Prophylaxis of venous thromboembolism (VTE) with low molecular weight heparin (LMWH) is now common for hospitalized non-surgical patients in British Columbia and much of North America. This includes patients who are at very low risk for a VTE. VTE events include deep vein thrombosis (DVT), usually in the legs, which can be either symptomatic or asymptomatic, as well as pulmonary embolism (PE).
Routine VTE prophylaxis for non-surgical patients in hospital (~85%)1,2 is driven by two assumptions: a) VTE risk is high, and b) unfractionated heparin (UFH) and LWMH are effective in preventing VTE events.3,4
Because of the inclusion of asymptomatic VTE events in trials, and flaws in interpreting evidence for heparin prophylaxis, a rethink is needed in our efforts to reduce VTE-related morbidity and mortality.5
What is the incidence of VTE in non-surgical hospitalized patients?
VTE occurs in less than 2% of medical patients, mostly in hospital or within three months of hospital discharge.8,9,10 Among the 15,000 patients enrolled in the International Medical Prevention Registry on VTE (IMPROVE) study, the 90-day incidence of symptomatic VTE was 1.2%. Symptomatic DVT, non-fatal PE and fatal PE were 0.44%, 0.32%, and 0.18% respectively.10 These observational findings mirror randomized clinical trials (RCTs), which found similar incidences in medical patients not receiving heparin.11,12,13
Evidence for thromboprophylaxis
A 2014 Cochrane systematic review (N=27,998) concluded that heparin prophylaxis (UFH or LMWH) versus placebo reduces the risk of DVT but increases the risk of bleeding, without reducing all-cause mortality. It considered the effects on non-fatal and fatal PE “imprecise”.13 Our detailed concerns about this Cochrane review are published as comments in the current version.14,15
The review did not analyze symptomatic DVT. The more frequently detected asymptomatic DVT is of debatable clinical importance.5 Another major failure in this review concerns missing outcomes and other data not reported. (Table) For example, the two largest RCTs lacked data for 889 (16%) of all randomized patients.11,12 DVT outcomes from three large RCTs comprising over 22,000 patients were not included in the Cochrane analysis because the RCTs did not report DVT as an outcome.16,17,18 The two RCTs that contribute the most data to the Cochrane review reported PE incidence based on a denominator of only 3% of all patients randomized (i.e. trials only reported PE for people who died and underwent autopsy).17,18
|Outcome||Heparin (LMWH or UFH)
Events/denominators reported for putative absolute differences in Cochrane meta-analysis
Events/denominators reported for putative absolute differences in Cochrane meta-analysis
|% of randomized patients on whom meta-analytic results are based|
|DVT (asymptomatic or symptomatic)||112 / 2,931||172 / 2,580||DVT not reported in 23,363 of 27,988 randomized patients (83%). Putative difference of 60 DVT derives from only 17% of all randomized patients.|
|PE (non-fatal and fatal)||33 / 14,100||50 / 13,871||PE not reported in 13,661 of 27,988 randomized patients (49%). Putative difference of 17 PE derives from only 51% of all randomized patients.|
|Major bleed (trial definitions vary)||44 / 7,094||24 / 6,710||Major bleeds not reported for 11,693 of 27,988 randomized patients (42%). Putative difference of 20 major bleeds derives from only 58% of all randomized patients.|
The assumption for all patients who were missing from these analyses is that they did not have a DVT or PE. This approach most often exaggerates treatment effect estimates.19 We have greater confidence in the Cochrane review conclusion that heparin prophylaxis does not reduce all-cause mortality, as 8 of the 10 largest trials reported on this outcome. Post-thrombotic syndrome is another morbidity arising from DVT, but no RCT reported on this outcome.
The Cochrane authors report that heparins increase the incidence of bleeding. Unfortunately, it is not possible to estimate the true magnitude of the increase because the review lacks data on bleeding from 42% of all patients randomized in RCTs.18 For PREVENT, a large trial of dalteparin that represents 13% of all patients randomized in all RCTs, we were able to confirm that total serious adverse events (including deaths, VTE and major bleeds) were not reduced despite a reported reduction in VTE.12,20
A 2018 American Society of Hematology guideline also notes that mortality is not reduced by VTE prophylaxis of medical patients.7 The authors report that any prevention of symptomatic VTE is counter-balanced by increased bleeding. Yet this guideline makes a “conditional recommendation” in favour of LMWH with “low certainty in the evidence of effects.”
Real world evidence from the US and British Columbia
A state-wide evaluation of over 20,000 medical patients in Michigan found that hospitals with high rates of prophylaxis (>86% of patients) did not achieve a lower 90-day rate of VTE compared with hospitals using less frequent prophylaxis (>55% of patients).21 Another analysis of 140,000 medical patients concluded that in-hospital thromboprophylaxis had no impact on the burden of VTE in the community.9
In British Columbia, an analysis of hospitals within Fraser Health and Vancouver Coastal Health found that of all the medical patients who received VTE prophylaxis, at least 70% were considered low risk when prophylaxis was started,22 basing “risk” on the predictive model derived from the IMPROVE study.10 This suggests that many patients at low risk of VTE now receive prophylaxis, despite its uncertain effect on VTE and an increased risk of harm.
Can we better identify people at risk?
The current flawed approach to routine VTE prophylaxis in medical patients risks overtreatment of low risk patients. Risk assessment tools such as the IMPROVE model are externally validated and could be used in clinical practice.9,10 The “IMPROVE RAM” quickly discriminates “low risk” patients from “higher risk” patients (previous VTE, current cancer, known thrombophilia, lower limb paralysis or immobilization for more than 7 days).9,10,23,24
- The risk of symptomatic VTE in hospitalized medical patients is less than 2%.
- Prophylaxis with low molecular weight heparins does not reduce all-cause mortality.
- Prophylaxis has unknown effects on PE/DVT (due to missing outcome data), but increases the risk of major bleeds.
- Risk assessment tools for DVT (such as IMPROVE RAM) can identify patients at low risk of VTE.
- Grant PJ, Conlon A, Chopra V, Flanders SA. Use of Venous Thromboembolism Prophylaxis in Hospitalized Patients. JAMA Internal Medicine. 2018 Aug 01;178(8):1122-1124. DOI: 10.1001/jamainternmed.2018.2022
- Canadian Venous Thromboembolism Audit. National Snapshot 2014. Patient Safety Institute. [Internet] https://www.patientsafetyinstitute.ca/en/toolsResources/Presentations/Documents/Canadian%20Venous%20Thromboembolism%20(VTE)%20Audit%20(2014)/Canadian%20Venous%20Thromboembolism%20Audit%20National%20Snapshot%202014.pdf
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed.). Chest. 2008 Jun;133(6 Suppl):381S-453S. DOI: 10.1378/chest.08-0656
- Accreditation Canada. Required organizational practices handbook 2017 – version 2. [Internet] https://accreditation.ca/required-organizational-practices
- Kotaska A. Venous thromboembolism prophylaxis may cause more harm than benefit: an evidence-based analysis of Canadian and international guidelines. Thrombosis Journal
[Electronic Resource]. 2018;16:25 DOI: 10.1186/s12959-018-0180-6
- Kahn SE, Lim W, Dunn AS, et al. Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb:141(2 suppl): e195S-e226S. DOI: 10.1378/chest.11-2296
- Schunemann H, Cuchman M, Burnett AE, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and non-hospitalized medical patients.Blood Advances. 2018;2(22):3198-3225. DOI: 10.1182/bloodadvances.2018022954
- Edelsberg J, Hagiwara M, Taneja C, Oster G. Risk of venous thromboembolism among hospitalized medically ill patients. Am J Health-Syst Pharm. 2006;63(20 Suppl 6):S16-22. DOI: 10.2146/ajhp060389
- Mahan CE, Fisher MD, Mills RM, et al. Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population. Thromb Res. 2013;132(5):520-6. DOI: 10.1016/j.thromres.2013.08.013
- Spyropoulos AC, Anderson FA Jr, FitzGerald G, et al. Predictive and Associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706-714. DOI: 10.1378/chest.10-1944
- Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999 Sep 09;341(11):793-800. DOI: 10.1056/NEJM199909093411103
- Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874-9. DOI: 10.1161/01.CIR.0000138928.83266.24
- Alikhan R, Forster R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database of Systematic Reviews. 2014, Issue 5. Art. No.: CD003747. DOI: 10.1002/14651858.CD003747.pub4
- Shah K, Tejani AM. Feedback, 2016 July in: Alikhan R, Forster R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database of Systematic Reviews. 2014, Issue 5. Art. No.: CD003747. DOI: 10.1002/14651858.CD003747.pub4
- Alia T, Wilson C, Tejani AM. Feedback, 2016 July in: Alikhan R, Forster R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database of Systematic Reviews. 2014, Issue 5. Art. No.: CD003747. DOI: 10.1002/14651858.CD003747.pub4
- Kakkar AK, Cimminiello C, Goldhaber SZ, et al. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011;365(26):2463-72. DOI: 10.1056/NEJMoa1111288
- Mahe I, Bergmann JF, d’Azemar P, et al. Lack of effect of low-molecular weight heparin (nadroparin) on mortality in bedridden in-patients; a prospective randomized double-blind study. Eur J Clin Pharmacol 2005;61(5-6):347-351. DOI: 10.1007/s00228-005-0944-3
- Gardlund B, >Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet. 1996;347(9012):1357-61. DOI: 10.5555/uri:pii:S0140673696910090
- Abraha I, Cherubini A, Cozzolino F, et al. Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. BMJ 2015;350:h2445. DOI: 10.1136/bmj.h2445
- Feugere, Guillaume (Pfizer), personal email communication, 03 January 2011.
- Flanders SA, Greene MT, Grant P, et al. Hospital performance for pharmacologic venous thromboembolism prophylaxis and rate of venous thromboembolism: a cohort study. JAMA Internal Medicine. 2014;174(10):1577-84. DOI: 10.1001/jamainternmed.2014.3384
- Tung EC, Yu SY, Shah K, et al. Reassessment of venous thromboembolism and bleeding risk in medical patients receiving VTE prophylaxis. J Eval Clin Prac. 2019 Jul 07. DOI: 10.1111/jep.13213
- Rosenberg D, Eichorn A, Alarcon M, et al. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc. 2014 Nov 17;3(6):e001152. DOI: 10.1161/JAHA.114.001152
- International Medical Prevention Registry on Venous Thromboembolism (IMPROVE). In-hospital risk assessment models. [Internet] https://www.outcomes-umassmed.org/improve/risk_score/index.html