Critical Appraisal Seminar

11/23/2021

Therapeutic Anticoagulation with Heparin in

Noncritically Ill Patients with COVID-19
ATTACC, The, et al. “Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19: Nejm.” New
England Journal of Medicine, 26 Aug. 2021, https://www.nejm.org/doi/full/10.1056/NEJMoa2105911.

Kyle Starkus
PGY1 Resident
Ascension St. Vincent Evansville
Background and Objective
• Background
• Patients hospitalized with COVID-19 have increased risk of macro and microvascular
thrombosis and inflammation associated with poor clinical outcomes
• Due to a high rate of vascular involvement in COVID-19 infected patients, it is
unclear if anticoagulation dosing strategies beyond standard prophylactic dosing
have a role in the management
• Objective
• To determine if therapeutic-dose unfractionated or low-molecular-weight heparin
improves outcomes in noncritically ill patients who are hospitalized with COVID-19
compared to prophylactic-dose, usual-care, anticoagulation

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Venous Thromboembolism Background

● Venous Thromboembolism (VTE) is an umbrella term comprising both deep

vein thrombosis (DVT) and pulmonary embolism (PE)
● D-dimer is a surrogate laboratory marker to help diagnosis VTE
○ D-dimer is a fibrin degradation product and is elevated when a blood clot is present and
being degraded via fibrinolysis
○ May be falsely elevated in those with liver disease, recent trauma, malignancy, and may
not be elevated if sample taken to early or late after thrombus formation
○ Our laboratory normal limit for D-Dimer is 0.00 - 0.49
● Those with COVID-19 are at increased risk of developing VTE, a large
systematic review and meta-analysis found that VTE rate was 21% among
those hospitalized with COVID-19
● What are our treatments?

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Study Design

• This was a multicenter, adaptive, randomized controlled platform trial (3)

• Enrollment was at 121 sites in 9 different countries in which treatment group
assignment was randomized between April 21, 2020 through January 22,
2021
• The trial was supported by multiple international funding organizations who
are stated to have had no role in the design, analysis, or reporting of trial
results
• With the exception of the ACTIV-4a study protocol, which received input on design from
the National Institutes of Health and from peer reviewers

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Study Design

• Population
• Moderate disease - as defined by hospitalized but non-critically ill at enrollment
• Non-critically ill - as defined by without the need for ICU-level care
• ICU-level care - as defined by the use of respiratory (oxygen delivered by high-flow nasal
cannula, noninvasive or invasive mechanical ventilation) or cardiovascular (vasopressor
or inotrope) organ support
• Inclusion criteria
• 18 years of age
• Microbiologically confirmed COVID-19
• Required hospitalization anticipated to last >72 hours
• Enrolled within 72 hours of hospital admission or upon COVID-19 confirmation

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Study Design

• Exclusion criteria
• History of heparin induced thrombocytopenia / heparin allergy
• Active bleeding
• Risk factors for bleeding
• Independent indication for therapeutic anticoagulation
• Use of dual antiplatelet therapy
• Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization

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 Study Design

• Randomization-- central internet-based systems were used to randomly assign

patients in a 1:1 ratio to receive either therapeutic-dose anticoagulation with
unfractionated or low-molecular-weight heparin or usual-care thromboprophylaxis in
an open-label fashion

• Blinding-- as above, internet-based systems were used to randomly assign patients,

with the possibility of response-adaptive randomization, in which group-assignment
ratios could be modified in a blinded fashion during the trial

• Method of analysis-- pseudo- intention-to-treat was utilized as patients who were

discharged from the hospital before day 21 were assumed to be alive and free of
organ support through day 21
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Study Design

• Study Procedures

• Study group treatment-- Therapeutic unfractionated heparin or low-molecular-weight

heparin (94.7%) dosed and monitored according to specific site policy and procedure
• stratified by age, sex, trial site, enrollment period, and D-dimer cohort
• High D-dimer >2x upper limit, Lower D-dimer <2x upper limit, unknown D-dimer

• Control group treatment-- Usual-care pharmacologic thromboprophylaxis in an open-label

fashion at a dose and duration determined by the treating clinician according to local
practice (71.7% low dose and 26.5% intermediate dose)

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Study Design

• Endpoints and Measurements

• Primary endpoint
• Organ support-free days, evaluated on an ordinal scale that combined in-hospital death and
the number of days free of cardiovascular or respiratory organ support up to 21 days
• Any death during the index hospitalization through 90 days was assigned -1 on the outcome
scale (higher values indicate better outcomes)

• Major safety endpoints

• Major bleeding (defined according to the criteria of the International Society on Thrombosis
and Haemostasis)
• Laboratory-confirmed HIT

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Study Design

• Statistical Analysis
• Sample size determination - not clearly defined, stated that a model was fitted for
100,000 samples from the joint posterior distribution which allowed for a 95% confidence
interval
• Primary endpoint was measured using a Bayesian cumulative logistic model that
calculated the posterior probability distribution for the proportional odds ratio for the
treatment group compared to usual-care group
• It was not explicitly stated in either the main publication or appendix how the secondary
safety data was measured besides a statement that secondary endpoints were modeled
without dynamic borrowing.

• How dropouts were handled - not explicitly addressed, stated that those discharged were
assumed to be alive and free of organ support through day 21

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Results

• Study Population--
• Stratified by baseline D-dimer, age, ethnic group, sex, mean BMI, chronic health
conditions, treatment, platform enrollment, and country of enrollment
• No major differences between the therapeutic-dose anticoagulation group and the usual-care
group
• Only difference was that there was a larger percentage of patients in the therapeutic-dose
group from the ATTACC platform (6.5%) and less from the ACTIV-4a platform (4.5%)
• N= 1181 in the therapeutic-dose group
• N = 1050 in the usual-care group

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 Results

• Primary Endpoint Result-- The study was ended early on the advice of the data and
safety monitoring boards after adaptive analysis showed superiority of
therapeutic-dose anticoagulation in both the high and low D-dimer cohorts
• Posterior probability that therapeutic-dose anticoagulation increased organ
support-free days compared to usual-care was 98.6% (mean adjusted odds ratio of
1.27)
• Of 1171 patients, 80.2% of the therapeutic treatment group survived until discharge
without use of organ support compared to 76.4% of 801 patients in the usual-care
group
• For every 1000 patients with moderate disease, therapeutic-dose anticoagulation will
result in 40 patients discharged without the use of organ support

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Results

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Results

● Summary -
○ Concluded that therapeutic-dose anticoagulation with heparin and low-molecular-weight
heparin increased the probability of survival until hospital discharge with a reduced need
for ICU-level organ support at 21 days
○ Benefit with therapeutic-dose anticoagulation was seen regardless of baseline D-dimer
level

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Results

• Major Safety Endpoint Results

• Major bleeding occurred in 22 of 1180 (1.9%) patients in the therapeutic-dose group
• Major bleeding occurred in 9 of 1047 (0.9%) in the usual-care group
• Fatal bleeding occurred in 3 patients in the therapeutic-dose group compared to 1 patient
in the usual-care group
• No confirmed HIT in either group
• For every 1000 hospitalized patients with moderate disease, therapeutic-dose
anticoagulation will result in 7 more major bleeding events compared to usual-care

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Evaluation

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Study Design Assessment

• This is a relevant research question as increased thrombotic events are well

documented with COVID-19 infection and different anticoagulant dosing
strategies are being used here at Ascension St. Vincent without strong guiding
literature
• Experimental study design allows one to draw conclusions from the findings,
opposed to an observation study and drawing associations
• Studied primary outcome was clinically significant, however days without organ
support is a surrogate marker severity of disease to which intubation, death,
length of stay or thromboembolic event could have been evaluated directly
• The primary endpoint was a composite of days free of organ support and
in-hospital death on an ordinal scale, to which death was only weighed at -1

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Selection Bias

• The studied population was appropriately defined

• Inclusion and exclusion criteria were appropriate and not directing results
• Baseline characteristics of age, sex, ethnicity, D-dimer level, other treatments, etc. were appropraite
• Limitation in amount of hospitalized patients meeting moderate severity disease
• Important to note the trial was stopped prior to the wide spread of virus variants
• The study has not adequately defined how many enrollments were needed or events to
meet power
• Provides primary endpoints and safety outcomes as probability of superiority / inferiority, but without
defined power uncertain the risk of type II error
• The treatment and control groups were well balanced
• The major difference was that the treatment group had ~6.5% more patients from the ATTACC
platform and ~4.5% less from the ACTIV-4a trial
• Decreases the internal validity of the study to a degree

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Performance Bias
• The study comparator group was a limiting factor
• The usual-care group could have consisted of any prophylactic anticoagulation
strategy preferred by the provider, and it was seen 71.7% received a low dose
thromboprophylactic drug and 26.5% received an intermediate dose
• Intermediate dose was not well defined, with the assumption being that
enoxaparin 40mg subq q12h was used, which would effect result interpretation

• The duration of analysis being 21 days was appropriate as average hospital stays for
COVID-19 fluctuates greatly
• Can decrease the internal validity that analysis was not performed for the entire
duration of hospital admission or 21 days if discharged early
• Decrease in internal validity that patients were assumed to be alive and free of
organ support through day 21 and that no 21 day assessment was performed on
patients discharged prior

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 Measurement and Attrition Bias

• Major bleeding was defined according to the validated criteria of the International
Society on Thrombosis and Haemostasis
• Bleeding in a critical area or organ
• Intracranial, intraspinal, pericardial, intraocular, etc.
• Bleeding causing a fall in hemoglobin level of >20 g/L
• Bleeding leading to transfusion of 2 or more units of blood

• All stated primary, secondary, and safety outcomes were measured and reported in the
study. However, as previously mentioned, measurements such as length of stay,
mortality - thrombotic event (separately), or intubation would have added to the clinical
utility of this study

• No analysis provided information pertaining to the type of organ support that these
patients ended up receiving

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Chance

• As previously mentioned, the number to meet power was not defined and
therefore the risk of type II error can not be assessed
• Confidence interval was set at 95% but does not explicitly state this is a one-tail or
two-tailed test
• Noted that the study was stopped early as analysis determined the therapeutic
anticoagulation group had met pre-specified criteria for superiority over the
usual-care group
• This trial included intricate statistical analysis, utilizing multiple platforms,
specified superiority stop criteria, used a logistic model that calculated posterior
probability distribution for proportional odds ratio while allowing for dynamic
borrowing
• As we are not statisticians, a degree of trust must be placed in the New England Journal
of Medicine and its peer review process that the statistics are sound

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Clinical Usefulness
• For every 1000 hospitalized patients with moderate disease, therapeutic-dose
anticoagulation will result in 40 additional patients discharged from the
hospital without having required organ support
• For every 1000 hospitalized patients with moderate disease, therapeutic-dose
anticoagulation will result in 7 additional major bleeding events
• The study maintained good external validity by having an limited exclusion
criteria and inclusive inclusion criteria. Similarly, the baseline patient
characteristics were diverse and reflective of a typical hospitalized patient
population

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Other Considerations

• Provider Perspective
• Use of high flow nasal cannula is not unusual for non-ICU COVID-19 patients at our
hospital and may not always result in further decline to mechanical ventilation
• This study did not select mortality or length of stay as primary outcomes to measure, and
therefore limited associations can be drawn from this trial
• Therapeutic anticoagulation requires more resources in administration, dosing, and
monitoring

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 Evidence Grade and Conclusion
• Evidence Grade (select grade and delete others)
• A—Useful
• Outstanding in design, methodology, execution, and reporting. Meets standards for clinical
meaningfulness and patient/prescriber acceptance. Clinical decisions can be made with reasonable
certitude. Rare.
• B—Possibly Useful
• Well-designed and executed, meets most “A” requirements
• Potentially strong and probably useful but with some threats to validity identified
• B-U—Possible to Uncertain Usefulness
• Possibly useful but sufficient uncertainty to not reach Grade B, but does not warrant Grade U

• Summary-- similar studies have already demonstrated that therapeutic

anticoagulation did not provide benefit in patients with severe COVID-19 infection,
and this study only demonstrated benefit in preventing organ support which could be
solely high flow nasal cannula and therefore extrapolation to improved mortality/
length of stay is difficult when weighed to the risk of major bleeding and increased
costs associated with providing therapeutic anticoagulation
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Questions?

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Works Cited
ATTACC, The, et al. “Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19: Nejm.” New England Journal of Medicine, 26 Aug. 2021,
https://www.nejm.org/doi/full/10.1056/NEJMoa2105911.

Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic
review and meta-analysis. EClinicalMedicine. 2020 Dec;29:100639. doi: 10.1016/j.eclinm.2020.100639. Epub 2020 Nov 20. PMID: 33251499; PMCID: PMC7679115.

Manolis, A. S., Manolis, T. A., Manolis, A. A., Papatheou, D., & Melita, H. (2021). COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and
Thromboembolism/Prophylactic and Therapeutic Management. Journal of cardiovascular pharmacology and therapeutics, 26(1), 12–24.
https://doi.org/10.1177/1074248420958973

Rees, E. M., Nightingale, E. S., Jafari, Y., Waterlow, N. R., Clifford, S., B Pearson, C. A., Group, C. W., Jombart, T., Procter, S. R., & Knight, G. M. (2020). COVID-19 length
of hospital stay: a systematic review and data synthesis. BMC medicine, 18(1), 270. https://doi.org/10.1186/s12916-020-01726-3

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