Christopher B. Granger

BACKGROUND: Oral anticoagulation (OAC) remains underused in patients with atrial fibrillation or flutter at high risk of ischemic stroke. We aimed to characterize documented OAC prescribing at diagnosis and during 1-year follow-up and identify factors associated with baseline OAC prescribing. METHODS: Using electronic health records from 7 US health systems participating in the National Patient-Centered Clinical Research Network between 2015 and 2019, we identified patients with newly diagnosed atrial fibrillation at high risk of ischemic stroke (CHA ₂ DS ₂ -VASc score ≥2 for men or ≥3 for women). The primary outcomes were documented OAC prescription at baseline and during 1-year follow-up. Exposures included demographic, clinical, and health-system characteristics. Multivariable logistic regression was used to identify factors associated with baseline OAC prescribing and loss of documented OAC prescribing during follow-up. RESULTS: Among 161 295 patients (median age, 76 years [interquartile range, 68–82]; 70 327 [43.6%] women), 92 518 (57.4%) had a documented OAC prescription at baseline, increasing from 56.6% in 2015 to 62.6% in 2019. Among those with a documented baseline OAC prescription, 45.6% had no documented OAC prescription during 1-year follow-up. Among 68 777 patients without a documented baseline OAC prescription, 12.5% had an OAC prescription documented during follow-up. Dementia (odds ratio, 0.58 [95% CI, 0.56–0.61]), prior major bleeding (odds ratio, 0.69 [95% CI, 0.63–0.75]), and renal disease (odds ratio, 0.84 [95% CI, 0.81–0.88]) were associated with lower odds of baseline OAC prescribing, whereas heart failure was associated with higher odds (odds ratio, 1.40 [95% CI, 1.37–1.43]). CONCLUSIONS: Among patients with newly diagnosed atrial fibrillation at high risk for ischemic stroke, OAC prescribing at diagnosis was suboptimal, and loss of documented OAC prescribing was common during the first year. Baseline OAC use was more strongly associated with bleeding risk, frailty, and comorbidity burden, and less consistently aligned with ischemic stroke risk.

BACKGROUND: Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS: We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS: Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%–35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%–7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%–28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS: Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

Background: Pragmatic trials commonly use remote follow‐up to reduce participant burden and costs. However, these approaches may increase the risk of lost to follow‐up (LTFU). We identified patient‐ and site‐level factors associated with LTFU in 2 large, pragmatic heart failure (HF) trials. Methods: We analyzed data from 2 pragmatic US trials (CONNECT‐HF [Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure], TRANSFORM‐HF [Torsemide Comparison With Furosemide for Management of Heart Failure]) following HF hospitalization. Both trials employed centralized call center–based follow‐up with supplemental data sources. For this analysis, LTFU was defined as the absence of both a completed 6‐month assessment and any subsequent clinical follow‐up throughout the study (confirmation of vital status alone was insufficient). Multivariable logistic regression models were used to identify factors associated with LTFU in each trial. Results: The LTFU rates were 7.6% (362/4771) in CONNECT‐HF and 10.5% (245/2334) in TRANSFORM‐HF. In multivariable analyses of both trials, younger age was consistently associated with increased LTFU. Conversely, implantable cardioverter‐defibrillator/cardiac resynchronization therapy was consistently associated with lower LTFU (CONNECT‐HF: adjusted odds ratio [aOR], 0.56 [95% CI, 0.43–0.75]; TRANSFORM‐HF: aOR, 0.59 [95% CI, 0.39–0.89]). In CONNECT‐HF, smaller hospital size (aOR per 100 beds, 0.90 [95% CI, 0.83–0.97]) was also associated with higher LTFU. Socioeconomic factors were not significantly associated with LTFU. Conclusions: In analyses of 2 pragmatic trials of patients hospitalized for HF in the United States, younger patients, those without implantable cardioverter‐defibrillator/cardiac resynchronization therapy, and smaller hospital size were associated with higher LTFU. Tailoring retention strategies to both patient and site characteristics should be explored in future work to help mitigate LTFU in pragmatic trials.

Decentralized clinical trials (DCTs) move trial activities—such as recruitment, consent, delivery of the intervention, data collection and assessment of outcomes—away from traditional research sites to the homes or communities of patients. This participant-centered approach is accomplished through the use of digital health technology, remote monitoring, electronic data capture, and home- or community-based procedures. The advantage of DCTs may include broader trial recruitment pools with greater representativeness, reduced participant burden, greater operational efficiency and the ability to generate evidence in real-world settings. These features are particularly relevant in cardiovascular disease, which imposes a disproportionate population burden in regions where clinical trial centers are lacking. In this Perspective, we outline the essential components of the DCT ecosystem, discuss how DCTs can address key challenges in cardiovascular disease research, and using case examples, highlight operational and regulatory considerations in designing fully or partially (hybrid) decentralized trials. We also review the potential risks of DCTs and propose mitigation strategies to ensure high-quality, safe and reliable trial execution.

BACKGROUND: Systemic embolic events (SEEs) are a serious but underrecognized complication of atrial fibrillation. Although non–vitamin K antagonist oral anticoagulants prevent ischemic stroke (IS), their efficacy in SEE and the clinical characteristics of patients who experience SEE remain poorly understood. METHODS: We analyzed individual patient data from 4 pivotal randomized trials enrolling patients between 2005 and 2010 comparing non–vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation. We characterized the incidence, clinical features, management, and outcomes of clinically overt SEE and compared results in these patients with patients who had an IS. RESULTS: Among 71 683 patients, 188 experienced SEE (26 with concurrent IS), yielding an annualized event rate of 0.13% per patient-year, compared with 1.25% per patient-year for IS (n=1797). Among 171 patients with SEE as their first event, median age was 75 years (interquartile range, 68–80), 49.7% were female, and mean±SD CHA ₂ DS ₂ -VASc score was 4. 7 ±1.5. Compared with IS, patients with SEE had higher rates of peripheral arterial disease (PAD, 16.5% versus 5.4%; P P =0.02), previous vitamin K antagonist exposure (57% versus 46%; P =0.007), worse renal function (median creatinine clearance 58 versus 62 mL/min; P =0.02), and higher incidence of nonparoxysmal atrial fibrillation (86% versus 80%; P =0.047). Interventions (surgical or percutaneous) were performed in 62 patients (31%) with SEE. Standard-dose non–vitamin K antagonist oral anticoagulants reduced the risk of SEE by 29% compared with warfarin over a median follow-up of 25.2 months (interquartile range, 17.5–32.0; hazard ratio, 0.71 [95% CI, 0.51–0.99]; P =0.04). Thirty-day mortality after SEE was similar to IS (18% versus 17%), and SEE was associated with a nearly 3-fold increased risk of long-term mortality compared with patients without SEE or IS (hazard ratio, 2.85 [95% CI, 2.11–3.85]). Independent predictors of SEE included peripheral artery disease, smoking, nonparoxysmal atrial fibrillation, female sex, previous myocardial infarction, previous stroke or transient ischemic attack, vitamin K antagonist experience, and renal dysfunction. CONCLUSIONS: In this large individual patient data meta-analysis, non–vitamin K antagonist oral anticoagulants significantly reduced the risk of SEE compared with warfarin. Although SEEs were approximately one-tenth as frequent as IS, they were associated with comparable mortality and substantial morbidity.

Background: Among patients with ST segment elevation myocardial infarction (STEMI), higher concentrations of high sensitivity troponin T (hs-cTnT) are associated with larger MI size and predict a worse prognosis. In the 2467 patient CELEBRATE trial, a single subcutaneous injection of the short-acting glycoprotein IIb/IIIa receptor blocker antagonist zalunfiban at first medical contact significantly improved the primary outcome including clinical endpoints. In this study, we assessed the impact of zalunfiban on MI size and association with downstream outcomes remains unclear. Methods: In a prespecified analysis, we studied results among study participants treated with two doses of zalunfiban who had core laboratory measurements concentrations of hs-cTnT. Results: The median concentration of hs-cTnT at presentation was 62 ng/L; at 24 hours it was 1962 ng/L. More elevated hs-cTnT concentrations at presentation were associated with less resolution of ST deviation after revascularization (P =0.006) and more frequent Q wave development (all P <0.001). At coronary angiography more elevated hs-cTnT at presentation was also associated with higher thrombus grade and worse epicardial and myocardial perfusion (all P <0.05). In multivariable analyses, higher hs-cTnT concentrations at 24 hours were associated with greater adjusted risk for all-cause death (odds ratio [OR] 1.83 per log unit increase; P=0.03), cardiovascular death (OR 1.83 per log unit increase; P=0.03), heart failure (OR 2.74 per log unit increase; P <0.001) or the composite of death (or cardiovascular death) and heart failure (P<0.001) by 30 days. At 24 hours, those treated with zalunfiban had lower hs-cTnT compared to placebo (1900 vs 2082 ng/L; P =0.04) and across multiples ≥10 to ≥1000 times elevation, treatment with zalunfiban resulted in smaller hs-cTnT determined MI size. Conclusion: Among patients with STEMI, higher concentrations of hs-cTnT are associated with worse angiographic and ECG measures of reperfusion. More elevated hs-cTnT predicted a higher risk for short-term death or heart failure. A single dose of zalunfiban at first medical contact reduced MI size, as judged by more study participants with lower hs-cTnT concentrations. These results provide a mechanistic basis for the improved clinical outcomes associated with zalunfiban treatment in the CELEBRATE Trial. Study registration: A Phase 3 Study of Zalunfiban in Subjects With ST-elevation MI (CELEBRATE); NCT04825743

The human metabolic and excretion profile of zalunfiban, a novel glycoprotein IIb/IIIa inhibitor, was studied in a phase 1 clinical trial. ¹⁴C-zalunfiban was administered subcutaneously as a single fixed dose (9.5 mg with 5 μCi total radioactivity).Zalunfiban whole blood concentrations were measured using liquid chromatography-mass spectrometry. ¹⁴C-zalunfiban and metabolites were measured using liquid scintillation counting and accelerator mass spectrometry in whole blood, urine, and feces. Eight participants were enrolled. Zalunfiban was well-tolerated.Following injection zalunfiban was detectable within 5 minutes and the last measurable concentration was observed within 4 hours. The median T_max was 0.25 hours and mean half-life was 0.96 hours. Zalunfiban accounted for 35.6% of total whole blood radioactivity AUC at 4 hours. The single major identified metabolite was des-gly-zalunfiban (M1), which has 90% by 240 hours.Zalunfiban is rapidly metabolized to the nearly inactive M1 metabolite, which is excreted primarily in urine. Renal impairment, therefore, is unlikely to significantly prolong zalunfiban effects and dose adjustment in patients with reduced renal function may not be required.

Acute coronary syndromes are caused by obstructive coronary thrombosis complicating myocardial ischaemic disease and are dichotomously classified according to their electrocardiographic presentation as ST-segment elevation myocardial infraction or non-ST-segment elevation acute coronary syndrome, either without or with elevated myocardial necrosis markers. Initial diagnosis and risk stratification are reliably guided by symptoms, electrocardiographic changes, and troponin elevation and require exclusion of alternative conditions, such as Type 2 myocardial infarction and myocardial injury due to systemic conditions. Timely coronary angiography is a key component of the initial diagnosis to assess the presence of occlusive coronary artery disease, rather than an myocardial infarction with non-occluded coronary arteries, and the suitability for revascularization. While clinical trials with randomization prior to angiography have shown reduction in recurrent myocardial infarction and urgent revascularization with a neutral effect on mortality from an early invasive approach, increased revascularization rates have been systematically associated with reduced mortality in registries and administrative databases. Complete revascularization in patients with multivessel disease has been shown to reduce mortality compared with culprit-only revascularization. The safety of this approach has been shown even in fragile, elderly, and multimorbid patients. Post-acute treatment should be focused on patient-tailored antithrombotic therapy and disease-modifying secondary prevention approaches. This review describes the complex spectrum of non-ST-segment elevation acute coronary syndrome and the importance of complete clinical and coronary angiographic assessment for optimal patient-centred treatment.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox—blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management. Clinical inertia represents a major barrier on the clinician side, as well as workload and limited education. Common barriers on the patient side include limited English proficiency, low health literacy, and nonadherence with misaligned incentives, limited resources, lack of structured clinical pathways, and reimbursement issues. New innovations in the field of RNA-targeted therapies and device-based interventions could prevent and potentially even cure diseases previously designated as chronic health conditions, such as hypertension. Such novel therapies could potentially overcome several major barriers to effective treatment, including nonadherence. Drug development of novel, long-acting treatments requires consideration of specific clinical trial design aspects, including safety collection, benefit: risk assessment, the development and assessment of novel, qualitative surrogate end points, such as time-in-therapeutic range, the use of representative trial settings as well as the definition of standard of care in placebo-controlled trials, which should be of reasonably high-quality allowing for credible evaluation of effectiveness. Here, we provide an overview on barriers to effective treatment and a framework for trials assessing novel treatments for cardiovascular disease risk factors, including early and broad implementation programs.