Anti-Coagulation – Tabs

COVID-19 infection contributes to a hypercoagulable state and thrombotic events are fairly common. Due to the frequency of arterial and venous thrombosis as well as microthrombosis demonstrated on lung histology, many clinicians all over the world have opted to use therapeutic anticoagulation in patients with severe or critical illness. In addition, there are numerous reports suggesting that the delta variant (B.1.617.2) now the predominant strain circulating widely in India results in many more thrombotic events and has also contributed to intrauterine deaths.

Overall among those with moderate, severe and critical COVID19, therapeutic dose anticoagulation appears to prevent clinically defined thrombotic events by 39%; RR=0.61 (95% CI 0.45-0.82) with moderate certainty of evidence. However it does not reduce mortality or organ support free days. It does however; seem to improve survival without organ support at 28 days by 6% [95% CI 1% to 10%].

When the moderate to severe group of patients were considered separately, the initiation of therapeutic anticoagulation also led to a decrease in thrombotic events by 37% (95% CI 7-57%), increase in Organ Support Free Days (OSFD) by 5% (95% CI 1 -10%), along with an increased risk of bleeding.

When the critical group was evaluated separately, therapeutic anticoagulation reduced thrombotic events by 43% (95% CI 11%-63%) with no decrease in all-cause mortality or OFSD. In addition there was no increase in bleeding RR 1.39 (95% CI 0.71 – 2.71). Due to the increasing evidence of thrombosis in all categories of patients, clinician discretion is required towards this category of patients. The group debated at length the advantages and disadvantages of therapeutic anticoagulation in this group. The group felt in the critical setting they are unable to pick up a thrombotic event easily which may impact eventual mortality and morbidity, and it is most often based on a clinical suspicion which are they are often unable to confirm as these patients are not amenable to easy shifting for a confirmatory radiology test. However the group felt it is easy to pick up major bleeding. In addition, fatal bleeding events which were reported only in the mpRCT (non-critical) were 3 in the therapeutic group as compared to 1 in the non-therapeutic group.  Despite the uncertainty reflected in the various guidelines from NIH or NICE (refs) where due to the lack of data they are unable to recommend prophylactic over therapeutic, clinicians in the country are increasingly recommending an intermediate or therapeutic dose of anticoagulation in severe and critical categories. However, more trials are required to support the conclusion that therapeutic dose anticoagulation is beneficial in the moderate, severe and critical categories. The cost of the intervention is low and needs to be weighed against hospitalization and ICU care costs that may result due to a thrombotic event. However, there is no data on cost-effectiveness of the intervention at present.

Date of latest search: 9^th June 2021.

Date of completion of Summary of findings table and presentation to Expert Working Group: 24^th May and 9^th June 2021.

Evidence synthesis team:  Sushil S(SS), Jisha Sara John(JS), Richard Kirubakaran, Bhagteshwar Singh & Priscilla Rupali.

We acknowledge gratefully the assistance received from the authors of the multi-platform RCT[mpRCT] (ATTACC, ACTIV-4a, and REMAP-CAP platforms),specifically Ewan Goligher, who provided valuable assistance in evidence clarification and sharing of additional protocol documents.

The Anticoagulation Expert Working Group met on 24^th May 2021 to consider the use of therapeutic Vs prophylactic dose anticoagulation in the management of COVID-19. A summary and then more detailed explanations of their judgements follow.

Summary of judgements – LOOKS DIFFERENT ONLINE

EtD summary table –

Problem

Hypercoagulability is a recognized phenomenon in COVID19 and is believed to be multifactorial. SARS CoV2 virus both directly and indirectly causes endothelial injury, microvascular inflammation, endothelial exocytosis, endothelitis contributing to acute respiratory distress syndrome. In post mortem studies microvascular occlusion with platelet-fibrin thrombi have been reported. In addition, changes in circulating prothrombotic factors and stasis due to immobility encountered in the critically ill has led to a recognized prothrombotic state in COVID19 infection, translating to increased arterial and venous thrombosis. This has led to the practice of prophylactic anticoagulation for all hospitalized COVID19 patients. However there exists an area of equipoise whether patients with severe or critical COVID19 infection will benefit with therapeutic (full dose) anticoagulation in the absence of a confirmed thrombotic event. This has especially become even more important as the country goes through a massive second wave probably caused by the delta variant B.1.617.2 starting in early February, which anecdotally seems to cause more thrombosis as per various reports in the media, however we need to await cohort studies for this to be accurately assessed.

Desirable effects

WHO Critical: At present, evidence shows that using TDA did not significantly reduce mortality in critical COVID19 but does appear to prevent thrombotic events by 42% (11-63%) with no statistically significant increase in bleeding with a moderate certainty of evidence. TDA also did not improve days free of organ support compared to PDA. DSMB stopped recruitment in this category as it felt that TDA did not offer any advantage towards OSFD (as a pre specified Bayesian post probability of futility was achieved). The group discussed this at length and felt that, preventing thrombosis was important even in the absence of mortality benefit. Panel also noted that most of the evidence was contributed to by the mPRCT with very few patients in HESACOVID.

WHO Moderate/Severe: The group noted that using TDA reduced thrombosis and increased the probability of OSFD but did not significantly reduce mortality or cause increased bleeding in moderate/severe category of COVID19. The group felt that right now thrombosis was an important event to prevent as it was difficult to recognize or confirm and probably would contributed to significant morbidity. However, the group felt that bleeding was easy to pick up and was rarely fatal. Hence the group that in an intensive care setting prevention of thrombosis was an important intervention. The various thrombotic events were reviewed and pulmonary embolism seemed to contribute to most of the events with other events recorded being myocardial infarction and strokes.

Undesirable effects

WHO Critical: The mPRCT (Critical) had around >500 patients in each arm and the incidence of bleeding in each group was similar. The actual difference in bleeding between the two groups was 1% suggesting that present evidence showed that the risk of bleeding was not increased. The DSMB of ACTIV-4 component of the mPRCT trial had recommended an early interim analysis to watch for the same, however the study was terminated as the futility threshold was reached suggesting that there was no benefit of TDA over PDA in the primary outcome of OSFD.

WHO Moderate/Severe: The mPRCT(Non critical) had around >1000 patients in each arm and the incidence of bleeding in the therapeutic dose group was slightly increased suggesting that in WHO moderate and severe COVID infection there seemed to be a mildly increased risk of bleeding.

The panel also discussed re the absence of data regarding anticoagulation in the mild and moderate groups without hypoxia and felt that decision re anticoagulation in those groups could be based on evidence from non-randomized studies and clinical experience.

Certainty of evidence

Overall the quality of evidence in the WHO moderate, severe and critical categories was felt to be moderate.  

Values 

Outcomes noted were considered to be important in overall patient management especially in setting of pandemic. The group felt that the outcomes of mortality, thrombotic events. Bleeding and Organ support free days were certainly important. They felt that there was no uncertainty or variability. However they did note some unusual points in the way outcomes were assessed.

Critical group: The group discussed the uncertainty as to whether thrombotic events could have contributed to mortality. There is no clear breakup of mortality in the pre-print or supplement. Clinically significant pulmonary embolism seems to have contributed to most of the thrombotic events, but it was not specified as to whether they were all major arterial or just segmental embolism. It also seemed unlikely that a patient who is severely or critically ill would have been shifted out for a CTPA. DVT was excluded in this group as a major thrombotic event.

Moderate: In the mpRCT (mod) group, Deep Venous Thrombosis was included as significant thrombosis which was excluded from mpRCT (critical) group.

Balance of effects

Given that the country is facing a shortage of beds, oxygen and intensive care units, if an intervention could reduce organ support and thrombosis it would be of benefit.

WHO Critical: There are very few trials overall to inform evidence and there seemed to be no mortality benefit or decrease in OSFD between TDA and PDA. There was a decrease in thrombotic events with no increase in bleeding noted. DSMB stopped the trial as futility end-point for OSFD was reached in interim assessment.

WHO Moderate/Severe: TDA appeared to increase OSFD, and prevent thrombotic events with a slightly increased risk for major bleeding. There was no mortality benefit between the 2 arms. OSFD should be given importance in the moderate category as it saves resources and prevents morbidity.

Resource requirements

There are likely to be negligible savings and costs pertaining to implementation of the TDA. Drugs used for this are relatively cheap, widely available and unlikely to incur a significant cost nor are they likely to result in significant savings. Health care workers in the country are fairly experienced with the use of the same and are aware of the various monitoring implications. Cost of implementation is low and needs to weighed against hospitalization and ICU care costs. Though monitoring of anticoagulation efficacy with Anti Xa testing will be possible only in an advanced hemostasis laboratory, if widely employed to ensure therapeutic efficacy it will likely also protect against unnecessary bleeding. However this will increase costs and probably unnecessary in most instances. There is also possible ineffectiveness of therapy in view of high rates of heparin resistance documented in published data but overall costs of implementing TDA are likely low if we are able to save on costs of hospitalisation and intensive care beds.

Certainty of evidence of required resources

Resources required for implementation of TDA are minimal and the certainty of evidence for this is high.

Cost effectiveness

At the moment there is no data regard to the cost effectiveness of this intervention and studies need to be done to be sure of the same. The group recognized the minimal costs and resources required to deliver as it is a subcutaneous injection which can be delivered by most HCWs easily. It is also likely that even if patients in the moderate category are given TDA, hospitalization will be dictated by disease severity rather than administration of anticoagulation, given that most health care settings and health professionals are comfortable with delivery of this intervention in the outpatient settings. There are also many novel oral anticoagulants available which have been proven to have similar efficacy as heparin and could potentially be employed as substitutes, however data with these are scarce in the COVID19 setting.

Equity

As the cost and requirements of anticoagulation delivery are reasonable, implementation can be equitable.

TDA is a feasible intervention which can be easily implemented in all health care settings by any health care professional.

There is anecdotal evidence that thrombotic risk is increased with the delta variant and this is increasingly being noticed in the second wave of COVID 19 in India. Whether this is more apparent due to the increased numbers or whether there is a true correlation of the delta variant with an increased risk of thrombosis remains to be determined. The working group felt that TDA in hospitalized patients with moderate disease (those who have progressively increasing O2 requirement) or severe disease might prevent thrombotic events, without any reduction in mortality.  This subset might have increased probability of surviving to hospital discharge with reduced need for ICU-level organ support, including invasive and non-invasive mechanical ventilation (OSFD), with slightly increased risk for major bleeding.

However the group was less certain in the critical category of illness. The data shows a decrease in thrombotic events with no reduction of mortality or organ support free days and no increased risk of bleeding. The trial also reported a median in organ support days 3 vs 5 days in TDA and PDA respectively. Anecdotally most reported that they often give either intermediate or therapeutic doses routinely in their intensive care areas and felt that this decision should be individualized according to the clinical picture of the patient.

There is no evidence thus far that this dose is beneficial in mild, or in non-hospitalized patients.

Though there was no data regard to the cost effectiveness of this intervention, resources required for implementation of therapeutic anticoagulation are minimal in this subgroup of patients. This intervention is feasible to implement widely and easily. The evidence is for Injectable low molecular weight heparin only and not for Unfractionated Heparin or oral anticoagulants.

The subgroups of children <18 years of age, pregnant women, asymptomatic mild and out-patients were excluded from most studies. Some studies also excluded those on dialysis for chronic kidney disease, chronic liver and lung diseases as well as those on antiplatelet therapy. The utility of D-dimer was also evaluated. In the mpRCT(non-critical) study it was noted that a high D-dimer is associated with a high risk of mortality and this was noted even in the mpRCT(non-critical) study, that participants with a high D-dimer were at increased risk of mortality and organ support and thus the adjusted absolute treatment benefits were more apparent. In the mpRCT – critical, the median D-dimer values were 827ng/ml in TDA vs 890 in the PDA group and about 48% of the patients in TDA vs 46% of PDA were noted to have a D-dimer twice the upper limit of normal.

There is no role for monitoring of D-dimer in non-hospitalised COVID 19 patients. A high D-dimer is known to be associated with an increased risk of venous thromboembolism in non covid patients and in Covid 19 infection it has been correlated with a poorer prognosis and increased mortality. However whether a high D-dimer value can be extrapolated to an increased risk of arterial or venous thrombosis in COVID19 infection is yet to be determined. Hence in hospitalized patients with COVID-19, there is insufficient data to recommend regular monitoring of D-dimer or base management strategies on the same.

In patients on therapeutic anticoagulation with unfractionated heparin, APTT monitoring can be done and maintained 1.5 to 2 times the control. In other anticoagulation regimens using low molecular weight heparin or Fondaparinaux, regular anti Xa monitoring is not recommended other than in obese patients. Anti Xa levels should be sent 3 hours after the dose of low molecular weight heparin. In the setting that heparin resistance is suspected, even in the setting of unfractionated heparin, anti Xa levels should be monitored. Target peak anti-Xa for the treatment doses of twice-daily enoxaparin is 0.6–1.0 IU/mL.

This conditional recommendation regarding use of anticoagulation may be revisited as evidence emerges. In addition to evidence of benefit, with its widespread use in India, there may be additional real-world reports regarding undesirable effects, which the group will monitor.

It has been shown that TDA may improve clinical outcomes in non-critically ill, but not critically ill COVID19 patients which seems counter intuitive though it can be explained away on the premise that critically ill patients are too far gone into the thromboinflammatory phase of illness where it may be futile. However, more studies are required to support a benefit with varying doses and in various subpopulation based on risk factors, comorbidities and utility of biomarkers like D-dimer. Studies also need to be done in mild and moderate COVID illness as to whether any form of anticoagulation can prevent progression of illness and/or hospital admission. Dose and duration of post discharge anticoagulation in the absence of a suspected or confirmed thrombotic event is another area where considerable equipoise exists. All of these are urgent research priorities considering the country is facing a manpower, oxygen, intensive care unit bed shortage.

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