The prevention of venous thromboembolism (VTE) has been a real concern in the management of hospitalised patients with COVID-19. We have previously discussed the role of prophylactic anticoagulation (thromboprophylaxis) for these patients as it was clear that practice varied widely. I’ll give some examples of strategies that I have heard implemented during the pandemic.
- Standard dose prophylactic anticoagulation for all
- Standard dose prophylactic anticoagulation, adjusted for weight
- Intermediate dose (double the standard dose) prophylactic anticoagulation
- Treatment dose prophylactic anticoagulation for critically ill patients (i.e. LMWH/DOAC treatment doses that we would use to treat an established VTE)
- Anticoagulation strategy based on d-dimer levels, ranging from prophylactic through to full dose anticoagulation
- Extended spectrum prophylactic anticoagulation for patients discharged from ED with COVID-19 diagnosis (I know!!)
- Diagnostic confusion too with questions on selection or routine use of CTPA
I’m sure there are other examples, with the bottom line being that there is considerable variation in practice. This is not surprising, nor really a criticism. The evidence base has just not been there and so we have had to make (lightly) informed judgements as to what to do. We have been practicing medicine in the time of Osler, as one colleague put it. However, the evidence base to inform practice in this area has been steadily building. We previously reviewed the evidence for different strategies on a recent blog post. New RCT evidence means that we can now update this discussion, and clinicians can start to base their decisions on a higher level of evidence
We are therefore pleased to see a pre-print from three international adaptive platform trials addressing the effectiveness of therapeutic dose prophylactic anticoagulation in COVID-19 patients. You can find the paper here, and the abstract below. As always we strongly recommend you read the full paper for yourself.
What kind of trial is this?
Well, it’s three trials, but they are all platform adaptive trials similar to the RECOVERY trial which we have extensively reviewed on the blog. In essence the entry and output elements of the trials are fixed (harmonised), but interventions can come and go as new drugs become available and/or enough are recruited to an intervention arm to provide an answer.
The three trials were the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP; NCT02735707), Accelerating Covid-19 Therapeutic Interventions and Vaccines-4 Antithrombotics Inpatient platform trial (ACTIV-4a; NCT04505774 and NCT04359277), and Antithrombotic Therapy to Ameliorate Complications of Covid-19 (ATTACC; NCT04372589). The investigators aligned their investigation of anticoagulation strategies to essentially provide a larger trial from the three, thus accelerating recruitment and getting us an answer faster (Ed – would this happen in non-COVID times I wonder).
What about the patients?
This paper essentially reports on the ‘severe’ subgroup of patients with COVID19 who were critically ill. Patients were eligible if they were admitted to a critical care area for respiratory or cardiovascular organ support. Respiratory support was defined as high flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation or ECMO This already raises some challenges with harmonising protocols; what defines a critical care area varies by geography and resource. In addition, there is a fairly vast difference between someone who is comfortable on high flow nasal oxygen with an FiO2 of 0.3, and someone requiring ECMO. This actually makes the ‘severe’ group fairly variable, and thus runs the risk of diluting any positive effect.
There were notable exclusions – patients were ineligible if they had been on ICU for >48h (REMAP-CAP), at high risk of bleeding or had a separate indication for therapeutic anticoagulation. The latter would allow clinicians to exclude patients from randomisation who they thought may already have a VTE.
What about the interventions?
Patients were randomised centrally between treatments. There were three treatment arms
- Standard dose prophylactic anticoagulation (as per local protocols)
- Therapeutic dose anticoagulation (as per local protocols equivalent to treatment of acute venous thromboembolism)
A range of anticoagulants were used. Most were low molecular weight heparins (Enoxaparin, Dalteparin, Tinzaparin comprised 88.7%) administered subcutaneously.
What about the outcomes?
The primary outcome was organ support free days up to day 21. This is an ordinal scale which includes survival to hospital discharge, and days free of organ support to day 21 in survivors. A relevant, but interesting choice – it assumes that we are happy with a composite outcome and one which is subject to clinical decision. There are often cases where it is down to individual clinicians when they stop the high flow nasal oxygen/NIV, rather than fixed protocols.
They also followed patients up to 90 days and looked at a number of secondary outcomes.
What about the analysis/stats?
Putting three trials together is not easy. In this trial they have analysed thromboprophylaxis in each patient as a separate event, rather than combine the three trials together as three separate entities as you might in a typical meta-analysis. A meta-analysis of individual patient data makes more sense in this setting.
The analysis is a Bayesian approach that essentially aims to determine the probability of the results found reflecting the truth.
What did they find?
1205 patients were recruited between April 2020 and December 2020. Analysis was available on 1074 patients, the majority of whom (987, 84%) were in the REMAP-CAP trial. This is good news for UK readers who recruited the vast majority of patients (777) and can probably therefore consider this data generalizable, but may concern others. The fact that REMAP-CAP contributed highly to the recruitment is reflected in the baseline severity of disease; the median P/F ratio for both intervention and control groups was 119, suggesting severe hypoxaemia and >60% of patients were receiving either NIV or invasive mechanical ventilation at baseline.
In terms of organ free days (the primary outcome) those in the therapeutic anticoagulation group had a mean of 3 days (IQR -1 to 16) those in usual care thromboprophylaxis had a mean of 5 days (IQR -1 to 16), with an adjusted proportional odds ratio of 0.87 CI 0.70-1.08 for therapeutic anticoagulation. This result is not statistically significant. The Bayesian analysis also suggests that there is an 89% chance of therapeutic anticoagulation being worse for patients.
In hospital mortality did not show any significant benefit: 63.4% vs. 65.3%, with a median adjusted odds ratio of 0.88 for therapeutic anticoagulation (95% CI 0.67-1.16).
Interestingly there were fewer major thromboembolic events in the therapeutic group (5.7% vs. 10.3%). These events were a composite of VTE events (PE) and arterial thrombotic events, including MI, stroke and systemic arterial thrombosis. The supplementary appendix details the PE burden, which was almost 3 times higher in the standard dose group. Major bleeding rates were similar at 3.1% with therapeutic anticoagulation vs. 2.4%.
Any concerns with the study?
In general this is a well designed platform adaptive set of trials that have given us a useful and fairly robust answer. The trial is dominated by the REMAP-CAP trial, and the treatments given were down to local protocols which inevitably led to variation between what was given. Such variation reflects real world practice, but it is possible that it may have introduced some bias. As an example, the usual care VTE prophylaxis group was a fairly even split between standard dose (41.3%) and intermediate dose (51.3%). Pooling these patients together may bias towards the null.
This was an open label trial and that too can introduce bias into the results through enrolment, observation and investigation. It is also an interim report, reflected in the numbers and detail of the supplementary appendix. Some patients are yet to complete follow up.
What should we do?
In severely unwell patients with COVID-19 this current evidence suggests that routine therapeutic dose thromboprophylaxis is unlikely to be beneficial. Remember that this relates to those patients who are not known to have a major thrombotic event. Clearly if your patient develops an acute VTE then a decision needs to be made on an individual patient basis as to whether anticoagulation is required.
It’s noteworthy that another trial of thromboprophylaxis was published in JAMA this month. The INSPIRATION trial failed to show a benefit to intermediate dose anticoagulation in a similar group of patients. As such, there is limited trial evidence at present to support any increase in pharmacological thromboprophylaxis dosing, above the standard dose adjusted for weight and renal function.
To help guide clinicians and disseminate this evidence, his week NICE have updated their guidance on thromboprophylaxis stating that patients should receive standard dose prophylactic anticoagulation.
It should be remembered that these results don’t apply to ward based patients on supplemental oxygen only. The suggestion from this multiplatform RCT is that in moderate state (hospitalised but not on ICU) groups. they may well benefit from prophylactic anticoagulation at therapeutic dose. However, all we have to support this at present is a social media release. We ideally need to see the preprint and the peer reviewed manuscript on this group of patients, before implementing a widespread change in practice.
The thromboprophylaxis in COVID is not quite fully answered yet.
Simon and Dan
- Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report https://www.medrxiv.org/content/10.1101/2021.03.10.21252749v1.full-text
- REMAP-CAP https://clinicaltrials.gov/ct2/show/NCT02735707
- ACTIV-4a https://clinicaltrials.gov/ct2/show/NCT04505774
- ATTACC https://clinicaltrials.gov/ct2/show/NCT04372589
- Meta-analysis of individual participant data: rationale, conduct, and reporting BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c221
- Richard Carden, “I’m all about the Bayes, ’bout the Bayes, no treble,” in St.Emlyn’s, August 14, 2016, https://www.stemlynsblog.org/im-bayes-bout-bayes-no-treble/.
- NICE. COVID-19 rapid guideline: Managing COVID-19. https://app.magicapp.org/#/guideline/L4Qb5n/rec/LwomXL
- The inspiration investigators. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit The INSPIRATION Randomized Clinical Trial JAMA. Published online March 18, 2021. doi:10.1001/jama.2021.4152
- Dan Horner, “VTE and COVID-19: Would you like to know more?,” in St.Emlyn’s, October 12, 2020, https://www.stemlynsblog.org/vte-and-covid-19-would-you-like-to-know-more/
- Dan Horner, “COVID-19 and Blood Clots: Diagnosis, D-dimers and Dilemmas,” in St.Emlyn’s, April 19, 2020, https://www.stemlynsblog.org/covid-19-and-clotting-diagnosis-d-dimers-and-dilemmas/.