Non-Vitamin K Antagonist Oral Anticoagulants and the Gastrointestinal Bleeding Risk in Real-World Studies
Abstract
:1. Introduction
2. Experimental Section
3. Results
3.1. Characteristics of Patients Included in the Studies
3.2. Gastrointestinal Bleeding Risk Comparing Each NOAC with Warfarin
3.3. Gastrointestinal Bleeding Risk by Direct Pairwise Comparison of Different NOACs
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Indication | Dabigatran | Apixaban | Rivaroxaban |
---|---|---|---|
Non-valvular atrial fibrillation | 150 mg b.i.d | 5 mg b.i.d | 20 mg daily |
110 mg b.i.d if age ≥ 80 years (may consider 110 mg b.i.d also if increased risk of bleeding) | 2.5 mg b.i.d if CrCl 15–29 mL/min OR two out of the following: age ≥ 80 years, BW ≤ 60 kg, Cr ≥ 1.5 mg/dL | - | |
Avoid if CrCl < 30 mL/min | Avoid if CrCl < 15 mL/min | Avoid if CrCl < 15 mL/min | |
Treatment and prevention of recurrent deep vein thrombosis/ pulmonary embolism | 150 mg b.i.d after 5 days of initial therapy with a parenteral anticoagulant | 10 mg b.i.d for 1 week, then 5 mg b.i.d | 15 mg b.i.d for 3 weeks, then 20 mg daily |
110 mg b.i.d after 5 days of initial therapy with a parenteral anticoagulant if age ≥ 80 years (may consider 110 mg b.i.d also if increased risk of bleeding) | - | - | |
Avoid if CrCl < 30 mL/min | Avoid if CrCl < 15 mL/min | Avoid if CrCl < 15 mL/min |
Risk Factors |
1. Higher dose of dabigatran: a dose of 150 mg b.i.d 2. Concomitant use of ulcerogenic agents like antiplatelet agents, non-steroidal anti-inflammatory drugs or steroid 3. Older age: ≥75 years 4. Renal impairment with a creatinine clearance <50 mL/min 5. Prior history of peptic ulcers or GIB 6. Helicobacter pylori infection 7. Pre-existing GI tract lesions such as: diverticulosis, angiodysplasias 8. Ethnicity: western population 9. HAS-BLED score ≥3 |
Protective Factors |
Gastroprotective agents: proton pump inhibitors or histamine H2-receptor antagonists |
Study | Country | Obser-Vation Period | Oral Anticoagu-Lants Analyzed | Methodology | Population | Endpoint |
---|---|---|---|---|---|---|
Abraham et al. [54] | USA | October 2010 to February 2015 | Apixaban, dabigatran or rivaroxaban | Retrospective cohort study based on medical and pharmacy claims data from OptumLabs Data Warehouse using PSM | 43,303 adults diagnosed with NVAF who had an indexprescription for apixaban, dabigatran, or rivaroxaban | Bleeding |
Adeboyeje et al. [55] | USA | November 2010 to February 2015 | Apixaban, dabigatran, rivaroxaban, warfarin | Retrospective cohort study based on data from a commercially insured population in the U.S. | 44,057 patients diagnosed with NAVF, who used warfarin (23,431), dabigatran (8539), apixaban (3689) and rivaroxaban (8398) | Bleeding |
Andersson et al. [30] | Denmark | July 2013 to March 2016 | Apixaban, dabigatran or rivaroxaban | Retrospective cohort study based on nationwide registers | 12,638 NVAF patients, propensity scores in a 1:1 ration comparing (apixaban vs. dabigatran = 6470; apixaban vs. rivaroxaban = 7352; rivaroxaban vs. dabigatran = 5440 patients) | Effective-ness + bleeding |
Forslund et al. [56] | Sweden | January 2012 to December 2015 | Apixaban, dabigatran, rivaroxaban, warfarin | Population-based retrospective cohort study based on data from the Stockholm Region administrative health data register containing healthcare utilization and prescription data | 22,198 adults with NVAF who were naive for either warfarin or one of the following NOACs: apixaban, dabigatran, or rivaroxaban during the study period. | Effective-ness + bleeding |
Graham et al. [57] | USA | October 2010 to September 2015 | Apixaban, dabigatran, rivaroxaban, warfarin | Retrospective new-users cohort study based on data from Medicare beneficiaries | 183,318 warfarin, 86,198 dabigatran, 106,389 rivaroxaban and 73,039 apixaban users | Effective-ness + bleeding |
Hernandez et al. [58] | USA | January 2013 to December 2014 | Apixaban, dabigatran, rivaroxaban, warfarin | Retrospective database analysis from a random sample of Medicare beneficiaries | 41,366 adults with NVAF who were naive for either warfarin or one of the following NOACs: apixaban, dabigatran or rivaroxaban during the study period. | Effective-ness + bleeding |
Larsen et al. [59] | Denmark | August 2011 to October 2015 | Warfarin, apixaban, dabigatran, rivaroxaban (only standard dose) | Retrospective database analysis using propensity score weighting (inverse probability of treatment weighting) | 61,678 NVAF patients, naive to OAC, first time on DOAC or warfarin | Effective-ness + bleeding |
Nielsen et al. [60] | Denmark | August 2011 to February 2016 | Warfarin, apixaban, dabigatran, rivaroxaban (only reduced dose) | Retrospective analysis using propensity score weighting (inverse probability of treatment weighting) | 55,644 NVAF patients, naïve to OAC, first time on DOAC or warfarin, all restricted to reduced dose | Effective-ness + bleeding |
Noseworthy et al. [61] | USA | October 2010 to June 2015 | Rivaroxaban, dabigatran, apixaban | Retrospective analysis using administrative claims, using PSM and Cox proportional hazards regression | 57,788 NVAF patients, including patients with prior warfarin exposure. Apixaban used as reference category | Effective-ness + bleeding |
Vinogradova et al. [62] | UK | January 2011 to October 2016 | Warfarin, apixaban, dabigatran, rivaroxaban | Prospective open cohort study using two primary care databases representative of the national population | 132,231 warfarin, 7744 dabigatran, 37,863 rivaroxaban and 18,223 apixaban users, subgrouped into 103,270 patients with atrial fibrillation and 92,791 without atrial fibrillation | Bleeding |
Yao et al. [63] | USA | October 2010 to June 2015 | Warfarin, apixaban, dabigatran, rivaroxaban | Retrospective database analyses using PSM | 125,243 NVAF patients, three 1:1 PSM cohorts (apixaban = 15,390; dabigatran = 28,614; rivaroxaban = 32,350) | Effective-ness + bleeding |
Dabigatran | Rivaroxaban | Apixaban | Warfarin | Maximum SMD | |
---|---|---|---|---|---|
Study Abraham et al. [54] | |||||
Age group (mean) | 68.8 (11.4) | 70.6 (11.4) | 72.3 (11.1) | NA | - |
Male | 60.5% | 57.1% | 54% | NA | - |
CHA2DS2-VASC (mean) | 3.6 (1.9) | 3.8 (1.9) | 4.0 (1.9) | NA | - |
HAS-BLED (mean) | 2.2 (1.2) | 2.4 (1.2) | 2.4 (1.2) | NA | - |
Antiplatelet or non-steroidal anti-inflammatory drugs | 10.7% | 12.1% | 12.3% | NA | - |
Study Adeboyeje et al. [55] | |||||
Age group (mean) | 70 (12.3) | 70 (12.3) | 70 (12.6) | 70 (12.2) | 0.01 |
Male | 58.9% | 58.7% | 59.5% | 59.1% | 0.01 |
CHA2DS2-VASC (mean) | 3.3 (1.9) | 3.3 (1.9) | 3.3 (1.9) | 3.3 (1.8) | 0.01 |
HAS-BLED (mean) | 2.1 (1.4) | 2.1 (1.4) | 2.1 (1.4) | 2.1 (1.4) | 0.01 |
Antiplatelet or non-steroidal anti-inflammatory drugs | 19.9% | 20.5% | 20.2% | 20.2% | 0.01 |
Study Andersson et al. [30] | |||||
Age group (mean) | 65.7 (7.3) | 72.0 (9.8) | 71.9 (9.1) | NA | - |
Male | 64% | 56% | 63% | NA | - |
CHA2DS2-VASC | - | - | - | NA | - |
HAS-BLED | - | - | - | NA | - |
Antiplatelet or non-steroidal anti-inflammatory drugs | 59.8% | 61.8% | 57.8% | NA | - |
Study Forslund et al. [56] | |||||
Age group (mean) | 69.9 (11.3) | 74.0 (10.3) | 75.0 (10.8) | 74.1 (11.0) | - |
Male | 60% | 54.6% | 54.6% | 55.4% | - |
CHA2DS2-VASC (mean) | 3. 01 (1.89) | 3.59 (1.88) | 3.69 (1.9) | 3.68 (1.91) | - |
HAS-BLED | - | - | - | - | - |
Antiplatelet drugs | 46.73% | 55.74% | 47.73% | 54.96% | - |
Study Graham et al. [57] | |||||
Age group (mean) | 75.5 | 74.9 | 75.2 | 75.8 | 0.15 |
Male | 52.4% | 53.9% | 52.2% | 52% | 0.04 |
CHA2DS2-VASC (≥2) | 96.7% | 96.6% | 97.4% | 97.1% | 0.04 |
HAS-BLED (≥3) | 44.7% | 43.7% | 47.8% | 45.8% | 0.03 |
Antiplatelet or non-steroidal anti-inflammatory drugs | 28.3% | 28.2% | 29.5% | 27.2% | 0.04 |
Study Hernandez et al. [58] | |||||
Age group (mean) | 74.9 (8.7) | 76.4 (8.6) | 77.4 (8.6) | 76.0 (10.3) | <0.001 |
Male | 47.0% | 43.7% | 42.5% | 43.1% | <0.001 |
CHA2DS2-VASC (mean) | 4.26 (1.74) | 4.55 (1.78) | 4.68 (1.73) | 4.8 (1.82) | <0.001 |
HAS-BLED (mean) | 3.49 (0.93) | 3.65 (0.95) | 3.71 (0.93) | 3.71 (1.0) | <0.001 |
Antiplatelet or non-steroidal anti-inflammatory drugs | 22.5% | 25.2% | 25.0% | 21.3% | <0.001 |
Study Larsen et al. [59] | |||||
Age group (mean) | 67.6 (5.6) | 71.8 (7.1) | 71.3 (5.9) | 72.4 (7.4) | 0.02 |
Male | 66.1% | 57.9% | 60.3% | 58.8% | 0.02 |
CHA2DS2-VASC (mean) | 2.2 (1.4) | 2.8 (1.6) | 2.8 (1.6) | 2.8 (1.7) | 0.02 |
HAS-BLED (mean) | 2.0 (1.1) | 2.2 (1.2) | 2.3 (1.2) | 2.2 (1.2) | 0.01 |
Aspirin or non-steroidal anti-inflammatory drugs | 62.7% | 60.4% | 60.2% | 66.3% | 0.01 |
Study Nielsen et al. [60] | |||||
Age group (mean) | 79.9 (9.0) | 77.9 (13.5) | 83.9 (8.2) | 71.0 (12.6) | 0.09 |
Male | 46.3% | 46.8% | 39.4% | 59.6% | 0.03 |
CHA2DS2-VASC (mean) | 3.8 (1.5) | 3.6 (1.8) | 4.3 (1.5) | 3.0 (1.7) | 0.04 |
HAS-BLED (mean) | 2.7 (1.0) | 2.5 (1.2) | 2.8 (1.1) | 2.4 (1.2) | 0.06 |
Aspirin or non-steroidal anti-inflammatory drugs | 74.8% | 66.2% | 66.7% | 70.2% | 0.03 |
Study Noseworthy et al. [61] | |||||
Age group (median) | 71 (62–78) | 73 (65–81) | 73 (65–81) | NA | - |
Male | 58.9% | 54.4% | 54.1% | NA | - |
CHA2DS2-VASC (median) | 4 (2–5) | 4 (3–5) | 4 (3–5) | NA | - |
HAS-BLED (median) | 2 (1–3) | 2 (2–3) | 2 (2–3) | NA | - |
Antiplatelet or non-steroidal anti-inflammatory drugs | 11.1% | 11.7% | 12.2% | NA | - |
Study Vinogradova et al. [62] | |||||
Age group (mean) | 74.5 (10.7) | 75.8 (10.8) | 76.5 (10.9) | 74.8 (10.4) | - |
Male | 59.5% | 54.3% | 53.4% | 55.6% | - |
CHA2DS2-VASC | - | - | - | - | - |
HAS-BLED | - | - | - | - | - |
Antiplatelet or non-steroidal anti-inflammatory drugs | 39.6% | 32.3% | 31.3% | 41.8% | - |
Study Yao et al. [63] | |||||
Age group (median) | 70 (62–78) | 72 (64–80) | 73 (66–81) | 73 (66–81) | - |
Male | 61.3% | 57.8% | 53.1% | 53.2% | - |
CHA2DS2-VASC (median) | 3 (2–5) | 4 (2–5) | 4 (3–5) | 4 (3–5) | - |
HAS-BLED (median) | 2 (1–3) | 2 (2–3) | 2 (2–3) | 2 (2–3) | - |
Antiplatelet or non-steroidal anti-inflammatory drugs | 10.3% | 11.6% | 12.1% | 12.5% | - |
Study | Dabigatran vs. Warfarin | Rivaroxaban vs. Warfarin | Apixaban vs. Warfarin |
---|---|---|---|
Forslund et al. [56] | 1.43 (1.07–1.9) | 1.28 (0.90–1.80) | 1.13 (0.79–1.63) |
Larsen et al. [59] | 0.58 (0.47–0.71) | 1.06 (0.91–1.23) | 0.61 (0.49–0.75) |
Nielsen et al. [60] | 0.87 (0.75–1.01) | 1.17 (0.94–1.45) | 1.04 (0.76–1.43) |
Vinogradova et al. [62] | 1.08 (0.83–1.41) | 1.21 (1.01–1.45) | 0.76 (0.58–0.99) |
Yao et al. [63] | 0.79 (0.67–0.94) | 1.04 (0.90–1.20) | 0.45 (0.34–0.59) |
Graham et al. [57] | 1.04 (0.9–1.21) | 1.38 (1.12–1.54) | 0.51 (0.42–0.61) |
Adeboyeje et al. [55] | 1.17 (1.04–1.32) | 1.00 (0.87–1.16) | 0.82 (0.63–1.06) |
Hernandez et al. [58] | 0.95 (0.75–1.19) | 1.35 (1.20–1.52) | 0.72 (0.57–0.90) |
Study | Rivaroxaban vs. Dabigatran | Apixaban vs. Dabigatran | Apixaban vs. Rivaroxaban |
---|---|---|---|
Andersson et al. [30] | 1.35 (0.91–2.00) | 0.94 (0.62–1.41) | 0.88 (0.64–1.22) |
Abraham et al. [54] | 1.20 (1.00–1.45) | 0.39 (0.27–0.58) | 0.33 (0.22–0.49) |
Noseworthy et al. [61] | 1.30 (1.10–1.53) | 0.50 (0.36–0.70) | 0.39 (0.28–0.54) |
Graham et al. [57] | 1.32 (1.21–1.45) | 0.56 (0.32–0.74) | 0.38 (0.27–0.59) |
Adeboyeje et al. [55] | 1.15 (0.99–1.36) | 0.95 (0.65–1.18) | 0.82 (0.62–1.08) |
Hernandez et al. [58] | 1.25 (1.06–1.39) | 0.76 (0.56–1.03) | 0.53 (0.42–0.68) |
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Anghel, L.; Sascău, R.; Trifan, A.; Zota, I.M.; Stătescu, C. Non-Vitamin K Antagonist Oral Anticoagulants and the Gastrointestinal Bleeding Risk in Real-World Studies. J. Clin. Med. 2020, 9, 1398. https://doi.org/10.3390/jcm9051398
Anghel L, Sascău R, Trifan A, Zota IM, Stătescu C. Non-Vitamin K Antagonist Oral Anticoagulants and the Gastrointestinal Bleeding Risk in Real-World Studies. Journal of Clinical Medicine. 2020; 9(5):1398. https://doi.org/10.3390/jcm9051398
Chicago/Turabian StyleAnghel, Larisa, Radu Sascău, Anca Trifan, Ioana Mădălina Zota, and Cristian Stătescu. 2020. "Non-Vitamin K Antagonist Oral Anticoagulants and the Gastrointestinal Bleeding Risk in Real-World Studies" Journal of Clinical Medicine 9, no. 5: 1398. https://doi.org/10.3390/jcm9051398