New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding

A Systematic Review and Meta-analysis

I. Lisanne Holster; Vera E. Valkhoff; Ernst J. Kuipers; Eric T. T. L. Tjwa


Gastroenterology. 2013;145(1):105-112. 

In This Article



Our initial search identified 375 records (Figure 1A). A total of 42 studies were eligible for inclusion. The agreement between reviewers for trial inclusion was excellent (κ, 0.94). The clinical indication comprised AF in 8 studies,[9,10,25–30] OS in 21 studies, [31–51] medically ill patients in 2 studies,[52,53] DVT/PE in 6 studies (reporting on 7 trials),[54–59] and ACS in 5 studies (Figure 1B).[60,61,62,63,64]

Figure 1.

(A) Flowchart of included studies. (B) Indications of included studies split by drug. (C) Drugs of included studies split by indication. *One of these studies describes 2 subsequent trials, and therefore is mentioned twice in the data extraction. Api, apixaban; ACS, acute coronary syndrome; AF, atrial fibrillation; bet, betrixaban; dab, dabigatran; DVT, deep vein thrombosis; edo, edoxaban; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism; riv, rivaroxaban.

To gain insight into the performance per drug, the information on bleeding risk was summarized per individual drug (Figure 1C). Rivaroxaban was studied most frequently (15 studies reporting on 16 trials),[10,32–35,39–41,44,54,55,58,59,61,63] followed by apixaban (12 trials),[28–30,38,45,48,49,52,53,56,60,62] dabigatran (10 trials),[9,25,31,36,37,42,46,51,57,64] edoxaban (4 trials),[26,27,47,50] and betrixaban (1 trial).[43] The main characteristics of the 43 included trials are summarized in Supplementary Tables 1–5.

Study Characteristics

A total of 151,578 patients were included in the 43 trials. Duration of follow-up evaluation ranged from 3 weeks to 31 months, with shorter durations of follow-up evaluation for the OS studies and longer durations for AF studies. Patients with a recent history of peptic ulcer disease or patients with an otherwise increased risk of GIB (eg, patients with a thrombocytopenia or coagulation disorder) were excluded in all 43 trials. Concomitant use of any co-medication affecting coagulation was prohibited in 19% of trials, only low-dose aspirin (<160 mg) was allowed in 14%, only short-acting nonsteroidal anti-inflammatory drugs (NSAIDs) (<17 hours) were allowed in 16%, and short-acting NSAIDs/cyclooxygenase-2 inhibitors and/or low-dose aspirin and/or thienopyridines was allowed in 44%, mostly with the addition that it was discouraged. Information on the allowance of antithrombotic co-medication was absent in 7% of trials (Supplementary Tables 1–5).

Study Exposure

First, the risk estimates from each study were pooled by indication because the registered/recommended dose for each individual nOAC differs per indication (Supplementary Table 6). A total of 125,354 patients (83%) were enrolled in the therapeutic arms relevant to this review. Of the 8 trials on AF, 7 trials compared one of the novel agents with dose-adjusted warfarin. Of the 21 trials on thromboprophylaxis after OS, 19 compared a nOAC with LMWH (Supplementary Tables 1–5). All trials, except one trial[58] on DVT/PE treatment, compared a nOAC with LMWH followed by VKA. The trials on treatment of ACS compared nOAC with placebo, in addition to standard (double) antiplatelet therapy.

Publication Bias

The result of the Egger regression test for publication bias was not significant (intercept, 0.7; 95% CI, –0.4 to 1.7; P = .20) and no funnel plot asymmetry was observed (Supplementary Figure 1), indicating no evidence of publication bias.

Methodologic Quality of Included Studies

Supplementary Table 7 presents an overview of the methodologic quality of included RCTs. The majority of trials mentioned the method used for randomization (93%) and adequate concealment of allocation (72%). Seventy percent of studies applied a double-blind design, 23% had a single-blind design, and 7% followed an open-label design. An independent blinded committee identified all suspected outcome events in each study. Ninety-three percent of studies used an intention-to-treat analysis at least for the safety analysis. The number of patients lost to follow-up evaluation varied between 0.1% and 2.5%, but were reported in only 53% of studies.

Gastrointestinal Bleeding

Nineteen trials (44%) reported separate data on GIB.[9,10,27–30,33,35,38,39,41,45,48,49,53,57,58,60,64] Two small trials yielded null events in both groups and therefore were excluded from the GIB analyses.[35,38] A total of 1101 GIB events in 75,081 patients were reported (1.5%) (Supplementary Table 8). These GIBs were predominantly major bleeds (89%). The percentage of GI bleeds per trial in the nOAC group was low in the trials on OS (nOAC, 0.1%; control, 0.2%), intermediate in the trials on AF (nOAC, 2.1%; control, 1.6%) and DVT/PE (nOAC, 3.0%; control, 1.9%), and high in the trials on ACS (nOAC, 5.3%; control, 1.0%). The NNH was 500 (95% CI, -10,000 to 200), meaning that if 1000 patients were treated with the nOAC instead of standard care, this would result in 2 additional GIBs.

Four of 17 studies showed an increased risk, 12 a comparable risk, and 1 a lower risk of GIB when the nOAC was administered compared with the standard care. After pooling the results of 17 RCTs, the nOAC were found to be associated with a higher risk of GIB compared with standard care (pooled OR, 1.45; 95% CI, 1.07–1.97), but with substantial heterogeneity (I2, 61%). First, a considerable part of the increased risk could be attributed to the 2 trials on ACS (pooled OR, 5.21; 95% CI, 2.58–10.53; I2, 0%). To illustrate, the NNH was 24 (95% CI, 17–42), meaning that per 24 patients treated with the nOAC on top of standard care for ACS, 1 extra GIB would occur. Second, the risk of GIB with nOAC was increased for the 2 trials on DVT/PE (pooled OR, 1.59; 95% CI, 1.03–2.44; I2 27%), but not for other indications for nOAC. The calculated OR (95% CI) of each trial is shown in Figure 2A and 2B. With post hoc meta-regression, we studied the effect of indication of use (therapeutic use of nOAC vs prophylactic use). This showed no difference between therapeutic or prophylactic use when adjusted for comparator (placebo vs antithrombotic agent).

Figure 2.

(A) Forrest plot of GIB with subgroup analysis by indication. (B) Forrest plot of GIB with subgroup analysis by drug. Data are presented as OR (95% CI) using a random-effects model and I2 test for heterogeneity. Api, apixaban; bet, betrixaban; dab, dabigatran; edo, edoxaban; riv, rivaroxaban; ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In a subgroup analysis of individual drugs, dabigatran (3 studies;[9,57,64] I2, 36%), and rivaroxaban (5 studies;[10,33,39,41,58] I2, 0%) were associated with a significant increase in risk of GIB, whereas apixaban (8 studies;[28,29,30,38,45,48,49,53,60] I2, 0%) and edoxaban (1 study[27]) were not. The pooled OR of GIB associated with dabigatran use was 1.58 (95% CI, 1.29–1.93) (Figure 2B). Expressed in terms of NNH: per 83 patients treated with dabigatran compared with standard care, 1 additional GIB would occur (95% CI, 59–143). The GIB risk associated with use of rivaroxaban had an OR of 1.48 (95% CI, 1.21–1.82). When adjusting for indication of use (therapeutic vs prophylactic), the risk of rivaroxaban remained significantly higher than that of apixaban (OR, 1.77; 95% CI, 1.32–2.38). Analysis by comparator, adjusted for indication of use, revealed no significant differences between different comparators.

In the sensitivity analysis, we excluded studies that compared nOAC with placebo therapy. No major deviations were seen, except for the risk of GIB during DVT/PE treatment, which reduced and became inconclusive (OR, 1.53; 95% CI, 0.99–2.36). Complete results of this sensitivity analysis are shown in Supplementary Table 8.

Clinically Relevant Bleeding

Because GIB is a substantial component of clinically relevant bleeding, we also included this in our analysis. All 43 trials reported on clinically relevant bleeding. The overall risk of clinically relevant bleeding was significantly higher with the use of nOAC compared with standard care (OR, 1.16; 95% CI, 1.00–1.34). Considerable overall heterogeneity, however, was observed (I2, 83%).

In a subgroup analysis in which different indications for nOAC therapy were considered, we found that patients treated for ACS have an increased risk of bleeding (OR, 2.06; I2, 22%) in contrast to patients receiving thromboprophylaxis during OS (OR, 1.05; I2, 36%). The other indications did not show a significantly increased risk, but this may be hampered by the substantial heterogeneity. Subgroup analysis by individual drug showed a slightly increased risk of rivaroxaban compared with standard care (OR, 1.31; 95% CI, 1.04–1.64), but likewise was marked by heterogeneity (I2, 85%), limiting a solid conclusion on the risk of clinically relevant bleeding (Figure 3 and Supplementary Table 8). The risk of clinically relevant bleeding did not differ by drug when adjusted for indication of use.

Figure 3.

Forrest plot of clinically relevant bleeding summarized by indication and by drug. Data are presented as OR (95% CI) using a random effects model and an I2 test for heterogeneity. ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In the sensitivity analysis, excluding studies comparing with placebo, the overall clinically relevant bleeding risk was not increased (OR, 0.98; 95% CI, 0.88–1.10; I2, 65%) (Supplementary Table 8).