Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs. © 2021 American College of Cardiology Foundatio

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies

Background: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. Methods: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 � 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count 3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. Conclusions: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19. © 2020 Elsevier Lt

Diagnostic Performance of Angiography-based Fractional Flow Reserve in Various Subgroups: Report from the FAST-FFR Study.

A large, prospective, multicenter trial recently showed that fractional flow reserve (FFR) derived from coronary angiography (FFRangio) has an accuracy of 92% compared with conventional guide-wire based FFR (FFRwire); however, little is known whether specific patient/lesion characteristics affect the diagnostic performance. FFRangio was measured in a blinded fashion in 301 patients (319 vessels) who were undergoing FFRwire assessment. Using an FFRwire ≤0.80 as a reference, the diagnostic performance of FFRangio was compared in pre-specified subgroups. The mean FFRwire and FFRangio were 0.81 ± 0.13 and 0.80 ± 0.12. Overall, FFRangio had a sensitivity of 93.5% and specificity of 91.2% for predicting FFRwire. Patient characteristics including age, sex, clinical presentation, body mass index, and diabetes did not affect sensitivity or specificity (p>0.05 for all). Similarly, lesion characteristics including calcification, tortuosity did not affect sensitivity or specificity (p>0.05 for all), nor did lesion location (proximal, middle, versus distal). Sensitivity was equally high across all target vessels, while specificity was highest in the LAD and lower (~85%) in the RCA and LCx (p<0.05). FFRangio derived from coronary angiography has a high diagnostic performance regardless of patient and most lesion characteristics. The interaction of vessel on the specificity will need to be confirmed in larger cohorts

Clinical Outcomes With Drug-Eluting and Bare-Metal Stents in Patients With ST-Segment Elevation Myocardial Infarction Evidence From a Comprehensive Network Meta-Analysis

Objectives The authors investigated the relative safety and efficacy of different drug-eluting stents (DES) and bare metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) using a network meta-analysis. Background The relative safety of DES and BMS in patients with STEMI continues to be debated, and whether advances have been made in this regard with second-generation DES is unknown. Methods Randomized controlled trials comparing currently U. S. approved DES or DES with BMS in patients with STEMI were searched using MEDLINE, EMBASE, and Cochrane databases. Information on study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. Results Twenty-two trials including 12,453 randomized patients were analyzed. At 1-year follow-up, cobalt-chromium everolimus eluting stents (CoCr-EES) were associated with significantly lower rates of cardiac death or myocardial infarction (MI) and stent thrombosis (ST) than BMS. Differences in ST were apparent as early as 30 days and were maintained for 2 years. CoCr-EES were also associated with significantly lower rates of 1-year ST than paclitaxel-eluting stents (PES). Sirolimus-eluting stents (SES) were also associated with significantly lower rates of 1-year cardiac death/myocardial infarction than BMS. CoCr-EES, PES, and SES, but not zotarolimus-eluting stents, had significantly lower rates of 1-year target vessel revascularization (TVR) than BMS, with SES also showing lower rates of TVR than PES. Conclusions In patients with STEMI, steady improvements in outcomes have been realized with the evolution from BMS to first-generation and now second-generation DES, with the most favorable safety and efficacy profile thus far demonstrated with CoCr-EES. (J Am Coll Cardiol 2013;62:496-504) (C) 2013 by the American College of Cardiology Foundatio

Accuracy of Fractional Flow Reserve Derived From Coronary Angiography.

Measuring fractional flow reserve (FFR) with a pressure wire remains underutilized because of the invasiveness of guide wire placement or the need for a hyperemic stimulus. FFR derived from routine coronary angiography (FFR <sub>angio</sub> ) eliminates both of these requirements and displays FFR values of the entire coronary tree. The FFR <sub>angio</sub> Accuracy versus Standard FFR (FAST-FFR) study is a prospective, multicenter, international trial with the primary goal of determining the accuracy of FFR <sub>angio</sub> . Coronary angiography was performed in a routine fashion in patients with suspected coronary artery disease. FFR was measured in vessels with coronary lesions of varying severity using a coronary pressure wire and hyperemic stimulus. Based on angiograms of the respective arteries acquired in ≥2 different projections, on-site operators blinded to FFR then calculated FFR <sub>angio</sub> using proprietary software. Coprimary end points were the sensitivity and specificity of the dichotomously scored FFR <sub>angio</sub> for predicting pressure wire-derived FFR using a cutoff value of 0.80. The study was powered to meet prespecified performance goals for sensitivity and specificity. Ten centers in the United States, Europe, and Israel enrolled a total of 301 subjects and 319 vessels meeting inclusion/exclusion criteria which were included in the final analysis. The mean FFR was 0.81 and 43% of vessels had an FFR≤0.80. The per-vessel sensitivity and specificity were 94% (95% CI, 88% to 97%) and 91% (86% to 95%), respectively, both of which exceeded the prespecified performance goals. The diagnostic accuracy of FFR <sub>angio</sub> was 92% overall and remained high when only considering FFR values between 0.75 to 0.85 (87%). FFR <sub>angio</sub> values correlated well with FFR measurements ( r=0.80, P<0.001) and the Bland-Altman 95% confidence limits were between -0.14 and 0.12. The device success rate for FFR <sub>angio</sub> was 99%. FFR <sub>angio</sub> measured from the coronary angiogram alone has a high sensitivity, specificity, and accuracy compared with pressure wire-derived FFR. FFR <sub>angio</sub> has the promise to substantially increase physiological coronary lesion assessment in the catheterization laboratory, thereby potentially leading to improved patient outcomes. URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03226262

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies. © 2022 Lippincott Williams and Wilkins. All rights reserved