Patrícia O. Guimarães

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy

We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ≥4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as #NCT00412984.

Accuracy of Medical Claims for Identifying Cardiovascular and Bleeding Events After Myocardial Infarction : A Secondary Analysis of the TRANSLATE-ACS Study

Importance Pragmatic clinical trial designs have proposed the use of medical claims data to ascertain clinical events; however, the accuracy of billed diagnoses in identifying potential events is unclear. Objectives To compare the 1-year cumulative incidences of events when events were identified by medical claims vs by physician adjudication and to assess the accuracy of bill-identified events using physician adjudication as the criterion standard. Design, Setting, and Participants This post hoc analysis of a clinical trial assessed the medical claims forms and records for all rehospitalizations at 233 US hospitals within 1 year of the index acute myocardial infarction (MI) of 12 365 patients enrolled in the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study between April 1, 2010, and October 31, 2012. Fourteen patients (0.1%) died during the index hospitalization and were excluded from analysis. Recurrent MI, stroke, and bleeding events were identified per the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedural codes in medical bills. These events were independently adjudicated by study physicians through medical record reviews using the prespecified criteria of recurrent MI and stroke and the bleeding definition by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scale. Medical claims were reported on a Uniform Bill-04 claims form; claims were collected from all hospitals visited by patients enrolled in TRANSLATE-ACS. Agreement between medical claims–identified events and physician-adjudicated events over the 12 months after discharge was assessed with the &kgr; statistic. Data were analyzed from January 30, 2015, to March 2, 2017. Main Outcomes and Measures Event rates within 1 year after MI. Results Among 12 365 patients with acute MI, 8890 (71.9%) were men and mean (SD) age was 60 (11.6) years. The cumulative 1-year incidence of events identified by medical claims was 4.3% for MI, 0.9% for stroke, and 5.0% for bleeding. Incidence rates based on physician adjudication were 4.7% for MI, 0.9% for stroke, and 5.4% for bleeding. Agreement between medical claims–identified and physician-adjudicated events was modest, with a &kgr; of 0.76 (95% CI, 0.73 to 0.79) for MI and 0.55 (95% CI, 0.41 to 0.68) for stroke events. In contrast, agreement between medical claims–identified and physician-adjudicated bleeding events was poor, with a &kgr; of 0.24 (95% CI, 0.19 to 0.30) for any hospitalized bleeding event and 0.15 (95% CI, 0.11 to 0.20) for moderate or severe bleeding on the GUSTO scale. Conclusions and Relevance Event rates at 1 year after MI were lower for MI, stroke, and bleeding when medical claims were used to identify events than when adjudicated by physicians. Medical claims diagnoses were only modestly accurate in identifying MI and stroke admissions but had limited accuracy for bleeding events. An alternative approach may be needed to ensure good safety surveillance in cardiovascular studies. Trial Registration clinicaltrials.gov Identifier: NCT01088503

Practical and clinical considerations in assessing patients with atrial fibrillation for switching to non-vitamin K antagonist oral anticoagulants in primary care

Atrial fibrillation (AF) is an important risk factor for thromboembolic events, and anticoagulation therapy can reduce this risk. Vitamin K antagonists (VKAs), such as warfarin, have been used for decades in patients with AF for stroke prevention. Currently, non-VKA oral anticoagulants (NOACs) are approved and available for non-valvular AF patients who are at increased risk of stroke. These agents are safe and effective and have important advantages over VKAs, such as significant reduction in intracranial hemorrhage and no need for routine laboratory monitoring. Thus, should all VKA-treated patients be switched to a NOAC? The aims of this article are: 1) to review the advantages of NOACs over VKAs; 2) to identify the group of patients who most benefit from receiving a NOAC and, therefore, are higher priority to be switched from VKAs; and 3) to provide clinical and practical guidance on how to switch patients safely from VKAs to NOACs.

Ticagrelor, prasugrel, or clopidogrel in ST-segment elevation myocardial infarction: which one to choose?

Introduction: Clopidogrel, prasugrel, and ticagrelor are the currently available oral P2Y12 inhibitors for the treatment of ST-segment elevation myocardial infarction (STEMI), in association with aspirin. These agents bind the P2Y12 platelet receptor and thus inhibit platelet aggregation. Large randomized clinical trials have provided efficacy and safety data on P2Y12 inhibitors in STEMI patients. Areas covered: This review focuses on key pharmacologic and clinical aspects of clopidogrel, prasugrel, and ticagrelor, highlighting their differences. Results from the main clinical trials are discussed, as well as the current STEMI guideline recommendations, to help inform agent selection for patients presenting with STEMI. Expert opinion: Clinical trials studying newer P2Y12 inhibitors with increased potency have shown further reduction of cardiovascular events compared with clopidogrel, therefore suggesting the use of ticagrelor or prasugrel as a first-line agent for STEMI treatment. There are still clinical situations – such as fibrinolysis, high risk of bleeding, use of oral anticoagulant, and financial hurdles – in which clopidogrel maintains a role in the treatment of STEMI.

Sex Differences in Clinical Characteristics, Psychosocial Factors, and Outcomes Among Patients With Stable Coronary Heart Disease: Insights from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial

Background Greater understanding of differences between men and women with coronary heart disease is needed. Methods and Results In this post hoc analysis of the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, we described psychosocial factors, treatments, and outcomes of men versus women with stable coronary heart disease and explored the association of sex with psychosocial characteristics and cardiovascular risk. Cox proportional hazards models were used to assess the relationship between sex and outcomes. Interactions among sex, psychosocial factors, and the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were tested. Of 15 828 patients, 2967 (19%) were women. Among women, 21.2% felt often or always stressed at home (versus 9.8% of men), and 19.2% felt often or always sad or depressed (versus 10.1% of men; all P<0.0001). The median duration of follow‐up was 3.7 years (25th–75th percentiles: 3.5–3.8 years). Use of evidence‐based medications for coronary heart disease at baseline and 24 months was similar between sexes, as were event rates for all outcomes analyzed. In the multivariable model including psychosocial measures, female sex was associated with lower cardiovascular risk. There was a statistically significant interaction (P=0.03) such that the lower risk in women varied by depressive symptom frequency, whereby women who were more depressed had a risk similar to men. Conclusions Female sex was independently associated with better long‐term clinical outcomes, although this was modified by frequency of depressive symptoms. This suggests that emotional state may be an important target for improving outcomes in patients with coronary heart disease, specifically in women. Clinical Trial Registration STABILITY ClinicalTrials.gov number (NCT00799903).

Association of standard clinical and laboratory variables with red blood cell distribution width

BACKGROUND Red blood cell distribution width (RDW) strongly predicts clinical outcomes among patients with coronary disease and heart failure. The factors underpinning this association are unknown. METHODS In 6,447 individuals enrolled in the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study who had undergone coronary angiography between 2001 and 2007, we used Cox proportional hazards modeling to examine the adjusted association between RDW and death, and death or myocardial infarction (MI). Multiple linear regression using the R(2) model selection method was then used to identify clinical factors associated with variation in RDW. RESULTS Median follow-up was 4.2 (interquartile range 2.3-5.9) years, and the median RDW was 13.5% (interquartile range 12.9%-14.3%, clinical laboratory reference range 11.5%-14.5%). Red blood cell distribution width was independently associated with death (adjusted hazard ratio 1.13 per 1% increase in RDW, 95% CI 1.09-1.17), and death or MI (adjusted hazard ratio 1.12, 95% CI 1.08-1.16). Twenty-seven clinical characteristics and laboratory measures were assessed in the multivariable linear regression model; a final model containing 18 variables explained only 21% of the variation in RDW. CONCLUSIONS Although strongly associated with death and death or MI, only one-fifth of the variation in RDW was explained by routinely assessed clinical characteristics and laboratory measures. Understanding the latent factors that explain variation in RDW may provide insight into its strong association with risk and identify novel targets to mitigate that risk.

Pooled analysis of adverse event collection from 4 acute coronary syndrome trials

BACKGROUND Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied. METHODS Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded. RESULTS In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs. CONCLUSIONS Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

Reporting Clinical End Points and Safety Events in an Acute Coronary Syndrome Trial: Results With Integrated Collection

Background End points and adverse events (AEs) are collected separately in clinical trials, yet regulatory requirements for serious AE reporting vary across regions, so classifying end points according to seriousness criteria can be useful in global trials. Methods and Results In the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE‐2) trial, patients with a recent acute coronary syndrome were randomized to apixaban or placebo for the prevention of recurrent ischemic events. Suspected end points (myocardial infarction, stroke, or bleeding) were adjudicated by an independent clinical events classification committee. Safety criteria were collected for suspected end points and AEs. Patient‐level event rates per 100 patient‐days of follow‐up, modeled using Poisson regression, explored the influence of region and patient characteristics on event reporting. Overall, 13 909 events were reported by 858 sites in 39 countries; 8.4% (n=1166) were suspected end points, and 91.6% (n=12 743) were AEs. Overall, 66.0% of suspected end points were confirmed by the clinical events classification committee. Most clinical events classification committee‐confirmed end points met criteria to be classified as serious (94.0%); many clinical events classification committee‐negated end points also did (63.2%), but fewer AEs met seriousness criteria (17.9%). The most common seriousness criterion was hospitalization (79.9%, n=2594). Region explained 28.7% of end point‐ and 26.4% of serious AE‐reporting variation, and patient characteristics explained an additional 25.4% of end point and 13.4% of serious AE variation. Nonserious AE‐reporting variation was not explained by adjustment. Conclusions An integrated collection of end points and serious AEs is feasible in a multinational trial and illustrates the shared characteristics of events. Tailoring event collection to fit the phase and purpose of the trial is achievable and informative. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00831441.

Highlights from the Tenth International Symposium of Thrombosis and Anticoagulation (ISTA X), September 22 and 23, 2017, Salvador, Bahia, Brazil

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Tenth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on September 22 and 23, 2017. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes—the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Usefulness of Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Myocardial Infarction

To examine patterns of preadmission and discharge antithrombotic therapies in coronary artery disease (CAD) and atrial fibrillation (AF) patients admitted for acute myocardial infarction (AMI), we performed a retrospective analysis of the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG), which captures consecutive AMI patients treated at participating US hospitals. We included patients with CAD, AF, and CHA2DS2-VASc score ≥2 admitted for AMI (07/01/2013-09/30/2016). In the 15,034 AMI patients with previous AF and CAD, median age was 75; 32% were female. Preadmission, 32% of patients were on P2Y12 inhibitors, 36% were anticoagulated, 72% were on aspirin, and 5% were on triple therapy. At discharge post-AMI, 73% were prescribed P2Y12 inhibitors and 41% anticoagulation. Discharge anticoagulation use did not vary directly with CHA2DS2-VASc score; 16% of previously anticoagulated patients had discontinued anticoagulation at discharge. In patients receiving anticoagulants at discharge, 27% used nonvitamin K antagonist oral anticoagulants. Triple therapy was prescribed in 23% at discharge; 27% of these were with nonvitamin K antagonist oral anticoagulants and 14% with prasugrel or ticagrelor. P2Y12 inhibitors and anticoagulants without aspirin were used in 2%. In conclusion, patients with previous CAD and AF are undertreated for both recurrent ischemic events and stroke prevention. After AMI hospitalization, P2Y12 inhibition was preferentially selected over oral anticoagulation.