Anticoagulation for Thromboprophylaxis in Patients with Intracerebral Hemorrhage: Less Room for Skepticism

Systematic Review and Meta-Analysis of Thromboprophylaxis with Heparins Following Intracerebral Hemorrhage

Epidemiological data show that in patients with intracerebral hemorrhage (ICH) the occurrence of venous thromboembolism (VTE) is quite common[1]; some recent reports from the United States estimate that up to 3% of ICH patients develop deep vein thrombosis (DVT) or pulmonary embolism (PE),[2] while other data indicate that the prevalence of symptomatic VTE could rise up to 10% of patients, of which 80% are asymptomatic episodes.[1] Still, thromboprophylaxis with heparin (either low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) is strongly underprescribed in ICH patients,[1] [3] being prescribed in 8 to 17% of patients.[1] [3] This is mainly driven by the fact that these patients are perceived to be of high risk for bleeding by the treating physicians, as well as the limited related evidence from randomized controlled trials which does not allow for high-quality strong clinical recommendations ([Table 1]). The major guidelines that focus on the management of VTE risk or on the clinical management of patients with ICH generally provide weak recommendation with an overall low quality of evidence.[4] [5] [6] [7] [8] [9] This is despite the intense interest into understanding the risk factors for bleeding (especially in high-risk patient groups,[10] [11] [12] the long-term risks of bleeding after discontinuing anticoagulation therapy,[13] and improved efforts at bleeding risk stratification and balancing the risk–benefits of reintroducing anticoagulation after a major bleeding event).[14] [15]

Table 1 Guideline recommendations regarding thromboprophylaxis in patients with intracerebral hemorrhage

Guideline	Year	Thromboprophylaxis recommended	Agent	Timing	Quality of evidence
ACCP[4]	2012	Yes[a]	LMWH/UFH	Not mentioned	Weak recommendation, low quality of evidence (Grade 2C)
ESO[5]	2014	No	–	–	No formal recommendation
AHA/ASA[6]	2015	Yes	LMWH/UFH	1–4 days	Class IIb, level of evidence B
NCS[7]	2016	Yes	LMWH/UFH	Within 2 days	Weak recommendation, low quality of evidence
ASH[8]	2018	Yes[a]	LMWH/UFH	Not mentioned	Strong recommendation, moderate certainty of evidence
HSFC[9]	2020	Yes	LMWH	After 2 days	Evidence level B

Abbreviations: ACCP, American College of Chest Physicians; AHA, American Heart Association; ASA, American Stroke Association; ASH, American Society of Hematology; ESO, European Stroke Organization; HSFC, Heart and Stroke Foundation of Canada; LMWH, low-molecular-weight heparin; NCS, Neurocritical Care Society; UFH, unfractionated heparin.

^a Refers generically to critically ill patients and not specifically to intracerebral hemorrhage.

In this issue of Thrombosis and Haemostasis, Chi and colleagues present a systematic review of the association between pharmacological thromboprophylaxis with LMWH or UFH and the risk of VTE in patients with ICH.[16] After a methodologically robust systematic search and study selection, the authors included 28 studies and a total of 3,697 hospitalized patients with ICH. The mean patient age ranged between 50 and 72 years. The prevalence of risk factors and comorbidities largely varied across studies. Among the studies which evaluated LMWH, dosing regimens ranged between 20 and 40 mg daily (equal to 1,900 and 9,500 IU daily, respectively), while among the studies evaluating UFH, doses varied between 5,000 IU/8 hours and 5,000 IU/12 hours. The outcomes assessed included DVT, PE, hematoma expansion or rebleeding, major disability, and mortality.[16]

The investigators show that the use of pharmacological thromboprophylaxis was associated with a significant reduction in the risk of DVT, both in fixed-effects model (risk reduction [RR]: 0.24, 95% confidence interval [CI]: 0.28–0.32) and in the random-effects model (RR: 0.27, 95% CI: 0.19–0.39). These estimates were corroborated by low grade of heterogeneity (I ² = 25%) and by a strict prediction interval (PI; 0.11–0.66), which is a statistical tool used to examine the possible variation of pooled estimates according to future studies performed in different clinical scenarios and with different clinical characteristics. Furthermore, pharmacological thromboprophylaxis (RR: 0.33, 95% CI: 0.19–0.57 for the fixed-effects model; RR: 0.37, 95% CI: 0.21–0.66 for the random-effects model) was associated with a lower risk of PE without any heterogeneity (I ² = 0%), with the PI substantially overlapping the estimates (CI: 0.20–0.69), strengthening the results of the meta-analysis.[16] Moreover, pharmacological thromboprophylaxis was not associated with increased risk for hematoma expansion or rebleeding (RR: 0.75, 95% CI: 0.48–1.18 for the fixed-effects model; RR: 0.80, 95% CI: 0.49–1.30 for the random-effects model), with no heterogeneity (I ² = 0%) and overlapping PI. Also, a trend of reduced mortality was identified in patients treated with pharmacological thromboprophylaxis (RR: 0.82, 95% CI: 0.65–1.03 for fixed-effects model; RR: 0.83, 95% CI: 0.66–1.04 for the random-effects model; I ² = 0%; PI: 0.60–1.15). Lastly, the fixed-effects model showed a higher risk for developing major disability in patients treated with a pharmacological thromboprophylaxis (RR: 1.20, 95% CI: 1.04–1.38), but this estimate was based only on two studies, was characterized by a high degree of heterogeneity (I ² = 83%), and was not confirmed in the random-effects model analysis (RR: 1.02, 95% CI: 0.62–1.65).[16]

To further support their results, the investigators performed several subgroup analyses (according to study design, type of ICH and type of anticoagulant), which substantially confirmed the main estimates. As a notable exception, the authors found that in patients with spontaneous ICH, the effect of pharmacological thromboprophylaxis was not associated with a reduction in VTE risk; however, this was based on a limited number of studies. Also, the additional analyses showed that among randomized controlled trials, patients receiving LMWH/UFH were associated with a lower risk of hematoma expansion or rebleeding (RR: 0.53, 95% CI: 0.28–0.99; I ² = 0%; p = 0.13 for test for subgroup differences).[16] Finally, it is noted that there was a significant overall risk of bias for most of the studies enrolled, with eight studies being at high risk of bias.

The result of this meta-analysis adds some reassurance for the use of pharmacological thromboprophylaxis with LMWH/UFH in patients with ICH and increases its implementation in this patient group, given the low risk of DVT/PE, the trend in lower risk of death, and the absence of any major bleeding complication (hematoma expansion or rebleeding). Still, this conclusion needs to be further confirmed in future randomized trials. During the last 13 years, the use of direct oral anticoagulants (DOACs) has increased substantially and they largely replaced vitamin K antagonists as the treatment of choice for most indications for oral anticoagulation.[17] [18] [19] [20] [21] In the management of VTE in medically ill patients, while DOACs showed a consistent superiority over LMWH in the reduction of thromboembolic events, they were also associated with an increase in the risk of major bleeding.[22] Notwithstanding this, a deeper analysis regarding the balance between the number of fatal bleeding and fatal VTE events showed that the rate of fatal VTE is higher than the rate of fatal bleeding. Also, a cost-effectiveness analysis indicated that the use of DOACs for the prevention of VTE is cost-effective compared with the use of LMWH.[22] Interestingly, none of the studies that tested DOACs for this indication included patients with ICH, and three out of four of these studies listed ICH as an exclusion criteria.[22] In this context, DOACs could be a candidate anticoagulation strategy to be tested in patients with this specific clinical scenario in future trials.

Finally, these results have implications also for the wider population of patients who have an indication for oral anticoagulation, but at the same time, they are at increased risk of bleeding. Not infrequently, treating physicians are frequently skeptic and reluctant to prescribe anticoagulant drugs in such patients and consequently, these patients are less likely to be treated with anticoagulants, as it is the case with atrial fibrillation patients who have a major bleeding during oral anticoagulant treatment or with significant liver disease.[23] [24] [25] [26] In these settings, the available evidence suggests an overall significant clinical benefit if treated with oral anticoagulants.[25] [26] The study by Chi and colleagues further strengthens this argument and underlines that bleeding risk should not be a reason to withhold anticoagulation, but it should rather serve as a flag for better control of bleeding risk factors.

In conclusion, in this large systematic review and meta-analysis, the authors demonstrated that a pharmacological thromboprophylaxis with LMWH or UFH is associated with a significant reduction in VTE ([Fig. 1]). While this study further underlines that higher bleeding risk should not be a reason to withhold anticoagulant treatment, further studies are still needed to support stronger recommendations and to further evaluate the use of other anticoagulant drugs (i.e., DOACs) in these patients. Other considerations include better patient engagement and highlighting the need for shared decision-making.[27]

Fig. 1 Risk reduction of venous thromboembolic events in patients with intracerebral hemorrhage receiving thromboprophylaxis. LMWH, low-molecular-weight heparin; RRR, relative risk reduction; UFH, unfractionated heparin.

 

Scroll to top

Conflict of Interest

None declared.

• References

• 1 Cherian LJ, Smith EE, Schwamm LH. et al. Current practice trends for use of early venous thromboembolism prophylaxis after intracerebral hemorrhage. Neurosurgery 2018; 82 (01) 85-92
• 2 Otite FO, Khandelwal P, Malik AM, Chaturvedi S, Sacco RL, Romano JG. Ten-year temporal trends in medical complications after acute intracerebral hemorrhage in the United States. Stroke 2017; 48 (03) 596-603
• 3 Prabhakaran S, Herbers P, Khoury J. et al. Is prophylactic anticoagulation for deep venous thrombosis common practice after intracerebral hemorrhage?. Stroke 2015; 46 (02) 369-375
• 4 Kahn SR, 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; 141 (2, Suppl): e195S-e226S
• 5 Steiner T, Al-Shahi Salman R, Beer R. et al; European Stroke Organisation. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9 (07) 840-855
• 6 Hemphill III JC, Greenberg SM, Anderson CS. et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46 (07) 2032-2060
• 7 Nyquist P, Bautista C, Jichici D. et al. Prophylaxis of venous thrombosis in neurocritical care patients: an evidence-based guideline: a statement for healthcare professionals from the Neurocritical Care Society. Neurocrit Care 2016; 24 (01) 47-60
• 8 Schünemann HJ, Cushman M, Burnett AE. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
• 9 Shoamanesh A, Patrice Lindsay M, Castellucci LA. et al. Canadian stroke best practice recommendations: Management of Spontaneous Intracerebral Hemorrhage, 7th Edition Update 2020. Int J Stroke 2021; 16 (03) 321-341
• 10 de Winter MA, Dorresteijn JAN, Ageno W. et al. Estimating bleeding risk in patients with cancer-associated thrombosis: evaluation of existing risk scores and development of a new risk score. Thromb Haemost 2022; 122 (05) 818-829
• 11 Frei AN, Stalder O, Limacher A. et al. Comparison of bleeding risk scores in elderly patients receiving extended anticoagulation with vitamin K antagonists for venous thromboembolism. Thromb Haemost 2021; 121 (11) 1512-1522
• 12 Montalto C, Crimi G, Morici N. et al. Validation and additive predictive value of the academic research consortium-high bleeding risk criteria in older adults. Thromb Haemost 2021; 121 (09) 1255-1257
• 13 Khan F, Rahman A, Tritschler T. et al. Long-term risk of major bleeding after discontinuing anticoagulation for unprovoked venous thromboembolism: a systematic review and meta-analysis. Thromb Haemost 2022; 122 (07) 1186-1197
• 14 Gorog DA, Gue YX, Chao T-F. et al. Assessment and mitigation of bleeding risk in atrial fibrillation and venous thromboembolism: a position paper from the ESC Working Group on Thrombosis, in collaboration with the European Heart Rhythm Association, the Association for Acute CardioVascular Care and the Asia-Pacific Heart Rhythm Society. Europace 2022;
• 15 Edlmann E, McMahon C. Balancing risks and benefits when recommencing oral anticoagulants after major bleeding. Thromb Haemost 2021; 121 (08) 979-981
• 16 Chi G, Lee JJ, Sheng S. et al. Systematic review and meta-analysis of thromboprophylaxis with heparins following intracerebral hemorrhage. Thromb Haemost 2022; 122 (07) 1159-1165
• 17 Zhuang Y, Dai LF, Chen MQ. Efficacy and safety of non-vitamin K antagonist oral anticoagulants for venous thromboembolism: a meta-analysis. JRSM Open 2021; 12 (06) 205 42704211010686
• 18 Romiti GF, Corica B, Proietti M. A comprehensive appraisal of dabigatran etexilate clinical evidence and applications: a 10-year-long story. Future Cardiol 2021; 17 (02) 215-226
• 19 Steffel J, Collins R, Antz M. et al; External reviewers. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021; 23 (10) 1612-1676
• 20 Camm AJ, Atar D. Use of non-vitamin K antagonist oral anticoagulants for stroke prevention across the stroke spectrum: progress and prospects. Thromb Haemost 2021; 121 (06) 716-730
• 21 Cavallari I, Verolino G, Romano S, Patti G. Efficacy and safety of nonvitamin K oral anticoagulants in patients with atrial fibrillation and cancer: a study-level meta-analysis. Thromb Haemost 2020; 120 (02) 314-321
• 22 Bhalla V, Lamping OF, Abdel-Latif A, Bhalla M, Ziada K, Smyth SS. Contemporary meta-analysis of extended direct-acting oral anticoagulant thromboprophylaxis to prevent venous thromboembolism. Am J Med 2020; 133 (09) 1074-1081
• 23 O'Brien EC, Simon DN, Allen LA. et al. Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J 2014; 168 (04) 487-494
• 24 O'Brien EC, Holmes DN, Ansell JE. et al. Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Am Heart J 2014; 167 (04) 601-609
• 25 Proietti M, Romiti GF, Romanazzi I. et al. Restarting oral anticoagulant therapy after major bleeding in atrial fibrillation: a systematic review and meta-analysis. Int J Cardiol 2018; 261: 84-91
• 26 Proietti M, Marzona I, Vannini T. et al. Impact of liver disease on oral anticoagulant prescription and major adverse events in patients with atrial fibrillation: analysis from a population-based cohort study. Eur Heart J Cardiovasc Pharmacother 2021; 7 (FI1): f84-f92
• 27 Ivany E, Lotto R, Lip GY, Lane D. Managing uncertainty: physicians' decision-making for stroke prevention for patients with atrial fibrillation and intracerebral haemorrhage. Thromb Haemost 2022;

Publication History

Received: 14 April 2022

Accepted: 22 April 2022

Accepted Manuscript online:
25 April 2022

Article published online:
28 June 2022