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Introduction: Inappropriate use of direct oral anticoagulants (DOACs) is common, affecting up to 30% of atrial fibrillation (AF) population receiving treatment for stroke prevention. This study assessed appropriateness of anticoagulation in anticoagulation-naive AF patients treated with DOACs during a 12-month prospective follow-up., Methods: This prospective cohort study included all anticoagulation-naive AF patients referred for anticoagulation for stroke prevention at a tertiary cardiovascular center. Participants were prospectively followed through phone call interviews by a dedicated nurse at 1, 3, 6, 9, and 12 months after enrollment., Results: Of 403 anticoagulation-naive AF patients, rivaroxaban was prescribed for 325 patients (80.7%) and apixaban for 78 (19.3%). Inappropriate therapy was observed in 23% (76/325) and 46% (36/78) of patients treated with rivaroxaban and apixaban, respectively. Undertreatment was predominant scenario for both drugs, detected in 78.5% (78/112) of patients treated inappropriately, and was more frequently observed with apixaban versus rivaroxaban (44.8% vs 16.3%). During 12 months, inappropriate treatment was corrected in only 13% of all patients. The multivariate regression model identified creatinine clearance ≤ 49 mL/min (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.12 to 4.21), female sex (OR, 1.81; 95% CI, 1.11 to 2.97), and age ≥ 80 years (OR, 1.85; 95% CI, 1.22 to 2.83) as independent covariates associated with inappropriate dosing., Conclusions: Inappropriate therapy with DOACs for stroke prevention in patients with AF is common, and the dosage were corrected in few patients during the 12-month follow-up. Our findings highlight the persistent lack of knowledge regarding appropriate DOAC dosage and need for continuous education., Competing Interests: Declarations. Competing interests: Dr. Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally.  He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multi morbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program me under grant agreement No 899871., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Interactions between food and oral anticoagulants (OACs), particularly vitamin K antagonists such as warfarin, are widely recognized and may also be clinically relevant for direct OACs. Pharmacokinetic and pharmacodynamic interactions with food or herbs can lead to anticoagulation potentiation, increased risk of bleeding, or reduced drug efficacy, all compromising patient safety. We conducted a systematic search for randomized controlled trials (RCTs) on PubMed for assessments of interactions between OACs and various ingestants. Since the RCT evidence was slim, we also reviewed prospective longitudinal studies, case series, and case reports to identify possible associations between foods and anticoagulation therapy. We referred to basic or translational studies that shared putative explanations for such interactions, but we failed to identify high-quality evidence in most cases. The limited evidence, small sample size of the studies, conflicting results, and possible heterogeneity in the contents of herbal products prevent a conclusive assessment of these interactions. Existing evidence suggests that (1) cranberry juice consumption (up to 240 mL/d and probably even more) with warfarin is safe; (2) use of green leafy vegetables with a high daily content (more than 250 µg) of vitamin K should be cautioned for patients receiving warfarin, because it may decrease warfarin efficacy. It is also advisable for patients to maintain highly constant intake of green leafy vegetables to ensure stable warfarin effectiveness; (3) ginger, even in small quantities (excluding commercial ginger-flavored beverages, which contain only negligible amounts of ginger), and mango (more than one fruit) can both potentiate warfarin effects; (4) patients taking OACs should avoid St. John's wort due to diminished anticoagulant effect; and (5) consumption of less than 240 mL of grapefruit juice daily is unlikely to interact with OACs. Future longitudinal observational cohort studies and RCTs with larger sample sizes are needed to study specific interactions between food or herbal products and OACs., Competing Interests: Outside the submitted work, A.C. has served as a consultant for MingSight, Pfizer, Sanofi, and Synergy and has received authorship royalties from UpToDate. G.P. received funding as Research Grants (paid to his institution from BMS/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Esperion, 1R01HL164717-01) and has Advisory Roles in BSC, Amgen, BCRI, PERC, NAMSA, BMS, Janssen, Regeneron. Outside the submitted work, B.B. is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814). B.B. was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at the Brigham and Women's Hospital, and the Heart and Vascular Center Junior Faculty Award from the Brigham and Women's Hospital. B.B. reports that he was a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of inferior vena cava (IVC) filters. B.B. has not been involved in the litigation in 2022 to 2024 nor has he received any compensation in 2022 to 2024. B.B. reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. B.B. is a collaborating consultant with the International Consulting Associates and the U.S. Food and Drug Administration in a study to generate knowledge about utilization, predictors, retrieval, and safety of IVC filters. B.B. receives compensation as an Associated Editor for the New England Journal of Medicine Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for JACC, and is a Section Editor for Thrombosis and Haemostasis (no compensation)., (Thieme. All rights reserved.)

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management., (© 2024 Pharmacotherapy Publications, Inc.)

Background: Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience., Objectives: To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population., Methods: By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS., Results: Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean time in therapeutic range was 57.3% before and 59% after WMS implementation [mean difference, 1.64; 95% confidence interval (CI), -1.12-4.40]. In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61; 95% CI, -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range., Conclusions: For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Heart rate (HR) stands as a prognostic indicator of cardiovascular disease and a modifiable risk factor in heart failure (HF). Medication intolerance can curtail the application of conventional HR-lowering β-blockers to the optimum target dose. Ivabradine (IVA), a specific negative-chronotropic agent, selectively inhibits I f current in pacemaker cells of the sinoatrial node without depressing myocardial contractility or comprising hemodynamics. This review summarized ivabradine's clinical labeled and off-label uses and mechanism of action focusing on the clinical outcomes. PubMed was searched up to January 2024 using the main keywords of IVA, coronary artery disease (CAD), HF, postural tachycardia syndrome (POTS), and tachyarrhythmia. To comprehensively review IVA's clinical indications, mechanisms, and therapeutic effects, all studies investigating treatment with IVA in humans were included, comprising different types of studies such as randomized controlled trials and longitudinal prospective observational studies. After screening, 141 studies were included in our review. A large number of reviewed articles were allocated to heart failure with reduced ejection fraction and CAD, suggesting IVA as an alternative to β-blockers in case of contraindications or intolerance. The beneficial effects of IVA as premedication for coronary computed tomography angiography, HR lowering in POTS, and inappropriate sinus tachycardia constituted most studies among off-label uses. The promising results have been reported on the efficacy of IVA in controlling HR, especially in patients with inappropriate sinus tachycardia or POTS. Owing to the unique mechanism of action, IVA has the potential to be used more frequently in future clinical practice., Competing Interests: The conflict of interest disclosure and funding declaration: Nothing to disclose, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors have no competing interests to declare.

Background: Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients undergoing cardiac surgery. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the newest antidiabetic drugs which can be therapeutic options for preventing POAF by different mechanisms., Methods: Empagliflozin to Prevent POAF (EMPOAF) is an interventional, investigator-initiated, double-blind, placebo-controlled, multicenter, randomized controlled trial which will be conducted in two referral teaching cardiology hospitals in Tehran. Four-hundred ninety-two adult patients who are scheduled for elective isolated coronary artery bypass graft (CABG) surgery will be randomly assigned to one of the groups of intervention (empagliflozin 10 mg daily) or placebo starting at least 3 days before surgery until discharge. Key exclusion criteria are a history of diabetes mellitus, AF, ketoacidosis, or recurrent urinary tract infections along with severe renal or hepatic impairment, unstable hemodynamics, and patients receiving SGLT2 inhibitors for another indication. The primary outcome will be the incidence of POAF. Key secondary endpoints will be the composite rate of life-threatening arrhythmias, postoperative acute kidney injury, hospitalization length, in-hospital mortality, stroke, and systemic embolization. Key safety endpoints will be the rate of life-threatening and/or genitourinary tract infections, hypoglycemia, and ketoacidosis., Conclusions: EMPOAF will prospectively evaluate whether empagliflozin 10 mg daily can reduce the rate of POAF in patients undergoing elective CABG. Enrolment into this study has started by November 2023 and is expected to be ended before the end of 2025., (© 2024 Wiley Periodicals LLC.)

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases., (© 2024. Springer Nature Limited.)

Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was cloned using recombinant DNA methods to produce alteplase. Several additional derivatives of tPA, such as tenecteplase and reteplase, were developed to extend the plasma half-life of tPA. Over the past decades, fibrinolytic medications have been widely used to manage patients with venous and arterial thromboembolic events. Currently, alteplase is approved by the U.S. Food and Drug Administration (FDA) for use in patients with pulmonary embolism with hemodynamic compromise, ST-segment elevation myocardial infarction (STEMI), acute ischemic stroke, and central venous access device occlusion. Reteplase and tenecteplase have also received FDA approval for treating patients with STEMI. This review provides an overview of the historical background related to fibrinolytic agents and briefly summarizes their approved indications across various thromboembolic diseases., Competing Interests: Dr. O'Donoghue has received grant funding from Amgen, Novartis, and AstraZeneca and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. O'Donoghue has advisory roles at AstraZeneca, Janssen, and NovoNordisk. Dr. Jimenez is a member of the Steering Committee of the PEITHO III. Dr. Monreal reports nonrestricted research grants to sponsor the RIETE registry from Sanofi and Rovi Laboratories. Dr. Anderson is supported by NIH R01NS103924, U01NS069673, AHA 18SFRN34250007, AHA-Bugher 21SFRN812095, and the MGH McCance Center for Brain Health. Dr. Anderson has received sponsored research support from Bayer AG, Massachusetts General Hospital, and the American Heart Association and has consulted for ApoPharma Inc. Dr. Elkind is an employee of the American Heart Association and has received study drug-in-kind from the BMS-Pfizer Alliance for Eliquis and ancillary funding from Roche for an NIH-funded trial of stroke prevention; honoraria from the Atria Academy of Science and Medicine; and royalties for chapters on stroke from UpToDate. Dr. Baumann Kreuziger has received sponsored research support from NHLBI, the American Society of Hematology, Takeda, and CSL Behring. Dr. Lang receives research support from AOP-Health, and consulting fees from AOP-Health, J&J, MSD, and United Therapeutics. Dr. Lang receives lecture fees from AOP-Health, J&J, MSD, Pulnovo, and United Therapeutics, and support for attending meetings from Medtronic. Dr. Konstantinides reports personal lecture and advisory fees as well as research grants via his institution from Bayer AG, Boston Scientific, Daiichi-Sankyo, LumiraDx, and Penumbra; he also reports personal lecture/advisory fees from MSD and Pfizer—Bristol-Myers Squibb. Dr. Piazza has received research grants from BMS/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Esperion, and 1R01HL164717–01. Dr. Piazza has advisory roles at BSC, Amgen, BCRI, PERC, NAMSA, BMS, Janssen, and Regeneron. Dr. Krumholz received expenses and/or personal fees from United-Health, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, Martin/Baughman Law Firm, and F-Prime; he is a co-founder of Refactor Health and Hugo-Health; and contracts through Yale New Haven Hospital from the Centers for Medicare & Medicaid Services and through Yale University from Johnson & Johnson. Dr. Braunwald reports research grants through his institution from Astra Zeneca, Daiichi Sankyo, and Novartis, and consultancy fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, Edgewise, and Verve. Dr. Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814). Dr. Bikdeli was supported by the Scott Schoen and Nancy Adams IGNITE Award and is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women's Hospital. Dr. Bikdeli reports that he was a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. Dr. Bikdeli has not been involved in the litigation in 2022–2024 nor has he received any compensation in 2022–2024. Dr. Bikdeli reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum, and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. Other authors report no disclosures., (Thieme. All rights reserved.)

Direct oral anticoagulants (DOACs) have become the preferred option for treatment of venous thromboembolism due to their favorable profile compared with other agents such as vitamin K antagonists or low-molecular-weight heparin. However, findings from randomized controlled trials suggest efficacy and/or safety concerns with DOAC use in some clinical contexts. This illustrated review will summarize indications where DOACs have proven efficacy and safety, situations where they fall short, and situations where uncertainty remains compared with other treatments for venous thromboembolism., (© 2024 The Author(s).)

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NG discloses consulting fees or travel awards by Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, LEO-Pharma and Diagnostica Stago. AHT has nothing to disclose.

Background: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed., Methods: We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra., Results: CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14)., Conclusion: Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels., Competing Interests: Declaration of Competing Interest Dr. Abbate and Dr. Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC in the past. Dr. Abbate has also served as a consultant to Cardiol Therapeutics, Kiniksa Pharmaceuticals, Implicit Biosciences, Novo Nordisk, Olatec, and R-Pharm. The remaining authors have no disclosures to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra., Methods: We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials., Results: We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05)., Conclusions: Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research., Competing Interests: Funding Support and Author Disclosures Dr Piazza has received research support paid to his institution from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Pfizer, Boston Scientific Corporation, Janssen, and Amgen. Dr Fanikos has served as a consultant to AstraZeneca, Mallinckrodt, and Pfizer. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Siegal is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease; declares that she has received honoraria paid indirectly to her research institute from AstraZeneca, Bristol Myers Squibb-Pfizer, Roche, and Servier. Dr Barnes has served as a consultant for Pfizer, Bristol Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Boston Scientific, and Abbott Vascular; and has received grant funding from Boston Scientific. Dr Martin is supported by National Institutes of Health K23HL157758; and has received research support paid to her institution from Janssen Scientific Affairs. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Kleindorfer has received other support from the University of Michigan College of Medicine. Dr Monreal has received unrestricted grants for research from Sanofi, Leo and Rovi; and has participated in advisory meetings sponsored by Sanofi. Dr Jimenez has served as an advisor or consultant for Pfizer and Sanofi; and has served as a speaker or a member of a Speakers Bureau for Bristol Myers Squibb, Pfizer and Sanofi. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Pfizer/Bristol Myers Squibb, Norgine, Viatris, and Sanofi, all paid to her institution and outside of the submitted work. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance; has received ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention; and has received royalties from UpToDate for chapters on stroke. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance and ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention, and royalties from UpToDate for chapters on stroke. Dr Ruff is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer, outside of the submitted work. In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Eyedentifeye, and F-Prime; is a co-founder of Refactor Health and HugoHealth; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and through Yale University from Janssen, Google, and Pfizer. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure Inc, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Magenta, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Vivasure, Zoll; has received personal fees from Ionis Pharmaceuticals, J-CalC, Novartis, NovoNordisk, Vectura, VoxMedia, WebMD, IQVIA, McVeigh Global, Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions, TARSUS Cardiology, and Esperion Science/Innovative Biopharma; has received honoraria from JAMA Cardiology (Associate Editor) and the ACC (BOT Member, SC Member CTR Program); and has equity <1% in Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse). Dr Eikelboom has received fees, honoraria and/or research support from Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DSI, Janssen, Pfizer, Servier, and Takeda. Dr Lip is a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, no fees are received personally; and is coprincipal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement #899871. Dr Weitz has served as a consultant and has received honoraria from Alnylam, Anthos, Bayer, Bristol Myers Squibb, Ionis, Janssen, Merck, Pfizer, Regeneron, and Servier. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi; funding for educational activities or lectures from Pfizer, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk, and AstraZeneca. Dr Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814); was supported by the Scott Schoen and Nancy Adams IGNITE Award; is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women’s Hospital; is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; has not been involved in the litigation in 2022 or 2023 nor has he received any compensation in 2022 or 2023; is a member of the Medical Advisory Board for the North American Thrombosis Forum; and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. All other authors have reported that they have no relationships related to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The 1-year incidence of heart failure (HF) after anterior wall ST-elevation acute myocardial infarction (STEMI) remains difficult to determine because of inconsistencies in reporting, definitions, and adjudication. The objective of this study was to evaluate the 1-year incidence of HF after anterior wall STEMI in a real-world data set using a variety of potential criteria and composite definitions. In a retrospective cohort study, anonymized patient data was accessed through a federated health research network (TriNetX Limited Liability Company (LLC)) of 56 US healthcare organizations (US Collaborative Network). Patients were identified based on the International Classification of Diseases, Tenth Revision criteria for anterior wall STEMI during the 10-year period from 2013 to 2022 and the absence of prespecified signs or symptoms of HF. Values for 1-year incidence were calculated as 1 minus Kaplan-Meier survival at 12 months after anterior wall STEMI. Univariate Cox proportional hazard ratio was calculated to compare risk associated with potential risk factors. The analysis utilized 5 different types of definition criteria for HF: Diagnosis codes, Signs and symptoms, Laboratory/imaging, Medications, and Composites. A total of 34,395 patients from the US Collaborative Network met eligibility criteria and were included in the analysis. The 1-year incidence of HF varied from 2% to 30% depending upon the definition criteria. Although no single criteria exceeded a 1-year incidence of 20%, a simple composite of HF diagnosis (International Classification of Diseases, Tenth Revision-I50) or use of loop diuretic produced a 1-year incidence 26.1% that was used as the benchmark outcome for evaluation of risk factors. Age ≥65 years, Black race, low-density lipoprotein ≥100 mg/100 ml, elevated hemoglobin A1c (7% to 9% and >9%), and body mass index≥35 kg/m 2 were also associated with increased risk of HF. In conclusion, patients with anterior wall STEMI continue to be at high risk for new-onset HF. In the absence of structured, prospective, systematically adjudicated diagnostic criteria, composite definitions are more likely to yield accurate estimates of HF incidence., Competing Interests: Declaration of Competing Interest Drs. Van Tassell and Abbate serve as consultants for Implicit Biosciences. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The objective of this report is to identify and characterize the relative likelihood of women and racially minoritized pharmacy faculty being promoted, advancing within leadership roles, and earning comparable salaries., Methods: Data from the 2010-2021 American Association of Colleges of Pharmacy Profile of Pharmacy Faculty surveys were analyzed to compare odds ratios for promotion, leadership roles, and salary gaps of pharmacy faculty according to race and gender. Changes in the odds ratios over time were characterized by linear regression and predictions about when and if equality would be achieved according to current trends were calculated., Results: Compared to White male counterparts, faculty identifying as women, Black, Hispanic, or Asian had a significantly lower odds ratio of promotion to associate or full professor. Women and Asian faculty also had a lower likelihood of promotion from assistant to associate or Chief Executive Officer (CEO) dean. No demographics studied were more likely than White men to advance in rank or attain associate or CEO dean leadership positions. Furthermore, negative salary gaps for women emerge after promotion from assistant professor, becoming significant and continuing to widen at the associate (-$20,419) and CEO dean (-$37,495) level., Conclusion: Despite attention to matters of diversity, equity, and inclusion, female and racially minoritized faculty continue to experience lower rates of promotion, leadership advancement, and wages compared to White male colleagues. These results have negative consequences for recruiting and retaining talented faculty and students, and compromise the benefits that a diverse faculty is known to provide on student learning outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest Drs. Abbate and Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC. Dr. Abbate has also served as a consultant to Cardiol Therapeutics, Kiniksa Pharmaceuticals, Implicit Biosciences, Novo Nordisk, Olatec, and R-Pharm. The remaining authors have no competing interest to declare.

COVID-19 is associated with endothelial activation in the setting of a potent inflammatory reaction and a hypercoagulable state. The end result of this thromboinflammatory state is an excess in thrombotic events, in particular venous thromboembolism. Pulmonary embolism (PE) has been of special interest in patients with COVID-19 given its association with respiratory deterioration, increased risk of intensive care unit admission, and prolonged hospital stay. The pathophysiology and clinical characteristics of COVID-19-associated PE may differ from the conventional non-COVID-19-associated PE. In addition to embolic events from deep vein thrombi, in situ pulmonary thrombosis, particularly in smaller vascular beds, may be relevant in patients with COVID-19. Appropriate prevention of thrombotic events in COVID-19 has therefore become of critical interest. Several changes in viral biology, vaccination, and treatment management during the pandemic may have resulted in changes in incidence trends. This review provides an overview of the pathophysiology, epidemiology, clinical characteristics, and risk factors of COVID-19-associated PE. Furthermore, we briefly summarize the results from randomized controlled trials of preventive antithrombotic therapies in COVID-19, focusing on their findings related to PE. We discuss the acute treatment of COVID-19-associated PE, which is substantially similar to the management of conventional non-COVID-19 PE. Ultimately, we comment on the current knowledge gaps in the evidence and the future directions in the treatment and follow-up of COVID-19-associated PE, including long-term management, and its possible association with long-COVID., Competing Interests: L.O-P: Nothing to disclose.A.H.T.: Nothing to disclose.P.S.: Nothing to disclose.T.S.P.: Nothing to disclose.H.D.A.: Outside the submitted work, H.A.D. is a consultant for Silk Road Medical for Philips.L.J-P.: Grants from Leo Pharma and MSD and personal fees from Daichii, Rovi, GlaxoSmithKline, and Actellion outside the submitted work.M.S.: Co-principal investigator of the RAPID trial.D.J.A.: Consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation.G.Y.H.L.: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally.B.B.: Reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters., (Thieme. All rights reserved.)

Purpose of Review: This review describes the discovery and development of ACE inhibitors as antihypertensive agents, compares their efficacy, tolerability, and safety to ARBs, and highlights the contemporary issues surrounding ACE inhibitor use for HTN., Recent Findings: Angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed medications for the management of hypertension (HTN) and other chronic conditions including heart failure and chronic kidney disease. These agents inhibit ACE, the enzyme that is responsible for converting angiotensin (AT) I to AT II. Inhibiting the synthesis of AT II causes arterial and venous vasodilation, natriuresis, and a decrease in sympathetic activity, resulting in the reduction of blood pressure. ACE inhibitors are first-line therapy in HTN management along with thiazide diuretics, calcium channel blockers, and angiotensin receptor blockers (ARB). Along with inhibiting AT II synthesis, inhibition of ACE causes accumulation of bradykinin, increasing the risk of bradykinin-mediated side effects like angioedema and cough. Since ARBs do not work on ACE in the renin-angiotensin system, the risk of angioedema and cough are lower with ARBs. Recent evidence has also suggested ARBs may have neuroprotective effects compared to other antihypertensives, including ACE inhibitors; however, this warrants further study. Currently, ACE inhibitors and ARBs have an equal class of recommendation for first-line treatment for the management of HTN. Recent evidence has shown ARBs to be just as effective as ACE inhibitors for HTN but with improved tolerability., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Anakinra is a recombinant human interleukin-1 receptor antagonist approved for the treatment of inflammatory diseases. Kineret is available as a solution prepared in a borosilicate glass syringe. For implementing a placebo-controlled double-blind randomized clinical trial, anakinra is commonly transferred into plastic syringes. However, there is limited data on anakinra's stability in polycarbonate syringes. We described the results of our previous studies on the use of anakinra in glass (VCUART3) versus plastic syringes (VCUART2) compared with placebo. These studies were conducted in patients with ST-segment elevation myocardial infarction (STEMI), and we assessed the anti-inflammatory effects of anakinra versus placebo by comparing the area under the curve for high-sensitivity cardiac reactive protein (AUC-CRP) levels during the first 14 days of STEMI, its clinical effects on heart failure (HF) hospitalization, cardiovascular death, or new diagnosis of HF as well as adverse events profile between groups. The levels of AUC-CRP were 75 (50-255 mg·day/l) for anakinra in plastic syringes versus 255 (116-592 mg·day/l) in placebo and 60 (24-139 mg·day/l) and 86 (43-123 mg·day/l) for anakinra once and twice daily in glass syringes, respectively, compared with placebo 214 (131-394 mg·day/l). The rate of adverse events was also comparable between groups. There were no differences in the rate of HF hospitalization or cardiovascular death in patients who received anakinra in plastic or glass syringes. Fewer cases of new-onset heart failure occurred in patients receiving anakinra in plastic or glass syringes compared with placebo. Anakinra stored in plastic (polycarbonate) syringes provides comparable biologic and clinical effect to glass (borosilicate) syringes. SIGNIFICANCE STATEMENT: Anakinra (Kineret) 100 mg administered subcutaneously in patients with ST-segment elevation myocardial infarction (STEMI) for a duration of up to 14 days appears to have comparable safety and biological efficacy signals when delivered in prefilled glass or transferred into plastic polycarbonate syringes. This may have important implications for the feasibility of designing clinical trials in STEMI and other clinical conditions., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Background:  In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days., Methods:  This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale., Results:  In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p  = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction  = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (OR ordinal : 0.64, 95% CI: 0.41-1.01, p  = 0.05)., Conclusion:  Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508)., Competing Interests: D. V. reports consultant and speaker for BMS/Pfizer, Daiichi-Sankyo, Rovi, and Sanofi. Dr. Gupta received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook inferior vena cava filter litigation. A. G. holds equity in a health care telecardiology startup, Heartbeat Health, Inc., and received consulting fees from Edwards LifeSciences. M. V. M. has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). S. S. S. reports honoraria from Janssen and Chiesi and research grant support from the American Heart Association. G. P. has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corporation, Janssen, Namsa, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. S. A. P. reports being on the Advisory Board for Abbott, Boston Scientific, Medtronic, CSI, Philips, Janssen; research grants: Abbott, Boston Scientific, Surmodics, TriReme Medical, Shockwave Medical; and receiving consulting fees from Terumo and Abiomed. M. M. received an unrestricted educational grant for research from Sanofi, Leo, and Rovi, and fees for participating in advisory meetings from Sanofi. A. J. K. reports institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CSI, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon, SoniVie, Shockwave Medical, and Merck. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr. Kirtane controlled the content. Personal: consulting from IMDS; Travel Expenses/Meals from Medtronic, Boston Scientific, Abbott Vascular, CSI, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. S. B. reports unrestricted research grants from Bayer, Concept Medical, INARI, Boston Scientific, Bard, and Sanofi; honoraria from Bayer, Concept Medical, INARI, and Boston Scientific. B. W. V. T. has received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, Serpin Pharm, and R-Pharm. He has been a consultant of R-Pharm and Serpin Pharma. G. W. S. has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and Cardiomech; and has received equity or options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. G. Y. H. L. reports consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally. H. M. K. reports personal fees from UnitedHealth, personal fees from IBM Watson Health, personal fees from Element Science, personal fees from Aetna, personal fees from Facebook, personal fees from Siegfried & Jensen Law Firm, personal fees from Arnold & Porter Law Firm, personal fees from Ben C. Martin Law Firm, personal fees from National Center for Cardiovascular Diseases, Beijing, ownership of HugoHealth, ownership of Refactor Health, contracts from the Centers for Medicare & Medicaid Services, grants from Medtronic and the Food and Drug Administration, grants from Medtronic and Johnson and Johnson, grants from Shenzhen Center for Health Information, and is a Venture Partner at FPrime. Outside the submitted work. B. B. is supported by a research grant from The Mary Horrigan Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital. B. B. reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. All other authors report no relevant disclosures., (Thieme. All rights reserved.)

Introduction: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US)., Methods: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates., Results: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate., Conclusions: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background: Interleukin-1 blockade with anakinra leads to a transient increase in eosinophil blood count (eosinophils) in patients with acute myocardial infarction. We aimed to investigate the effect of anakinra on changes in eosinophils in patients with heart failure (HF) and their correlation with cardiorespiratory fitness (CRF)., Methods: We measured eosinophils in 64 patients with HF (50% females), 55 (51-63) years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF, measuring peak oxygen consumption (VO 2 ) with a treadmill test., Results: Treatment with anakinra significantly and transiently increased eosinophils, from 0.2 [0.1-0.3] to 0.3 [0.1-0.4] × 10 3 cells/µL ( p < 0.001) and from 0.3 [0.2-0.5] to 0.2 [0.1-0.3] × 10 3 cells/µL, with suspension ( p < 0.001). Changes in eosinophils correlated with the changes in peak VO 2 (Spearman's Rho = +0.228, p = 0.020). Eosinophils were higher in patients with injection site reactions (ISR) ( n = 8, 13%; 0.5 [0.4-0.6] vs. 0.2 [0.1-0.4] × 10 3 cells/µL, p = 0.023), who also showed a greater increase in peak VO 2 (3.0 [0.9-4.3] vs. 0.3 [-0.6-1.8] mLO 2 ·kg -1 ·min -1 , p = 0.015)., Conclusion: Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and a greater improvement in peak VO 2 .

Ischemia reperfusion injury can lead to further myocardiocyte damage in patients with ST-elevation myocardial infarction (STEMI). Pentoxifylline is a methylxanthine derivative with known anti-inflammatory, antioxidant, vasodilator, and rheological properties which can be a promising agent in preventing reperfusion injury. PENTOS-PCI is a single-center, randomized, double-blind, placebo-controlled trial which evaluated the efficacy and safety of preprocedural administration of intravenous pentoxifylline in patients undergoing primary percutaneous coronary intervention (PCI). Patients with acute STEMI who were eligible for PCI were randomized to receive either 100-mg intravenous infusion of pentoxifylline or placebo, prior to transferring to catheterization laboratory. Overall, 161 patients were included in our study of whom 80 patients were assigned to pentoxifylline and 81 to the control groups. Per-protocol analysis of primary endpoint indexing PCI's success rate as measured by thrombolysis in myocardial infarction (TIMI) flow grade 3 was not significantly different between pentoxifylline and placebo (71.3% and 66.3% respectively, P = 0.40). In addition, pentoxifylline could not improve secondary angiographic endpoints including myocardial blush grade 3 (87.5% and 85.2%, P = 0.79) and corrected TIMI frame count (22.8 [± 9.0] and 24.0 [± 5.1], P = 0.33) in the intervention and placebo groups respectively. The rates of major adverse cardiac and treatment emergent adverse effects were not significantly different between the two groups. Administration of intravenous pentoxifylline before primary PCI did not improve the success rate of the procedure in patients with STEMI. Intravenous administration of pentoxifylline was well tolerated, and there were no significant differences regarding adverse drug reactions in the two groups. Panel A, background: pentoxifylline is a methylxanthine derivative with known anti-inflammatory, antioxidant, vasodilator, and rheological properties which can be a promising agent in preventing reperfusion injury. Panel B: study design and main results of the PENTOS-PCI trial. cTFC corrected TIMI frame count, ED emergency department, IRI ischemia reperfusion injury, MBG myocardial blush grade, PCI percutaneous coronary intervention, PPCI primary PCI, PTX pentoxifylline, ROS reactive oxygen species, SD standard deviation, STEMI ST-elevation myocardial infarction, TIMI thrombolysis in myocardial infarction., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Data suggest that coronavirus disease 2019 (COVID-19) results in a prothrombotic state leading to arterial and venous thromboses. Vaccination, novel antiviral drugs, and emerging variants have changed the course of the disease in many ways; however, their effects on the incidence of thrombotic events and the efficacy of preventative antithrombotic agents have not been yet evaluated. A systematic search was conducted to identify studies reported on the incidence of thrombotic events based on vaccination status, use of novel antiviral drugs, and emerging viral variants. Similarly, we screened the ongoing/published randomized trials of preventative antithrombotic therapy in any COVID-19 population to assess whether subgroup-specific results were reported based on any of these variants. Upon searching a total of 3,451 records, only one entry fulfilled the inclusion criteria of our systematic review, which was a self-controlled case series on 29,121,633 vaccinated individuals, the incidence rate ratio of thrombotic complication after breakthrough infection was 13.86 (95% confidence interval [CI]: 12.76-15.05) compared with 1.10 (95% CI: 1.02-1.18) during the 28-day postvaccination. In conclusion, although the mortality benefit of mass vaccination and the early promising results of the new antiviral therapies are well known, we were unable to find clinical evidence on whether vaccination, the use of novel antiviral agents, and emerging viral variants have affected the incidence rate of thrombotic events or impacted the efficacy of prophylactic antithrombotic therapy in patients with COVID-19. Analyses from existing trials and large-scale registries can provide interim knowledge and any findings of relevance should be incorporated in the design of future trials., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Dyslipidemia is a major modifiable risk factor for developing atherosclerotic cardiovascular disease. Despite increasing high intensity statin prescription and adherence to statin therapy, a considerable number of patients will not reach the guideline directed goals due to statin intolerance, lack of adherence or treatment efficacy. Several new lipid lowering medications have received approval by regulatory agencies in the past decade including proprotein convertase subtilisin/kexin type 9 modulators, ATP-citrate lyase inhibitors, angiopoietin-like 3 inhibitors, lomitapide, and icosapent ethyl. Although approved by regulatory agencies, these medications are still under-prescribed worldwide which may be related to cost issues, lack of cardiovascular outcome results, or clinicians not being familiar with their use. In this review, we propose a practical stepwise approach including each class' efficacy, place in therapy, adverse effects, warnings and precautions, and monitoring parameters. This information can help the clinicians to prescribing these novel lipid lowering medications to achieve treatment goals and reduce the risk of atherosclerotic cardiovascular disease. The aim is to shift the paradigm for high-intensity statins from watch and wait to initial combination therapy for high-risk patients., Competing Interests: Declaration of Competing Interest Hessam Kakavand: none declared Maryam Aghakouchakzadeh: none declared Ali Shahi: none declared Salim S. Virani: Grant support: Department of Veterans Affairs, NIH, World Heart Federation, Tahir and Jooma Family; Honorarium: American College of Cardiology (Associate Editor for Innovations, acc.org) Dave L. Dixon: none declared Benjamin W. Van Tassell: none declared Azita H. Talasaz: none declared., (Copyright © 2022. Published by Elsevier Inc.)

Abstract: Primary percutaneous coronary intervention (PPCI) is the gold standard of treatment in patients with acute ST-elevation myocardial infarction (STEMI). The no-reflow phenomenon (NRP) is a detrimental consequence of STEMI. Colchicine is an anti-inflammatory drug that may help prevent the NRP and improve patient outcomes. In a randomized, double-blind, placebo-controlled clinical trial, 451 patients with acute STEMI who were candidates for PPCI and eligible for enrollment were randomized into the colchicine group (n = 229) and the control group (n = 222). About 321 patients were eligible to participate; 161 patients were assigned to the colchicine group, whereas 160 patients were assigned to the control group. Colchicine was administered 1 mg before PCI and 0.5 mg daily after the procedure until discharge. NRP, measured by angiographic findings including the thrombolysis in myocardial infarction flow grade and the thrombolysis in myocardial infarction myocardial perfusion grade, was reported as the primary outcome. Secondary end points included ST resolution 90 minutes after the procedure, P-selectin, high-sensitivity C-reactive protein, and troponin levels postprocedurally, predischarge ejection fraction, and major adverse cardiac events (MACE) at 1 month and 1 year after PPCI. NRP rates did not show a significant difference between the 2 groups ( P = 0.98). Moreover, the levels of P-selectin, high-sensitivity C-reactive protein, and troponin were not significantly different. MACE and predischarge ejection fraction were also not significantly different between the groups. In patients with STEMI treated by PPCI, colchicine administered before PPCI was not associated with a significant reduction in the NRP and MACE prevention (trial registration: IRCT20120111008698N23)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Several randomized clinical trials have demonstrated the clinical utility of colchicine in the prevention and management of various cardiovascular conditions, including secondary prevention of atherosclerotic cardiovascular disease, acute and chronic pericarditis, and atrial fibrillation. As a result, it is reasonable to anticipate increased use of colchicine within the cardiovascular specialty. However, colchicine is metabolized by cytochrome P450 3A4 (CYP3A4) and a substrate of the efflux transporter, P-glycoprotein (P-gp), creating the potential for clinically significant drug-drug interactions (DDIs). Therefore, when colchicine is administered concomitantly with other cardiovascular agents that inhibit CYP3A4 or P-gp, there is an increased risk of significant DDIs, potentially leading to negative sequelae. This article summarizes the evidence supporting the use of colchicine for cardiovascular disease, describes the mechanisms behind DDIs with select cardiovascular medications, and provides suggestions regarding colchicine dosing and management of DDIs to minimize the risk of poor tolerability and colchicine toxicity., (Copyright © 2022. Published by Elsevier Inc.)

Cardiac arrhythmias, characterized by an irregular heartbeat, are associated with high mortality and morbidity. Because of the narrow therapeutic window of antiarrhythmic drugs (AADs), the management of arrhythmia is still challenging. Therefore, searching for new safe, and effective therapeutic options is unavoidable. In this study, the antiarrhythmic effects of medicinal plants and their active constituents were systematically reviewed to introduce some possible candidates for mechanism-based targeting of cardiac arrhythmias. PubMed, Embase, and Cochrane library were searched from inception to June 2021 to find the plant extracts, phytochemicals, and multi-component herbal preparations with antiarrhythmic activities. From 7337 identified results, 57 original studies consisting of 49 preclinical and eight clinical studies were finally included. Three plant extracts, eight multi-component herbal preparations, and 26 phytochemicals were found to have antiarrhythmic effects mostly mediated by affecting K + channels, followed by modulating Ca 2+ channels, upstream target pathways, Na v channels, gap junction channels, and autonomic receptors. The most investigated medicinal plants were Rhodiola crenulata and Vitis vinifera. Resveratrol, Oxymatrine, and Curcumin were the most studied phytochemicals found to have multiple mechanisms of antiarrhythmic action. This review emphasized the importance of research on the cardioprotective effect of medicinal plants and their bioactive compounds to guide the future development of new AADs. The most prevalent limitation of the studies was their unqualified methodology. Thus, future well-designed experimental and clinical studies are necessary to provide more reliable evidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Soltani, Azizi, Rahimi, Talasaz, Rezaeizadeh and Vasheghani-Farahani.)

Introduction: Postoperative atrial fibrillation (POAF) as a common complication of coronary artery bypass grafting (CABG) surgery is associated with increased mortality and morbidity rates. Vitamin D deficiency increases the prevalence of POAF; however, the effects of vitamin D supplementation on the incidence of POAF have not yet been completely elucidated., Methods: In this prospective, open-label, randomized clinical trial the level of 25-hydroxy vitamin D (25(OH) D) was measured in patients undergoing CABG surgery. Patients with vitamin D insufficiency (defined as 25(OH) D level < 30 ng/ml) were included and randomly assigned to control group to receive either the general standard of care (Group A) or to study group to receive the general standard of care plus oral vitamin D 3 , 600,000 IU 5 days before surgery (Group B). The primary outcome of our study was the occurrence of POAF during the first 5 days after CABG surgery., Results: Totally, 93 patients in group B and 103 patients in group A completed the study. The occurrence of POAF was significantly lower in group B as compared to group A (9.68% vs. 20.39%, p = .038). The length of intensive care unit (ICU) stay and hospital stay were reduced in group B patients (2.21 vs. 3.86 days, p < .001 and 7.40 vs. 9.58 days, p = .022, respectively)., Conclusion: Our study demonstrated that vitamin D supplementation reduces the incidence of POAF, duration of ICU, and hospital stay following CABG surgery., (© 2022 Wiley Periodicals LLC.)

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; β = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; β = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF., Competing Interests: Disclosures Dr. Van Tassell and Dr. Abbate were co-prinicpal investigators on the NIH funding for this study. Please list both of them as receiving financial support from NIH., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs., Observations: Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities., Conclusions and Relevance: Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.

Background: Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF., Method: We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO 2 ) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO 2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes., Discussion: The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF., Trial Registration: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001., (© 2022. The Author(s).)

Background: The optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) for vitamin K antagonists (VKAs) reversal is unknown., Methods: We conducted systematic search on the PubMed, SCOPUS, and Embase databases from inception to December 2020 for clinical studies that compared the fixed-dose versus variable-dose of 4-PCC for VKAs reversal with at least one reported clinical outcome. The treatment effects were expressed as relative ratios (RR) with 95% confidence intervals (CIs) and pooled by a random-effects model., Results: Ten studies, including 988 patients, were included. Fixed-dose 4-PCC was associated with lower rate of mortality (RR= 0.65, 95% CI 0.47 to 0.9, p= 0.009), comparable rate of thromboembolic event (TEE) (RR= 1.10, 95%CI 0.44 to 2.80, p= 0.826), and lower goal INR reached (RR= 0.87, 95%CI 0.78 to 0.96, p= 0.007). Less 4-PCC cumulative dose, shorter duration of order-to-needle time, similar hospital length of stay, the comparable time required for INR reversal, higher post-4-PCC INR, and a higher need for additional dose were observed in fixed-dose., Conclusions: The use of a fixed-dose of 4-PCC may be considered an effective and safe dosing strategy for VKAs reversal in various clinical situations. However, further well-designed, controlled studies should be conducted focusing on clinical outcomes to determine the optimal dose of 4-PCC for VKAs reversal., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Atrioventricular block (AVB) is an important complication following valvular surgery. Several factors including inflammation-mediated injury might trigger AVB., Methods: Patients with advanced postoperative AVB were randomly assigned to receive either dexamethasone (0.4 mg/kg, maximum 30 mg/day) intravenously for 3 days or conservative care only. Primary endpoint was recovery rate in Day 5 since randomization. Secondary endpoints were recovery rate in Day 7 and Day 10, cumulative AVB time, permanent pacemaker (PPM) implantation rate, length of stay in critical care units, and postoperative major adverse events (MAE)., Results: We enrolled 139 subjects (48.9% male) with mean age of 59.9 years randomly allocated to intervention group (n = 69) and control group (n = 70). Dexamethasone led to higher recovery rates at Day 5 (82.6% vs. 62.9%, p = .009) and Day 7 (88.4% vs. 61.4%, p < .0001) respectively. This benefit ceased at Day 10 (83.05% vs. 78.6%, p = .547). Median cumulative AVB time was shorter in dexamethasone group compared with control group (41 h vs. 64 h, p = .044). PPM implantation rates were similar between the dexamethasone and control groups (15.9% vs. 17.1%, respectively, p = .849). Median length of stay in intensive care unit (ICU) (10 days vs. 12 days, p = .03) and MAE (17.4% vs. 25.7%, p = .133) tended to be lower with dexamethasone., Conclusion: Dexamethasone may serve as a safe and effective medication to help hasten recovery of advanced AVB after valvular surgery., (© 2022 Wiley Periodicals LLC.)

Background: Cardiac remodeling following myocardial infarction is a pathological process. We aimed to examine the effect of early short-term minocycline on the left ventricular function following ST-elevation myocardial infarction treated by the primary percutaneous coronary intervention., Methods: In this double-blind, randomized controlled trial, data of 73 patients STEMI patients who were candidates for primary PCI were enrolled. Patients were then randomized to receive minocycline 50 mg orally, followed by 50 mg once a day for 5 days or a placebo with the same schedule. Measurement of serum matrix metalloproteinase-9 (MMP-9) and 2-dimensional speckle tracking echocardiography was performed at baseline and between 4 and 6 months after discharge. Then the demographic, clinical, echocardiographic, and angiographic data, as well as the levels of MMP-9, were compared between the study groups., Results: There was no statistically significant difference between the study groups regarding the baseline characteristics. Serum levels of MMP-9 did not change following the intervention within each group and were not significantly different between the groups after follow-up. In the follow-up echocardiography, we also did not observe any difference between the two groups CONCLUSION: In this study, we did not observe any effect of minocycline on cardiac remodeling based on 2-dimensional speckle tracking echocardiography and MMP-9 levels., Trial Registration: Iranian Registry of Clinical Trials IRCT201411188698N15 . Registered on 22 June 2015, prospectively., (© 2021. The Author(s).)

Background: Preoperative anemia is an independent risk factor for higher rates of blood transfusion in cardiac surgery. This study aimed to evaluate the effects of intravenous iron sucrose and erythropoietin on transfusion requirements in patients with preoperative iron deficiency anemia (IDA) undergoing on-pump coronary artery bypass graft (CABG) surgery. Methods: In this open-label, randomized clinical trial, patients with preoperative IDA who were candidates for on-pump CABG were randomized into intervention (iron plus erythropoietin) or control groups. Iron sucrose was administered as a 200 mg intravenous dose and erythropoietin as a 100 IU/kg bolus 1 to 2 days before surgery. The primary outcome was the amount of blood transfusion during the first 4 postoperative days. Results: The study population consisted of 114 patients. The mean age was 64.11±8.18 years in the intervention group and 63.35±8.70 years in the control group. Twenty-seven patients (47.4%) in the intervention group and 25 (43.9%) in the control group were males. The number of red blood cell units transfused per patient exhibited a significant fall in the intervention group compared with the control group (P˂0.001). The ferritin level showed a significant rise in the intervention group on postoperative day 7 (P=0.027). The length of stay in the intensive care unit and the hospital was significantly lower in the intervention arm (P=0.041 and P=0.006, respectively). No adverse events were reported in both groups. Conclusion: The use of erythropoietin and iron sucrose 1 to 2 days before surgery significantly decreased the need for blood transfusion in patients with IDA undergoing CABG without any significant adverse events., (Copyright © 2022 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.)

Background: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown., Methods: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding., Results: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p  = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24)., Conclusion: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up., Competing Interests: Dr. Parikh reports being on the Advisory Board for Abbott, Boston Scientific, Medtronic, CSI, Philips, Janssen; research grants: Abbott, Boston Scientific, Surmodics, TriReme Medical, Shockwave Medical; and receiving consulting fees from Terumo and Abiomed. Dr. Gupta received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook inferior vena cava filter litigation. Dr. Gupta holds equity in a health care telecardiology startup, Heartbeat Health, Inc. and received consulting fees from Edwards LifeSciences. Dr. Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr. Sethi reports honoraria from Janssen and Chiesi and research grant support from the American Heart Association. Dr. Piazza has received research grant support to Brigham and Women's Hospital from EKOS, a BTG International Group company, Bayer, the Bristol Myers Squibb/Pfizer Alliance, Portola, and Janssen. He has received consulting fees from Amgen, Pfizer, Boston Scientific Corporation, and Thrombolex. Dr. Kirtane reports institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, and ReCor Medical. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for speaking engagements and/or consulting. Personal: travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr. Van Tassell received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma. He is a consultant of R-Pharm, Serpin Pharma. Dr. Stone has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has received equity or options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. Dr. Lip reports consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are received personally. Dr. Krumholz reports personal fees from UnitedHealth, personal fees from IBM Watson Health, personal fees from Element Science, personal fees from Aetna, personal fees from Facebook, personal fees from Siegfried & Jensen Law Firm, personal fees from Arnold & Porter Law Firm, personal fees from Ben C. Martin Law Firm, personal fees from National Center for Cardiovascular Diseases, Beijing, ownership of HugoHealth, ownership of Refactor Health, contracts from the Centers for Medicare & Medicaid Services, grants from Medtronic and the Food and Drug Administration, grants from Medtronic and Johnson and Johnson, grants from Shenzhen Center for Health Information, and is a Venture Partner at FPrime, outside the submitted work. Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. All other authors report no relevant Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and atorvastatin and matching placebo were provided by Sobhan Darou. None of these companies were study sponsors and they had no other role and will not have a role in the design, conduct, analysis, or interpretation of the ongoing results or the decision to submit the resultant manuscript(s)., (Thieme. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies., Objectives: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population., Methods: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19., Results: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized., Conclusion: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19., (© 2021 International Society on Thrombosis and Haemostasis.)

The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum., (© 2021 Pharmacotherapy Publications, Inc.)

Background: The coronary no-reflow phenomenon is an adverse complication of percutaneous coronary interventions (PCI) which significantly worsens the outcome and survival. In this study, we have evaluated the correlation of no-reflow phenomenon with demographic, biochemical and anatomical factors., Methods: We included 306 patients (193 male) with acute ST-elevation myocardial infarction (STEMI) who undergone primary PCI in our center. Demographic factors, as well as biochemistry test results were obtained. Also, the Thrombolysis in Myocardial Infarction (TIMI) grade and TIMI frame count (TFC) was measured. The correlation of no-reflow phenomenon with demographic, biochemical and anatomical factors was analyzed., Results: Patients with a mean age of 56.41 ± 11.8 years were divided into two groups depending on the TIMI score (Group 1 or Normal flow and Group 2 or No-reflow). Symptom-to-procedure time, door-to-procedure time, serum creatinine level, hs-CRP level, and Neutrophil to Lymphocyte Ratio (NLR) were significantly higher among group 2. TFC had negative significant correlation with male gender, and positive significant correlation with age, diabetes mellitus, hs-CRP level, WBC count, and NLR. Age of more than 62.5 years and serum creatinine level of more than 0.89 mg/dL can optimally predict the no reflow phenomena., Conclusions: According to our results, it seems that female gender, older ages, DM, multi-vessel involvement, delayed reperfusion, and increased NLR can predict the risk of no-reflow after primary PCI in the setting of Acute Myocardial Infarction.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management., Competing Interests: Funding Support and Author Disclosures Dr Gupta received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to an inferior vena cava filter litigation; received consulting fees from Edward Lifesciences; and holds equity in the health care telecardiology startup Heartbeat Health. Dr Madhavan was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr Van Tassell has received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma; and is a consultant of R-Pharm and Serpin Pharma. Dr Jimenez has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; has served as a speaker or a member of a speaker bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; and has received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. Dr Monreal has served as an advisor or consultant for Sanofi, Leo Pharma, and Daiichi-Sankyo; and has received a nonrestricted educational grant by Sanofi and Bayer to sponsor the Computerized Registry of Patients with Venous Thromboembolism. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, and Relypsa; participates in speaker engagements with Novartis and Roche Diagnostics; and participates on clinical endpoint committees for studies sponsored by Galmed, Novartis, and the National Institutes of Health. Dr Fanikos has served as a consultant for Portola, Inc and Pfizer, Inc. Dr Piazza has received research grant support from BSC, Bayer, Bristol Myers Squibb/Pfizer Alliance, Portola, Amgen, and Janssen; and has received consulting fees from Amgen, Pfizer, and BSC. Dr Parikh has served as a noncompensated advisor to Abbott Vascular, Boston Scientific, Cardiovascular Systems Inc, Cordis, Janssen, Medtronic, and Philips; receives institutional research support from Abbott Vascular, Boston Scientific, SurModics, TriReme, and Veryan Medical; and is a consultant to Abiomed, Inari Medical, Penumbra, and Terumo. Dr Bhatt has served on the advisory board for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, and Regado Biosciences; has served on the Board of Directors for the Boston VA Research Institute, Society of Cardiovascular Patient Care, and ToBeSoft; serves as Chair of the American Heart Association Quality Oversight Committee; has served on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); other, Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has been a site co-investigator, Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; has been a trustee for the American College of Cardiology; and has received unfunded research from FlowCo, Merck, and Takeda. Dr Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo (no fees are received personally). Dr Stone has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; has been a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and CardioMech; and has equity/options from Ancora, Cagent, Applied Therapeutics, BioStar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Med Focus family of funds, and Valfix. Dr Krumholz has received personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Ben C. Martin Law Firm, and the National Center for Cardiovascular Diseases (Beijing, China); has ownership in Hugo Health and Refactor Health; has contracts from the U.S. Centers for Medicare & Medicaid Services; and has received grants from Medtronic, the U.S. Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information, outside the submitted work. Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Beren, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, Inc; and is a member of the scientific advisory board for Amgen, Corvidia Therapeutics, CSL Behring, DalCor Pharmaceuticals, Genentech, Kowa Pharmaceuticals, Olatec Therapeutics, PlaqueTec, Kancera, Medimmune, Novartis, Novo Nordisk, and XBiotech, Inc. Dr Libby is on the Board of Directors of XBiotech, Inc; and has a financial interest in XBiotech, a company developing therapeutic human antibodies. Dr Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. Dr Libby’s laboratory has received research funding in the last 2 years from Novartis. Dr Goldhaber has received research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute; and has received consulting fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim. Dr Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis., Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU)., Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020., Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up., Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated., Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01)., Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

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., Competing Interests: Funding Support and Author Disclosures Dr. Van Tassell has received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma; and is a consultant of R-Pharm and Serpin Pharma. Dr. Monreal has served as an advisor or consultant for Sanofi, Leo Pharma, and Daiichi-Sankyo; and has received a nonrestricted educational grant by Sanofi and Bayer to sponsor the Computerized Registry of Patients with Venous Thromboembolism. Dr. Jimenez has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; has served as a speaker or a member of a speaker bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; and has received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. Dr. Piazza has received research grant support from Boston Scientific Corporation, Bayer, Bristol Myers Squibb/Pfizer, Portola/Alexion Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Agile, and Prairie Education and Research Cooperative. Dr. Parikh has received institutional research support from Abbott Vascular, TriReme Medical, SurModics, and Shockwave Medical; is an advisory board member for Abbott Vascular, Boston Scientific, Cardinal Health, Medtronic, Janssen, CSI, and Philips; and receives honoraria from Abiomed and Terumo. Dr. Kirtane has received institutional funding from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, and ReCor Medical; and has received travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron, all outside the submitted work. Dr. Eikelboom has received honoraria and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi, and Eli Lilly, as well as a personal award from the Heart and Stroke Foundation. Dr. Konstantinides has received research grants from Bayer AG, Boehringer Ingelheim, and Actelion-Janssen; has received educational grants from Biocompatibles Group UK, Boston Scientific, and Daiichi-Sankyo; and has received lecture fees from Bayer AG, Bristol Myers Squibb/Pfizer, and Merck Sharp and Dohme. Dr. Weitz serves as a consultant and has received honoraria from Bayer, Janssen, Johnson & Johnson, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Novartis, Daiichi-Sankyo, Merck, Servier, Anthos, Ionis, and PhaseBio. Dr. Stone has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; has been a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and CardioMech; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. Dr. Krumholz has received personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Ben C. Martin Law Firm, and the National Center for Cardiovascular Diseases (Beijing, China); has ownership in Hugo Health and Refactor Health; and has contracts from the U.S. Centers for Medicare & Medicaid Services; and has received grants from Medtronic, the U.S. Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information, outside the submitted work. Dr. Lip is a consultant for Bayer/Janssen, Bristol Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo; and is a speaker for Bayer, Bristol Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo (no fees are directly received personally). Dr. Goldhaber has received research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute; and has received consulting fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim. Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Abstract: Establishing efficient perfusion into the myocardium is the main purpose in patients with acute coronary syndrome, but the process of reperfusion is not without risk and can damage the myocardium paradoxically. Unfortunately, there is no effective treatment for reperfusion injury, and efforts to find an efficient preventive approach are still ongoing. In the past 3 decades, there have been many successful animal studies on how to prevent reperfusion injury; nonetheless, translation to the clinical setting has almost always proven disappointing. In this article, we review clinical studies on the prevention of reperfusion injury in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention in a pharmacologic-based approach. We categorize all the agents that are evaluated for the prevention of myocardial reperfusion injury based on their mechanisms of action into 5 groups: drugs that can reduce oxidative stress, drugs that can affect cellular metabolism, rheological agents that target microvascular obstruction, anti-inflammatory agents, and agents with mixed mechanisms of action. Then, review all the clinical studies of these agents in the setting of primary percutaneous coronary intervention. Finally, we will discuss the possible reasons for the failure in translation of studies into practice and propose potential solutions to overcome this problem., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)