To the editor
We read with interest the recent log articles (Aug. 26 issue)1.2 on therapeutic anticoagulation in patients with Covid-19. We applaud the researchers for conducting rigorous studies to address this important clinical concern in Covid-19. Remarkably, these studies show that the therapeutic benefit of anticoagulation does not lie in preventing acute pulmonary embolism. The incidence of prospectively diagnosed acute pulmonary embolism in patients hospitalized for Covid-19 was relatively low: 1.3% (29 of 2226) among non-critically ill patients and 5.1% (55 of 1089) among seriously ill. These incidences were comparable to those observed in other prospective studies involving patients with Covid-19.3
Early retrospective reports suggested alarmingly high incidences of pulmonary embolism in patients hospitalized for Covid-19. However, these studies preferably included patients who had already received contrast-enhanced computed tomographic pulmonary angiography for clinical reasons, including suspected acute pulmonary embolism.4 Excluding such studies, a meta-analysis of studies that included patients hospitalized for Covid-19 found incidences of acute pulmonary embolism comparable to those seen in comparably ill patients without Covid-19.5 The recently published studies confirmed that acute pulmonary embolism is not as common in patients with Covid-19 as previously believed.
Timothy M. Fernandes, MD, MPH
W. Cameron McGuire, MD, MPH
Timothy A. Morris, MD
University of California, San Diego, School of Medicine, La Jolla, CA
dr. Fernandes reports that he has received consultancy fees from Bayer and Bristol Myers Squibb. No other potential conflict of interest has been reported that is relevant to this letter.
1. The REMAP-CAP, ACTIV-4a, and ATTACC investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med 2021;385:777–789.
2. The ATTACC, ACTIV-4a, and REMAP-CAP investigators. Therapeutic anticoagulation with heparin in non-critically ill patients with Covid-19. N Engl J Med 2021;385:790–802.
3. Beigel JH, Tomashek KM, dodd LE, et al. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med 2020;383:1813–1826.
4. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Res Pract Tromb Haemost 2020;4:1178–1191.
5. Gallastegui N, Zhou JY, Drygalski AV, Barnes RFW, Fernandes TM, Morris TA. Pulmonary embolism does not have an unusually high incidence in hospitalized COVID19 patients. Clin Appl Thromb Hemost 2021;27:107602962996471–107602962996471.
To the editor
Contrasting results have been reported on the preferred anticoagulant therapy in patients with SARS-CoV-2 infection. The two recent articles published in the log can help to understand the reasons for these contrasts. The main findings were that therapeutic dose heparin or low molecular weight heparin reduced mortality in patients with moderate infection, but not in those with severe infection.1
One possible explanation for this difference is that SARS-CoV-2 infection, once it reaches a severe state, can become an irreversible condition. The similarities between the hematologic changes associated with severe SARS-CoV-2 infection and disseminated intravascular coagulation support the hypothesis that SARS-CoV-2 infection may initially lead to functional changes of the endothelial barrier that are irreversible over time. can become organic changes. Even if this is not mentioned in the two articles, we can assume that patients with severe disease came into that situation after a longer infection period.
Therefore, we emphasize the importance of an aggressive therapeutic approach for all patients hospitalized for Covid-19. This aggressive approach must encompass all therapeutic tools to address a disease that, in its more severe forms, is the result of multiple factors.
Antonio V. Sterpetti, MD
Sapienza University, Rome, Italy
No potential conflict of interest was disclosed with respect to this letter.
1. Ten Cate H. Surviving Covid-19 with Heparin? N Engl J Med 2021;385:845–846.
To individualize the benefits and balance the risk, identifying factors that may contribute to heterogeneous treatment effects is important and is currently being evaluated by our team in secondary analyses. We agree with Sterpetti that once a patient becomes seriously ill, the clinical course may be too advanced to be favorably affected by heparin. However, what defines such a state is unknown and may be related to the clinical time course, spectrum of coagulation activation, host response, or the integration of several known or yet to be recognized factors. Baseline NSdimer levels did not appear to discriminate between relative therapeutic benefit based on the NSdimer cutoff used, although absolute benefit was more apparent in people with elevated NS-dimer levels given higher event frequencies.
Fernandes et al. are correct to emphasize that the benefit of therapeutic dose heparin in non-critically ill patients could not be fully attributed to a reduced incidence of pulmonary embolism and that the incidences of venous thromboembolism (VTE) occurring early in the pandemic were reported were higher than those currently observed. This may be related to confounding by indication in observational studies that may include patients who had already been diagnosed with and treated for VTE,1 as well as the use of active screening in some studies. Randomized studies of heparin at therapeutic doses involving patients with Covid-19 were also completed after glucocorticoids were introduced as standard of care and against a background of increased use of interleukin-6 receptor antagonists – both factors that can reduce the occurrence of VTE. In an evolving pandemic that includes changes in circulating variants, standards of care and the population at risk, the true incidence of VTE due to Covid-19 is uncertain and deserves further investigation. The reduced use of organ support may mean that heparin may also have beneficial effects on microvascular thrombosis, anti-inflammatory effects and possibly antiviral effects,2 all of which reduce organ damage.
Ryan Zarychanski, MD
University of Manitoba, Winnipeg, MB, Canada
Patrick R. Lawler, MD, MPH
Peter Munk Cardiac Centre, Toronto, ON, Canada
Ewan Goligher, MD, Ph.D.
University of Toronto, Toronto, ON, Canada
Since the publication of their article, the authors have reported no further potential conflicts of interest.
1. Psaty BM, Koepsell TD, Lin D, et al. Assessment and control for confounding by indication in observational studies. J Am Geriatr Soc 1999;47:749–754.
2. Clausen TM, Sandoval DR, Split CB, et al. SARS-CoV-2 infection is dependent on cellular heparan sulfate and ACE2. Cell 2020;183(4):1043–1057.e15.