Publications by authors named "Gregory Piazza"

169 Publications

Rivaroxaban and Risk of Venous Thromboembolism in Patients With Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization.

JAMA Netw Open 2022 Jun 1;5(6):e2215580. Epub 2022 Jun 1.

Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora.

Importance: Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER).

Objective: To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER.

Design, Setting, And Participants: This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021.

Exposure: Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician.

Main Outcomes And Measures: Symptomatic VTE was a prespecified secondary outcome and prospectively collected.

Results: Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67).

Conclusions And Relevance: In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.15580DOI Listing
June 2022

Extended Anticoagulation After Pulmonary Embolism: A Multicenter Observational Cohort Analysis.

J Am Heart Assoc 2022 Jun 22:e024425. Epub 2022 Jun 22.

Department of Cardiology University Hospital Jean Minjoz Besançon France.

Background Pulmonary embolism (PE) has a long-term risk of adverse events, which can be prevented by extended anticoagulation. We compared clinical characteristics and outcomes between patients treated with 2-year extended anticoagulation and those who were not, in a population who had completed an initial phase of 3 to 6 months of anticoagulant therapy after acute PE. Methods and Results Observational cohort analysis of patients with PE who survived an initial phase of 3 to 6 months anticoagulation. Primary efficacy outcome was all-cause death or recurrent venous thromboembolism. Primary safety outcome was major bleeding. In total, 858 (71.5%) patients were treated with and 341 (28.5%) were treated without extended anticoagulant therapy during the active study period. Age <65 years, intermediate-high or high-risk index PE, normal platelet count, and the absence of concomitant antiplatelet treatment were independently associated with the prescription of extended anticoagulation. The mean duration of the active phase was 2.1±0.3 years. The adjusted rate of the primary efficacy outcome was 2.1% in the extended group and 7.7% in the nonextended group (<0.001) for patients treated with extended anticoagulant therapy. Rate of bleeding were similar between the extended anticoagulant group and the nonextended group. Conclusions Extended oral anticoagulation over 2 and a half years after index PE seems to provide a net clinical benefit compared with no anticoagulation in patients with PE selected to receive extended anticoagulation. Randomized clinical trials are warranted to explore the potential benefit of extended anticoagulation in patients with PE, especially those with transient provoking factors but residual risk.
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http://dx.doi.org/10.1161/JAHA.121.024425DOI Listing
June 2022

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants: A Review.

JAMA Cardiol 2022 Jun 1. Epub 2022 Jun 1.

Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, United Kingdom.

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.
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http://dx.doi.org/10.1001/jamacardio.2022.1292DOI Listing
June 2022

Call for Formalized Pathways in Vascular Medicine Training: JACC Review Topic of the Week.

J Am Coll Cardiol 2022 05;79(21):2129-2139

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

The burden of vascular diseases and complexity of their management have been growing. Vascular medicine specialists may help to bridge gaps in care, especially as part of multidisciplinary teams. However, there is a limited number of vascular medicine specialists because of constraints in training. Despite established pathways for training in vascular medicine, there are obstacles that restrict completion of training in dedicated programs. A key factor is lack of funding as a result of inadequate recognition by key national accrediting and credentialing organizations. A concerted effort is required to overcome the obstacles to expand vascular medicine training programs and ultimately the pool of vascular medicine specialists. Well-trained vascular medicine specialists will be well positioned to ease the burden of vascular disease and optimize patient outcomes.
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http://dx.doi.org/10.1016/j.jacc.2022.03.365DOI Listing
May 2022

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study.

Am Heart J 2022 May 16;251:43-53. Epub 2022 May 16.

Center for Thrombosis and Heamostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece. Electronic address:

Background: Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE).

Methods And Results: The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium.

Conclusions: Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future.
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http://dx.doi.org/10.1016/j.ahj.2022.05.011DOI Listing
May 2022

Sex Differences in PrEsentation, Risk Factors, Drug and Interventional Therapies, and OUtcomes of Elderly PatientS with Pulmonary Embolism: Rationale and design of the SERIOUS-PE study.

Thromb Res 2022 Jun 4;214:122-131. Epub 2022 May 4.

YNHH/Yale Center for Outcomes Research and Evaluation (CORE), New Haven, CT, USA; Department of Health Policy and Mangement in Dr. Krumholz's, Yale School of Public Health, New Haven, CT, USA; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Background: Sex is an important factor associated with pulmonary embolism (PE) disease presentation and outcomes, which may be related to pathobiological, social, and treatment-based differences. We are seeking to illuminate sex differences in pulmonary embolism presentation, care, and outcomes using an international registry and a national US database of people 65 years and older, the age group in which the majority of these events occur.

Methods: The Sex Differences in PrEsentation, Risk Factors, Drug and Interventional Therapies, and OUtcomes of Elderly PatientS with Pulmonary Embolism (SERIOUS-PE) study has been designed to address knowledge gaps in this area. This study will use data from the Registro Informatizado Enfermedad TromboEmbolica (RIETE) registry and the US Medicare Fee-For-Service beneficiaries. RIETE is a large international registry of patients with venous thromboembolism with data collected on PE presentation, risk factors, co-morbidities, drug and interventional therapies, as well as 30-day and 1-year outcomes (including recurrent VTE, major bleeding, and mortality). Data from US Medicare Fee-For-Service beneficiaries will be used to understand the sex differences in PE hospitalizations, advanced therapies, and outcomes at 30-day and 1-year follow-up. Assessment of outcomes in both databases will be performed in unadjusted models, as well as those adjusted for demographics, co-morbidities, and treatments, to understand whether the potential sex differences in outcomes are related to differences in risk factors and co-morbidities, potential disparities in treatment, or a plausible biological difference in women versus men. Linear trends will be assessed over time.

Results: RIETE data from March 2001 through March 2021 include 33,462 elderly patients with PE, of whom 19,294 (57.7%) were women and 14,168 (42.3%) were men. In the Medicare Fee-For-Service database, between January 2001 and December 31, 2019, 1,030,247 patients were hospitalized with a principal discharge diagnosis of PE, of whom 599,816 (58.2%) were women and 430,431 (41.8%) were men.

Conclusions: Findings from the SERIOUS-PE study will help address important knowledge gaps related to sex differences in presentation and risk factors, treatment patterns, and outcomes of older adults with PE. The results may guide changes in prognostic prediction rules based on sex-specific findings, identify sex-based disparities in care delivery that should be addressed by quality improvement, or uncover potential differences in response to available therapies that warrant testing in dedicated randomized trials.
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http://dx.doi.org/10.1016/j.thromres.2022.04.019DOI Listing
June 2022

Thrombotic and bleeding events, mortality, and anticoagulant use among 546,656 hospitalized patients with COVID-19 in the United States: a retrospective cohort study.

J Thromb Thrombolysis 2022 May 30;53(4):766-776. Epub 2022 Apr 30.

Brigham and Women's Hospital, Boston, MA, USA.

This study describes demographics, thrombotic and bleeding events, mortality, and anticoagulant use among hospitalized patients with COVID-19 in the United States. Premier Healthcare Database data were analyzed to identify inpatients with a discharge diagnosis for COVID-19 (ICD-10-CM code: U07.1) from April 1, 2020 to March 31, 2021, and matched historical controls without COVID-19 (inpatients discharged between April 1, 2018 and March 31, 2019). Thrombotic [including venous thromboembolism (VTE)] and bleeding events were based on ICD-10-CM discharge diagnosis codes. Of the 546,656 patients hospitalized with COVID-19, 20.1% were admitted to the ICU, 62.8% were aged ≥ 60 years, 51.5% were male, and 31.0% were non-white. Any thrombotic event was diagnosed in 10.0% of hospitalized and 20.8% of ICU patients with COVID-19 versus (vs) 11.5% and 24.4% for historical controls, respectively. More VTE events were observed in hospitalized and ICU patients with COVID-19 than historical controls (hospitalized: 4.4% vs 2.7%, respectively; ICU: 8.3% vs 5.2%, respectively; both P < 0.0001). Bleeding events were diagnosed in 10.2% of hospitalized and 21.8% of ICU patients with COVID-19 vs 16.0% and 33.2% for historical controls, respectively. Mortality among hospitalized (12.4%) and ICU (38.5%) patients with COVID-19 was higher vs historical controls (2.4%, P < 0.0001 and 9.4%, P < 0.0001, respectively) and higher in hospitalized patients with COVID-19 who had thrombotic events (29.4%) vs those without thrombotic events (10.8%, P < 0.0001). VTE and mortality were higher in hospitalized and ICU patients with COVID-19 vs historical controls. The presence of thrombotic events was associated with worse outcomes.
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http://dx.doi.org/10.1007/s11239-022-02644-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055213PMC
May 2022

Optimal reperfusion strategy in acute high-risk pulmonary embolism requiring extracorporeal membrane oxygenation support: a systematic review and meta-analysis.

Eur Respir J 2022 May 20. Epub 2022 May 20.

Department of Cardiology, University Hospital Jean Minjoz, Besançon, France

Background And Objectives: The optimal pulmonary revascularization strategy in high-risk pulmonary embolism (PE) requiring implantation of extra corporeal membrane oxygenation (ECMO) remains controversial. We conducted a systematic review and meta-analysis of evidence comparing mechanical embolectomy and other strategies, including systemic, catheter-directed thrombolysis, or ECMO as stand-alone therapy, with regard to mortality and bleeding outcomes.

Methods And Results: We identified 835 studies, 17 of which were included, comprising 327 PE patients. Overall, 32.4% were treated with mechanical pulmonary reperfusion, (of whom 85.9% had surgical embolectomy), while 67.61% received other strategies. The mortality rate was 26.4% in the mechanical reperfusion group, and 42.8% in the other strategy group. The pooled OR for mortality with mechanical reperfusion was 0.43 (95%CI, 0.23-0.997); p=0.009; =35.2%) other reperfusion strategies; and 0.36 (95% CI, 0.18-0.73; p=0.009; =32.9%) for surgical embolectomy thrombolysis. The rate of bleeding in patients under ECMO was 24.5% in the mechanical reperfusion group and 19.6% in the other reperfusion group (OR, 1.26; 95% CI, 0.54-2.92; , 7.7%). The meta-regression model did not identify any relationship between the covariates "more than one pulmonary reperfusion therapy", "ECMO implantation before pulmonary reperfusion therapy", clinical presentation of PE, or cancer-associated PE, and the associated outcomes.

Conclusions: The results of the present meta-analysis and meta-regression suggest that mechanical reperfusion, notably by surgical embolectomy, may yield favorable results regardless of the timing of ECMO implantation in the reperfusion timeline, independent of thrombolysis administration or cardiac arrest presentation.
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http://dx.doi.org/10.1183/13993003.02977-2021DOI Listing
May 2022

Women's representation in venous thromboembolism randomized trials and registries: The illustrative example of direct oral anticoagulants for acute treatment.

Contemp Clin Trials 2022 04 21;115:106714. Epub 2022 Feb 21.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Thrombosis Research Group, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.cct.2022.106714DOI Listing
April 2022

Validation of the Khorana score for predicting venous thromboembolism in 40 218 patients with cancer initiating chemotherapy.

Blood Adv 2022 05;6(10):2967-2976

Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

The Khorana score is recommended for guiding primary venous thromboembolism (VTE) prophylaxis in cancer patients, but its clinical utility overall and across cancer types remains debatable. Also, some previous validation studies have ignored the competing risk of death, hereby potentially overestimating VTE risk. We identified ambulatory cancer patients initiating chemotherapy without other indications for anticoagulation using Danish health registries and estimated 6-month cumulative incidence of VTE stratified by Khorana levels. Analyses were conducted with and without considering death as a competing risk using the Kaplan-Meier method vs the cumulative incidence function. Analyses were performed overall and stratified by cancer types. Of 40 218 patients, 35.4% were categorized by Khorana as low risk (score 0), 53.6% as intermediate risk (score 1 to 2), and 10.9% as high risk (score ≥3). Considering competing risk of death, the corresponding 6-month risks of VTE were 1.5% (95% confidence interval [CI], 1.3-1.7), 2.8% (95% CI, 2.6-3.1), and 4.1% (95% CI, 3.5-4.7), respectively. Among patients recommended anticoagulation by guidelines (Khorana score ≥2), the 6-month risk was 3.6% (95% CI, 3.3-3.9). Kaplan-Meier analysis overestimated incidence up to 23% compared with competing risk analyses. Using the guideline-recommended threshold of ≥2, the Khorana score did not risk-stratify patients with hepatobiliary or pancreatic cancer, lung cancer, and gynecologic cancer. In conclusion, the Khorana score was able to stratify ambulatory cancer patients according to the risk of VTE, but not for all cancer types. Absolute risks varied by methodology but were lower than in key randomized trials. Thus, although certain limitations with outcome identification using administrative registries apply, the absolute benefit of implementing routine primary thromboprophylaxis in an unselected cancer population may be smaller than seen in randomized trials.
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http://dx.doi.org/10.1182/bloodadvances.2021006484DOI Listing
May 2022

Case 39-2021: A 26-Year-Old Woman with Respiratory Failure and Altered Mental Status.

N Engl J Med 2021 Dec;385(26):2464-2474

From the Department of Pulmonary and Critical Care Medicine, Newton-Wellesley Hospital, Newton (A.K.), and the Department of Pulmonary and Critical Care Medicine, Tufts Medical School (A.K.), the Departments of Pulmonary and Critical Care Medicine (V.S.S.), Radiology (D.P.M.), Medicine (P.S.L., G.P.), Neurology (Y.A., E.C.C.), and Pathology (K.V.), Massachusetts General Hospital, the Departments of Pulmonary and Critical Care Medicine (V.S.S.), Radiology (D.P.M.), Medicine (P.S.L., G.P.), Neurology (Y.A., E.C.C.), and Pathology (K.V.), Harvard Medical School, and the Department of Medicine, Brigham and Women's Hospital (G.P.), Boston - all in Massachusetts.

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http://dx.doi.org/10.1056/NEJMcpc2107355DOI Listing
December 2021

Reply: The pathway to the 'truth' in the study of recurrent pregnancy loss and thrombophilia.

Hum Reprod 2021 12;37(1):191-193

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1093/humrep/deab248DOI Listing
December 2021

Thrombophilia, Antithrombotic Therapy, and Recurrent Pregnancy Loss: A Call for Pragmatism in the Face of Unknowns.

Semin Reprod Med 2021 11 8;39(5-06):167-169. Epub 2021 Nov 8.

Thrombosis and Haemostasis Unit, Fondazione I.R.C.C.S. "Casa Sollievo della Sofferenza," S. Giovanni Rotondo, Foggia, Italy.

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http://dx.doi.org/10.1055/s-0041-1735628DOI Listing
November 2021

Off the beaten path: the need for innovation in medical therapy to improve outcomes in acute pulmonary embolism.

Authors:
Gregory Piazza

Eur Heart J Acute Cardiovasc Care 2022 Jan;11(1):10-12

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

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http://dx.doi.org/10.1093/ehjacc/zuab100DOI Listing
January 2022

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 10;78(16):1635-1654

Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA; Division of Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2021.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504484PMC
October 2021

Loss of Pulmonary Vascular Volume as a Predictor of Right Ventricular Dysfunction and Mortality in Acute Pulmonary Embolism.

Circ Cardiovasc Imaging 2021 09 21;14(9):e012347. Epub 2021 Sep 21.

University of Pennsylvania, Philadelphia. Division of Pulmonary and Critical Care Medicine (S.M.H., E.H., S.A., S.M., A.B.W., G.R.W., F.N.R.), Brigham and Women's Hospital, Harvard Medical School, Boston.

Background: In acute pulmonary embolism, chest computed tomography angiography derived metrics, such as the right ventricle (RV): left ventricle ratio are routinely used for risk stratification. Paucity of intraparenchymal blood vessels has previously been described, but their association with clinical biomarkers and outcomes has not been studied. We sought to determine if small vascular volumes measured on computed tomography scans were associated with an abnormal RV on echocardiography and mortality. We hypothesized that decreased small venous volume would be associated with greater RV dysfunction and increased mortality.

Methods: A retrospective cohort of patients with intermediate risk pulmonary embolism admitted to Brigham and Women's Hospital between 2009 and 2017 was assembled, and clinical and radiographic data were obtained. We performed 3-dimensional reconstructions of vasculature to assess intraparenchymal vascular volumes. Statistical analyses were performed using multivariable regression and cox proportional hazards models, adjusting for age, sex, lung volume, and small arterial volume.

Results: Seven hundred twenty-two subjects were identified of whom 573 had documented echocardiography. A 50% reduction in small venous volume was associated with an increased risk of RV dilation (relative risk: 1.38 [95% CI, 1.18-1.63], <0.001), RV dysfunction (relative risk: 1.62 [95% CI, 1.36-1.95], <0.001), and RV strain (relative risk: 1.67 [95% CI, 1.37-2.04], <0.001); increased cardiac biomarkers, and higher 30-day and 90-day mortality (hazard ratio: 2.50 [95% CI, 1.33-4.67], =0.004 and hazard ratio: 1.84 [95% CI, 1.11-3.04], =0.019, respectively).

Conclusions: Loss of small venous volume quantified from computed tomography angiography is associated with increased risk of abnormal RV on echocardiography, abnormal cardiac biomarkers, and higher risk of 30- and 90-day mortality. Small venous volume may be a useful marker for assessing disease severity in acute pulmonary embolism.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462092PMC
September 2021

Use of novel antithrombotic agents for COVID-19: Systematic summary of ongoing randomized controlled trials.

J Thromb Haemost 2021 12 30;19(12):3080-3089. Epub 2021 Sep 30.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1111/jth.15533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646701PMC
December 2021

Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in Patients with Provoked Venous Thromboembolism and Enduring Risk Factors: Rationale and Design of the HI-PRO Trial.

Thromb Haemost 2021 Sep 16. Epub 2021 Sep 16.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.

Patients with acute venous thromboembolism (VTE) in the setting of transient provoking factors are typically treated with short-term anticoagulation. However, the risk of recurrence may be increased in the presence of enduring risk factors. In such patients, the optimal duration of treatment remains uncertain. HI-PRO is a single-center, double-blind randomized trial. Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) following a major provoking factor, including major surgery or major trauma, who completed at least 3 months of standard-dose therapeutic anticoagulation and have at least one enduring risk factor (such as obesity or heart failure) will be considered for inclusion. Patients will be randomized to apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome will be symptomatic recurrent VTE-a composite of DVT and/or PE at 12 months after randomization. Secondary efficacy outcomes include a composite of death due to cardiovascular causes, nonfatal myocardial infarction, stroke or systemic embolism, major adverse limb events, or coronary or peripheral ischemia requiring revascularization at 12 months, and individual components of these outcomes. The primary safety outcome is major bleeding according to the International Society on Thrombosis and Haemostasis definition. The study plans to enroll 600 patients (300 per arm) to have 80% power for detecting a 75% relative risk reduction in the primary outcome. Active recruitment began in March 2021. HI-PRO will provide clinically meaningful data on whether patients with provoked VTE and enduring risk factors have fewer adverse clinical outcomes if prescribed low-intensity extended-duration anticoagulation.
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http://dx.doi.org/10.1055/a-1646-2244DOI Listing
September 2021

Stability of alteplase for ultrasound-facilitated catheter-directed thrombolysis.

Blood Adv 2021 12;5(23):5283-5289

Division of Cardiovascular Medicine, and.

Ultrasound-facilitated catheter-directed thrombolysis is used with low-dose alteplase to treat pulmonary embolism. This reduces the risk of bleeding that accompanies systemic administration of higher alteplase doses. Some studies suggest that alteplase given over 2 to 6 hours is safe and effective, but there are few data to support the stability of alteplase under these conditions. Therefore, we undertook this in vitro study to determine the duration of alteplase stability. Alteplase was prepared in solutions of 8 mg in 100 mL, 6 mg in 150 mL, and 8 mg in 200 mL. Solutions were administered through the EkoSonic Endovascular System (with and without ultrasound) to simulate administration over 2, 4, and 6 hours. Alteplase was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). Assays were performed at time 0 and at 30-minute intervals during simulated infusion. An enzyme-linked immunosorbent assay was used to measure alteplase concentrations at time 0 and at 15-minute intervals during simulated infusion. By using RP-HPLC in the absence of ultrasound, the alteplase concentration remained within 1% of the original concentration through 120, 240, and 360 minutes of infusion. By using RP-HPLC for measurement, alteplase in the presence of ultrasound degraded steadily over time to ∼90% of its original amount in 120 minutes, ∼80% in 240 minutes, and ∼70% in 360 minutes. The remaining alteplase was available for enzymatic activity. Alteplase solutions of 0.04 and 0.08 mg/mL degraded steadily over time during simulated ultrasound-facilitated catheter-directed administration. Alteplase that did not degrade remained available for enzymatic activity.
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http://dx.doi.org/10.1182/bloodadvances.2021005001DOI Listing
December 2021

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism.

J Am Heart Assoc 2021 09 28;10(17):e021467. Epub 2021 Aug 28.

Hospital Universitari Germans Trias i Pujol Badalona, Barcelona Spain.

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.
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http://dx.doi.org/10.1161/JAHA.121.021467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649245PMC
September 2021

Impact of Atrial Fibrillation on In-Hospital Mortality and Stroke in Acute Aortic Syndromes.

Am J Med 2021 11 7;134(11):1419-1423. Epub 2021 Jul 7.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

Background: Acute aortic syndromes may present with a number of cardiovascular complications, including atrial fibrillation. We assessed the prevalence of atrial fibrillation in patients presenting with acute aortic syndromes and evaluated atrial fibrillation's association with in-hospital mortality and stroke.

Methods: Consecutive patients with acute aortic syndromes admitted to a single tertiary care center from January 2015 to March 2020 were included. We identified patients with atrial fibrillation on the presenting electrocardiogram.

Results: A total of 309 patients with acute aortic syndromes were included in our analyses: 148 (48%) presented with Stanford type A and 161 (52%) with Stanford type B acute aortic syndromes. Twenty-seven (8.7%) patients had atrial fibrillation on the presenting electrocardiogram: 12 (44%) with type A and 15 (56%) with type B acute aortic syndromes. Patients with atrial fibrillation were older, more likely to be white, had a higher frequency of history of cancer, peripheral artery disease, cerebrovascular disease, and heart failure with preserved ejection fraction, compared with those without atrial fibrillation. Acute aortic syndromes patients with atrial fibrillation had higher frequencies of in-hospital mortality compared with those without atrial fibrillation (40.7% vs 12.4%, P < .0001). However, stroke frequencies did not differ between the 2 groups.

Conclusion: In patients presenting with acute aortic syndromes and atrial fibrillation, we observed higher frequencies of in-hospital mortality, without differences in the frequencies of stroke.
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http://dx.doi.org/10.1016/j.amjmed.2021.06.012DOI Listing
November 2021

An Original Risk Score to Predict Early Major Bleeding in Acute Pulmonary Embolism: The Syncope, Anemia, Renal Dysfunction (PE-SARD) Bleeding Score.

Chest 2021 11 2;160(5):1832-1843. Epub 2021 Jul 2.

Department of Cardiology, University Hospital Jean Minjoz, Besançon, France; EA3920, University of Burgundy Franche-Comté, Besançon, France; F-CRIN, INNOVTE network, France.

Background: Improved prediction of the risk of early major bleeding in pulmonary embolism (PE) is needed to optimize acute management.

Research Question: Does a simple scoring system predict early major bleeding in acute PE patients, identifying patients with either high or low probability of early major bleeding?

Study Design And Methods: From a multicenter prospective registry including 2,754 patients, we performed post hoc multivariable logistic regression analysis to build a risk score to predict early (up to hospital discharge) major bleeding events. We validated the endpoint model internally, using bootstrapping in the derivation dataset by sampling with replacement for 500 iterations. Performances of this novel score were compared with that of the VTE-BLEED (Venous Thrombo-Embolism Bleed), RIETE (Registro informatizado de la enfermedad tromboembólica en España; Computerized Registry of Patients with Venous Thromboembolism), and BACS (Bleeding, Age, Cancer, and Syncope) models.

Results: Multivariable regression identified three predictors for the occurrence of 82 major bleeds (3.0%; 95% CI, 2.39%-3.72%): Syncope (+1.5); Anemia, defined as hemoglobin <12 g/dL (+2.5); and Renal Dysfunction, defined as glomerular filtration rate <60 mL/min (+1 point) (SARD). The PE-SARD bleeding score was calculated by summing all the components. Overall, 52.2% (95% CI, 50.29%-54.11%) of patients were classified as low bleeding-risk (score, 0 point), 35.2% (95% CI, 33.39%-37.04%) intermediate-risk (score, 1-2.5 points), and 12.6% (95% CI, 9.30%-16.56%) high-risk (score >2.5 points). Observed bleeding rates increased with increasing risk group, from 0.97% (95% CI, 0.53%-1.62%) in the low-risk to 8.93% (95% CI, 6.15%-12.44%) in the high-risk group. C-index was 0.74 (95% CI, 0.73-0.76) and Brier score 0.028 in the derivation cohort. Similar values were calculated from internal bootstrapping. Performance of the PE-SARD score was better than that observed with the VTE-BLEED, RIETE, and BACS scores, leading to a high proportion of bleeding-risk reclassification in patients who bled and those who did not.

Interpretation: The PE-SARD bleeding risk score is an original, user-friendly score to estimate risk of early major bleeding in patients with acute PE.
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http://dx.doi.org/10.1016/j.chest.2021.06.048DOI Listing
November 2021

Thrombophilia, Inflammation, and Recurrent Pregnancy Loss: A Case-Based Review.

Semin Reprod Med 2021 03 2;39(1-02):62-68. Epub 2021 Jul 2.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies and is often multifactorial with the majority of miscarriages being due to aneuploidy and anatomic or physiological abnormalities. However, inherited or acquired thrombophilias have also been associated with RPL, albeit inconsistently. While inherited thrombophilias, such as factor V Leiden and prothrombin gene mutation, are relatively prevalent in women with RPL compared with the general population, a causal link has yet to be definitively established. Recently, systemic inflammation, as measured by high-sensitivity C-reactive protein, has also been hypothesized to play a role in infertility. Based on limited prospective trial data, antithrombotic therapy and antiplatelet agents have been proposed as possible tools for the prevention of RPL. Because of the multifactorial nature of RPL and infertility, various clinicians, as obstetricians and gynecologists, endocrinologists, hematologists, or vascular medicine specialists, may be requested to counsel these women. This, together with evidence gaps, frequently leads to distinctly different diagnostic and therapeutic recommendations, especially regarding thrombophilia testing and treatment. Using four case vignettes in this review, we critically appraise the literature and highlight how two clinicians from different subspecialties approach the relationship between RPL, inflammation, and thrombophilia.
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http://dx.doi.org/10.1055/s-0041-1731827DOI Listing
March 2021

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

Hum Reprod 2021 07;36(8):2083-2090

Medical Genetics, University of Foggia, Foggia, Italy.

Study Question: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes?

Summary Answer: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA).

What Is Known Already: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity.

Study Design, Size, Duration: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019.

Participants/materials, Setting, Methods: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics.

Main Results And The Role Of Chance: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9).

Limitations, Reasons For Caution: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding.

Wider Implications Of The Findings: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia.

Study Funding/competing Interest(s): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest.

Trial Registration Number: NCT02385461.
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http://dx.doi.org/10.1093/humrep/deab153DOI Listing
July 2021

Stroke risk factors and outcomes among hospitalized women with atrial fibrillation.

J Thromb Thrombolysis 2021 Nov 26;52(4):1023-1031. Epub 2021 May 26.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Observational cohort analyses suggest that women with atrial fibrillation (AF) endure a greater burden of stroke. We conducted an analysis of an observational cohort study completed at our tertiary care medical center to assess sex-related differences in cardiovascular risk factors, prescription of antithrombotic therapy, and 90-day outcomes. We analyzed 5000 hospitalized patients with AF: 1888 women and 3112 men. Clinical characteristics of AF, risk of stroke and bleeding, prescription of antithrombotic therapy, and 90-day clinical outcomes, including stroke and all-cause mortality, were compared. We observed a 50% higher relative frequency of stroke in hospitalized women with AF compared with men. While the frequencies of prescription of antithrombotic therapy at discharge were similar, anticoagulation was omitted in 40% of women with AF. The 90-day frequencies of major adverse events and mortality were increased in hospitalized women with AF not prescribed antithrombotic therapy at discharge. Prescription of anticoagulation in women with AF at hospital discharge was associated with a 60% and 40% relative reduction in the odds of mortality and major adverse events at 90 days. In conclusion, women hospitalized with AF have a higher risk of stroke at 90 days compared with men. Anticoagulation at hospital discharge was omitted in 40% of women with AF, but when prescribed, was associated with a reduction in mortality and major adverse events at 90 days, respectively. We analyzed 5000 hospitalized patients with atrial fibrillation (AF) (1888 women and 3112 men) in an observational cohort study completed at our tertiary care medical center to assess sex-related differences in cardiovascular risk factors, prescription of antithrombotic therapy, and 90-day outcomes. We observed a 50% higher relative frequency of stroke in hospitalized women with AF compared with men. The 90-day frequencies of major adverse events and mortality were increased in hospitalized women with AF not prescribed antithrombotic therapy at discharge. Prescription of anticoagulation in women with AF at hospital discharge was associated with a 60% and 40% relative reduction in the odds of mortality and major adverse events at 90 days.
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http://dx.doi.org/10.1007/s11239-021-02482-8DOI Listing
November 2021

Trailblazing in pulmonary embolism research: the importance of extending beyond randomized controlled trials.

Authors:
Gregory Piazza

Eur Heart J Acute Cardiovasc Care 2021 May;10(3):237-239

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

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http://dx.doi.org/10.1093/ehjacc/zuab002DOI Listing
May 2021

Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials.

medRxiv 2021 May 4. Epub 2021 May 4.

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They 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 triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.
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http://dx.doi.org/10.1101/2021.05.03.21256468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109185PMC
May 2021

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

Thromb Haemost 2022 Jan 17;122(1):131-141. Epub 2021 Apr 17.

Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.

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,  = 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.
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http://dx.doi.org/10.1055/a-1485-2372DOI Listing
January 2022
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