Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis

Summary.  Background: Inherited thrombophilia is only weakly associated with recurrence in patients with a first venous thrombosis (VT). In spite of this, thrombophilia testing is often performed in these patients. Positive results may influence patient management such as prolonged anticoagulant treatment or intensified prophylaxis in high-risk situations. Objective: To investigate whether thrombophilia testing reduces the risk of recurrent VT by virtue of these management alterations. Methods: From a large case–control study of patients (MEGA study), aged 18–70 years, with a first VT between 1999 and 2004, we selected 197 patients who had had a recurrence during follow-up. We compared the incidence of thrombophilia testing to that of a control cohort of 324 patients. We calculated the odds ratio (OR) for recurrent thrombosis in tested vs. non-tested patients. Only patients who were tested before recurrence were regarded as tested. All first and recurrent thrombotic events were objectively confirmed. Results: Thrombophilia tests were performed in 35% of cases and in 30% of controls. The OR for recurrence was 1.2 [95% confidence interval (CI) 0.9–1.8] for tested vs. non-tested patients. After correction for age, sex, family history, geographic region, presence of clinical risk factors, and year of first VT, the OR remained unchanged. Discussion: Thrombophilia testing in patients with a first VT does not reduce the incidence of recurrence in clinical practice.     

Pregnancy and thrombophilia

The physiological changes that occur during pregnancy create a hypercoagulable milieu. This hypercoagulable state is thought to be protective, especially at the time of labor, preventing excessive hemorrhage. The presence of hereditary or acquired causes of thrombophilia during pregnancy tilts the balance in favor of unwanted venous thromboembolism and adverse pregnancy outcomes due to vascular uteroplacental insufficiency. These adverse pregnancy outcomes include recurrent pregnancy losses, intrauterine fetal death, intrauterine growth retardation, preeclampsia and placental abruption. Much of the current data with regards to the association of the different thrombophilias and pregnancy-related complications are based on retrospectively designed studies. This lack of randomization, in-homogeneity of patient populations, varying case definitions, selection biases and inadequately matched control populations, have given rise to conflicting data with regard to screening for, and treatment of, pregnant women with suspected thrombophilias. The limited data that we have support the use of anticoagulant drugs for the prevention of pregnancy-related complications in the setting of thrombophilia. Heparin and low-molecular-weight heparins are the anticoagulant drugs of choice as they do not cross the placental barrier and, hence, do not cause fetal anticoagulation or teratogenicity. Warfarin can be used from the 12th week of gestation onwards but is preferably reserved for the postpartum period.     

Family history and inherited thrombophilia

BACKGROUND: It is a common belief that patients with venous thrombosis and a positive family history for venous thromboembolism (VTE) have an increased likelihood of having an inherited thrombophilic defect. METHODS: We analyzed the relation between family history, qualified with three different methods, and thrombophilic status in 314 patients with proven VTE. A positive family history (one or more first-degree relatives with VTE) and a strongly positive family history (two or more first-degree relatives with VTE). In 118 of the patients a third, more precise method was analyzed: the family history score, which compares the observed and the expected number of first-degree family members with VTE. RESULTS: Patients with a positive or strongly positive family history had a slightly increased chance of having inherited thrombophilia compared to those without a positive family history. For positive family history this was 42% vs. negative 32%, likelihood ratio 1.3 (95% confidence interval; CI 0.9-2.1) and for strongly positive family history this was 46% vs. negative 34%, likelihood ratio 1.6 (95% CI 0.7-3.3). The family history score correlated with the chance of having inherited thrombophilia [OR 1.23 per score point (95% CI 1.01-1.48)]. However, even with this method the chance of having inherited thrombophilia is lower than 50% in 97% of the cases. CONCLUSIONS: Family history of VTE is not a precise tool in clinical practice to identify patients with inherited thrombophilia among patients with VTE. The family history score is more precise, but probably only useful for research purposes and not for daily practice.     

The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study

While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100,000 person-years]. VTE incidence rates for ages 15-29, 30-44, 45-59 and > or = 60 years were 0, 61, 244 and 764 per 100,000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those > or = 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100,000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those > or = 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.     

Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis.

BACKGROUND: The post-thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). OBJECTIVES: To evaluate predictors of the post-thrombotic syndrome, including intensity of long-term anticoagulation, and to assess the impact of the post-thrombotic syndrome on quality of life. PATIENTS AND METHODS: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty-five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional-intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long-term warfarin therapy (target INR 2.5 vs. INR 1.7). Post-thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease-specific quality of life was compared in patients with and without the post-thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post-thrombotic syndrome and of its severity. RESULTS: After an average follow-up of 2.2 years, the prevalence of post-thrombotic syndrome was 37% and of severe post-thrombotic syndrome was 4%. Quality of life was worse in patients with the post-thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post-thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post-thrombotic syndrome. CONCLUSIONS: The post-thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long-term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post-thrombotic syndrome, this finding requires further evaluation in prospective studies.     

The epidemiology of venous thromboembolism in Caucasians and African‐Americans: the GATE Study1

Summary. The aim of this study was to assess, comprehensively, medical and genetic attributes of venous thromboembolism (VTE) in a multiracial American population. The Genetic Attributes and Thrombosis Epidemiology (GATE) study is an ongoing case–control study in Atlanta, Georgia, designed to examine racial differences in VTE etiology and pathogenesis. Between 1998 and 2001, 370 inpatients with confirmed VTE, and 250 control subjects were enrolled. Data collected included blood specimens for DNA and plasma analysis and a medical lifestyle history questionnaire. Comparing VTE cases, cancer, recent surgery, and immobilization were more common in caucasian cases, while hypertension, diabetes, and kidney disease were more prevalent in African‐American cases. Family history of VTE was reported with equal frequency by cases of both races (28–29%). Race‐adjusted odds ratios for the associations of factor V Leiden and prothrombin G20210A mutations were 3.1 (1.5, 6.7) and 1.9 (0.8, 4.4), respectively. Using a larger external comparison group, the odds ratio for the prothrombin mutation among Caucasians was a statistically significant 2.5 (1.4, 4.3). A case‐only analysis revealed a near significant interaction between the two mutations among Caucasians. We found that clinical characteristics of VTE patients differed across race groups. Family history of VTE was common in white and black patients, yet known genetic risk factors for VTE are rare in African‐American populations. Our findings underscore the need to determine gene polymorphisms associated with VTE in African‐Americans.     

Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A

Summary.  Background : Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives : To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods : In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results : The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions : Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients.     

Risk of obstetric and thromboembolic complications in family members of women with previous adverse obstetric outcomes carrying common inherited thombophilias

Summary. Background: Factor (F)V Leiden and the prothrombin 20210A mutation (PTm) are associated with the occurrence of obstetric complications, including pregnancy‐related venous thromboembolism (VTE). It is not known whether family members of women with FV Leiden or PTm and previous obstetric complications have a higher risk of VTE or adverse obstetric outcomes. Methods: A retrospective family study including 563 relatives of 177 women with previous adverse outcomes carrying FV Leiden or PTm, referred between April 1993 and June 2010. A history of obstetric complications and VTE was obtained. Prevalence of VTE and obstetric complications in relatives with and without inherited thrombophilias was compared. Adjusted odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models that controlled for predictors (age, FV Leiden and PTm). Results: Relatives carrying FV Leiden had a significant and independent risk for obstetric complications (OR: 1.98, 95% CI 1.03–3.83); this risk was not observed in the presence of PTm (OR: 1.03, 95% CI 0.46–2.32). The presence of FV Leiden or PTm in heterozygosis was significantly and independently associated with the occurrence of VTE (OR: 5.2, 95% CI: 1.70–15.91). Severe thrombophilias were strong risk factors for VTE (OR: 23.2, 95% CI: 6.0–89.85). Male gender was a significant and independent risk factor for VTE (OR: 3.49, 95% CI: 1.51–8.05). The risk did not change when relatives of women with a previous pregnancy‐related VTE were excluded (OR: 3.49, 95% CI: 1.51–8.05). Conclusions: Knowledge of thrombophilia status may help to better define the obstetric and thromboembolic risks in asymptomatic family members of women who suffered from obstetric complications.     

Knowledge and educational needs of individuals with the factor V Leiden mutation

Summary.  Background : Genetic testing for factor (F)V Leiden is widely performed in an effort to prevent thrombosis-related morbidity. The implications of a positive test for patients' health perception and the extent of patients' understanding of results are not known. Objectives : This study examined patient experience of genetic testing for FV Leiden. Patients and methods : The study was a cross-sectional, mailed survey of 110 patients who tested positive for the FV Leiden gene mutation at an academic medical center between 1995 and 2001. Patient knowledge about FV Leiden, satisfaction with available information, and psychosocial reactions to testing were assessed and the influence of demographic and clinical characteristics on outcome measured. Results : The magnitude of thrombosis risk associated with FV Leiden was incorrectly estimated by 79% of participants. Many patients (64%) stated that they had not been given much information about FV Leiden and 68% still had many questions. Most patients (53%) felt that their healthcare providers do not understand FV Leiden. Patients who had been seen by a hematologist or in a specialized thrombosis clinic were more knowledgeable and had less information need. Most patients (88%) were glad to know genetic test results, despite negative psychosocial implications such as increased worry (43%). Conclusions : Knowledge of genetic status increases awareness of thrombosis risk among patients, but magnitude of risk is often overestimated. Affected individuals indicate that there is a lack of available information about FV Leiden and that additional educational resources are needed.     

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations

BACKGROUND: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. OBJECTIVE: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. METHODS: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. RESULTS: Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy [25 vs. 12%, relative risk (RR) 2.0, 95% CI 1.4-3.0]. The live birth rate of the second pregnancy after an early first loss ( 12 weeks), the live birth rates were 68% (95% CI 46-85) and 80% (95% CI 49-94) for carriers and non-carriers, respectively (RR 0.9, 95% CI 0.5-1.3). CONCLUSIONS: Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.     

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis

BACKGROUND: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. METHODS: To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. RESULTS: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4). CONCLUSIONS: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.     

The factor V Glu1608Lys mutation is recurrent in familial thrombophilia

BACKGROUND: Co-inheritance of heterozygous factor V deficiency with FV Leiden enhances the activated protein C resistance (APCR) associated with this mutation, resulting in pseudo-homozygous APCR. The role of FV deficiency in modulating thrombotic risk in this rare condition is poorly understood. METHODS AND RESULTS: We have identified in thrombophilic patients with FV deficiency a novel FV gene mutation (c. 4996G>A), predicting the Glu1608Lys substitution in the A3 domain. The heterozygous mutation was detected in three unrelated patients, two carriers of the FV Leiden mutation, and one of the FVHR2 haplotype. The Glu1608Lys change was also present in two subjects with mild FV deficiency, and absent in 200 controls. The FV1608Lys carriers showed reduced mean FV activity (42% +/- 12%) and antigen (53% +/- 18%) levels and, in Western blot analysis, reduced amounts of intact platelet FV. The restriction fragment length polymorphism (RFLP) study identified two haplotypes underlying the mutation, which suggests that it is recurrent. In heterozygous subjects the amount of FV1608Lys mRNA in white blood cells was similar to that produced by the counterpart alleles (FVWt or FVHR2). Recombinant FV1608Lys (rFV1608Lys), detected by Western blot in the conditioned medium, was indistinguishable from rFVWt and FV antigen and activity were found to be respectively 44% +/- 20% and 13% +/- 4% of rFVWt. CONCLUSIONS: Our data indicate that FVGlu1608Lys predicts a CRM (plasma)/CRMred (cell culture) FV deficiency, and may contribute to thrombophilia in carriers of FV Leiden and FVHR2 haplotype via a pseudo-homozygosity mechanism. Our findings help to define the molecular bases of FV deficiency and thrombophilia.     

Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Summary. Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta‐analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I² 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy‐related VTE, but the optimal dosing regimens remain uncertain.     

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.     

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Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms

Background: Pregnancy is associated with a 10‐fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy‐related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. Materials and Methods: The study comprised 377 155 women with 613 232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. Results: The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1–8.3] and 9.4 (95% CI 2.1–42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy‐related VT occurred in 1.1/1000 non‐carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. Conclusions: Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy‐related VT was low.     

A systematic review and Bayesian network meta‐analysis of risk of intracranial hemorrhage with direct oral anticoagulants

Essentials

• Risk of intracranial hemorrhage (ICH) may differ between direct oral anticoagulants (DOACs).
• We compared the risk of ICH between DOACs using network meta‐analysis.
• Dabigatran 110 mg and 150 mg were safer than rivaroxaban on Bayesian analysis.
• Dabigatran 110 mg ranked as the safest DOAC while rivaroxaban ranked last.

Summary

Background

The comparative risk of intracranial hemorrhage (ICH) among direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban and edoxaban) remains unclear.

Objective

To determine the difference in risk of ICH between DOACs

Methods

Seventeen randomized controlled trials (RCTs) were selected using PubMed/MEDLINE, EMBASE and CENTRAL (Inception, 31 December 2017). Estimates were reported as odds ratio (OR) with 95% credible interval (CR.I) in Bayesian network meta‐analysis (NMA), and OR with 95% confidence interval (CI) in traditional meta‐analyses. Relative ranking probability of each group was generated based on surface under the cumulative ranking curve (SUCRA).

Results

In NMA of 116 618 patients from 17 RCTs (apixaban = 19 495 patients, rivaroxaban = 14 157 patients, dabigatran = 16 074 patients, edoxaban = 11 652 patients, and comparator = 55 315 patients), all DOACs were safer than warfarin for risk of ICH. Dabigatran 110 mg ranked as the safest drug (SUCRA, 0.85) and reduced the risk of ICH by 56% compared to rivaroxaban (OR, 0.44; 95% Cr.I, 0.22–0.82). Pairwise meta‐analysis validated these findings, showing that DOACs were safer than warfarin (OR, 0.46; 95% CI, 0.35–0.59). Subgroup analysis showed that the benefit was present when DOACs were used in non‐valvular atrial fibrillation (NVAF) (OR, 0.51; 95% CI, 0.38–0.68) or venous thromboembolism (VTE) (OR, 0.32; 95% CI, 0.18–0.58).

Conclusion

Dabigatran 110 mg may be the safest choice among any anticoagulant regarding risk of ICH. Both dabigatran 110 mg and 150 mg were safer than rivaroxaban.