower exercise capacity. CONCLUSIONS: Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the presence of HF risk factors and type of echo abnormality should be considered so as to distinguish adverse from benign adaptation and to stratify HF risk.

Multi-dimensional characterization of prediabetes in the Project Baseline Health Study.

BACKGROUND: We examined multi-dimensional clinical and laboratory data in participants with normoglycemia, prediabetes, and diabetes to identify characteristics of prediabetes and predictors of progression from prediabetes to diabetes or reversion to no diabetes. METHODS: The Project Baseline Health Study (PBHS) is a multi-site prospective cohort study of 2502 adults that conducted deep clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys. Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on glucose, HbA1c, medications, and self-report. Principal component analysis (PCA) was performed to create factors that were compared across groups cross-sectionally using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM and for reversion from preDM to noDM. RESULTS: At enrollment, 1605 participants had noDM; 544 had preDM; and 352 had DM. Over 4 years of follow-up, 52 participants with preDM developed DM and 153 participants reverted to noDM. PCA identified 33 factors composed of clusters of clinical variables; these were tested along with eight individual variables identified a priori as being of interest. Six PCA factors and six a priori variables significantly differed between noDM and both preDM and DM after false discovery rate adjustment for multiple comparisons (q < 0.05). Of these, two factors (one comprising glucose measures and one of anthropometry and physical function) demonstrated monotonic/graded relationships across the groups, as did three a priori variables: ASCVD risk, coronary artery calcium, and triglycerides (q < 10-21 for all). Four factors were significantly different between preDM and noDM, but concordant or similar between DM and preDM: red blood cell indices (q = 8 × 10-10), lung function (q = 2 × 10-6), risks of chronic diseases (q = 7 × 10-4), and cardiac function (q = 0.001), along with a priori variables of diastolic function (q = 1 × 10-10), sleep efficiency (q = 9 × 10-6) and sleep time (q = 6 × 10-5). Two factors were associated with progression from prediabetes to DM: anthropometry and physical function (OR [95% CI]: 0.6 [0.5, 0.9], q = 0.04), and heart failure and c-reactive protein (OR [95% CI]: 1.4 [1.1, 1.7], q = 0.02). The anthropometry and physical function factor was also associated with reversion from prediabetes to noDM: (OR [95% CI]: 1.9 [1.4, 2.7], q = 0.02) along with a factor of white blood cell indices (OR [95% CI]: 0.6 [0.4, 0.8], q = 0.02), and the a priori variables ASCVD risk score (OR [95% CI]: 0.7 [0.6, 0.9] for each 0.1 increase in ASCVD score, q = 0.02) and triglycerides (OR [95% CI]: 0.9 [0.8, 1.0] for each 25 mg/dl increase, q = 0.05). CONCLUSIONS: PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function and sleep measures that precede DM; some changes predicted an increased risk of progression to DM. A factor with measures of anthropometry and physical function was the most important factor associated with progression to DM and reversion to noDM. Future studies may determine whether these changes elucidate pathways of progression to DM and related complications and whether they can be used to identify individuals at higher risk of progression to DM for targeted preventive interventions. Trial registration ClinicalTrials.gov NCT03154346.

Importance of Social Determinants in Screening for Depression.

IMPORTANCE: The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease. OBJECTIVE: To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of clinical and socioeconomic status (SES). RESULTS: In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics. CONCLUSIONS AND RELEVANCE: Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.

Modes and timing of death in 66 252 patients with non-ST-segment elevation acute coronary syndromes enrolled in 14 TIMI trials.

Aims: Although presenting features and early sequelae of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are well described, less is known about longer-term risks and modes of death. The purpose of this study was to characterize modes of death following NSTE-ACS in clinical trial populations. Methods and results: We evaluated 66 252 patients with NSTE-ACS enrolled in 14 Thrombolysis in Myocardial Infarction (TIMI) trials, examining baseline characteristics and modes and timing of death. Of the 66 252 patients followed for a median of 372 (interquartile range 218-521) days, 3147 (4.8%) died by the time of last follow-up. Of the 2606 patients (82.8%) with known modes of death, 75.1% were related to a cardiovascular (CV) event, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. The most common modes of CV death were sudden death (SD) and recurrent myocardial infarction (MI) (36.4% and 23.4%, respectively, of CV deaths). The proportion of CV deaths related to recurrent MI was higher in the first 30 days than it was after 30 days following NSTE-ACS (30.6% vs. 18.7%), whereas the proportion of SD was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Conclusion: Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS. Further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD following NSTE-ACS may be critical to reducing late mortality.

Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments.

Antithrombotic drugs, which include antiplatelet and anticoagulant therapies, prevent and treat many cardiovascular disorders and, as such, are some of the most commonly prescribed drugs worldwide. The first drugs designed to inhibit platelets or coagulation factors, such as the antiplatelet clopidogrel and the anticoagulant warfarin, significantly reduced the risk of thrombotic events at the cost of increased bleeding in patients. However, both clopidogrel and warfarin have some pharmacological limitations including interpatient variability in antithrombotic effects in part due to the metabolism, interactions (eg, drug, environment, and genetic), or targets of the drugs. Increased knowledge of the pharmacology of antithrombotic drugs and the mechanisms underlying thrombosis has led to the development of newer drugs with faster onset of action, fewer interactions, and less interpatient variability in their antithrombotic effects than previous antithrombotic drugs. Treatment options now include the next-generation antiplatelet drugs prasugrel and ticagrelor, and, in terms of anticoagulants, inhibitors that directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, edoxaban) are available. In this Series paper we review the pharmacological properties of these most commonly used oral antithrombotic drugs, and explore the development of antiplatelet and anticoagulant therapies.

Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial.

BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. METHODS: ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0-3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1. The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov, number NCT00781391. FINDINGS: 14,348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0-20·2; 8·4%, 0-25·8; and 18·3%, 0-32·6; ptrend<0·0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1·31, 95% CI 1·05-1·64, p=0·0179; highly sensitive responders 2·66, 1·69-4·19, p<0·0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban pinteraction=0·0066; lower-dose edoxaban pinteraction=0·0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes. INTERPRETATION: CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. FUNDING: Daiichi Sankyo.

Role of oral anticoagulants in patients after an acute coronary syndrome.

After an acute coronary syndrome, patients continue to be at risk of adverse cardiovascular events despite treatment with the current standard of antithrombotic therapy. The risk may be in part secondary to thrombin, which remains elevated after an acute coronary syndrome event. Several studies have investigated the utility of adding oral anticoagulation to post-acute coronary syndrome medical regimens, with the most promising results coming from the addition of low-dose oral direct anticoagulants. Focusing on optimal dosing strategies and applying therapies to the appropriate populations provide the ability to maximize benefit and minimize risk.

PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes.

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.

Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs.

Importance: Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation. Objective: To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs. Design and Setting: A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency. Exposure: Deep learning-trained algorithm. Main Outcomes and Measures: The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity. Results: The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images [7.8%]); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images [14.6%]). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%. Conclusions and Relevance: In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment.

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Rivaroxaban in patients with a recent acute coronary syndrome.

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

Addressing barriers to optimal oral anticoagulation use and persistence among patients with atrial fibrillation: Proceedings, Washington, DC, December 3-4, 2012.

Approximately half of patients with atrial fibrillation and with risk factors for stroke are not treated with oral anticoagulation (OAC), whether it be with vitamin K antagonists (VKAs) or novel OACs (NOACs); and of those treated, many discontinue treatment. Leaders from academia, government, industry, and professional societies convened in Washington, DC, on December 3-4, 2012, to identify barriers to optimal OAC use and adherence and to generate potential solutions. Participants identified a broad range of barriers, including knowledge gaps about stroke risk and the relative risks and benefits of anticoagulant therapies; lack of awareness regarding the potential use of NOAC agents for VKA-unsuitable patients; lack of recognition of expanded eligibility for OAC; lack of availability of reversal agents and the difficulty of anticoagulant effect monitoring for the NOACs; concerns with the bleeding risk of anticoagulant therapy, especially with the NOACs and particularly in the setting of dual antiplatelet therapy; suboptimal time in therapeutic range for VKA; and costs and insurance coverage. Proposed solutions were to define reasons for oral anticoagulant underuse classified in ways that can guide intervention and improve use, to increase awareness of stroke risk as well as the benefits and risks of OAC use via educational initiatives and feedback mechanisms, to better define the role of VKA in the current therapeutic era including eligibility and ineligibility for different anticoagulant therapies, to identify NOAC reversal agents and monitoring strategies and make knowledge regarding their use publicly available, to minimize the duration of dual antiplatelet therapy and concomitant OAC where possible, to improve time in therapeutic range for VKA, to leverage observational data sets to refine understanding of OAC use and outcomes in general practice, and to better align health system incentives.

Autoantibodies to phosphorylcholine and cardiovascular outcomes in patients with acute coronary syndromes in the ATLAS ACS-TIMI 46 trial.

Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7 days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6 months. The median baseline anti-PC concentration was 40.9 U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8 %, Q2: 4.2 %, Q3: 7.8 %, Q4: 5.4 %, p-trend = 0.87), all-cause mortality (Q1: 1.4 %, Q2: 0.7 %, Q3: 2.4 %, Q4: 0.9 %, p-trend = 0. 96), or any of the other individual endpoint components (MI: p-trend = 0.87, Stroke: p-trend = 0.43, SRI: p-trend = 0.66). Using the previously reported anti-PC cutpoint of 17 U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17 U/mL: 8.1 % vs. ≥17 U/mL: 5.8 %; p = 0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p = 0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.

Diversity, Equity, and Inclusion in Clinical Research: A Path Toward Precision Health for Everyone.

Healthcare disparities are a persistent societal problem. One of the contributing factors to this status quo is the lack of diversity and representativeness of research efforts, which result in nongeneralizable evidence that, in turn, provides suboptimal means to enable the best possible outcomes at the individual level. There are several strategies that research teams can adopt to improve the diversity, equity, and inclusion (DEI) of their efforts; these strategies span the totality of the research path, from initial design to the shepherding of clinical data through a potential regulatory process. These strategies include more intentionality and DEI-based goal-setting, more diverse research and leadership teams, better community engagement to set study goals and approaches, better tailored outreach interventions, decentralization of study procedures and incorporation of innovative technology for more flexible data collection, and self-surveillance to identify and prevent biases. Within their remit of overlooking research efforts, regulatory authorities, as stakeholders, also have the potential for a positive effect on the DEI of emerging clinical evidence. All these are implementable tools and mechanisms that can make study participation more approachable to diverse communities, and ultimately generate evidence that is more generalizable and a conduit for better outcomes. The research community has an imperative to make DEI principles key foundational aspects in study conduct in order to pursue better personalized medicine for diverse patient populations.

Cytochrome p-450 polymorphisms and response to clopidogrel.

BACKGROUND: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. METHODS: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. RESULTS: In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02). CONCLUSIONS: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study.

OBJECTIVES: We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status. DESIGN, SETTING AND PARTICIPANTS: We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings. IMPORTANCE: Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests. RESULTS: Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001). CONCLUSIONS: Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease. TRIAL REGISTRATION NUMBER: NCT03154346.

Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36).

BACKGROUND: The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women. METHODS AND RESULTS: We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors (P<0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis >or=50% on angiography, 19.4% versus 8.6%; P<0.001) or elevated troponin (57.1% versus 68.9%; P<0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P<0.001), worse median angina frequency scores (80 versus 100; P<0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P=0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P=0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P=0.002). CONCLUSIONS: Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.

BACKGROUND: Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. METHODS: We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. FINDINGS: In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. INTERPRETATION: Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. FUNDING: Daiichi Sankyo Company Ltd and Eli Lilly and Company.