Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases

doi:10.1016/S0140-6736(96)91009-0

The Lancet

Volume 347, Issue 9012, 18 May 1996, Pages 1357-1361

https://doi.org/10.1016/S0140-6736(96)91009-0 Get rights and content

Abstract

Summary

Background Fatal pulmonary embolism and other thromboembolic complications are common in hospital inpatients. However, there is little evidence on the routine use of pharmacological thromboprophylaxis in non-surgical patients. We assessed the efficacy and safety of low-dose heparin in the prevention of hospital-acquired, clinically relevant, fatal pulmonary embolism in patients with infectious diseases.

Methods Our study used the postrandomisation consent design. 19 751 consecutive patients, aged 55 years or older, admitted to departments of infectious diseases in six Swedish hospitals, were screened for inclusion in the randomised, controlled, unblinded, multicentre trial. Of the eligible patients, 5776 were assigned subcutaneous standard heparin (5000 IU every 12 h) until hospital discharge or for a maximum of 3 weeks; 5917 were assigned no prophylactic treatment (control group). We sought consent only from the heparin group. Follow-up was for 3 weeks after discharge from hospital or for a maximum of 60 days from randomisation. The primary endpoint was necropsy-verified pulmonary embolism of predefined clinical relevance.

Findings By intention-to-treat analysis mortality was similar in the heparin and control groups (5·3 vs 5·6%, p=0·39) and the median time from admission to death was 16 days in both groups (IQR 8-31 vs 6-28 days). Necropsy-verified pulmonary embolism occurred in 15 heparin-treated and 16 control-group patients. There was a significant difference between heparin and control groups in median time from randomisation to fatal pulmonary embolism (28 [24-36] vs 12·5 [10-20] days, p=0·007). This difference corresponds to the duration of heparin prophylaxis. Non-fatal thromboembolic complications occurred in more of the control than of the heparin group (116 vs 70, p=0·0012).

Interpretation Our findings do not support the routine use of heparin prophylaxis for 3 weeks or less in large groups of non-surgical patients. Further studies are needed to investigate whether heparin prophylaxis of longer duration may prevent fatal pulmonary embolism.

References (35)

As Gallus
Anticoagulants in the prevention of venous thromboembolism
Clin Haematol
(1990)
W. Saeger et al.
Venous thromboses and pulmonary embolisms in post-mortem series: probable causes by correlations of clinical data and basic diseases
Pathol Res Pract
(1994)
C. Warlow et al.
A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction
Lancet
(1973)
St McCarthy et al.
Low-dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke
Lancet
(1977)
A. Pitt et al.
Low dose heparin in the prevention of deep-vein thromboses in patients with acute myocardial infarction
Am Heart J
(1980)
Agg Turpie et al.
Double-blind randomised trial of Org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke
Lancet
(1987)
Mt Nurmohamed et al.
Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis
Lancet
(1992)
R. Collins et al.
Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery
N Engl J Med
(1988)
Thromboembolic Risk Factors (THRIFT) Consensus Group
Risk of and prophylaxis for venous thromboembolism in hospital patients
BMJ
(1992)
Vv Kakkar
Prevention of fatal pulmonary embolism
Haemostasis
(1993)

D. Green et al.

Low molecular weight heparin: a critical analysis of clinical trials

Pharmacol Rev

(1994)

Da Sandler et al.

Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?

J R Soc Med

(1989)

B. Lindblad et al.

Incidence of venous thromboembolism verified by necropsy over 30 years

BMJ

(1991)

Ö. Havig

Pulmonary thromboembolism: clinicopathological correlations and multiple regression analysis of possible risk factors

Acta Chir Scand

(1977)

Ww Coon et al.

Some epidemiologic considerations of thromboembolism

Surg Gynecol Obstet

(1959)

B. Gårdlund

Fatal pulmonary embolism in hospitalized non-surgical patients

Acta Med Scand

(1985)

R. Wray et al.

Prophylactic anticoagulant therapy in the prevention of calf-vein thrombosis after myocardial infarction

N Engl J Med

(1973)

Cited by (235)

The effect of antithrombotic treatment on mortality in patients with acute infection: A meta-analysis of randomized clinical trials
2023, International Journal of Cardiology
Acute infections cause relevant activation of innate immunity and inflammatory cascade. An excessive response against pathogens has been proved to trigger the pathophysiological process of thrombo-inflammation. Nevertheless, an association between the use of antithrombotic agents and the outcome of critically ill patients with infectious diseases is lacking. The aim of this meta-analysis is to determine the impact of antithrombotic treatment on survival of patients with acute infective disease.
MEDLINE, Embase, Cinahl, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched from inception to March 2021. We included randomized controlled trials (RCTs) that evaluated any antithrombotic agent in patients with infectious diseases other than COVID-19. Two authors independently performed study selection, data extraction and risk of bias evaluation. The primary outcome was all-cause mortality. Summary estimates for mortality were calculated using the inverse-variance random-effects method.
A total of 16,588 patients participating in 18 RCTs were included, of whom 2141 died. Four trials evaluated therapeutic-dose anticoagulation, 1 trial prophylactic-dose anticoagulation, 4 trials aspirin, and 9 trials other antithrombotic agents. Overall, the use of antithrombotic agents was not associated with all-cause mortality (relative risk 0.96; 95% confidence interval, 0.90–1.03).
The use of antithrombotics is not associated with all-cause mortality in patients with infectious disease other than COVID-19. Complex pathophysiological interplays between inflammatory and thrombotic pathways may explain these results and need further investigation.
REGISTRATION: PROSPERO, CRD42021241182.
Association between risk of venous thromboembolism and mortality in patients with COVID-19
2021, International Journal of Infectious Diseases
To investigate the association of risk of venous thromboembolism with 30-day mortality in COVID-19 patients.
A total of 1030 COVID-19 patients were retrospectively collected, with baseline data on demographics, sequential organ failure assessment (SOFA) score, and VTE risk assessment models (RAMs), including Padua prediction score (PPS), International Medical Prevention Registry (IMPROVE), and Caprini.
Thirty-day mortality increased progressively from 2% in patients at low VTE risk to 63% in those at high risk defined by PPS. Similar findings were observed in IMPROVE and Caprini scores. Progressive increases in VTE risk were also associated with higher SOFA score. High risk of VTE was independently associated with mortality regardless of adjusted gender, smoking status and some comorbidities, with hazard ratios of 29.19, 37.37 and 20.60 for PPS, IMPROVE and Caprini RAM, respectively (P < 0.001 for all comparisons). The predictive accuracy of PPS (area under curve (AUC) 0.900), IMPROVE (AUC 0.917), or Caprini (AUC 0.861) RAM for risk of hospitalized mortality was unexpectedly strong.
We established that the presence of a high risk of VTE identifies a group of COVID-19 patients at higher risk for mortality. Furthermore, there is a high accuracy of VTE RAMs to predict mortality in these patients.
American Society of Hematology 2021 guidelines for management of venous thromboembolism: Prevention and treatment in patients with cancer
2021, Blood Advances
Citation Excerpt :
We found 17 systematic reviews that addressed VTE prophylaxis for medically ill patients,60-76 with 24 studies in these reviews evaluating thromboprophylaxis vs no prophylaxis in acutely ill medical patients. All studies included hospitalized acutely ill medical inpatients but only a small proportion of patients had cancer.57,77-97 The panel also considered the RCT by Cohen et al57 (ARTEMIS) that compared fondaparinux against placebo and believed that the results were similar enough to include fondaparinux along with UFH and LMWH.
Venous thromboembolism (VTE) is a common complication among patients with cancer. Patients with cancer and VTE are at a markedly increased risk for morbidity and mortality.
These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.
ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The guideline development process was supported by updated or new systematic evidence reviews. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess evidence and make recommendations.
Recommendations address mechanical and pharmacological prophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure, and ambulatory patients receiving cancer chemotherapy. The recommendations also address the use of anticoagulation for the initial, short-term, and long-term treatment of VTE in patients with cancer.
Strong recommendations include not using thromboprophylaxis in ambulatory patients receiving cancer chemotherapy at low risk of VTE and to use low-molecular-weight heparin (LMWH) for initial treatment of VTE in patients with cancer. Conditional recommendations include using thromboprophylaxis in hospitalized medical patients with cancer, LMWH or fondaparinux for surgical patients with cancer, LMWH or direct oral anticoagulants (DOAC) in ambulatory patients with cancer receiving systemic therapy at high risk of VTE and LMWH or DOAC for initial treatment of VTE, DOAC for the short-term treatment of VTE, and LMWH or DOAC for the long-term treatment of VTE in patients with cancer.
Thrombotic Risk and Covid-19: Review of Current Evidence for a Better Diagnostic and Therapeutic Approach
2021, Archivos de Bronconeumologia
El nuevo coronavirus SARS-CoV-2 ha supuesto un problema sanitario mundial sin precedentes, y ha ocasionado más de 250.000 muertes confirmadas. La enfermedad producida por este virus, denominada COVID-19, cursa con presentaciones clínicas variables, desde cuadros paucisintomáticos y procesos catarrales hasta neumonías graves que evolucionan rápidamente a síndrome de distrés respiratorio agudo (SDRA) y fallo multiorgánico. En las últimas semanas se han publicado algunos trabajos que describen alteraciones de la coagulación y complicaciones trombóticas arteriales y venosas en estos pacientes, principalmente entre aquellos ingresados en unidades de cuidados intensivos. Las infecciones desencadenan una respuesta inmunitaria, que provoca la liberación de distintos mediadores inflamatorios a la sangre. Entre ellos se encuentran las citocinas, que interaccionan con las plaquetas y con distintas proteínas de la coagulación, y favorecen la trombogénesis. Uno de los marcadores de la coagulación más estudiados en la COVID-19 es el dímero D (DD), y su elevación tiene implicaciones pronósticas, aunque no se ha aclarado el mejor punto de corte para el diagnóstico de enfermedad tromboembólica venosa (ETEV) en esta población ni su utilidad para decidir la intensidad de la tromboprofilaxis para estos pacientes. Hasta disponer de información suficientemente robusta (preferentemente de ensayos clínicos bien diseñados), se deberían seguir las recomendaciones de las guías de práctica clínica para la profilaxis, diagnóstico y tratamiento de la ETEV en los pacientes COVID-19.
The new SARS-CoV-2 coronavirus has created an unprecedented global health problem, resulting in more than 250,000 confirmed deaths. The disease produced by this virus, called Covid-19, presents with variable clinical manifestations, from practically asymptomatic patients with catarrhal processes to severe pneumonias that rapidly evolve to acute respiratory distress syndrome (ARDS) and multiorgan failure. In recent weeks, papers have been published describing coagulation disorders and arterial and venous thrombotic complications in these patients, mainly among those admitted to intensive care units. The infection triggers an immune response, which causes different inflammatory mediators to be released into the blood. These include cytokines, which interact with platelets and different coagulation proteins, and promote thrombogenesis. One of the most widely studied coagulation markers in Covid-19 is D-dimer (DD), raised levels of which have prognostic implications, although the best cut-off point for the diagnosis of venous thromboembolism (VTE) in this population has not been clarified, nor has its usefulness in determining the intensity of thromboprophylaxis required in these patients. Until sufficiently robust information (preferably from well-designed clinical trials) is available, the recommendations of clinical practice guidelines for the prophylaxis, diagnosis and treatment of VTE should be followed in Covid-19 patients.
Mortality risk associated with venous thromboembolism: a systematic review and Bayesian meta-analysis
2020, The Lancet Haematology
Venous thromboembolism is associated with increased mortality risk in some populations, but how frequently it is a direct cause of death is unclear. We used data from venous thromboembolism prevention trials to evaluate the causal effect of venous thromboembolism reduction on mortality.
We did a systematic review and meta-analysis of randomised controlled trials (RCTs) evaluating venous thromboembolism prevention. We searched MEDLINE, Embase, PubMed, and Web of Science starting from Jan 1, 1993, to March 19, 2018. We included studies of patients who were at elevated risk of venous thromboembolism and were randomly assigned to either anticoagulant or antiplatelet therapy versus placebo or no treatment. We excluded studies with an active control agent (which might mitigate the lethality of venous thromboembolism) and those for which mortality data were unavailable. We modelled heterogeneity in a Bayesian framework, taking overall mortality as a primary endpoint, and pulmonary embolism, fatal pulmonary embolism, and major bleeding as secondary endpoints. We focused our analyses on studies reporting statistically significant effects of prevention on venous thromboembolism endpoints. We report treatment effects as median risk ratios (RRs), wherein a null effect equals 1, with 95% credible intervals (CrIs). This meta-analysis was registered with PROSPERO, CRD42018089697.
From 4229 studies screened, we identified 86 eligible RCTs; 52, with data from over 70 000 patients, were positive, with significantly increased venous thromboembolism risk in patients in control groups versus treatment groups (RR 2·74, 95% CrI 2·32–3·31, p<0·0001). The meta-analysis established that the causal effect of venous thromboembolism prevention on mortality was null (control group mortality was 3391 [9·8%] of 34 537 patients; treatment group mortality was 3498 [9·8%] of 35 795 patients [RR 1·01, 95% CrI 0·97–1·06; p=0·58]) with low heterogeneity (τ 0·02, 95% CrI 0·00–0·07, p=0·89). Patients in control groups had more pulmonary embolism (RR 2·22, 95% CrI 1·78–2·89, p<0·0001) and fatal pulmonary embolism (1·58, 1·14–2·19, p=0·01), but less major bleeding (0·60, 0·47–0·75, p<0·0001) than those in treatment groups. A meta-analysis with the additional 34 negative studies yielded similar results for all endpoints except fatal pulmonary embolism, where evidence of an effect was weaker (1·42, 1·05–1·91, p=0·02).
The perception that venous thromboembolism is a common cause of mortality should be revised considering the null effect of venous thromboembolism prevention on mortality. Our findings call into question the use of composite endpoints in venous thromboembolism-prevention trials and provide rationale for de-escalation trials.
None.
American Society of Hematology 2018 guidelines for management of venous thromboembolism: Prophylaxis for hospitalized and nonhospitalized medical patients
2018, Blood Advances
In October 2022, these guidelines were reviewed by an expert work group convened by ASH. Review included limited searches for new evidence and discussion of the search results. Following this review, the ASH Committee on Quality agreed to continue monitoring the supporting evidence rather than revise or retire these guidelines at this time. Limited searches and expert review will be repeated annually going forward until these guidelines are revised or retired.
Background: Venous thromboembolism (VTE) is the third most common vascular disease. Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk.
Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about preventing VTE in these groups.
Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess evidence and make recommendations, which were subject to public comment.
Results: The panel agreed on 19 recommendations for acutely ill and critically ill medical inpatients, people in long-term care facilities, outpatients with minor injuries, and long-distance travelers.
Conclusions: Strong recommendations included provision of pharmacological VTE prophylaxis in acutely or critically ill inpatients at acceptable bleeding risk, use of mechanical prophylaxis when bleeding risk is unacceptable, against the use of direct oral anticoagulants during hospitalization, and against extending pharmacological prophylaxis after hospital discharge. Conditional recommendations included not to use VTE prophylaxis routinely in long-term care patients or outpatients with minor VTE risk factors. The panel conditionally recommended use of graduated compression stockings or low-molecular-weight heparin in long-distance travelers only if they are at high risk for VTE.

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ArticlesRandomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases

Abstract

Clin Haematol

Pathol Res Pract

Lancet

Lancet

Am Heart J

Lancet

Lancet

Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery

N Engl J Med

Risk of and prophylaxis for venous thromboembolism in hospital patients

BMJ

Prevention of fatal pulmonary embolism

Haemostasis

Low molecular weight heparin: a critical analysis of clinical trials

Pharmacol Rev

Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?

J R Soc Med

Incidence of venous thromboembolism verified by necropsy over 30 years

BMJ

Pulmonary thromboembolism: clinicopathological correlations and multiple regression analysis of possible risk factors

Acta Chir Scand

Some epidemiologic considerations of thromboembolism

Surg Gynecol Obstet

Fatal pulmonary embolism in hospitalized non-surgical patients

Acta Med Scand

Prophylactic anticoagulant therapy in the prevention of calf-vein thrombosis after myocardial infarction

N Engl J Med

Articles
Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases