Antitrombotisch beleid

Initiatief: NIV Aantal modules: 89

Tromboseprofylaxe op de Intensive Care

Uitgangsvraag

Wat is de plaats van tromboseprofylaxe bij COVID-19 patiënten op de intensive care?

Aanbeveling

Geef een standaard profylactische dosis antistolling aan patiënten met COVID-19 op de intensive care.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Er is literatuuronderzoek verricht naar de verschillen in klinische uitkomsten tussen 1) behandeling met therapeutische dosis antistolling versus standaard of intermediaire dosis tromboseprofylaxe, en 2) behandeling met intermediaire dosis tromboseprofylaxe versus standaard dosis tromboseprofylaxe, bij patiënten met COVID-19 op de intensive care (IC). Tot op heden zijn 3 RCTs gevonden die de vergelijking in de eerste PICO – therapeutische dosis versus profylactische of intermediaire dosis - hebben onderzocht. Er is één studie gevonden, waarvan de resultaten op twee meetmomenten in twee artikelen beschreven werden, die de vergelijking in de tweede PICO – intermediaire dosis versus profylactische dosis - heeft onderzocht. Tabel 1 geeft een overzicht van voorbeelddoseringen voor drie soorten low-molecular-weight heparines (LMWHs).

 

Tabel 1. Voorbeelddoseringen voor de meest gebruikte LMWHs in Nederland

 

Doseringen

Nadroparine

Dalteparine

Enoxaparine

Standaard profylactische dosering

2850 IU eenmaal daags

2500 IU eenmaal daags

20 mg eenmaal daags

 

Intermediair profylactische dosering

5700 IU eenmaal daags (of 2 dd 2850 IU)

5000 IU eenmaal daags

40 mg eenmaal daags

 

Therapeutisch profylactische dosering

11.400 IU per dag voor gewicht tussen 50 en 70 kg;

15.200 IU per dag voor gewicht boven de 70 kg; en

17.100 IU per dag voor gewicht boven de 90 kg

200 IU per kg per dag met een maximum van 18.000 IU per dag

1,5 mg per kg per dag of 1,0 mg tweemaal daags

LMWH, low-molecular-weight heparin; IU, International Unit.

 

Cruciale uitkomstmaten

Voor de cruciale uitkomstmaten mortaliteit, veneuze trombo-embolie, en het aantal dagen vrij van mechanische ventilatie is het op basis van de gevonden resultaten onzeker of het gebruik van een therapeutische dosis antistolling zou kunnen resulteren in een verschil in deze uitkomstmaten, vergeleken met een profylactische dosis antistolling. Hetzelfde geldt voor de vergelijking tussen een intermediaire dosis en profylactische dosis antistolling. De bewijskrachten voor beide vergelijkingen waren voor deze drie uitkomstmaten zeer laag.

 

Voor trombo-embolische complicaties samengenomen (arteriële en veneuze trombo-embolie) werd gevonden dat behandeling met een therapeutische dosis antistolling mogelijk kan resulteren in een reductie in trombo-embolische complicaties vergeleken met een profylactische dosis antistolling. De bewijskracht hiervoor was laag. Het is onduidelijk of een intermediaire dosis antistolling zou kunnen leiden tot een verschil in trombo-embolische complicaties vergeleken met een profylactische dosis antistolling. De bewijskracht was zeer laag.

 

Behandeling met therapeutische dosis antistolling zou kunnen resulteren in geen tot een klein verschil in ernstige bloedingen vergeleken met een profylactische of intermediaire dosis antistolling. De bewijskracht hiervoor was laag. Het is onduidelijk of behandeling met een intermediaire dosis antistolling zou ook kunnen resulteren in een verschil in ernstige bloedingen vergeleken met een profylactische dosis antistolling. De bewijskracht hiervoor was zeer laag.

 

Belangrijke uitkomstmaten

Voor de belangrijke uitkomstmaat duur van ziekenhuisopname is het onduidelijk of behandeling met een therapeutische dosis antistolling zou kunnen resulteren in een verschil in de duur van ziekenhuisopname vergeleken met een profylactische dosis antistolling. De bewijskracht hiervoor was zeer laag. Er is geen bewijs gevonden voor het effect van een intermediaire dosis antistolling vergeleken met en profylactische dosis antistolling op de duur van ziekenhuisopname. Voor de duur van IC opname is het ook onduidelijk of behandeling met een therapeutische dosis antistolling zou kunnen resulteren in een verschil in de duur van IC opname vergeleken met een profylactische dosis antistolling. Hetzelfde geldt voor de vergelijking tussen een intermediaire dosis antistolling vergeleken met en profylactische dosis antistolling. De bewijskracht voor beide vergelijkingen was zeer laag.

 

Er is geen bewijs gevonden voor het effect van een therapeutische dosis antistolling vergeleken met een profylactische dosis antistolling op orgaan support anders dan mechanische ventilatie. Het is onduidelijk of behandeling met een intermediaire dosis antistolling vergeleken met een profylactische dosis antistolling zou kunnen resulteren in een verschil in orgaan support anders dan mechanische ventilatie, meer specifiek nier vervangende therapie. De bewijskracht hiervoor was zeer laag.

 

Er is geen bewijs gevonden voor het effect op het aantal dagen vrij van orgaan ondersteuning anders dan mechanische ventilatie voor de vergelijking tussen 1) een therapeutische dosis antistolling vergeleken met een profylactische dosis antistolling, en 2) een intermediaire dosis antistolling vergeleken met een profylactische dosis antistolling. Voor de uitkomstmaten heparine geïnduceerde trombocytopenie en cumulatieve transfusie zijn geen resultaten beschreven in de geselecteerde studies.

 

Interpretatie

De interpretatie van de studies is om meerdere redenen complex. De INSPIRATION studie komt qua populatie niet overeen met de Nederlandse populatie op de Intensive Care Unit (ICU), gezien het relatief lage percentage invasieve beademing (dat samengenomen met non-invasieve beademing rond de 50% lag) en de lage APACHE II score van de geïncludeerde patiënten (mediaan 8, IQR 5-11). In de multiplatform studie van Goligher (2021) is dit percentage ook laag, maar daar kregen patiënten high flow nasal oxygen of non invasive ventilation en slechts 1,5% van de patiënten zuurstof via masker of low flow nasal oxygen. Ook was de APACHE II score beduidend hoger (mediaan 14, IQR 8-21), hetgeen meer in lijn is met de Nederlandse situatie op de ICU. De studie van Lemos (2020) uit Brazilië met tweemaal 10 patiënten is heel klein en daarom niet representatief. Met betrekking tot bepaalde subgroepen, zoals leeftijd of D-dimeer niveau bij presentatie, kon geen onderscheid worden gevonden in de analyse van de studies. Daarom konden geen aanbevelingen worden gedaan voor deze subgroepen. Alle cruciale uitkomsten waren secundaire uitkomsten in de studies. De studies hadden samengestelde primaire eindpunten die onderling onvergelijkbaar bleken. Zo werden bijvoorbeeld non-invasieve en invasieve beademing samen genomen, of sterfte en trombotische complicaties. Door deze verschillende samengestelde uitkomstmaten kon deze data niet gepoold worden. Een ander belangrijk punt van overweging is het feit dat de behandeling van patiënten met COVID-19 in 2021 in Nederland veranderd is ten opzichte van 2020, het jaar waarin de studies zijn verricht. Zo is er nu standaardbehandeling met IL-6 remmers en monoklonale antistoffen. In verschillende van de gevonden studies kreeg een substantieel deel van de patiënten bijvoorbeeld geen behandeling met steroïden en werd slechts een kleine minderheid behandeld met IL-6 remmers. Alle studies hadden een zogenaamd ‘open label design’, waardoor bias kan zijn opgetreden bij zachtere uitkomstmaten als veneuze trombo-embolie en bloeding. De artsen wisten welke behandeling een patiënt kreeg, hetgeen de klinische verdenking en diagnostische strategie heeft kunnen beïnvloeden. Eindpunten werden slechts deels centraal of lokaal geadjudiceerd, waardoor de validiteit van de diagnose longembolie (overgrote meerderheid van de trombotische events) niet in alle studies is na te gaan. De inclusiecriteria tussen de studies waren ook erg wisselend, met soms -maar niet altijd - selectie van patiënten met hoge tot zeer hoge D-dimeerwaarden. Patiënten met een van tevoren ingeschat hoog bloedingsrisico werden uitgesloten. De incidentie van bloedingscomplicaties zou daarom bij toepassing van therapeutische antistolling in de dagelijkse praktijk hoger kunnen uitvallen. Naast beademing was er voor andere orgaanondersteuning (zoals nierfunctievervangende therapie en extracorporele membraanoxygenatie (ECMO)) alleen literatuur beschikbaar met een zeer lage bewijskracht. Wat betreft veiligheid was er alleen rapportage van bloedingen en niet van cumulatieve transfusie, en kan er niet uitgesloten worden dat er een onderrapportage is geweest van milde bloedingscomplicaties. Ook is er geen data gerapporteerd over het voorkomen van van heparine geïnduceerde trombocytopenie (HIT). Dit alles maakt dat er nog kennislacunes zijn. Het zal moeten blijken of resultaten van nieuwe studies de conclusies van de samenvatting van de literatuur zullen veranderen.

 

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Het doel van toedienen van antistolling is het voorkómen van veneuze en, in mindere mate, arteriële trombose. Er is geen verschil in toediening of impact van de profylactische of intermediaire versus de therapeutische dosis LMWH; beide worden op dezelfde manier subcutaan geïnjecteerd. Er zijn geen subgroepen met andere uitkomsten gevonden.

 

Patiënten die een behandeling met medicijnen voor antistolling krijgen vinden complete en eenduidige informatievoorziening belangrijk, o.a. over de indicatie en de veiligheid en risico’s van de behandeling (onderwerpen die van belang zijn in de communicatie met patiënten zijn terug te vinden in de Landelijke Transmurale Afspraak antistollingszorg (https://lta-antistollingszorg.nl/communicatie-met-patienten).

 

Kosten (middelenbeslag)

Er is geen doorslaggevend verschil in de kosten voor de profylactisch of therapeutisch gedoseerde LMWH of ongefractioneerde heparine.

 

Aanvaardbaarheid, haalbaarheid en implementatie

Door de opzet en uitkomsten van de onderzochte studies is geen definitief bewijs gevonden voor de cruciale uitkomsten. Het was volgens de werkgroep onzeker of het gebruik van therapeutische of intermediaire dosis antistolling tot een klinisch relevant verschil in cruciale uitkomsten zou leiden.

 

Rationale van de aanbeveling

De individuele studies rapporteerden vaak gecombineerde uitkomstmaten, waarbij (niet-invasieve) beademing, IC opnameduur, trombotische complicaties, ECMO, nierfunctievervangende therapie en sterfte in verschillende combinaties waren samengenomen. Bij de analyses van de individuele eindpunten bleek het voordeel van therapeutische antistolling onzeker te zijn of onder de van tevoren vastgestelde grens van klinische relevantie te liggen ten opzichte van een profylactische of intermediaire dosis antistolling. Ook bleek het voordeel van een intermediaire dosis antistolling onzeker te zijn of onder de van tevoren vastgestelde grens van klinische relevantie te liggen ten opzichte van een profylactische dosis antistolling. Eerder waren voor de Nederlandse situatie geen grenzen van klinische relevantie vastgesteld voor het instellen van tromboseprofylaxe. De werkgroep heeft zich bij het vaststellen van die grenzen geconformeerd aan de grenzen voor sterfte en IC opname, zoals vastgesteld door de werkgroep voor medicamenteuze behandeling van COVID-19. De grens voor een klinisch relevant verschil in trombotische complicaties werd indirect afgeleid uit de ACCP richtlijn tromboseprofylaxe uit 2012. Uit de onderzochte studies bleek ook dat therapeutische antistolling niet klinisch relevant meer schade berokkende dan een profylactische of intermediaire dosis: het optreden van bloedingen is mogelijk niet klinisch relevant verschillend tussen de groepen. De werkgroep kwam tot de conclusie dat er op grond van de onderzochte studies onvoldoende grond is om een therapeutische of een intermediair profylactische dosis antistolling te adviseren boven een standaard profylactische dosering antistolling voor patiënten met COVID-19 op de intensive care.  

Onderbouwing

Ondanks tromboseprofylaxe en een verbeterde behandeling van COVID-19 komen trombotische complicaties nog frequent voor, met een geschatte incidentie van 23-28% in ICU patiënten en 7-9% in afdelingspatiënten (Jiménez, 2021; Tan, 2021; Nopp, 2021). Het is niet bekend wat de beste dosis van tromboseprofylaxe is (laag, intermediair of therapeutisch). Mede hierdoor verschillen ziekenhuisprotocollen.

1. Mortality

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with therapeutic dose of anticoagulation on mortality when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Goligher, 2021; Lemos, 2020.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on mortality when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

2. Length of hospital or ICU stay

 

Length of hospital stay

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with therapeutic dose of anticoagulation on length of hospital stay when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Lemos, 2020.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of intermediate dose of prophylactic anticoagulation when compared to standard dose of prophylactic anticoagulation on length of hospital stay in adult COVID-19 patients admitted to the ICU.

 

 

Length of ICU stay

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with therapeutic dose of anticoagulation on length of ICU stay when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Lemos, 2020.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on length of ICU stay when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

3. Organ support

Ventilator-free days

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with therapeutic dose of anticoagulation on ventilator-free days when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Lemos, 2020.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on ventilator-free days when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

Other organ support free days


Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of therapeutic dose of anticoagulation when compared to standard (or intermediate) dose of prophylactic anticoagulation on other organ support free days in adult COVID-19 patients admitted to the ICU.

 

 

Intermediate dose versus standard dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of intermediate dose of prophylactic anticoagulation when compared to standard dose of prophylactic anticoagulation on other organ support free days in adult COVID-19 patients admitted to the ICU.

 

 

Organ support other than mechanical ventilation

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of therapeutic dose of anticoagulation when compared to standard prophylactic anticoagulation on organ support other than mechanical ventilation in adult COVID-19 patients admitted to the ICU.

 

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on organ support other than mechanical ventilation when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

4. Venous thromboembolism

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with therapeutic dose of anticoagulation on venous thromboembolism when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Goligher, 2021.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on venous thromboembolism when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.



Thromboembolic complications (VTE/ATE)

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Low GRADE

Treatment with therapeutic dose of anticoagulation may result in a decrease in thromboembolic complications (VTE/ATE) when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Goligher, 2021.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on thromboembolic complications (VTE/ATE) when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

5. Major bleeding

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Low GRADE

Treatment with therapeutic dose of anticoagulation may result in little to no difference in major bleedings when compared to standard (or intermediate) dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Sources: Goligher, 2021; Lemos, 2020; Spyropoulos, 2021.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Very low GRADE

The evidence is very uncertain about the effect of treatment with intermediate dose of prophylactic anticoagulation on major bleedings when compared to standard dose of prophylactic anticoagulation in adult COVID-19 patients admitted to the ICU.

 

Source: Sadeghipour, 2021.

 

6. Heparin induced thrombocytopenia (HIT)

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of therapeutic dose of anticoagulation when compared to standard (or intermediate) dose of prophylactic anticoagulation on HIT in adult COVID-19 patients admitted to the ICU.

 

 

Intermediate dose versus standard dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of intermediate dose of prophylactic anticoagulation when compared to standard dose of prophylactic anticoagulation on HIT in adult COVID-19 patients admitted to the ICU.

 

 

7.Cumulative transfusion

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of therapeutic dose of anticoagulation when compared to standard prophylactic (or intermediate) dose of anticoagulation on cumulative transfusion in adult COVID-19 patients admitted to the ICU.

 

 

Intermediate dose versus standard dose of prophylactic anticoagulation

- GRADE

No studies were found that could answer the question what the effect is of intermediate dose of prophylactic anticoagulation when compared to standard dose of prophylactic anticoagulation on cumulative transfusion in adult COVID-19 patients admitted to the ICU.

 



Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Spyropoulos (2021) describes a multicenter open label randomized clinical trial evaluating the effects of therapeutic-dose low-molecular-weight heparin vs institutional standard or intermediate prophylactic dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. Patients were enrolled from March 8, 2020, through May 14, 2021, at 12 centers in the US. A total of 11649 patients were assessed for eligibility. Eligible patients consisted of hospitalized nonpregnant adults 18 years or older with COVID-19 diagnosed by nasal swab or serologic testing. Moreover, there was a requirement for supplemental oxygen per investigator judgment and a plasma D-dimer level greater than 4 times the upper limit of normal based on local laboratory criteria or a sepsis-induced coagulopathy score of 4 or greater. 257 patients were randomized into the therapeutic heparin dose group (n= 130) or standard/intermediate prophylactic heparin dose group (n = 127). 45 out of 129 patients in the therapeutic dose group were admitted to the ICU, versus 38 out of 124 in the standard prophylactic dose group. Treatment began after randomization and was stopped at hospital discharge or upon occurrence of a primary efficacy outcome, key secondary outcome, or principal safety outcome requiring study drug discontinuation. All patients without a primary or key secondary outcome event underwent lower extremity Doppler compression ultrasonography at hospital day 10 + 4 or at discharge if sooner. The length of follow-up was 30 +2 days after randomization. For the primary efficacy outcome (venous thromboembolism, arterial thromboembolism or death) and major bleeding, patients were stratified based on intensive care unit (ICU) or non-ICU status. For all other outcomes, no stratification was performed. Patients in the therapeutic dose group had a mean age of 65.8 years (SD 13.9) versus 67.7 years (SD 14.1) in the standard prophylactic dose group and the small majority was male (52.7% in the intervention versus 54.8% in the control group). The study groups were comparable with respect to baseline characteristics.

 

Goligher (2021) describes an open-label, adaptive, multiplatform RCT (mpRCT). In this mpRCT, three platforms (REMAPCAP, ATTACC and ACTIV-4a) were integrated to evaluate therapeutic dose anticoagulation versus usual-care pharmacologic thromboprophylaxis in critically ill patients with COVID-19. Patients were recruited from different countries, e.g. the United Kingdom, United States, Canada, Brazil. Patients were included in the mpRCT if they had a laboratory confirmed COVID-19 infection, they had severe COVID-19 (which was defined as COVID-19 that led to receipt of ICU-level respiratory or cardiovascular organ support in an ICU). A total of 1207 patients underwent randomization at 393 sites in 10 countries, until the pre-specified criterion for futility had been met. Patients were randomized to receive therapeutic dose anticoagulation with heparin (n=591) or usual-case thromboprophylaxis (n=616). After exclusion, 534 patients in the therapeutic dose group and 564 patients in the usual-care group were included in the primary analysis. The mean age of patients in the therapeutic dose group was 60.4 years (SD 13.1) versus 61.7 years (SD 12.5) in the usual-care group. The majority in both groups was male: 387 patients (72.2%) in the therapeutic dose group, versus 385 patients (67.9%) in the usual-care group. The study groups were comparable with respect to baseline characteristics.

 

Lemos (2020) describes a randomized, controlled, open-label, single-center, phase II study conducted in Brazil, evaluating therapeutic dose enoxaparin versus standard anticoagulant thromboprophylaxis in COVID-19 patients requiring mechanical ventilation. Adult patients (>18 years of age) were included in this study if they suffered from respiratory failure requiring mechanical ventilation and laboratory confirmed SARS-CoV-2 infection. Twenty patients were randomized to receive therapeutic enoxaparin (n=10) or prophylactic anticoagulation (UFH and LMWH, n=10). All patients who were randomized were included in the primary analysis. The mean age of patients in the therapeutic dose group was 55 years (SD 10) versus 58 years (SD 16) in the prophylactic dose group. The majority was male: nine out of ten patients in the therapeutic dose group, versus seven out of ten patients in the prophylactic dose group. The study groups were comparable with respect to baseline characteristics.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) describes a multicenter open-label randomized clinical trial (INSPIRATION trial) comparing intermediate versus standard dose of prophylactic anticoagulation in adult patients with COVID-19 admitted to the ICU. Patients were recruited between July 29, 2020, and November 19, 2020, conducted in Iran at 10 academic centers in Tehran and Tabriz. Patients were eligible if they were admitted to the ICU with polymerase chain reaction testing–confirmed COVID-19 within 7 days of the index hospitalization. Patients were excluded when their life expectancy was less than 24 hours. Also, patients with an established indication for therapeutic-dose anticoagulation, weight less than 40 kg, pregnancy, history of heparin-induced thrombocytopenia, platelet count less than 50 ×103 /μL, or overt bleeding were excluded. A total of 600 patients were randomized into the intermediate prophylactic dose group (n=299) or the standard dose prophylactic anticoagulation group (n=299). The primary anticoagulant agent in both groups was enoxaparin. In case a patient had severe kidney insufficiency, an unfractionated heparin was used. Treatments were continued until 30 days of follow-up, irrespective of hospital discharge status. Ultimately, 562 patients were included in the prespecified primary analysis. The median age of patients in the intermediate prophylactic dose group (n=276) was 62 years (IQR 51 to 70.7), versus 61 years (IQR 47 to 71) in the standard prophylactic dose group (n=286). The majority in both groups was male: 162 patients (58.7%) in the intermediate prophylactic dose group, versus 163 patients (57.0%) in the standard prophylactic dose group. Except for history of cigarette smoking, which was more frequent in the intermediate prophylactic dose group, the study groups were comparable with respect to baseline characteristics.

 

Bikdeli (2021) reports the final 90-day follow-up results of the INSPIRATION trial by Sadeghipour (2021). Therefore, the study design and included patients were the same as described above. The number of patients included in the primary analysis were not altered (n=276 in the intermediate prophylactic dose group versus n=286 in the standard prophylactic dose group). These articles are therefore taken together for the literature analysis.

 

Table 2. Overview of included RCTs that compared therapeutic dose anticoagulation with standard (or intermediate) dose anticoagulation and intermediate dose anticoagulation with standard dose anticoagulation in COVID-19 patients admitted to the ICU

 

Author, year and trial name

Intervention (I) and control (C)

Sample size for analysis

Doses

Duration

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Spyropoulos, 2021

 

HEP-COVID Randomized Clinical Trial

I: therapeutic-dose low-molecular-weight heparin (enoxaparin)

 

C: institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis

 

I: N= 45 ICU admitted patients

C: N= 38 ICU admitted patients

Total = 83

 

 

I: 1 mg/kg subcutaneously twice daily if CrCl was 30 mL/min/1.73 m2 or greater or 0.5 mg/kg twice daily if CrCl was 15-29 mL/min/ 1.73 m2

 

C: could include unfractionated heparin (UFH), up to 22 500 IU subcutaneously (divided twice or thrice daily); enoxaparin, 30 mg or 40 mg subcutaneously once or twice daily (weight based enoxaparin 0.5 mg/kg subcutaneously twice daily was permitted but strongly discouraged); or dalteparin, 2500 IU or 5000 IU subcutaneously daily

Study drug was administered for the duration of hospitalization, including patient transfers to ICU settings.

Goligher, 2021

 

The REMAP-CAP, ACTIV-4a, and ATTACC Investigators

I: therapeutic-dose anticoagulation with heparin

 

C: pharmacologic thromboprophylaxis in accordance with local usual care

I: N= 534

C: N= 564

Total = 1098

 

 

I: Therapeutic-dose anticoagulation was administered according to local site protocols for the treatment of acute venous thromboembolism

 

C: Usual-care thromboprophylaxis was administered at a dose and duration determined by the treating clinician

according to local practice, which included

either standard low-dose thromboprophylaxis or enhanced intermediate-dose thromboprophylaxis.

 

The anticoagulation and thromboprophylaxis

regimens that were specified by each platform are detailed in the Supplementary Appendix (page 49-51 and Table S1 at page 65).

I: Up to 14 days or until recovery (defined as either hospital discharge or discontinuation of supplemental oxygen for at least 24 hours).

 

C: Up to 14 days or hospital discharge, whichever comes first. After this period, decisions regarding thromboprophylaxis are at discretion of treating clinician

 

The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation.

Lemos, 2020

 

HESACOVID trial

I: therapeutic enoxaparin

 

C: standard anticoagulant thromboprophylaxis

I: N= 10

C: N= 10

Total = 20

I: subcutaneous (SC) enoxaparin with the dose according to age and adjusted daily by the creatinine clearance (CrCl) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. See article for exact doses per age group.

 

C: subcutaneous unfractionated heparin (UFH) at a dose of 5000 IU TID (if weight < 120 kg) and 7500 IU TID (if weight > 120 kg) or enoxaparin at a dose of 40 mg OD (if weight < 120 kg) and 40 mg BID (if weight > 120 Kg) according to the doctor's judgment.

I: The median of the therapeutic enoxaparin treatment duration was 14 days, ranging from 9 to 14 days

 

C: ?

Intermediate dose versus standard dose of prophylactic anticoagulation

INSPIRATION trial

 

Sadeghipour, 2021 (initial study)

 

Bikdeli, 2021

(extension of initial study/follow-up measurements at day 90)

I: intermediate-dose enoxaparin

 

C: standard prophylactic anticoagulation enoxaparin

I: N= 276

C: N= 286

Total = 562

 

 

I: 1 mg/kg daily, with modification according to body weight and creatinine clearance.

 

C: 40 mg daily, with modification according to body weight and creatinine clearance.

Irrespectively of hospital discharge status, the assigned treatments were planned to be continued until the 30-day follow-up (Sadeghipour, 2021) or 90-day follow-up (Bikdeli, 2021).

 

 

 

 

 

Table 3. Overview of composite outcomes and results per study

 

Study

Primary composite outcome

Results

INSPIRATION trial

 

  1. Sadeghipour, 2021 (30 days)
  2. Bikdeli, 2021 (90 days)

Composite of adjudicated acute venous thromboembolism, arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality.

  1. Intermediate prophylactic dose group: 126 out of 276 (45.7%) patients

    Standard prophylactic dose group: 126 out of 286 (44.1%) patients

  2. Intermediate prophylactic dose group: 132 out of 276 (47.8%) patients

    Standard prophylactic dose group: 130 out of 286 (45.4%) patients

Goligher, 2021

Multiplatform trial

Median number of days free of cardiovascular or respiratory organ support. This was evaluated on an ordinal scale that combined in-hospital death and the number of organ support free days up to day 21 among patients who survived to hospital discharge. If a patient died, they were assigned a value of -1.

 

In the therapeutic dose group, the median number of organ support-free days was 1 day (IQR -1 to 16), versus 4 days (IQR -1 to 16) in the standard prophylactic dose group.

Spyropoulos, 2021

HEP-COVID trial

Composite outcome: VTE, ATE, or death

Measured in the ICU-stratum

Therapeutic dose group: 23 out of 45 (51.1%) patients

Standard prophylactic dose group: 21 out of 38 (55.3%) patients

 

Results

 

1. Mortality

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) reported death in hospital. A total of 199 out of 534 (37.3%) patients died in the therapeutic dose group, versus 200 out of 564 (35.5%) in the standard prophylactic dose group. The risk difference (RD) was 1.8% in favor of the standard prophylactic dose group (95%CI -3.9% to 7.5%). The corresponding NNT was 56. This was not considered to be a clinically relevant difference.

 

Lemos (2020) reported in-hospital mortality. A total of 2 out of 10 (20.0%) patients died in the therapeutic dose group, versus 5 out of 10 (50.0%) in the standard prophylactic dose group. The RD was 30.0% in favor of the therapeutic dose group (95%CI -69.7% to 9.7%). The corresponding NNT was 3. This was considered to be a clinically relevant difference.

 

Level of evidence

The level of evidence regarding the outcome measure mortality was downgraded from high to very low because in Goligher (2021) some patients are missing from the analyses and it is not clear why, and many patients were excluded after randomization in both groups (risk of bias, -1), and the confidence interval around the RD crossing the upper and lower thresholds for clinical relevance (imprecision, -2). Lemos (2020) was given few weight in the determination of the level of evidence, because of the very small study population.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) reported all-cause mortality at day 30. In the intermediate prophylactic dose group, 119 out of 276 (43.1%) patients died, versus 117 out of 286 (40.9%) patients in the standard prophylactic dose group. The RD was 2.2% in favor of the standard prophylactic dose group (95%CI -6.0% to 10.4%). The corresponding NNT was 45. This was not considered to be a clinically relevant difference.

At day 90, Bikdeli (2021) reported that 127 out of 276 (46.0%) patients died, versus 123 out of 286 (43.0%) patients in the standard prophylactic dose group.

 

Level of evidence

The level of evidence regarding the outcome measure mortality was downgraded from high to very low because of the study population differing from what was defined in the PICO (indirectness, -1), the confidence interval around the RD crossing the upper and lower thresholds for clinical relevance (imprecision, -2). The level of evidence is based on the results reported in Sadeghipour (2021).

 

2. Length of hospital or ICU stay

 

Length of hospital stay

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Lemos (2020) reported the median length of hospital stay. The median length of hospital stay was 31 days (IQR 22 to 35) in the therapeutic dose group, versus 30 days (IQR 23 to 38) in the standard prophylactic dose group. The difference in median days was 1 day. This was not considered to be a clinically relevant difference.

 

Goligher (2021) did not report length of hospital stay.

 

Level of evidence

The level of evidence regarding the outcome measure length of hospital stay was downgraded from high to very low because of the small sample size and wide interquartile range (imprecision, -3).

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) did not report length of hospital stay.

 

Length of ICU stay

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Lemos (2020) also reported the median number of ICU-free days. This was 12 days (IQR 2 to 12) in the therapeutic dose group, versus 0 days (IQR 0 to 10) in the standard prophylactic dose group.

 

Goligher (2021) did not report length of ICU stay.

 

Level of evidence

The level of evidence regarding the outcome measure length of ICU stay was downgraded from high to very low because of the outcome measure not being the same as defined in the PICO (indirectness, -1), and the small sample size and wide interquartile range (imprecision, -2).

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) reported the median length of ICU stay. The median length of ICU stay for the intermediate prophylactic dose group was 5 days (IQR 2 to 10), versus 6 days (IQR 3 to 11) in the standard prophylactic dose group. The difference in median days was 1 day. This was not considered to be a clinically relevant difference.

 

Sadeghipour (2021) also reported the number of patients discharged from the ICU. The number of patients discharged from the ICU in the intermediate prophylactic dose group was 169 out of 276 (61.2%), versus 174 out of 286 (60.8%) in the standard prophylactic dose group.

 

Bikdeli (2021) did not report length of ICU stay at day 90.

 

Level of evidence

The level of evidence regarding the outcome measure length of ICU stay was downgraded from high to very low because of the study population differing from what was defined in the PICO (indirectness, -1), and the wide interquartile range in both groups (imprecision, -2).

 

3. Organ support free days

 

Ventilator-free days

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Lemos (2020) reported the median number of ventilator-free days. In the therapeutic dose group, the median number of ventilator-free days was 15 days (IQR 6 to 16), versus 0 days (IQR 0 to 11) in the standard prophylactic dose group.

 

Goligher (2021) did not report ventilator-free days.

 

Level of evidence

The level of evidence regarding the outcome measure ventilator-free days was downgraded from high to very low because of the small sample size and the wide interquartile range in both groups (imprecision, -3).

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) reported the median number of ventilator-free days. In the intermediate prophylactic dose group, the median number of ventilator-free days was 30 days (IQR 3 to 30), versus 30 days (IQR 1 to 30) in the standard prophylactic dose group. The difference in median days was zero days. This was not considered to be a clinically relevant difference.

 

Bikdeli (2021) did not report ventilator-free days at day 90.

 

Level of evidence

The level of evidence regarding the outcome measure ventilator-free days was downgraded from high to very low because of the study population differing from what was defined in the PICO (indirectness, -1), and the wide interquartile range in both groups (imprecision, -2).

 

Other organ support free days

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) and Lemos (2020) did not report on other organ support free days.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) did not report on other organ support free days.

 

Organ support other than mechanical ventilation

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) and Lemos (2020) did not report on other organ support than mechanical ventilation.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) reported extracorporeal membrane oxygenation (ECMO) as part of the primary composite outcome (see Table 2), but not on its own. In addition, Sadeghipour (2021) reported new in-hospital kidney replacement therapy. In the intermediate prophylactic dose group, 10 out of 276 (3.6%) patients needed kidney replacement therapy, versus 7 out of 286 (2.4%) patients in the standard prophylactic dose group. The difference was 1.2% in favor of the standard prophylactic dose group (95%CI -1.7% to 4.0%). This was not considered to be a clinically relevant difference. Bikdeli (2021) reported the same numbers at day 90.

 

Level of evidence

The level of evidence regarding the outcome measure organ support other than mechanical ventilation was downgraded from high to very low because of the study population differing from what was defined in the PICO (indirectness, -1), and the low number of events (imprecision, -2).

 

 

4. Venous thromboembolism

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) and Lemos (2020) did not report the number of patients with VTE.

 

However, Goligher (2021) did report the number of events for deep venous thrombosis and pulmonary embolism separately. In the therapeutic dose group 6 events for deep venous thrombosis were reported, versus 6 events in the standard prophylactic dose group. For pulmonary embolism, 13 events were reported in the therapeutic dose group, versus 42 events in the standard prophylactic dose group.

 

Level of evidence

The level of evidence regarding the outcome measure venous thromboembolism was downgraded from high to very low because in Goligher (2021) some patients are missing from the analyses and it is not clear why, and many patients were excluded after randomization in both groups (risk of bias, -1), indirectness in the outcome measure (indirectness, -1), the low number of events (imprecision, -1).

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) reported adjudicated venous thromboembolism at day 30. In the intermediate prophylactic dose group 9 out of 276 patients (3.3%) developed adjudicated venous thromboembolism, versus 10 out of 286 (3.5%) in the standard prophylactic dose group. The RD was 0.24% in favor of the intermediate prophylactic dose group (95%CI -3.2% to 2.8%). The NNT was 417. This was not considered to be a clinically relevant difference.

 

Bikdeli (2021) reported the same outcome in the same patients at day 90. No differences occurred in the incidence between day 30 and 90.

 

Level of evidence

The level of evidence regarding the outcome measure venous thromboembolism was downgraded from high to very low because of the open-label study design (risk of bias, -1), the study population differing from what was defined in the PICO (indirectness, -1), and the confidence interval around the RD crossing the lower threshold for clinical relevance (imprecision, -1).

 

Thromboembolic complications (VTE/ATE)

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) reported the number of patients with any thrombotic event (defined as pulmonary embolism, myocardial infarction, ischemic cerebrovascular event, systemic arterial thromboembolism): 38 out of 530 patients (7.2%) experienced a thrombotic event in the therapeutic dose group, versus 62 out of 559 patients (11.1%) in the standard prophylactic dose group. The RD was 3.9% in favor of the therapeutic dose group (95%CI -7.3% to 0.5%). The corresponding NNT was 26. This was considered to be a clinically relevant difference.

 

Lemos (2020) reported the number of patients with thrombotic events: 2 out of 10 (2.0%) patients experienced a thrombotic event in the therapeutic dose group, versus 2 out of 10 (2.0%) patients in the standard prophylactic dose group. The RD was 0.0% (95%CI -35.1% to 35.1%). This was not considered to be a clinically relevant difference. 

 

Level of evidence

The level of evidence regarding the outcome measure thromboembolic complications was downgraded from high to low because in Goligher (2021) some patients are missing from the analyses and it is not clear why, and many patients were excluded after randomization in both groups (risk of bias, -1), and the confidence interval around the RD crossing the lower threshold for clinical relevance (imprecision, -1). Lemos (2020) was given no weight in the determination of the level of evidence, because of the very small study population.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) did not report the number of patients with thromboembolic events (VTE/ATE).

 

However, Sadeghipour (2021) reported the number of patients with acute peripheral arterial thrombosis, ischemic stroke, and type I acute myocardial infarction, all three objectively clinically diagnosed. None of the 276 patients in the intermediate prophylactic dose group and none of the 286 patients in the standard prophylactic dose group were diagnosed with acute peripheral arterial thrombosis and/or type I acute myocardial infarction. In the intermediate prophylactic dose group, 1 out of 276 (0.4%) patients developed ischemic stroke, versus 1 out of 286 (0.3%) patients in the standard prophylactic dose group.

 

Level of evidence

The level of evidence regarding the outcome measure thromboembolic complications was downgraded from high to very low because of the open-label study design (risk of bias, -1), indirectness in the outcome measure and study population (indirectness, -1), and the low number of events (imprecision, -1).

 

5. Major bleeding

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

 

Figure 1: Major bleeding in COVID-19 patients admitted to the ICU

Figure 1: Major bleeding in COVID-19 patients admitted to the ICU

Z: p-value of overall effect; df: degrees of freedom; I2: statistical heterogeneity; CI: confidence interval

 

A total of 24 out of 584 (4.1%) patients developed a major bleeding in the therapeutic dose group, versus 13 out of 610 (2.1%) in the standard/intermediate prophylactic dose group. The pooled risk difference (RD) was 2.5% in favor of the standard/intermediate prophylactic dose group (95%CI -1.4% to 6.4%; figure 1). The corresponding NNH was 40. This was not considered to be a clinically relevant difference.

 

Level of evidence

The level of evidence regarding the outcome measure major bleeding was downgraded from high to low because in Goligher (2021) some patients are missing from the analyses and it is not clear why, and many patients were excluded after randomization in both groups (risk of bias, -1), and the confidence interval around the RD crossing the upper threshold for clinical relevance (imprecision, -1).

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) reported major bleeding. In the intermediate prophylactic dose group 7 out of 276 (2.5%) patients developed a major bleeding, versus 4 out of 286 (1.4%) patients in the standard prophylactic dose group. The RD was 1.14% in favor of the standard prophylactic dose group (95%CI -1.16% to 3.44%). The corresponding NNH was 88. This was not considered to be a clinically relevant difference. Bikdeli (2021) reports the same numbers at day 90.

 

Level of evidence

The level of evidence regarding the outcome measure major bleeding was downgraded from high to very low because of the open-label study designs (risk of bias, -1), the study population differing from what was defined in the PICO (indirectness, -1), and the confidence interval around the RD crossing the upper threshold for clinical relevance (imprecision, -1).

 

6. Heparin induced thrombocytopenia (HIT)

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) and Lemos (2020) did not report HIT.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) did not report HIT.

 

7. Cumulative transfusion

 

Therapeutic dose versus standard (or intermediate) dose of prophylactic anticoagulation

Goligher (2021) and Lemos (2020) did not report cumulative transfusion.

 

Intermediate dose versus standard dose of prophylactic anticoagulation

Sadeghipour (2021) and Bikdeli (2021) did not report cumulative transfusion.

 

However, Sadeghipour (2021) reported a sub-category of major bleeding: ‘BARC Type 3a- hemoglobin drop of 3 to 5 g/dL or any transfusion’. In the intermediate prophylactic dose group, 3 out of 276 (1.1%) patients reported this outcome, versus 4 out of 286 (1.4%) patients in the standard prophylactic dose group. Bikdeli (2021) reported the same numbers at day 90.

A systematic review of the literature was performed to answer the following question:

What is the efficacy and safety of anticoagulation therapy in COVID-19 patients at the ICU?

 

PICO 1

P: all adult COVID-19 patients admitted to the ICU who are not already on chronic therapeutic anticoagulants

I: therapeutic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)

C: standard or intermediate prophylactic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin) or no use of standard or intermediate prophylactic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)

O: mortality, major bleeding, venous thromboembolism, thromboembolic complications,  length of hospital or ICU stay, organ support (ventilator-free days, other organ support free days, and organ support other than mechanical ventilation), heparin induced thrombocytopenia, and cumulative transfusion

 

PICO 2

P: all adult COVID-19 patients admitted to the ICU who are not already on chronic therapeutic anticoagulants

I: intermediate prophylactic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)

C: standard prophylactic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin) or no use of standard or intermediate prophylactic dose (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)

O: mortality, major bleeding, venous thromboembolism, thromboembolic complications,  length of hospital or ICU stay, organ support (ventilator-free days, other organ support free days, and organ support other than mechanical ventilation), heparin induced thrombocytopenia, and cumulative transfusion

 

We searched for standard dose of prophylaxis and intermediate dose of prophylaxis; the latter is typically a doubling of the standard dose of prophylaxis. We also searched for a therapeutic dose of prophylaxis (intensive dose of prophylaxis; referred to as therapeutic dose). For aspirin only one dose (80-100 mg per day) was searched.

 

Relevant outcome measures

The guideline development group considered mortality, ventilator-free days, venous thromboembolism, thromboembolic complications (venous and arterial thrombotic complications combined) and major bleeding as critical outcome measures for decision making; and length of hospital or ICU stay, other organ support free days, organ support other than mechanical ventilation, heparin induced thrombocytopenia, and cumulative transfusion as important outcome measures for decision making.

 

The working group defined a risk difference of 3% as a minimal clinically (patient) important difference for mortality, venous thromboembolism, thromboembolic complications (venous and arterial thrombotic complications combined) and major bleeding; 3 days for length of hospital(/ICU) stay, ventilator-free days, and other organ support free days; a risk difference of 5% for organ support other than mechanical ventilation (yes/no), an absolute risk difference of 0.5 % for heparin induced thrombocytopenia; and an absolute risk difference of 10% for cumulative transfusion.

 

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until October 18th 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 686 hits. Studies were selected based on the following criteria:

  • randomized controlled trial (RCT)
  • peer reviewed and published in indexed journal or pre-published
  • comparing treatment with
  1. a therapeutic dose of anticoagulant (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin) with a prophylactic dose or no dose of anticoagulant (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)
  2. an intermediate prophylactic dose of anticoagulant (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin) with a standard prophylactic dose or no dose of anticoagulant (low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, vitamin K-antagonists, aspirin)
  • in critically ill patients with COVID-19 admitted to the ICU.

 

Fourteen studies were initially selected based on title and abstract screening. After reading the full text, nine studies were excluded (see the table with reasons for exclusion under the tab Methods), and five studies were included.

 

Results

Five studies were included in the analysis of the literature. Three studies investigated a therapeutic dose anticoagulant versus standard (or intermediate) prophylactic dose anticoagulant in COVID-19 patients admitted to the ICU (PICO 1). One study (for which different follow-up times – day 30 and day 90 – are described in two articles) investigated an intermediate prophylactic dose anticoagulant versus standard prophylactic dose anticoagulant in COVID-19 patients admitted to the ICU (PICO 2). No subgroups were made based on the type of anticoagulant used, as all studies used a heparin. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

  1. Bikdeli B, Talasaz AH, Rashidi F, Bakhshandeh H, Rafiee F, Rezaeifar P, Baghizadeh E, Matin S, Jamalkhani S, Tahamtan O, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, Sezavar SH, Payandemehr P, Dabbagh A, Moghadam KG, Khalili H, Yadollahzadeh M, Riahi T, Abedini A, Lookzadeh S, Rahmani H, Zoghi E, Mohammadi K, Sadeghipour P, Abri H, Tabrizi S, Mousavian SM, Shahmirzaei S, Amin A, Mohebbi B, Parhizgar SE, Aliannejad R, Eslami V, Kashefizadeh A, Dobesh PP, Kakavand H, Hosseini SH, Shafaghi S, Ghazi SF, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Piazza G, Kirtane AJ, Van Tassell BW, Stone GW, Lip GYH, Krumholz HM, Goldhaber SZ, Sadeghipour P. Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial. Thromb Haemost. 2021 Apr 17. doi: 10.1055/a-1485-2372. Epub ahead of print. PMID: 33865239.  
  2. REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Džavík V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4. PMID: 34351722; PMCID: PMC8362592  
  3. Jiménez D, García-Sanchez A, Rali P, Muriel A, Bikdeli B, Ruiz-Artacho P, Le Mao R, Rodríguez C, Hunt BJ, Monreal M. Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. Chest. 2021 Mar;159(3):1182-1196. doi: 10.1016/j.chest.2020.11.005. Epub 2020 Nov 17. PMID: 33217420; PMCID: PMC7670889.  
  4. Lemos ACB, do Espírito Santo DA, Salvetti MC, Gilio RN, Agra LB, Pazin-Filho A, Miranda CH. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020 Dec;196:359-366. doi: 10.1016/j.thromres.2020.09.026. Epub 2020 Sep 21. PMID: 32977137; PMCID: PMC7503069.  
  5. 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 Thromb Haemost. 2020 Sep 25;4(7):1178–91. doi: 10.1002/rth2.12439. Epub ahead of print. PMID: 33043231; PMCID: PMC7537137.  
  6. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, Sezavar SH, Payandemehr P, Dabbagh A, Moghadam KG, Jamalkhani S, Khalili H, Yadollahzadeh M, Riahi T, Rezaeifar P, Tahamtan O, Matin S, Abedini A, Lookzadeh S, Rahmani H, Zoghi E, Mohammadi K, Sadeghipour P, Abri H, Tabrizi S, Mousavian SM, Shahmirzaei S, Bakhshandeh H, Amin A, Rafiee F, Baghizadeh E, Mohebbi B, Parhizgar SE, Aliannejad R, Eslami V, Kashefizadeh A, Kakavand H, Hosseini SH, Shafaghi S, Ghazi SF, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Piazza G, Kirtane AJ, Van Tassell BW, Dobesh PP, Stone GW, Lip GYH, Krumholz HM, Goldhaber SZ, Bikdeli B. 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. 2021 Apr 27;325(16):1620-1630. doi: 10.1001/jama.2021.4152. PMID: 33734299; PMCID: PMC7974835.  
  7. Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G, Lund JM, Tafur A, Lewis PA, Cohoon KP, Rahman H, Sison CP, Lesser ML, Ochani K, Agrawal N, Hsia J, Anderson VE, Bonaca M, Halperin JL, Weitz JI; HEP-COVID Investigators. Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Dec 1;181(12):1612-1620. doi: 10.1001/jamainternmed.2021.6203. PMID: 34617959; PMCID: PMC8498934.  
  8. Tan BK, Mainbourg S, Friggeri A, Bertoletti L, Douplat M, Dargaud Y, Grange C, Lobbes H, Provencher S, Lega JC. Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax. 2021 Oct;76(10):970-979. doi: 10.1136/thoraxjnl-2020-215383. Epub 2021 Feb 23. PMID: 33622981; PMCID: PMC7907632.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

 

Follow-up

Outcome measures and effect size

 

Comments

Spyropoulos, 2021

 

HEP-COVID Randomized Clinical Trial

 

AND

 

corresponding

Trial protocol design paper

(Goldin, 2021)

Type of study:

Randomized controlled trial

 

Setting and country:

Multicenter study in the US (12 centers)

 

Funding and conflicts of interest:

Support from

Feinstein Institutes for Medical Research, the

Broxmeyer Fellowship in Clinical Thrombosis, and

grant R24AG064191 from the National Institute on

Aging. The funders had no

role in the design and conduct of the study;

collection, management, analysis, and

interpretation of the data; preparation, review, or

approval of the manuscript; and decision to submit the manuscript for publication.

Inclusion criteria:

  • Hospitalized patients
  • Nonpregnant patients
  • Adults 18 years or older
  • COVID-19 diagnosed by nasal swab or serologic testing
  • Requirement for supplemental oxygen per investigator judgment
  • Plasma D-dimer levle greater than 4 times the upper limit of normal based on local laboratory criteria or a sepsis-induced coagulopathy score of 4 or greater.

 

Exclusion criteria:

  • Physician-determined need for full-dose anticoagulation or dual antiplatelet therapy
  • bleeding within the past month
  • active gastrointestinal or intracranial cancer
  • bronchiectasis or pulmonary cavitation
  • hepatic dysfunction with baseline international
    normalized ratio greater than 1.5
  • creatinine clearance (CrCl) less than 15mL/min/1.73m2
  • Platelet count less than 25 000/μL
  • a history of heparin-induced thrombocytopenia (HIT) within 100 days
  • hypersensitivity/intolerance to study drug or components

 

Patients were stratified into two subgroups: non-intensive care unit patients and intensive care unit patients. ICU status was defined by mechanical ventilation, noninvasive positive pressure ventilation or high-flow nasal cannula, vasopressors, or vital sign monitoring more often than every 4 hours.

ICU: 83 patients (32.8%)

Non-ICU: 170 patients (67.2%)

 

N total at baseline:

N = 257 participants randomized (130 to the intervention group and 127 to the control group) at baseline.

 

Important prognostic factors2:

 

Age, mean (SD):

I: 65.8 (13.9)

C: 67.7 (14.1)

 

Sex, No./total No. (%) male

I: 68/129 (52.7%)

C: 68/124 (54.8%)

 

BMI, mean (SD)

I: 31.2 (9.3)

C: 29.8 (13.6)

 

Race and ethnicity, No. (%) (I/C)

Asian 11 (8.5) / 14 (11.3)

Black 33 (25.6) / 37 (29.8)

White 56 (43.4) / 46 (37.1)

Multiracial/unknown 29 (22.5) / 27 (21.8)

 

ICU, No./total No. (%)

I: 45/129 (34.9)

C: 38/124 (30.6)

 

Comorbidities, No./total No. (%) (I/C)

Hypertension 81/129 (62.8) / 70/123 (56.9)

Heart failure 0 / 2/124 (1.6)

Diabetes mellitus 51/128 (39.8) / 43/124 (34.7)

Dyslipidemia 48/129 (37.2) / 39/124 (31.5)

Coronary artery disease 7/129 (5.4) / 11/124 (8.9)

Valvular heart disease 1/129 (0.8) / 3/124 (2.4)

History of ischemic stroke 5/129 (3.9) / 3/124 (2.4)

History of carotid occlusive disease 0 / 0

Peripheral artery disease 4/129 (3.1) / 1/124 (0.8)

Chronic kidney disease 5/129 (3.9) / 4/124 (3.2)

Chronic lung disease 9/129 (7.0) / 8/124 (6.5)

Chronic liver disease/cirrhosis 2/129 (1.6) / 1/124 (0.8)

Pulmonary hypertension 1/127 (0.8) / 2/124 (1.6)

 

VTE risk factors, , No./total No. (%) (I/C)

Personal history of VTE 6/129 (4.7) / 2/124 (1.6)

History of cancer 16/129 (12.4) / 10/124 (8.1)

Active cancer 1/129 (0.8) / 4/124 (3.2)

Autoimmune disease 1/128 (0.8) / 2/124 (1.6)

Hormonal therapy/oral contraceptives 1/129 (0.8) / 1/124 (0.8)

Known thrombophilia 0 / 0

Recent stroke with paresis 1/129 (0.8) / 1/124 (0.8)

 

Clinical scores, mean (SD) (I/C)

IMPROVEDD VTE risk score 4.33 (1.48) / 4.22 (1.36)

Sepsis-induced coagulopathy score 2.35 (0.73) / 2.31 (0.85)

 

Laboratory parameters, mean (SD) (I/C)

White blood cell count, /μL 9600 (5800) / 9800 (8200)

Platelets, ×103/μL 287.7 (119.8) / 269.7 (108.2)

Serum creatinine, mg/dL 0.94 (0.45) / 1.00 (0.50)

Prothrombin time, s 13.5 (1.6) /13.6 (2.6)

D-dimer, ng/mL 3837 (6166) / 3183 (5409)

 

Medications prior to randomization, No./total No. (%)(I/C)

Low-molecular-weight heparin 106/128 (82.8) / 97/124 (78.2)

Unfractionated heparin 18/127 (14.2) / 23/121 (19.0)

Remdesivir 93/129 (72.1) / 85/124 (68.6)

Glucocorticoids 111/127 (87.4) / 93/123 (75.6)

Antiplatelets 40/129 (31.0) / 24/124 (19.4)

 

Oxygen therapy, No./total No. (%) (I/C)

Nasal cannula 80/129 (62.0) / 83/124 (66.9)

Nonrebreather mask 12/129 (9.3) / 11/124 (8.9)

Ventilation mask 4/129 (3.1) / 2/124 (1.6)

High-flow or noninvasive positive-pressure ventilation 20/129 (15.5) / 19/124 (15.3)

Invasive mechanical ventilation 8/129 (6.2) / 5/124 (4.0)

 

Length of hospital stay, mean (SD), d

I: 12.2 (9.3)
C: 11.6 (8.2)

 

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

 

Patients in the therapeutic dose group received enoxaparin at a dose of 1 mg/kg subcutaneously twice daily if CrCl was 30 L/min/1.73m2 or greater or 0.5 mg/kg twice daily if CrCl was 15-29 mL/min/1.73m2. Study drug was administered for the duration of hospitalization, including patient transfers to ICU settings.

 

Study protocol (Goldin, 2021):

Individual dose modification is not permitted unless the CrCl falls below 15 mL/min in the treatment arm (arm 0). In that case, conversion to dose-adjusted intravenous (IV) UFH is acceptable. The investigator is encouraged to convert back to treatment-dose enoxaparin as per protocol once the CrCl returns to values higher than or equal to 15 mL/min.

 

 

 

 

Describe control (treatment/procedure/test):

 

Patients in the standard-dose group received prophylactic or intermediate-dose heparin regimens per local institutional standard and could include UFH, up to 22500 IU subcutaneously (divided twice or thrice daily); enoxaparin, 30 mg or 40 mg subcutaneously once or twice daily (weight based enoxaparin 0.5mg/kg subcutaneously twice daily was permitted but strongly discouraged); or dalteparin, 2500 IU or 5000 IU subcutaneously daily. If CrCl fell below15 mL/min/ 1.73 m2, enoxaparin was converted to treatment-dose intravenous UFH until kidney function improved to CrCl greater than 15 mL/min/1.73 m2, when blinded-dose subcutaneous enoxaparin was resumed. Study drug was administered for the

duration of hospitalization, including patient transfers to ICU settings.

In the standarddose group, 76 patients (61.3%) received prophylactic doses of

heparin (enoxaparin, ≤40mg daily), while 48 patients (38.7%) received intermediate doses of heparin (enoxaparin, 30 mg

twice daily, 3 patients [2.4%]; enoxaparin, 40mg twice daily, 43 patients [34.7%]; enoxaparin, 0.5mg/kg twice daily, 2 patients [1.6%]).

 

Goldin, 2021:

Dose modification is allowed in the prophylactic/intermediate group (arm 1) if the CrCl falls below15 mL/min so that UFH up to 22,500 U daily (i.e., UFH 5,000 U SQ BID or TID or 7,500 IU SQ BID or TID) can be used. The investigator is encouraged to convert back to prophylactic-/intermediate dose LMWH/UFH as per protocol once the CrCl returns to values higher than or equal to 15 mL/min.

Length of follow-up:

Until 30 + 2 days after randomization.

 

Loss-to-follow-up:

4 patients did not receive study drug (2 withdrew consent and 2 reached end points prior to the first dose). That resulted in 253 patients in the modified intention-to-treat population for analysis:

Intervention: 129

Control: 124

 

The primary analysis was based on the modified intention to-treat population, followed by the per-protocol population.

 

 

 

Clinical Outcomes During the 30-Day, stratified for ICU and non-ICU:

 

Mortality

Not reported

 

Length of hospital stay

Not reported

 

ICU-admission

Not reported

 

Organ support free days

Not reported

 

Venous thromboembolism

Not reported

 

Major bleeding
No./total No. (%)

ICU patients:

I: 4/45 (8.9)

C: 0

RR (95% CI): 7.62 (0.42-137.03)

 

Non-ICU patients:

I: 2/84 (2.4)

C: 2/86 (2.3)

RR (95% CI): 1.02 (0.15-7.10)

 

 

Author’s conclusions:

Therapeutic dose LMWH reduced

the composite of thromboembolism and death compared with standard heparin thromboprophylaxis without increased major bleeding among hospitalized patients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients.

Sadeghipour, 2021

 

INSPIRATION trial – initial study

Type of study:

Open-label RCT [multicenter]

 

Setting:

10 academic centers in Tehran and Tabriz; recruitment: July 29, 2020, and Nov 19, 2020. Final follow-up date for 30-day primary outcome: Dec 19, 2020

 

Country:

Iran

 

Source of funding:

“The study was funded by the Rajaie Cardio-vascular Medical and Research Center. Some study authors, including the lead author, are affiliated with the Rajaie Cardio-vascular Medical and Research Center. Enoxaparin was provided through Alborz Darou, Pooyesh Darou, and Caspian Pharmaceuticals companies, and  atorvastatin and

matching placebo was provided by Sobhan Darou. None of these companies were study sponsors.”

 

 

 

 

 

COVID-19 patients admitted to ICU, within 7 days of hospitalization

 

Inclusion criteria:

  • admitted to the ICU
  • PCR confirmed COVID-19
  • within 7 days of the index hospitalization

 

Exclusion criteria:

  • life expectancy < 24 hours
  • established indication for
  • therapeutic-dose anticoagulation
  • weight < 40 kg,
  • pregnancy,
  • history of heparin-induced thrombocytopenia
  • platelet count < 50 ×103/μL,
  • overt bleeding

 

N total at baseline:

N = 600 randomized, after eligibility check and consent; n=566

Intervention: 280 (276 included in primary analysis)

Control: 286 (286 included in primary analysis)

 

Important characteristics:

Age, median (IQR:

I: 62 (51-70.7) y

C: 61 (47-71) y

Sex, n/N (%) male:

I: 162/276 (58.7%)

C: 163/286 (57.0%)

 

Duration of symptoms prior

to hospitalization, d, median (IQR)

I: 7 (4-8)

C: 7 (5-10)

 

Duration of hospitalization

before randomization, d, median (IQR)

I: 4 (2-6)

C: 4 (3-6)

 

Baseline indicators of illness severity, No. (%)

Patients with systolic blood pressure <100mmHg at the time of randomization

I: 25/276 (9.0%)

C: 33/286 (11.5%)

 

Vasopressor agent support

within 72 h of enrolment

I: 63/276 (22.8%)

C: 64/286 (22.3%)

 

Fraction of inspired oxygen >50% at the time of randomization

I: 112/276 (40.5%)

C: 122/286 (42.6%)

 

Acute Physiology and Chronic Health Evaluation II score at the time of randomization

I: median 8 (IQR 5-11)

C: median 8 (IQR 5-11)

 

Acute respiratory support, No. (%)

Nasal cannula

I: 10/276 (3.6%)

C: 14/286 (4.9%)

 

Face mask

I: 33/276 (12.0%)

C: 27/286 (9.4%)

 

Reservoir mask

I: 76/276 (27.5%)

C: 96/286 (33.6%)

 

High-flow nasal cannula

I: 9/276 (3.3%)

C: 6/286 (2.1%)

 

Non-invasive positive pressure

ventilation

I: 93/276 (33.7%)

C: 85/286 (29.7%)

 

Invasive positive pressure ventilation (endotracheal intubation)

I: 55/276 (19.9%)

C: 58 (20.3%)

 

Groups comparable at baseline? Yes, expect for history of cigarette smoking, which was more frequent in the intermediate dose group.

Intermediate-dose Prophylactic

Anticoagulation

 

Enoxaparin, 1mg/kg daily)

 

 

 

Standard-dose Prophylactic

Anticoagulation

 

Enoxaparin, 40mg daily

Length of follow up:

30 days

 

Not included in follow-up:

I: 4/280 (1.4%)

Reasons: ‘did not receive at least 1 dose of the assigned treatment’

C: 0/286 (0%)

 

Clinical outcomes at 30 days follow-up

 

Mortality

All-cause mortality, 30 days

I: 119/276 (43.1%)

C: 117/286 (40.9%)

Diff 2.2 (−5.9 to 10.3)

OR 1.09 (0.78 to 1.53)

P=0.50

 

Length of ICU stay

ICU length of stay, median (IQR)

I: 5 (2-10)

C: 6 (3-11)

 

Patients discharged from the ICU, n/total (%)

I: 169 / 276 (61.2%)

C: 174 / 286 (60.8%)

 

Organ support free days

Ventilator-free days, median (IQR)

I: 30 (3 to 30)

C: 30 (1 to 30)

 

New in-hospital kidney replacement therapy, n (%)

I: 10 out of 276 (3.6%) patients

C: 7 out of 286 (2.4%) patients

 

Venous thromboembolism

Adjudicated venous thromboembolism, n/total (%)

I: 9 / 276 (3.3%)

C: 10 / 286 (3.5%)

 

Objectively clinically diagnosed acute peripheral arterial thrombosis

I: 0 / 276

C: 0 / 286

 

Objectively clinically diagnosed stroke, n/total (%)

I: 1/276 (0.4%)

C: 1/286 (0.3%)

 

Objectively clinically diagnosed type I acute myocardial infarction, n/total

I: 0/276

C: 0/286

 

Major bleeding*, n/total (%)

I: 7/276 (2.5%)

C: 4/286 (1.4%)

Definitions:

Definitions of outcome Events are described in the study protocol

 

Remarks:

* Major bleeding consisted of Bleeding Academic Research Consortium (BARC) type 3 and 5, which defines type 3a as overt bleeding plus hemoglobin drop of 3 to 5 g/dL or any transfusion with overt bleeding; type 3b as overt bleeding plus hemoglobin drop 5 g/dL, cardiac tamponade, or bleeding requiring surgical intervention for control; type 3c as intracranial hemorrhage; and type 5 as fatal bleeding

 

Authors conclusion:

Among patients admitted to the ICU with COVID-19,

intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic

anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal

membrane oxygenation, or mortality within 30 days. These results do not support the routine

empirical use of intermediate-dose prophylactic anticoagulation in unselected patients

admitted to the ICU with COVID-19.

 

Bikdeli, 2021

 

INSPIRATION trial – extension 90 days follow-up of Sadeghipour (2021)(follow-up 30 days)

See Sadeghipour (2021)

See Sadeghipour (2021)

See Sadeghipour (2021)

See Sadeghipour (2021)

Length of follow up:

90 days

 

90-day outcome data were available for all 562 participants.

 

Not included in follow-up

See Sadeghipour (2021)

 

 

Clinical outcomes at 90 days follow-up

 

Mortality

All-cause mortality, no./total no. of patients (%)

I: 127 276 (46.0%)

C: 123/286 (43.0%)

HR (95%CI): 1.24 (0.97–1.60)

 

Length of ICU stay

Not reported

 

Organ support free days

Not reported

 

Venous thromboembolism

Adjudicated venous thromboembolism, no./total no. of patients (%)

I: 9/276 (3.3%)

C: 10/286 (3.5%)

HR (95%CI): 0.93 (0.48–1.76)

 

Objectively clinically diagnosed acute peripheral arterial thrombosis, no./total no. of patients (%)

I: 0/276

C: 0/286

 

Objectively clinically diagnosed stroke, no./total no. of patients (%)

I: 1/276 (0.4)

C: 1/286 (0.3)

HR (95%CI): 1.03 (0.06–16.56)

 

Objectively clinically diagnosed type I acute myocardial infarction, no./total no. of patients (%)

I: 0/276

C: 0/286

 

Major bleeding n/total (%)

I: 7/276 (2.5%)

C: 4/286 (1.4%)

Author’s conclusions:

By the end of 90-day clinical follow-up, intermediate dose prophylactic anticoagulation compared with standard-dose prophylactic anticoagulation did not result in a reduction in the 90-day composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality. Collectively, these findings do not support the routine use of intermediate-dose prophylactic anticoagulation in ICU patients with COVID-19.

Goligher, 2021

 

The REMAP-CAP, ACTIV-4a, and ATTACC Investigators

Type of study: open-label, international, adaptive, multiplatform RCT (mpRCR)

 

Setting and country:

The lead investigators of three international adaptive platform

trials harmonized their protocols to study the effect of therapeutic anticoagulation in patients hospitalized for Covid-19 into one integrated mpRCT. The participating platforms included the REMAP-CAP; ACTIV-4a andATTACC. Patients were included in the UK, USA, Canada, Brazil, Ireland, Netherlands, Australia, Nepal, Saudi Arabia, and Mexico.

 

Funding and conflicts of interest:

The trial was supported by multiple international funding organizations who had no role in the design, analysis or reporting of the trial result.

 

REMAP-CAP was supported by the European Union through FP7-HEALTH-2013-INNOVATION: the PREPARE consortium (grant 602525) and the Horizon 2020 research and innovation program: the RECOVER consortium (grant 101003589) and by grants from the Australian National Health and Medical Research Council (APP1101719 and APP1116530), the Health Research Council of New Zealand (16/631), the Canadian Institutes of Health Research (Strategy for Patient-Oriented

Research Innovative Clinical Trials Program Grant 158584 and COVID-19 Rapid Research Operating Grant 447335), the U.K. National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522).

 

The ATTACC platform was supported by grants from the Canadian Institutes of Health Research, LifeArc, Thistledown Foundation, Research Manitoba, CancerCare Manitoba Foundation, Victoria General Hospital Foundation, Ontario Ministry of Health, and the Peter Munk Cardiac Centre.

 

The ACTIV-4a platform was supported by the National Heart, Lung, and Blood Institute of the NIH and administered through OTA-20-011 and was supported in part by NIH agreement 1OT2HL156812-01.

 

Inclusion criteria:

Patients hospitalized for severe COVID-19* with confirmed infection.

 

Exclusion criteria:

Patients were ineligible if they had been admitted to the ICU with Covid-19 for 48 hours or longer (in REMAP-CAP) or to a hospital for 72 hours or longer (in ACTIV-4a and ATTACC) before randomization.

 

REMAP-CAP:

  • Known or suspected previous adverse reaction to unfractionated heparin or low molecular weight heparin including HIT
  • Intention to continue or commence dual antiplatelet therapy
  • Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker, or attending physician are not committed to full active treatment
  • Enrollment in a trial evaluating anticoagulation for proven or suspected COVID-19 infection, where the protocol of that trial requires continuation of the treatment assignment specified in that trial
  •  Clinical and/or laboratory bleeding risk or both that is sufficient to contraindicate therapeutic anticoagulation
  • Treating physician does not feel trial participation is in the best interest of the patient

 

ACTIV-4a:

  • Platelet count < 50x 109/L
  • Hemoglobin <80 g/L (8 g/dL)
  • History of heparin-induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
  • Patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely
  • Chronic mechanical ventilation via tracheostomy prior to hospitalization
  • Imminent death
  • Co-enrollment in other trials is permitted as long as the other trial does not test agents with antithrombotic properties and there is no other scientific contraindication
  • Contraindication to anticoagulation
  • Pregnancy

 

ATTACC:

  • Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds
  • Hemoglobin <80 g/L (8 g/dL)
  • History of heparin-induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
  • Current use of dual antiplatelet therapy
  • Chronic mechanical ventilation via tracheostomy prior to hospitalization
  • Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention
  • Enrollment in other trials related to anticoagulation or antiplatelet therapy
  • Bleeding risk

 

N total at baseline:

N = 1207 randomized; primary analysis involved 1103 patients

Intervention: 591 (534 with data on primary outcome available)

Control: 616 (564 with data on primary outcome available)

 

Important characteristics:

Age, mean (SD)

I: 60.4 y (13.1)

C: 61.7 y (12.5)

 

Sex, n/N (%) male

I: 387/536 (72.2%)

C: 385/567 (67.9%)

 

Country, n (%) (i/C)

UK: 389 (72.6%)/395 (69.7%)

USA: 79 (14.7%)/97 (17.1%)

Canada: 40 (7.5%)/54 (9.5%)

Brazil: 12 (2.2%)/6 (1.1%)

Other: 16 (3.0%/15 (2.6%)

 

BMI, median (IQR)

I: 30.4 (26.9-36.1)

C: 30.2 (26.4-34.9)

 

Baseline organ support, n/N (%)

Low-flow nasal cannula or face mask or no supplemental oxygen

I: 8/536 (1.5%)

C: 7/567 (1.2%)

High-flow nasal cannula

I: 170/536 (31.7%)

C: 188/567 (33.2%)

Non-invasive ventilation

I: 215/536 (40.1%)

C: 200/567 (35.3%)

Invasive mechanical ventilation

I: 143/536 (26.7%)

C: 172/567 (30.3%)

Vasopressors or inotropes

I: 94/536 (17.5%)

C: 109/567 (19.2)

 

Pre-existing conditions, n/ N (%)

Diabetes mellitus (type 1 or 2)

I: 171/536 (31.9%)

C: 191/567 (33.7%)

Severe cardiovascular disease

I: 44/524 (8.4%)

C: 45/558 (8.1%)

Chronic kidney disease

I: 58/509 (11.4%)

C: 43/521 (8.3%)

Chronic respiratory disease

I: 129/517 (25.0%)

C: 129/537 (24.0%)

Chronic liver disease

I: 6/516 (1.2%)

C: 3/548 (0.5%)

 

Baseline treatments, n/N (%)

Antiplatelet agent

I 37/485 (7.6%)

C: 38/494 (7.7%)

Remdesivir

I: 174/532 (32.7%)

C: 172/564 (30.5%)

Glucocorticoids

I: 426/522 (81.6%)

C: 458/555 (82.5%)

Tocilizumab

I: 11/532 (2.1%)

C: 9/564 (1.6%)

 

D-dimer level ≥ 2 times ULN at site, n/N (%)

I: 100/210 (47.6%)

C: 107/223 (48.0%)

 

Laboratory values, median (IQR)

D-dimer (ng/ml)

I: 823 (433–1740) (n = 189)

C: 890 (386–1844) (n = 196)

 

International normalized ratio

I: 1.1 (1-1.2) (n = 327)

C: 1.1 (1-1.2) (n = 324)

 

Neutrophil count per mm3

I: 7900 (5500-10,600) (n = 446)

C: 7800 (5600-10,700) (n = 478)

 

Lymphocyte count per mm3

I: 700 (500-1000) (n = 447)

C: 700 (500-900) (n = 482)

 

Platelet count per mm3

I: 247,000 (190,200-3167,500) (n = 530)

C: 244.000 (182,000–312,000) (n = 561)

 

Groups comparable at baseline? Yes

Therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin, administered according to local site protocols for the treatment of acute venous thromboembolism for up to 14 days or until recovery (defined as either hospital discharge or discontinuation of supplemental oxygen for at least 24 hours).

Usual-care pharmacologic thromboprophylaxis, administered at a dose and duration determined by the treating clinician according to local practice, which included either standard low-dose thromboprophylaxis or enhanced intermediate-dose thromboprophylaxis.

Length of follow-up:

The primary outcome, organ support–free days,

was evaluated on an ordinal scale indicating the

number of days free of cardiovascular or respiratory

organ support up to day 21 among patients

who survived to hospital discharge; patients who

died in the hospital by day 90 were assigned a

value of –1.

 

Loss-to-follow-up:

1207 patients initially included and randomized

 

Intervention:

N = 591

Exclusion:

57 (9.6%)

Reasons:

10 withdrew consent

2 did not have outcome data available

45 did not have confirmed COVID-19

 

Control:

N = 616

Exclusie:

52 (8.4%)

Reasons

13 withdrew consent

3 did not have outcome data available

36 did not have confirmed COVID-19

Clinical outcomes

Mortality

Death in hospital, n/total (%)

I: 199/534 (37.3)

C: 200/564 (35.5)

 

Length of ICU stay

Not reported

 

Organ support

Organ support–free days up to day 21, median (IQR)

I: 1 day (–1 to 16)

C: 4 days (–1 to 16)

 

Venous thromboembolism

Number of patients with VTE not specifically reported.

 

Deep venous thrombosis events

I: 6

C: 6

 

Systemic Arterial Thromboembolism events

I: 8

C: 3

 

Pulmonary embolism events

I: 13

C: 42

 

Ischemic cerebrovascular events

I: 8

C: 9

 

Myocardial infarction events

I: 7

C: 10

 

Number of patients with any thrombotic event (defined as pulmonary embolism, myocardial infarction, ischemic cerebrovascular event, systemic arterial thromboembolism).

I: 38/530 (7.2%)

C: 62/559 (11.1%)

 

Major bleeding

I: 20/529 (3.8%)

C: 13/562 (2.3%)

 

 

 

Definitions:

* Severe COVID-19 was defined as COVID-19 that led to receipt of ICU-level respiratory or cardiovascular organ support (oxygen through a highflow nasal cannula, noninvasive or invasive mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) in an ICU.

 

Definitions of major thrombotic and any thrombotic events are described in the study protocol.

 

Remarks:

-

 

Authors conclusion:

In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation

with heparin did not result in a greater probability of survival to hospital

discharge or a greater number of days free of cardiovascular or respiratory organ

support than did usual-care pharmacologic thromboprophylaxis.

Lemos, 2020

 

Type of study: randomized, open-label, phase II study

 

Setting and country:

Probably Brazil, but not mentioned in the article

 

Funding and conflicts of interest:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 

All authors declare no conflicts of interest.

Inclusion criteria:

Patients with age over 18 years-old, SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR), presence of acute respiratory distress syndrome (ARDS) according to the Berlin definition, severe clinical presentation with respiratory failure requiring mechanical ventilation, D-dimer levels greater than 1000 μg/L; prothrombin time/international normalized ratio (INR) < 1.5; activated partial thromboplastin time (aPTT)/ratio < 1.5, and platelet count greater than 100,000/mm3.

 

Exclusion criteria:

Patients with age greater than 85 years-old, creatinine clearance (CrCl) < 10 mL/min, severe circulatory shock with a dose of norepinephrine higher than 1.0 μg/kg/min, chronic renal failure in renal replacement therapy, Child B and C chronic liver disease, advanced diseases, such as active cancer, heart failure with functional class III and IV (New York Heart Failure Association), chronic obstructive pulmonary disease using home oxygen, advanced dementia, significant disability from stroke or severe head injury, cardiorespiratory arrest, pregnant women, recent major surgery or severe trauma in the last 3 weeks, recent stroke in the last 3 months, active bleeding, blood dyscrasia such as hemophilia, Von Willebrand factor deficiency, participation in another clinical investigation, indication for therapeutic anticoagulation due to pulmonary embolism, and acute coronary syndrome.

 

N total at baseline:

Intervention: 10

Control: 10

 

Important prognostic factors2:

Age, mean (SD):

I: 55 (10)

C: 58 (16)

 

Sex, male, n (%):

I: 9 (90%)

C: 7 (70%)

 

Clinical features

Fever, n (%)

I: 9 (90%)

C: 8 (80%)

 

Cough, n (%)

I: 9 (90%)

C: 8 (80%)

 

Dyspnea, n (%)

I: 9 (90%)

C: 9 (90%)

 

Myalgia, n (%)

I: 5 (50%)

C: 4 (40%)

 

Time from illness onset to hospital admission (days), mean (SD)

I: 7 (2)

C: 6 (3)

 

Medical history

 

Diabetes mellitus, n (%)

I: 4 (40%)

C: 3 (30%)

 

Hypertension, n (%)

I: 4 (40%)

C: 3 (30%)

 

Cardiovascular disease, n (%)

I: 1 (10%)

C: 1 (10%)

 

Immunocompromise, n (%)

I: 1 (10%)

C: 0 (0%)

 

BMI (Kg/m2), mean (SD)

I: 33 (8)

C: 34 (8)

 

Physical examination

 

Systolic blood pressure (mmHg), mean (SD)

I: 125 (20)

C: 120 (25)

 

Diastolic blood pressure (mmHg), mean (SD)

I: 78 (12)

C: 72 (14)

 

Heart rate (beats per minute), mean (SD)

I: 80 (20)

C: 77 (14)

 

Mechanical ventilation, n (%)

I: 10 (100%)

C: 10 (100%)

 

Previous condition before enrollment

 

ICU stay before enrollment (days), median (IQR)

I: 0 (0–2)

C: 1 (0–2)

 

Prophylactic anticoagulation, n (%)

I: 4 (40%)

C: 7 (70%)

 

Therapeutic anticoagulation, n (%)

I: 0 (0%)

C: 0 (0%)

 

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

 

therapeutic dose subcutaneous (SC) enoxaparin with the dose according to age and adjusted daily by the creatinine clearance (CrCl) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. See article for elaboration on the doses per age.

 

Describe control (treatment/procedure/test):

 

prophylactic anticoagulation (UFH and LMWH):

subcutaneous unfractionated heparin (UFH) at a dose of 5000 IU TID (if weight < 120 kg) and 7500 IU TID (if weight > 120 kg) or enoxaparin at a dose of 40 mg OD (if weight < 120 kg) and 40 mg BID (if weight > 120 Kg) according to the doctor's judgment.

Length of follow-up:

28 days

 

Loss-to-follow-up:

No loss to follow-up, 10 patients in each treatment arm.

 

 

Mortality

All cause 28-day mortality, n (%)

I: 1/10 (10%)

C: 3/10 (30%)

 

In-hospital mortality, n (%)

I: 2/10 (20%)

C: 5/10 (50%)

 

Length of ICU stay

Length of hospital stay; days, median (IQR)

I: 31 (22–35)

C: 30 (23–38)

 

ICU-free days, median (IQR)

I: 12 (2−12)

C: 0 (0−10)

 

Organ support

Ventilator-free days, median (IQR)

I: 15 (6–16)

C: 0 (0−11)

 

Venous thromboembolism

VTE not reported

 

Thrombotic events, n (%)

I: 2 (20%)

C: 2 (20%)

 

Major bleeding, m (%)

I: 0 (0%)

C: 0 (0%)

Author’s conclusions:

Therapeutic enoxaparin improved gas exchange over time and increased the ratio of successful liberation from mechanical ventilation.

 

Risk of bias table for intervention studies (randomized controlled trials)

 

Study reference

 

(first author, publication year)

Was the allocation sequence adequately generated? 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed? 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

 

Were patients blinded?

 

Were healthcare providers blinded?

 

Were data collectors blinded?

 

Were outcome assessors blinded?

 

Were data analysts blinded?

 

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting? 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

LOW

Some concerns

HIGH

 

Spyropoulos, 2021

 

HEP COVID trial

Definitely yes

 

Reason:

Randomization well-described and well-performed

 

Study protocol

The Feinstein Institutes Biostatistics Unit (Northwell Health) developed and implemented the randomization procedure using the Biostatistics Randomization Management System (BRMS). BRMS is a secure, HIPAA-compliant, web-based application that allows investigators to randomize subjects into randomized clinical trials (RCTs) using their personal computer. BRMS allows for multicenter, stratified, and single/double-blinded RCTs, using permuted blocks. Eligible patients will be stratified according to whether their level of care corresponds to intensive care unit (ICU) care or not. Subjects will be randomly assigned to the treatment arm (arm 0: treatment dose of LMWH) or the prophylactic-/ intermediate-dose arm (arm 1: prophylactic/intermediate dose of LMWH or UFH) in a 1:1 ratio.

 

Spyropoulos, 2021:

Randomization was performed using a secure web application

and was stratified based on noncritical care (non– intensive care unit [ICU]) or critical care (ICU) status at the time of randomization. Participants were

randomly assigned 1:1 to therapeutic-dose enoxaparin or institutional

standard prophylactic or intermediate-dose heparins.

Definitely yes

 

Reason:

 

Study protocol

BRMS is a secure, HIPAA-compliant, web-based application that allows investigators to randomize subjects into randomized clinical trials (RCTs) using their personal computer.

 

Spyropoulos, 2021:

The study pharmacists as well as data abstractors and designated randomization personnel (i.e., research coordinators and/or research nurses performing the randomization process) will be unblinded.

Were patients blinded?

Definitely yes

 

Were healthcare providers blinded?

Definitely no

 

Were data collectors blinded?

Definitely yes

 

Were outcome assessors blinded?

Unknown

 

Were data analysts blinded?

Unknown

 

Reason:

Study protocol (Goldin, 2021):

Due to the pragmatic nature of this study and pseudoblinded trial design, at the time of randomization the study subject and corresponding site PIs will be blinded (unaware of specific treatment arm to which the patient is assigned). The study pharmacists as well as data abstractors and designated randomization personnel (i.e., research coordinators and/or research nurses performing the randomization process) will be unblinded.

 

Spyropoulos, 2021:

Patients and investigators were blinded to treatment assignment

as much as possible.

 

Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data.

 

Discussion part: Although both investigators

and patients were blinded to study drug regimen,

other unblinded personnel may have introduced bias affecting

outcome ascertainment.

Probably yes

 

Reason:

There was no loss to follow-up. However, the primary analysis was based on the modified intention to-treat population, followed by the per-protocol population. We assumed that the modified ITT did not have an influence on the risk of bias, as the number of patients that was different between the ITT and modified ITT population was very small (1 in the intervention group and 3 in the control group).

Definitely yes

 

Reason:

Study protocol available, all reported outcomes in study protocol reported in trial.

Probably yes

 

Reason:

Funding/Support: This work was supported by the Feinstein Institutes for Medical Research, the Broxmeyer Fellowship in Clinical Thrombosis, and

grant R24AG064191 from the National Institute on Aging.

Role of the funder/Sponsor: The funders had no role in the design and conduct of the study;

collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit

the manuscript for publication.

 

Modified intention-to-treat analysis performed. However, only 1 and 3 patients in the intervention and control group, respectively, were not analysed.

LOW (mortality, length of hospital or ICU stay, organ support and organ support free days, ventilator-free days)

 

 

HIGH (venous thromboembolism, thromboembolic complications, major bleeding, heparin induced thrombocytopenia, and cumulative transfusion)

 

Reasons:

- patients and data collections blinded, but all other personnel including the healthcare providers were not blinded and could therefore have influenced the ‘soft’ outcome measures

 

 

Sadeghipour, 2021

 

INSPIRATION trial – initial study

Definitely yes

 

Reason:

‘Randomization was done using an electronic web-based system with permuted blocks of 4 and allocation sequence concealment.

Eligible patients were allocated in 1:1 ratio to receive intermediate-dose or standard-dose prophylactic

anticoagulation.’

Definitely yes

 

Reason:

Protocol: ‘1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.’

Hard clinical outcomes and laboratory values: Probably yes

 

Other clinical outcomes:

Probably no

 

Reason:

‘anticoagulation assignment was open-label. Using a double-dummy design during the COVID-19 pandemic was not considered feasible. However, the allocation sequence was concealed and outcomes were blindly adjudicated and analyzed.’

Probably yes

 

Reason:

4% of patients in the intervention group was not included in the primary analysis and 0% of patients in the control group. Reasons for not including patients are described.

Unlikely to induce a bias in the results.

 

Probably yes

 

Reason:

Elaborate protocol; publication in line with protocol; distinction made between prespecified and post hoc subgroup analyses.

 

 

Probably yes

 

Reason:

Some study authors are affiliated with the study funder (Rajaie Cardiovascular and Medical Research Center). Neither the funder, nor the companies who donated the study drugs (Alborz Darou, Pooyesh Darou and Caspian Pharmaceuticals) had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

 

Analyses not performed according to intention-to-treat protocol, however small number of patients excluded;

I: N=280 met criteria and did not withdraw consent, of which 276 (98.6%) included in primary analysis

C: 286 met criteria and did not withdraw consent, of which 286 (100%) included in primary analysis

 

LOW (mortality, length of hospital or ICU stay, organ support and organ support free days, ventilator-free days)

 

 

HIGH (venous thromboembolism, thromboembolic complications, major bleeding, heparin induced thrombocytopenia, and cumulative transfusion)

 

Reasons:

- open-label trial, no use of blinding could have influenced the ‘soft’ outcome measures

 

 

Bikdeli, 2021

 

INSPIRATION trial – extension 90 day follow-up Sadeghipour (2021)(follow-up 30 days)

See Sadeghipour, 2021

 

See Sadeghipour, 2021

 

See Sadeghipour, 2021

 

See Sadeghipour, 2021

See Sadeghipour, 2021

 

See Sadeghipour, 2021

 

LOW (mortality, length of hospital or ICU stay, organ support and organ support free days, ventilator-free days)

 

 

HIGH (venous thromboembolism, thromboembolic complications, major bleeding, heparin induced thrombocytopenia, and cumulative transfusion)

 

Reasons:

- open-label trial, no use of blinding could have influenced the ‘soft’ outcome measures

 

 

Goligher, 2021

 

The REMAP-CAP, ACTIV-4a, and ATTACC Investigators

Definitely yes

 

ReasonL

Randomization was performed with the use of separate central Web-based systems for each platform.

Definitely yes

 

Reason:

Protocol: ‘Allocation concealment will be maintained by using centralized randomization that is remote from

study sites.’

Hard clinical outcomes and laboratory values: Probably yes

 

Other clinical outcomes:

Probably no

 

Reason:

Open-label trial

Probably yes

 

Reason:

Loss to follow-up was comparable in both groups and reasons are described.

 

Missing data were queried with the site. Data imputed where appropriate.

Probably yes

 

Reason:

Elaborate protocol; publication in line with protocol

 

Definitely no

 

Reason:

The trial was supported

by multiple international funding organizations

that had no role in the design, analysis, or reporting

of the trial results, with the exception of the

ACTIV-4a protocol, which received input on design

from professional staff members at the National

Institutes of Health and from peer reviewers.

 

High numbers of patients excluded in both groups after randomization. No ITT analysis performed. Different numbers of total patients in Table 2.

 

Studie is stopped due to meeting the stopping criteria for futility. However, this would probably not have caused risk of bias, as the study was not stopped in a ‘random high’ effect.

 

HIGH (all outcome measures)

 

Reasons:

- open-label trial, no use of blinding could have influenced the ‘soft’ outcome measures

- No ITT performed and many patients excluded after randomization in both groups

Lemos, 2021

Defnitely yes

 

Reason:

We used blocked randomization, and the participants were randomized in a 1:1 ratio within two blocks of ten patients each. The patients were assigned to each treatment by drawing the sequential numbering of opaque envelopes containing the treatment allocation

Probably yes

 

Reason:

We used blocked randomization, and the participants were randomized in a 1:1 ratio within two blocks of ten patients each. The patients were assigned to each treatment by drawing the sequential numbering of opaque envelopes containing the treatment allocation

Definitely no

 

Reason:

Open-label trial

Definitely yes

 

Reason:

No loss to follow-up

Unknown

 

No protocol

Definitely yes

 

Reason:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 

All authors declare no conflicts of interest.

 

 

LOW (mortality, length of hospital or ICU stay, organ support and organ support free days, ventilator-free days)

 

 

HIGH (venous thromboembolism, thromboembolic complications, major bleeding, heparin induced thrombocytopenia, and cumulative transfusion)

 

Reason:

open-label trial, no use of blinding could have influenced the ‘soft’ outcome measures

 

Table of excluded studies

Author and year

Reason for exclusion

Connors, 2021

Outpatients, does not fit PICO

Perepu, 2021

Exclusion, no difference made between ICU and non-ICU patients

Diep, 2021

No publication available

Ananworanich, 2021

Outpatients, does not fit PICO

Cuker, 2021

Is not an RCT but a guideline based on observational studies

Sholzberg, 2021

Included in non-ICU submodule, but not in the ICU submodule

Lawler, 2021

Included in non-ICU submodule, but not in the ICU submodule

Lopes, 2021

Included in non-ICU submodule, but not in the ICU submodule

Marcos, 2021

Included in non-ICU submodule, but not in the ICU submodule

 

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 14-04-2022

Laatst geautoriseerd  : 14-04-2022

Van NVSHA en NVVC wordt de goedkeuring binnenkort verwacht.

 

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten en werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS).

 

De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

 

Deze richtlijnmodule is ontwikkeld in samenwerking met:

  • Nederlandse Vereniging voor Intensive Care
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging voor Cardiologie
  • Nederlandse Vereniging voor Ziekenhuisapothekers
  • Nederlandse Vereniging van Spoedeisende Hulp Artsen
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Harteraad

Initiatief en autorisatie

Initiatief:
  • Nederlandse Internisten Vereniging
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging van Ziekenhuisapothekers
  • Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
  • Nederlandse Vereniging voor Intensive Care
  • Patiëntenfederatie Nederland
  • Harteraad

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodules is in 2020 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen die betrokken zijn bij de behandeling van patiënten met COVID-19.

 

Werkgroep

  • Prof. dr. M.V. Huisman (voorzitter), internist-vasculair geneeskundige, Leids Universitair Medisch Centrum (LUMC), NIV
  • Dr. F.A. Klok, internist-vasculair geneeskundige, Leids Universitair Medisch Centrum (LUMC), NIV
  • Prof. dr. H.C.J. Eikenboom, internist-vasculair geneeskundige/hematoloog, Leids Universitair Medisch Centrum (LUMC), NIV
  • Prof. dr. S. Middeldorp, internist-vasculair geneeskundige, Radboud Universitair Medisch Centrum (Radboudumc), NIV
  • Dr. M.J.H.A. Kruip, internist-hematoloog, Erasmus Medisch Centrum (Erasmus MC), NIV
  • Prof. dr. K. Meijer, internist-hematoloog, Universitair Medisch Centrum Groningen (UMCG), NIV
  • Dr. M. Coppens, internist-vasculair geneeskundige, Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Prof. dr. P.W. Kamphuisen, internist-vasculair geneeskundige, Tergooi Medisch Centrum (Tergooi MC), Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Dr. M.C.A. Müller, internist-intensivist, Amsterdam University Medical Centers (Amsterdam UMC), NVIC
  • Dr. J.P.J. Wester, internist-intensivist, OLVG, NVIC
  • Dr. R. Vink, internist-intensivist, Tergooi Medisch Centrum (Tergooi MC), NVIC
  • Dr. L.M. van den Toorn, longarts, Erasmus Medisch Centrum (Erasmus MC), NVALT
  • Dr. R.G. Tieleman, cardioloog, Martini Ziekenhuis, NVVC
  • Dr. J. Diepstraten, ziekenhuisapotheker, Amphia ziekenhuis, NVZA
  • Dr. N. van Rein, ziekenhuisapotheker, Leids Universitair Medisch Centrum (LUMC), NVZA
  • Drs. N. Buenen, SEH-arts, Máxima Medisch Centrum (MMC), NVSHA
  • Prof. dr. Ir. Y.C.M. Henskens, klinisch chemicus, Maastricht Universitair Medisch Centrum (Maastricht UMC), NVKC

 

Meelezer:

  • Dr. I. Schalkers, Beleidsadviseur Patientenparticipatie, Harteraad

 

Onafhankelijke reviewers:

  • Dr. E. van Dijk, neuroloog, Radboud Universitair Medisch Centrum, (Radboudumc), NVN
  • Drs. P.R. van der Valk, internist-vasculair geneeskundige, Universitair Medisch Centrum Utrecht (UMC Utrecht), NIV

 

Met ondersteuning van:

  • F.M. Janssen, MSc, junior adviseur, Kennisinstituut van Medisch Specialisten
  • dr. S.N. Hofstede, senior adviseur, Kennisinstituut van Medisch Specialisten
  • drs. I. van Dusseldorp, senior literatuurspecialist, Kennisinstituut van Medisch Specialisten

 

In 2020 is een multidisciplinair expertiseteam behandeling COVID-19 ingesteld, bestaande uit vertegenwoordigers van alle relevante die betrokken zijn bij de zorg voor patiënten met COVID-19. Dit expertiseteam fungeerde als stuurgroep, welke opdracht heeft gegeven tot het ontwikkelen van de module, alsmede fungeerde als klankbordgroep.

 

Stuurgroep (expertiseteam Behandeling COVID-19)

  • Dr. L.M. van den Toorn (voorzitter), longarts, Erasmus Medisch Centrum (Erasmus MC), NVALT
  • Dr. M.G.J. de Boer, internist-infectioloog, Leids Universitair Medisch Centrum (LUMC), SWAB/NIV)
  • Drs. A.J. Meinders, internist-intensivist, St. Antonius Ziekenhuis, NVIC
  • Prof. dr. D.W. de Lange, intensivist-toxicoloog, Universitair Medisch Centrum Utrecht (UMC Utrecht), NVIC
  • Dr. C.H.S.B. van den Berg, infectioloog-intensivist Universitair Medisch Centrum Groningen (UMCG), NVIC
  • Dr. S.U.C. Sankatsing, internist-infectioloog, Diakonessenhuis, NIV
  • Dr. E.J.G. Peters, internist-infectioloog, Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Drs. M.S. Boddaert, arts palliatieve geneeskunde, Leids Universitair Medisch Centrum (LUMC), IKNL
  • Dr. P.L.A. Fraaij, kinderarts-infectioloog, Erasmus Medisch Centrum (Erasmus MC), Sophia Kinderziekenhuis, NVK
  • Dr. E. van Leeuwen, gynaecoloog, Amsterdam University Medical Centers (Amsterdam UMC), NVOG
  • Dr. J.J. van Kampen, arts-microbioloog, Erasmus Medisch Centrum (Erasmus MC), NVMM
  • Dr. M. Bulatović-Ćalasan, internist allergoloog-immunoloog en klinisch farmacoloog, Universitair Medisch Centrum Utrecht (UMC Utrecht), Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Drs. A.F.J. de Bruin, anesthesioloog-intensivist, St. Antonius Ziekenhuis, NVA
  • Drs. A. Jacobs, klinisch geriater, Catharina Ziekenhuis, NVKG
  • Prof. dr. P.H.M. van der Kuy, ziekenhuisapotheker, Erasmus Medisch Centrum (Erasmus MC), NVZA

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

 

Werkgroep

Achternaam werkgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Huisman (voorzitter)

internist vasculaire geneeskunde Leids Universitair Medisch Centrum

hoogleraar Interne Geneeskunde

voorzitter commissie herziening Antitrombotisch Beleid - onbetaald
voorzitter commissie landelijke transmurale afspraak antistolling - onbetaald
voorzitter werkgroep met inspectie over indicator antistolling – onbetaald

voorzitter Dutch Thrombosis Network – onbetaald

member European Society of Cardiology Guideline on Pulmonary Embolism – onbetaald

member American College of chest Physicians VTE update – onbetaald

- adviseur farmaceutische bedrijven die (nieuwe) antistollingsmiddelen maken - betaald; gelden gaan naar afdeling Interne Geneeskunde LUMC

 

- ZoNMw grant Dutch-AF - registry met onderzoek op het gebied van antistolling bij patienten met atriumfibrilleren; betaald, gelden gaan naar afdeling Interne Geneeskunde LUMC

- ZonMw - Hartstichting grant Coronis - onderzoek naar herseninfarct bij COVID -19

 

- Research grants van farmaceutische bedrijven die (nieuwe) antistollingsmiddelen maken - betaald; gelden gaan naar afdeling Interne Geneeskunde LUMC

Zie overkoepelende actie

Klok

Internist, LUMC, Leiden

Gastwetenschapper, Universiteit Mainz, Mainz, Duitsland (0-uren contract)

Algemeen commissiewerk voor ISTH, ESC, ERS. Richtlijncommissie voor ESC.

Richtlijncommissie voor ASH die zich buigt over tromboseprofylaxe bij COVID-19

Unrestricted research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Daiichi-Sankyo, Actelion, the Dutch thrombosis association, The Netherlands Organisation for Health Research and Development and the Dutch Heart foundation

Zie overkoepelende actie

Eikenboom

Hoogleraar medisch specialist (fte 1,0)

LUMC, afdeling Interne geneeskunde, divisie Trombose en Hemostase

Sectie editor van tijdschrift HemaSphere (honorarium naar instituut)

Voorzitter Nederlandse Vereniging voor Hemofilie Behandelaars (NVHB) (onbetaald)
Wetenschappelijk advies raad Trombosestichting Nederland (TSN) (onbetaald)
Lid werkgroep horizonscan Zorginstituut Nederland (ZIN) (onbetaald)

 

 

- LSBR: Modelling Von Willebrand disease with patient-specific
induced pluripotent stem cells - projectleider
TSN: Lowering von Willebrand factor as a therapeutic approach to reduce the risk of arterial thrombosis - projectleider
NWO (TTW) (deel via CSL Behring): Gene-targeted treatment strategies for the management of Von Willebrand Disease - projectleider
NWO (NWA): SYMPHONY: Orchestrating personalised treatment
for patients with bleeding disorders - geen projectleider
CSL Behring: BOECs to study Pathogenic Mechanisms and Potential Therapies for Bleeding Disorders - projectleider
Stichting van den Tol: Von Willebrand ziekte in Nederland – Prospectieve studie (WiN-Pro) – projectleider

 

- Sprekersgeld: Roche, Cellgene
Congresreis vergoeding: Roche

Zie overkoepelende actie

Middeldorp

- Internist-vasculaire geneeskunde
- Afdelingshoofd Afdeling Interne Geneeskunde Radboudumc.
- Kernhoogleraar Interne Geneeskunde Radboud Universiteit.
- Hoogleraar Inwendige Geneeskunde ihb Trombose en Hemostase Universiteit van Amsterdam

Onbetaald:
- Council member en Vice-chair van de Guidance and Guidelines Committee van de International Society of Thrombosis and Haemostasis (ISTH)
- ASH VTE Richtlijn commissielid/chair (Thrombophilia en Pregnancy, geen betrokkenheid bij de ASH richtlijn antistolling bij COVID19)

- Betaald adviseurschap NB - alle honoraria (personal fees) gaan naar mijn ziekenhuis, geen persoonlijk financieel belang of eigen stichting:

AbbVie
Bayer
BMS/Pfizer
Boehringer Ingelheim
Daichi Sankyo
GSK
Norgine
Portola/Alexion
Sanofi

 

- Financiele bijdragen aan investigator-initiated onderzoek:
Bayer
Boehringer Ingelheim
Daichi Sankyo
Pfizer

 

- Academisch belang:
Lid van het Steering Committee en medeauteur van de RAPID trial (https://www.bmj.com/lookup/doi/10.1136/bmj.n2400).
Lid en medeauteur van het Anticoagulation Domain van de Remap-Cap studies (http://www.nejm.org/doi/10.1056/NEJMoa2103417 en http://www.nejm.org/doi/10.1056/NEJMoa2105911)

 

Lid richtlijn COVID coagulopathie ISTH (gestart december 2021).

Zie overkoepelende actie

Kruip

Internist-hematoloog Erasmus MC

Medisch leider trombosedienst Star-shl, gedetacheerd vanuit het Erasmus MC (betaald) voorzitter Federatie Nederlandse Trombosediensten (FNT, onbetaald)

- "Caging the dragon: translation approach to unravel and prevent COVID-19 associated thrombosis" gefinancieerd door ZonMW en Trombose Stichting Nederland

 

- Financiële bijdrage aan investigator-initiated onderzoek, gelden ten gunste van afdeling hematologie Erasmus MC:

Sobi

 

- Sprekersvergoeding, gelden ten gunste van afdeling hematologie Erasmus MC:

Bayer, Roche, Sobi, BMS

 

Zie overkoepelende actie

Meijer

Internist-hematoloog, UMCG

Voorzitter Nederlandse Vereniging voor Hematologie, onbetaald
adviseur College ter Beoordeling van Geneesmiddelen, ad hoc adviezen over middelen binnen benigne hematologie, betaald (aan afdeling)
gedeeld voorzitter Transmuraal Trombose Expertise Centrum Noord Nederland, onbetaald
Lid Wetenschappelijke Adviesraad Landsteiner Stichting voor Bloedtransfusie Research, onbetaald

- NWO: Ethische aspecten van gentherapie, binnen Symphony project - projectleider voor Symphony

 

- Rollen als voorzitter van de NVvH en gedeeld voorzitter Trombose Expertise Centrum Noord Nederland kunnen gezien worden als boegbeeldfunctie, ik heb daarmee belang DAT er een richtlijn komt, maar niet bij hoe de inhoud is.

 

- In de afgelopen drie jaar
speaker fees from Alexion, Bayer and CSL Behring
participation in trial steering committee for Bayer (factor VIII concentraat voor
hemofilie)
Consulting fees from Uniqure (gentherapie voor hemofilie)
participation in data monitoring and endpoint adjudication committee for Octapharma
(PCC voor DOAC gerelateerde bloedingen)

Zie overkoepelende actie

Coppens

Internist-vasculaire geneeskunde en hemofilie. Hoofd Antistollingscommissie. Amsterdam
Universitair Medische Centra.

Voorzitter werkgroep trombose en hemostase, Nederlandse Vereniging van Internisten
Vasculaire Geneeskunde (NVIVG). Werkzaamheden: voornamelijk beoordeling richtlijnen
en afvaardiging in richtlijncommissies op gebied van bloedstolling. Onbetaald.
Lid Wetenschappelijke Adviesraad Trombosestichting Nederland (TSN).
Werkzaamheden: inhoudelijke beoordeling projectvoorstellen bij jaarlijkse TSN
subsidieronde. Onbetaald.

- Daiichi Sankyo. Lid Steering Committee van de ETNA-VTE Europe studie. Een
post-marketing studie naar veiligheid en effectiviteit van edoxaban in de behandeling
van veneuze trombo-embolie.

- Bayer. Fase 1-2 onderzoek naar gentherapie voor hemofilie A.
[Bayer is tevens fabrikant van het antistollingsmiddel rivaroxaban dat ingezet zou
kunnen worden als tromboseprofylaxe.]
Dutch COVID & Thrombosis Coalition. Door ZonMW en Trombosestichting
Nederland gefinancierd onderzoek naar de rol van stolling en trombose bij COVID-19
infecties o.l.v. Marieke Kruip, Erasmus MC. Participatie in enkele, klinisch
georiënteerde deelstudies.

 

- Het hoge risico op veneuze trombose bij COVID-19 en de zeldzame, maar ernstige
trombotische bijwerking van sommige SARS-CoV-2 vaccins heeft geleid tot veel
media-aandacht voor mijn veld van onderzoek en expertise, nl. veneuze trombose en
antitrombotische behandeling. Betrokkenheid bij deze richtlijn draagt die mogelijk tot
media-aandacht kan leiden, kan bijdragen aan mijn reputatie en naamsbekendheid.

Zie overkoepelende actie

Kamphuisen

Internist, Tergooi MC, 0,8 fte
Hoogleraar Vasculaire Geneeskunde Amsterdam UMC, 0.2 fte

Geen

Mijn wetenschappelijk onderzoek wordt gesubsidieerd door Tergooi MC, Trombose stichting Nederland, Nederlandse Hartstichting. Verder investigator grant van Daiichi Sankyo en Roche diagnostics

Zie overkoepelende actie

Müller

internist-intensivist, Amsterdam UMC, lokatie AMC

Geen

Geen

Geen

Wester

Internist-intensivist
OLVG Oost|West, Amsterdam

Geen

Geen

Geen

Vink

Internist-intensivist
Intensive care Tergooi Medisch Centrum

Geen

Geen

Geen

Van den Toorn

Voorzitter NVALT
Longarts in Erasmus MC Rotterdam

Geen

Voorzitter NVALT, ik heb geen baat bij welke uitkomst dan ook

Geen

Tieleman

Cardioloog, electrofysioloog Martiniziekenhuis Groningen 0,8 FTE en UMCG 0,2 FTE

Voorzitter pijler Implementatie DCVA 0,1 FTE

- Ik heb sponsoring, onderzoeksgeld en honoraria voor nascholing ontvangen van Boehringer Ingelheim, Bayer en BMS/Pfizer, Daichi Sankyo

 

- Boehringer Ingelheim: Covid en cardiovasculair lijden (CAPACITY studie) - geen projectleider
Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo: RACE 4 studie (atriumfibrilleren en gespecialiseerde AF poliklinieken) - projectleider

Zie overkoepelende actie

Diepstraten

Ziekenhuisapotheker en Medisch manager Amphia Ziekenhuis

SIG Hematologie NVZA onbetaald
Programmacommissie Ziekenhuisfarmaciedagen NVZA onbetaald

Stichting Phoenix
Boehringer Ingelheim
Daiichi Sankyo
Bayer
Pfizer
Antithrombotic stewardship: a multidisciplinary team approach towards improving antithrombotic therapy during and after hospitalization. - geen projectleider

Zie overkoepelende actie

Van Rein

Ziekenhuisapotheker, Klinische Farmacie en Toxicologie, LUMC (32 uur per week)
Postdoctoraal onderzoeker, Klinische Epidemiologie, LUMC (8 uur per week)

Geen

Trombose Stichting Nederland: Balans bloedingen trombose atrium fibrilleren patienten tijdens behandeling met antistolling optimaliseren - projectleider
ZonMw: Balans bloedingen+ trombose voor veneus trombose patienten optimaliseren - geen projectleider
Haga Wetenschapsfonds: DOAC spiegels voor OK meten - projectleider

Geen

Buenen

SEH-arts KNMG - Máxima MC - vaste dienst
SEH-arts KNMG - Bernhoven - incidentele diensten

Geen

Geen

Geen

Henskens

0,9 fte Klinisch chemicus, waarnemend hoofd Centraal Diagnostisch Laboratorium Maastricht UMC+
0,1 fte Universiteit Maastricht, Faculty Health Medicine Life Sciences, hoogleraar Klinische Chemie, in het bijzonder hemostase

Voorzitter concilium NVKC sinds 2020, vacatiegelden
lid Raad Opleiding FMS namens NVKC
voorzitter Vereniging Hematologische Laboratoria, geen vergoeding
Voorzitter Regionale gebruikersraad ZON Sanquin, geen vergoeding
lid Landelijke gebruikersraad Sanquin, geen vergoeding
lid landelijke werkgroep Tijd voor Verbinding, antistollingszorg, namens NFU, vacatiegelden
lid richtlijn werkgroep, Hemofilie en verwante hemostasestoornissen, vacatiegelden
lid richtlijn werkgroep, Peri-operatief bloed- en (anti)stollingsmanagement, vacatiegelden

Geen

Geen

 

Overkoepelende actie

Om potentiële belangenverstrengelingen te voorkomen is de module tegengelezen door twee onafhankelijke reviewers. Dit betreft één onafhankelijke reviewer van de regiehoudende vereniging (Nederlandse Internisten Vereniging) en één onafhankelijke reviewer van een wetenschappelijke vereniging die niet in de werkgroep zitting heeft genomen (Nederlandse Vereniging voor Neurologie). Zij controleren of de aanbeveling duidelijk volgt uit de overwegingen en niet mogelijk gekleurd wordt door potentiële belangen. Daarnaast is de module tegengelezen door de stuurgroep.

 

Stuurgroep

Achternaam stuurgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Van den Toorn (voorzitter)

Voorzitter NVALT
Longarts in Erasmus MC

Geen

Geen

Geen actie nodig

De Boer

Internist-Infectioloog, senior medisch specialist, LUMC, afdeling infectieziekten

- Voorzitter Stichting Werkgroep Antibioticabeleid (onkostenvergoeding)
- Voorzitter NIV-COIG commissie Immuniteit en Infectieziekten (beperkt honorarium)
- Sectieredacteur Infectieziekten Nederlands Tijdschrift voor Geneeskunde (onbetaald)
- Lid FMS Expertiseteam behandeling COVID-19 (onbetaald)

Geen

Geen actie nodig

Meinders

Internist-intensivist, St.-Antonius ziekenhuis, Nieuwegein

commissie werk
geen betaalde nevenfunctie of relatie industrie

Geen

Geen actie nodig

De Lange

Afdelingshoofd Nationaal Vergiftigingen Informatie Centrum (NVIC) van het UMC Utrecht
Intensivist, afdeling Intensive Care, UMC Utrecht

secretaris Stichting Nationale Intensive Care Evaluatie (Stichting NICE) (onbetaald)

Geen

Geen actie nodig

Van den Berg

Infectioloog-intensivist, UMCG

Geen

Geen

Geen actie nodig

Sankatsing

Internist-infectioloog/internist-acute geneeskunde, Diakonessenhuis, Utrecht

- Bestuurslid Nederlandse Vereniging van Internist-Infectiologen (NVII) (onbetaald).
- Lid Commissie Richtlijnen Nederlandse Internisten Vereniging (NIV) (betaald).
- Lid Werkgroep Richtlijn Sepsis II en III van de FMS (betaald).
- Lid Regionaal Coördinatieteam van het Regionaal Zorgnetwerk Antibioticaresistentie Utrecht (betaald).

Geen

Geen actie nodig

Peters

Internist - aandachtsgebieden infectieziekten en Acute Geneeskunde Amsterdam UMC, locatie Vumc.
Opleider Infectieziekten Vumc
Plaatsvervangend Hoofd Infectieziekten Amsterdam UMC

Wetenschappelijk Secretaris International Working Group on the Diabetic Foot (onbetaald)
Voorzitter Werkgroep Behandeling Gewrichtsprotheseinfecties voor Stichting Werkgroep Antibioticabeleid (onbetaald)

Geen

Geen actie nodig

Boddaert

Medisch adviseur bij Integraal Kankercentrum Nederland (IKNL) en Palliatieve Zorg Nederland (PZNL)

Arts palliatieve geneeskunde in LUMC

Geen

Geen

Geen actie nodig

Fraaij

Kinderarts infectioloog- immunoloog, Erasmus MC-Sophia, Rotterdam
Klinische wetenschapper, Viroscience, ErasmusMC, Rotterdam

Bestuur Stichting Infecties bij Kinderen (onbetaald)

deelname aan RECOVER, European Union's Horizon 2020 research

Geen actie nodig

Van Leeuwen

Gyaecoloog Amsterdam Universitair Medisch Centra
Bestuurder Stichting Prenatale Screening Amsterdam en Omstreken (SPSAO)

Geen

Geen

Geen actie nodig

Van Kampen

Arts-microbioloog, afdeling Viroscience, Erasmus MC

- associate editor antimicrobial resistance & infection control (onbetaald)
- lid sectie virusdetectie SKML (onbetaald)

- lid antibioticacommissie Erasmus MC (onbetaald)
- plaatsvervangend lid infectiecommissie Erasmus MC (onbetaald)

1. Mede uitvinder patent: 1519780601-1408/3023503

2. R01AI147330 (NIAID/NH) (HN onderzoek

(1+2 niet gerelateerd aan COVID-19)

 

 

 

 

 

 

Geen actie nodig

Bulatovic

Internist allergoloog-immunoloog en klinische farmacoloog, UMC Utrecht en Diakonessenhuis Utrecht
Onderzoeker Amsterdam Medisch Centrum

Functie 1: arts
Functie 2: onderzoeker
(Beide betaald)

Geen

Geen actie nodig

De Bruin

Anesthesioloog - Intensivist St. Antonius ziekenhuis Nieuwegein en Utrecht
Sectie voorzitter IC&PACU NVA

Geen

Geen

Geen actie nodig

Jacobs

Klinisch geriater en klinisch farmacoloog

Geen

Geen

Geen actie nodig

Van der Kuy

Afdelingshoofd Ziekenhuisapotheek Erasmus MC
Hoogleraar Klinische Farmacie, Erasmus MC

Ziekenhuisapotheker/onder-zoeker Zuyderland MC (betaald)
- Lid wetenschappelijk raad Sarcoidosevereniging (onbetaald)
- Lid Wetenschappelijk raad ItsME (Meningitis/Encephalitis) (onbetaald)
- Lid METC Erasmus MC (onbetaald)
- Lid METC Brabant (betaald)
- Associate editor EJHP (onbetaald)
- Raad van Toezicht A 15 apotheek (onbetaald)
- DSMB Pentoxifylline studie (onbetaald)

betrokkenheid bij 2 ZonMw gefinancieerde studies (CHECkUP, AMUSE)

Geen actie nodig

 

Meelezer

Achternaam meelezer

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Schalkers

Beleidsadviseur bij Harteraad

Geen

Geen

Geen actie nodig

 

Onafhankelijke reviewers

Achternaam onafhankelijke reviewer

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Van der Valk

Als internist werkzaam in het UMC Utrecht, bij van Creveldkliniek - centrum voor benigne hematologie. Expert centrum voor o.a. stollingsstoornissen. Het behelst patientenzorg en onderzoek (PI voor studies naar cardiovasculaire ziekten bij Hemofilie, gentherapie bij hemofilie)

Lid van de richtlijn commissie NIV. Onbetaald.

Geen

Geen

Van Dijk

Neuroloog, Radboudumc
Kwartiermaker/medisch directeur Centrum voor Hersenen en Zintuigen, Radboudumc

Voorzitter bestuur Nederlandse Vereniging voor Neurologie (0,1fte, betaald aan Radboudumc)
Secretaris Jan Meerwaldt stichting, onbezoldigd.

Geen

Geen

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door het meelezen van de patiëntenvereniging Harteraad. De verkregen input is meegenomen bij het opstellen van de module. De conceptrichtlijn is tevens voor commentaar voorgelegd aan Harteraad en de Patiëntenfederatie Nederland en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

 

Wkkgz & Kwalitatieve raming van mogelijke substantiële financiële gevolgen

Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling zijn richtlijnmodules op verschillende domeinen getoetst (zie het stroomschema).

 

Uit de kwalitatieve raming blijkt dat er waarschijnlijk geen substantiële financiële gevolgen zijn, zie onderstaande tabel.

 

Module

Uitkomst raming

Toelichting

Module Tromboseprofylaxe op de afdeling

Geen financiële gevolgen

Hoewel uit de toetsing volgt dat de aanbevelingen breed toepasbaar zijn (>40.000 patiënten), volgt uit de toetsing dat het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft, het geen toename in het aantal in te zetten voltijdsequivalenten aan zorgverleners betreft en het geen wijziging in het opleidingsniveau van zorgpersoneel betreft. Er worden daarom geen financiële gevolgen verwacht.

Methode ontwikkeling

Evidence based

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

 

Knelpuntenanalyse en uitgangsvragen

Tijdens de COVID-19 pandemie zijn knelpunten op verschillende manieren geïnventariseerd:

  1. De expertiseteams benoemde de knelpunten in de zorg voor patiënten met COVID-19.
  2. Er is een mailadres geopend (covid19@demedischspecialist.nl) waar verschillende partijen knelpunten konden aandragen, die vervolgens door de expertiseteams geprioriteerd werden.
  3. Door de Federatie van Medisch Specialisten zijn webinars georganiseerd waarbij vragen konden worden ingestuurd. Deze vragen zijn na afloop van de webinars voorgelegd aan de expertiseteams en geprioriteerd.

 

Op basis van de uitkomsten van de bovenstaande knelpuntenanalyses zijn door de expertiseteams concept-uitgangsvragen opgesteld en definitief vastgesteld.

 

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

 

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur en de beoordeling van de risk-of-bias van de individuele studies is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

 

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

 

GRADE

Definitie

Hoog

  • er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Redelijk

  • er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Laag

  • er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Zeer laag

  • er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • de literatuurconclusie is zeer onzeker.

 

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

 

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

 

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

 

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

 

Sterke aanbeveling

Zwakke (conditionele) aanbeveling

Voor patiënten

De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.

Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.

Voor behandelaars

De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.

Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.

Voor beleidsmakers

De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.

Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

 

Organisatie van zorg

Bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen.

 

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd. Betrokken partijen (NVIC en NVVC) hebben geen bezwaar geuit tegen de inhoud van deze module.

 

Literatuur

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Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. https://richtlijnendatabase.nl/over_deze_site/richtlijnontwikkeling.html

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Zoekverantwoording

Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Volgende:
Hormonale anticonceptie en VTE