Browsing by Author "McVerry, Bryan J"
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Item Open Access Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.(Nature communications, 2021-05-14) Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin AH; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus VG; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy IM; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shahzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John PA; Hemkens, Lars GThe original version of this Article contained an error in the spelling of the author Muhammad Shahzad, which was incorrectly given as Muhammad Shehzad. This has now been corrected in both the PDF and HTML versions of the Article.Item Open Access Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.(Nature communications, 2024-02) Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin AH; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus VG; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy IM; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shahzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John PA; Hemkens, Lars GCorrection to: Nature Communicationshttps://doi.org/10.1038/s41467-021-22446-z, published online 15 April 2021 The original version of this article contained an error in Table 1, which misidentified the trial included in the meta-analysis registered as NCT04323527 as CloroCOVID19II instead of CloroCOVID19III. The NCT04323527 registration includes the trials CloroCOVID19I and CloroCOVID19III. CloroCOVID19I was not included in the meta-analysis. In addition, the original version of the Methods section inadvertently omitted details of which formulations of hydroxychloroquine or chloroquine the reported dosages refer to. The following information has been included in the legend for Table 1 and in the corrected methods section: “In all trials that used hydroxychloroquine, dosages refer to hydroxychloroquine sulfate. In trials that used chloroquine, the dosages for ARCHAIC, ChiCTR2000030054 and ChiCTR2000031204 refer to chloroquine phosphate, while those for CloroCOVID19II and CloroCOVID19III refer to chloroquine base. The American Journal of Tropical Medicine and Hygiene has issued a retraction note (1) for one of the trials (2) that had been included in the calculations of our meta-analysis. Exclusion of the data from this trial changes neither the results nor inferences of the meta-analysis. For hydroxychloroquine, the original odds ratio for mortality was 1.11 (95% CI: 1.02–1.20; I2 = 0%; 26 trials; 10,012 patients) and excluding the retracted trial the odds ratio for mortality would remain 1.11 (95% CI: 1.02–1.20, I2 = 0%; 25 trials; 9818 patients). Retraction Notice. The American Journal of Tropical Medicine and Hygiene 107, 728-728, https://doi.org/10.4269/ajtmh.1073ret (2022). Abd-Elsalam, S. et al. RETRACTED: Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study. Am J Trop Med Hyg 103, 1635-1639, https://doi.org/10.4269/ajtmh.20-0873 (2020). The errors in Table 1 and in the Methods section have been corrected in both the PDF and HTML versions of the Article.Item Open Access Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non–Critically Ill Hospitalized Patients With COVID-19(JAMA, 2022-01-18) Berger, Jeffrey S; Kornblith, Lucy Z; Gong, Michelle N; Reynolds, Harmony R; Cushman, Mary; Cheng, Yu; McVerry, Bryan J; Kim, Keri S; Lopes, Renato D; Atassi, Bassel; Berry, Scott; Bochicchio, Grant; de Oliveira Antunes, Murillo; Farkouh, Michael E; Greenstein, Yonatan; Hade, Erinn M; Hudock, Kristin; Hyzy, Robert; Khatri, Pooja; Kindzelski, Andrei; Kirwan, Bridget-Anne; Baumann Kreuziger, Lisa; Lawler, Patrick R; Leifer, Eric; Lopez-Sendon Moreno, Jose; Lopez-Sendon, Jose; Luther, James F; Nigro Maia, Lilia; Quigley, John; Sherwin, Robert; Wahid, Lana; Wilson, Jennifer; Hochman, Judith S; Neal, Matthew D; ACTIV-4a InvestigatorsItem Open Access Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.(Nature communications, 2021-04-15) Axfors, Cathrine; Schmitt, Andreas M; Janiaud, Perrine; Van't Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F; Abella, Benjamin S; Akram, Javed; Amaravadi, Ravi K; Angus, Derek C; Arabi, Yaseen M; Azhar, Shehnoor; Baden, Lindsey R; Baker, Arthur W; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin AH; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z; Cowan, Lisa N; Dalgard, Olav; de Almeida E Val, Fernando F; de Lacerda, Marcus VG; de Melo, Gisely C; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C; Hernandez-Cardenas, Carmen M; Hills, Thomas; Hoepelman, Andy IM; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S; Kremsner, Peter G; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J; Meza-Meneses, Patricia; Monteiro, Wuelton M; Morpeth, Susan C; Mourad, Ahmad; Mulligan, Mark J; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A; O'Brien, Sean M; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E; Rockhold, Frank W; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S; Seto, Todd B; Shahzad, Muhammad; Soliman, Shaimaa; Stout, Jason E; Thirion-Romero, Ireri; Troxel, Andrea B; Tseng, Ting-Yu; Turner, Nicholas A; Ulrich, Robert J; Walsh, Stephen R; Webb, Steve A; Weehuizen, Jesper M; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G; Zhong, Wu; Moher, David; Goodman, Steven N; Ioannidis, John PA; Hemkens, Lars GSubstantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.Item Open Access SARS-CoV-2 Viremia is Associated with COVID-19 Severity and Predicts Clinical Outcomes.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08-10) Jacobs, Jana L; Bain, William; Naqvi, Asma; Staines, Brittany; Castanha, Priscila MS; Yang, Haopu; Boltz, Valerie F; Barratt-Boyes, Simon; Marques, Ernesto TA; Mitchell, Stephanie L; Methé, Barbara; Olonisakin, Tolani F; Haidar, Ghady; Burke, Thomas W; Petzold, Elizabeth; Denny, Thomas; Woods, Chris W; McVerry, Bryan J; Lee, Janet S; Watkins, Simon C; St Croix, Claudette M; Morris, Alison; Kearney, Mary F; Ladinsky, Mark S; Bjorkman, Pamela J; Kitsios, Georgios D; Mellors, John WBackground
SARS-CoV-2 viral RNA (vRNA) is detected in the bloodstream of some patients with COVID-19 ("RNAemia") but it is not clear whether this RNAemia reflects viremia (i.e., virus particles) and how RNAemia/viremia is related to host immune responses and outcomes.Methods
SARS-CoV-2 vRNA was quantified by ultra-sensitive RT-PCR in plasma samples (0.5-1.0 ml) from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non-ICU), and 23 ICU patients, and vRNA levels compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in pelleted plasma.Results
SARS-CoV-2 vRNA was detected in plasma of 100%, 52.6% and 11.1% of ICU, non-ICU, and outpatients respectively. Virions were detected in plasma pellets by electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (p<0.0001); and for inpatient, plasma vRNA levels were strongly associated with higher WHO score at admission (p=0.01), maximum WHO score (p=0.002) and discharge disposition (p=0.004). A plasma vRNA level >6,000 copies/ml was strongly associated with mortality (HR: 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (p<0.01) but not with plasma neutralizing antibody titers (p=0.8).Conclusions
Visualization of virus particles in plasma indicates that SARS-CoV-2 RNAemia is due, at least in part, to viremia. The levels of SARS-CoV-2 RNAemia quantified by ultrasensitive RT-PCR correlate strongly with disease severity, patient outcome and specific inflammatory biomarkers but not neutralizing antibody titers.Item Open Access Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.(The New England journal of medicine, 2021-08-04) REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher, Ewan C; Bradbury, Charlotte A; McVerry, Bryan J; Lawler, Patrick R; Berger, Jeffrey S; Gong, Michelle N; Carrier, Marc; Reynolds, Harmony R; Kumar, Anand; Turgeon, Alexis F; Kornblith, Lucy Z; Kahn, Susan R; Marshall, John C; Kim, Keri S; Houston, Brett L; Derde, Lennie PG; Cushman, Mary; Tritschler, Tobias; Angus, Derek C; Godoy, Lucas C; McQuilten, Zoe; Kirwan, Bridget-Anne; Farkouh, Michael E; Brooks, Maria M; Lewis, Roger J; Berry, Lindsay R; Lorenzi, Elizabeth; Gordon, Anthony C; Ahuja, Tania; Al-Beidh, Farah; Annane, Djillali; Arabi, Yaseen M; Aryal, Diptesh; Baumann Kreuziger, Lisa; Beane, Abi; Bhimani, Zahra; Bihari, Shailesh; Billett, Henny H; Bond, Lindsay; Bonten, Marc; Brunkhorst, Frank; Buxton, Meredith; Buzgau, Adrian; Castellucci, Lana A; Chekuri, Sweta; Chen, Jen-Ting; Cheng, Allen C; Chkhikvadze, Tamta; Coiffard, Benjamin; Contreras, Aira; Costantini, Todd W; de Brouwer, Sophie; Detry, Michelle A; Duggal, Abhijit; Džavík, Vladimír; Effron, Mark B; Eng, Heather F; Escobedo, Jorge; Estcourt, Lise J; Everett, Brendan M; Fergusson, Dean A; Fitzgerald, Mark; Fowler, Robert A; Froess, Joshua D; Fu, Zhuxuan; Galanaud, Jean P; Galen, Benjamin T; Gandotra, Sheetal; Girard, Timothy D; Goodman, Andrew L; Goossens, Herman; Green, Cameron; Greenstein, Yonatan Y; Gross, Peter L; Haniffa, Rashan; Hegde, Sheila M; Hendrickson, Carolyn M; Higgins, Alisa M; Hindenburg, Alexander A; Hope, Aluko A; Horowitz, James M; Horvat, Christopher M; Huang, David T; Hudock, Kristin; Hunt, Beverley J; Husain, Mansoor; Hyzy, Robert C; Jacobson, Jeffrey R; Jayakumar, Devachandran; Keller, Norma M; Khan, Akram; Kim, Yuri; Kindzelski, Andrei; King, Andrew J; Knudson, M Margaret; Kornblith, Aaron E; Kutcher, Matthew E; Laffan, Michael A; Lamontagne, Francois; Le Gal, Grégoire; Leeper, Christine M; Leifer, Eric S; Lim, George; Gallego Lima, Felipe; Linstrum, Kelsey; Litton, Edward; Lopez-Sendon, Jose; Lother, Sylvain A; Marten, Nicole; Saud Marinez, Andréa; Martinez, Mary; Mateos Garcia, Eduardo; Mavromichalis, Stavroula; McAuley, Daniel F; McDonald, Emily G; McGlothlin, Anna; McGuinness, Shay P; Middeldorp, Saskia; Montgomery, Stephanie K; Mouncey, Paul R; Murthy, Srinivas; Nair, Girish B; Nair, Rahul; Nichol, Alistair D; Nicolau, Jose C; Nunez-Garcia, Brenda; Park, John J; Park, Pauline K; Parke, Rachael L; Parker, Jane C; Parnia, Sam; Paul, Jonathan D; Pompilio, Mauricio; Quigley, John G; Rosenson, Robert S; Rost, Natalia S; Rowan, Kathryn; Santos, Fernanda O; Santos, Marlene; Santos, Mayler O; Satterwhite, Lewis; Saunders, Christina T; Schreiber, Jake; Schutgens, Roger EG; Seymour, Christopher W; Siegal, Deborah M; Silva, Delcio G; Singhal, Aneesh B; Slutsky, Arthur S; Solvason, Dayna; Stanworth, Simon J; Turner, Anne M; van Bentum-Puijk, Wilma; van de Veerdonk, Frank L; van Diepen, Sean; Vazquez-Grande, Gloria; Wahid, Lana; Wareham, Vanessa; Widmer, R Jay; Wilson, Jennifer G; Yuriditsky, Eugene; Zhong, Yongqi; Berry, Scott M; McArthur, Colin J; Neal, Matthew D; Hochman, Judith S; Webb, Steven A; Zarychanski, RyanBackground
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.Methods
In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.Results
The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.Conclusions
In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).Item Open Access Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.(The New England journal of medicine, 2021-08-04) ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler, Patrick R; Goligher, Ewan C; Berger, Jeffrey S; Neal, Matthew D; McVerry, Bryan J; Nicolau, Jose C; Gong, Michelle N; Carrier, Marc; Rosenson, Robert S; Reynolds, Harmony R; Turgeon, Alexis F; Escobedo, Jorge; Huang, David T; Bradbury, Charlotte A; Houston, Brett L; Kornblith, Lucy Z; Kumar, Anand; Kahn, Susan R; Cushman, Mary; McQuilten, Zoe; Slutsky, Arthur S; Kim, Keri S; Gordon, Anthony C; Kirwan, Bridget-Anne; Brooks, Maria M; Higgins, Alisa M; Lewis, Roger J; Lorenzi, Elizabeth; Berry, Scott M; Berry, Lindsay R; Aday, Aaron W; Al-Beidh, Farah; Annane, Djillali; Arabi, Yaseen M; Aryal, Diptesh; Baumann Kreuziger, Lisa; Beane, Abi; Bhimani, Zahra; Bihari, Shailesh; Billett, Henny H; Bond, Lindsay; Bonten, Marc; Brunkhorst, Frank; Buxton, Meredith; Buzgau, Adrian; Castellucci, Lana A; Chekuri, Sweta; Chen, Jen-Ting; Cheng, Allen C; Chkhikvadze, Tamta; Coiffard, Benjamin; Costantini, Todd W; de Brouwer, Sophie; Derde, Lennie PG; Detry, Michelle A; Duggal, Abhijit; Džavík, Vladimír; Effron, Mark B; Estcourt, Lise J; Everett, Brendan M; Fergusson, Dean A; Fitzgerald, Mark; Fowler, Robert A; Galanaud, Jean P; Galen, Benjamin T; Gandotra, Sheetal; García-Madrona, Sebastian; Girard, Timothy D; Godoy, Lucas C; Goodman, Andrew L; Goossens, Herman; Green, Cameron; Greenstein, Yonatan Y; Gross, Peter L; Hamburg, Naomi M; Haniffa, Rashan; Hanna, George; Hanna, Nicholas; Hegde, Sheila M; Hendrickson, Carolyn M; Hite, R Duncan; Hindenburg, Alexander A; Hope, Aluko A; Horowitz, James M; Horvat, Christopher M; Hudock, Kristin; Hunt, Beverley J; Husain, Mansoor; Hyzy, Robert C; Iyer, Vivek N; Jacobson, Jeffrey R; Jayakumar, Devachandran; Keller, Norma M; Khan, Akram; Kim, Yuri; Kindzelski, Andrei L; King, Andrew J; Knudson, M Margaret; Kornblith, Aaron E; Krishnan, Vidya; Kutcher, Matthew E; Laffan, Michael A; Lamontagne, Francois; Le Gal, Grégoire; Leeper, Christine M; Leifer, Eric S; Lim, George; Lima, Felipe Gallego; Linstrum, Kelsey; Litton, Edward; Lopez-Sendon, Jose; Lopez-Sendon Moreno, Jose L; Lother, Sylvain A; Malhotra, Saurabh; Marcos, Miguel; Saud Marinez, Andréa; Marshall, John C; Marten, Nicole; Matthay, Michael A; McAuley, Daniel F; McDonald, Emily G; McGlothlin, Anna; McGuinness, Shay P; Middeldorp, Saskia; Montgomery, Stephanie K; Moore, Steven C; Morillo Guerrero, Raquel; Mouncey, Paul R; Murthy, Srinivas; Nair, Girish B; Nair, Rahul; Nichol, Alistair D; Nunez-Garcia, Brenda; Pandey, Ambarish; Park, Pauline K; Parke, Rachael L; Parker, Jane C; Parnia, Sam; Paul, Jonathan D; Pérez González, Yessica S; Pompilio, Mauricio; Prekker, Matthew E; Quigley, John G; Rost, Natalia S; Rowan, Kathryn; Santos, Fernanda O; Santos, Marlene; Olombrada Santos, Mayler; Satterwhite, Lewis; Saunders, Christina T; Schutgens, Roger EG; Seymour, Christopher W; Siegal, Deborah M; Silva, Delcio G; Shankar-Hari, Manu; Sheehan, John P; Singhal, Aneesh B; Solvason, Dayna; Stanworth, Simon J; Tritschler, Tobias; Turner, Anne M; van Bentum-Puijk, Wilma; van de Veerdonk, Frank L; van Diepen, Sean; Vazquez-Grande, Gloria; Wahid, Lana; Wareham, Vanessa; Wells, Bryan J; Widmer, R Jay; Wilson, Jennifer G; Yuriditsky, Eugene; Zampieri, Fernando G; Angus, Derek C; McArthur, Colin J; Webb, Steven A; Farkouh, Michael E; Hochman, Judith S; Zarychanski, RyanBackground
Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.Methods
In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.Results
The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.Conclusions
In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT02735707, and NCT04359277.).