So now YOU need to find out what the difference is between preemptive therapeutic-dose anticoagulation versus standard
prophylactic dosing. I had several Lovenox shots when my INR was out of whack but have no clue if that was
therapeutic or prophylactic. I'm still going to be requesting heparin or Lovenox shots because I don't want all the microthrombi circulating in my blood causing all kinds of havoc. But don't listen to me, I'm not medically trained, you'll just have to hope your doctor guesses correctly because there is not enough information yet to create protocols. I suppose you'll just have to wait a couple of years before you get COVID-19 to allow the research to inform practice.
The latest here:
Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients
Risk of in-hospital mortality 2.3 times greater versus prophylactic anticoagulation, but many questions remain
Study Authors: Jishu K. Motta, Rahila O. Ogunnaike, et al.
Target Audience and Goal Statement: Infectious disease specialists, hematologists, pulmonologists, critical care specialists
The goal of this study was to compare clinical outcomes of patients with COVID-19 who received preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.
Question Addressed:
- What was the impact of preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing on in-hospital mortality among COVID-19 patients?
Study Synopsis and Perspective:
Researchers have sought to examine the possible benefits of using anticoagulants to treat COVID-19 patients, with mixed results. In one study of patients with severe COVID-19, use of prophylactic low-molecular-weight heparin (LMWH) seemed to improve survival compared with no anticoagulation therapy.
Action Points
- Among patients hospitalized with COVID-19, risk of in-hospital mortality was 2.3 times greater in those receiving preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing, according to a study from two acute care U.S. hospitals.
- Note that study limitations included the retrospective study design, lack of randomization, no capture of mortality after the patients left the hospital, unmeasured confounding, and limited generalizability.
In another study, there was no significant change in in-hospital mortality in COVID-19 patients who received anticoagulants compared with those who did not, though a decreased length of hospital stay was noted. In addition, use of anticoagulation was associated with a significant decrease in mortality among mechanically ventilated patients.
In a retrospective study published on the medRxiv preprint server, Jishu Kaul Motta, MD, of Danbury Hospital in Connecticut, and colleagues hypothesized that preemptive treatment with therapeutic anticoagulation could lower the risk of a COVID-19-associated prothrombotic state leading to increased mortality.
However, they observed more deaths among those treated preemptively versus prophylactically with anticoagulants, and they also showed that patients with more severe disease (C-reactive protein ≥200 mg/L) did not experience clinical improvement in outcomes with preemptive therapeutic anticoagulation.
These findings highlight the need to consider the risks and benefits for the patient and the healthcare system when using preemptive therapeutic-dose anticoagulation in hospitalized patients with COVID-19.
Of 501 hospitalized SARS-CoV-2-positive adults across two acute care hospitals located in western Connecticut, 374 patients were included in the study in April 2020, with follow-up through June 12. The study excluded patients who received therapeutic-dose anticoagulation specifically for a thrombotic indication.
Demographic variables were collected via hospital billing inquiries, while clinical variables were taken from patients' medical records.
Patients had an average age of 64.7 years, and men made up more than half of the sample (58.6%). The majority were white (54%); African-Americans constituted 9.9% of the full sample. A third of the patients smoked, and heart disease was the most common comorbidity (56.7%), followed by diabetes (31.6%). The prophylactic and therapeutic anticoagulation groups consisted of 299 and 75 patients, respectively.
The risk of mortality was also determined among 104 patients with C-reactive protein levels ≥200 mg/L.
Most of the patients took enoxaparin(Lovenox) during their inpatient stay (93.5%), and 14.8% took heparin. The prophylactic dosage of enoxaparin was defined as 30 or 40 mg given subcutaneously every day, while the therapeutic dose was defined as 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously daily or based on renal function, or higher doses titrated to an anti-factor Xa range of 0.6 to 1 IU/mL (for twice daily dosing) and 1 to 2 IU/mL (for daily dosing). The prophylactic dosage of heparin was defined as 5,000 units given subcutaneously every 8 hours, and the therapeutic dose was defined as intravenous heparin titrated to an activated partial thromboplastin time between 70 and 110 seconds.
Variables in the full logistic model included anticoagulant dosage, age, ethnicity, diabetes, history of cancer or heart disease, hyperlipidemia, peak C-reactive protein level, and need for intensive care, mechanical ventilation, or use of antibiotics.
Motta and team found that the relative risk of in-hospital mortality was 2.3 times greater (P=0.04) in patients who received preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing on multivariate analysis, with 38.7 vs 14.4 deaths per 100 patients.
For the patient subgroup with elevated C-reactive protein levels, the researchers found no difference in the risk of mortality between those who received therapeutic versus prophylactic anticoagulation (adjusted risk ratio 1.0, 95% CI 0.2-4.5, P=0.97).
Most patients expired due to worsening oxygenation (71.8%) and acute respiratory failure with hypoxia. Other causes of death included anoxic brain injury due to hemorrhage (n=1), kidney dysfunction with inability to access hemodialysis port (n=1), and failure to thrive with encephalopathy (n=1). Just under two-thirds of patients (64.4%) elected to receive comfort measures only for end-of-life care.
The retrospective study design, lack of randomization, and no capture of mortality after the patients left the hospital were listed as study limitations. Unmeasured confounding and limited generalizability were additional limitations.
Source Reference: medRxiv 2020; DOI: 10.1101/2020.07.20.20147769
Study Highlights and Explanation of Findings:
A retrospective cohort study of hospitalized patients with COVID-19 showed an increase in in-hospital mortality following preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.
These findings countered those of a larger observational study that suggested better survival with therapeutic anticoagulation in hospitalized COVID-19 patients, although others have suggested no effect.
It was possible that stronger thrombosis prevention is effective but just can't overcome competing risk of death from other disease processes in COVID-19, Motta's group suggested. "Regardless it does not seem from our analyses that therapeutic dosing of anticoagulation prevented overall disease progression," they noted.
However, "any interpretation other than acknowledging the need to study this prospectively in a randomized, controlled trial would be invalid," said Jason Katz, MD, director of cardiovascular critical care at the Duke University Health System in Durham, North Carolina, who was not involved with the study.
Aside from the small size, confounding and bias were also likely due to the "huge differences in patient characteristics between those who got prophylactic-dose anticoagulation and those that got full-dose anticoagulation," Katz pointed out.
Lack of data on bleeding events was another limitation, said Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard University in Boston.
None of the studies done so far are able to really inform practice, he said. "What I do take out from this is the heterogeneity, the variability in the signals, and the effect sizes we keep seeing from these studies."
His group consensus, supported by the International Society on Thrombosis and Haemostasis and four other professional societies, recommended standard-dose prophylactic anticoagulation in most cases, despite noting a lack of data. The World Health Organization and NIH guidelines also suggest only using a higher-dose anticoagulant if there is a strong suspicion of thrombosis or in the context of a prospective study.
More than nine randomized controlled trials are underway to address questions of type and dose of antithrombotics for prophylaxis in COVID-19, Bikdeli noted.
The NIH has announced the ACTIV-4 set of adaptive platform clinical trials to evaluate safety and effectiveness of varying types of antithrombotics for adults diagnosed with COVID-19.
Well-designed studies that include enrollment of patients in areas with higher case loads should be able to deliver some answers in 2 to 3 months, Bikdeli predicted. "Because if you practice in the ICU, these questions come up for almost every single patient with COVID-19. We see abnormal coagulation parameters and we ask ourselves, 'Do we increase the dose, do we not increase the dose?'"
But with the real risk of clinically important, even fatal, bleeding(We should have had research decades ago that would instantly identify patients at risk for this bleeding. ), "it's not really something that you can do just by clinical gestalt," he said. "Once we have the data, yes, clinical experience would be important to make patient-by-patient decisions. But without that prospective, ideally randomized, data, we're just going blindly."
Primary Source
medRxiv
Source Reference: Motta JK, et al "Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19" medRxiv 2020; DOI: 10.1101/2020.07.20.20147769.
Secondary Source
MedPage Today
Source Reference: Phend C "Full-Dose Clot Prophylaxis for COVID-19 Tied to Mortality" 2020.
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