NEWS & VIEWS GASTROINTESTINAL BLEEDING
Gastrointestinal bleeding risk is increased by novel anticoagulants Don C. Rockey
A report has demonstrated that in patients with atrial fibrillation the novel oral anticoagulant, dabigatran, increases the risk of gastrointestinal bleeding by nearly twofold compared with warfarin. Here, the risk of gastrointestinal bleeding associated with anticoagulants and antiplatelet agents is placed into clinical context and key management principles are emphasized. Rockey, D. C. Nat. Rev. Gastroenterol. Hepatol. 12, 131–132 (2015); published online 20 January 2015; doi:10.1038/nrgastro.2015.7
The use of anticoagulants and antiplatelet agents to treat patients with cardiovascular disease is widespread. Over the past decade, novel anticoagulants including rivaroxaban, apixaban, edoxaban, betrixaban and dabi gatran have gained acceptance in clinical practice for use in treating a variety of indica tions such as prevention of stroke in patients with atrial fibrillation and for the prophy laxis and treatment of venous thrombo embolism and acute coronary syndromes. Novel anticoagulants represent a substan tial advance in clinical practice as they do not require typical monitoring, which is required with warfarin, and do not require injection as is required when administering the low‑molecular‑weight heparins. Although traditional and novel anti coagulants and antiplatelet agents reduce the risk of cardiovascular complications, they are also clearly associated with an increased risk of gastrointestinal bleeding.1–4 Whether the risk-benefit profile of novel anticoagu lants favours a cardiovascular protective effect over an increased risk of any type of bleeding remains extremely controversial. A 2013 systematic review and meta-analysis evaluating the risk of gastrointestinal bleed ing associated with novel oral anticoagu lants revealed that there was a pooled OR of 1.45 (95% CI 1.07–1.97) for gastrointestinal bleeding associated with novel oral anti coagulants compared with standard therapy (defined as the use of any of the following: low-molecular-weight heparin; a vitamin K antagonist; antiplatelet therapy; placebo; or no additional therapy).5 The risk of gastro intestinal bleeding varied depending on
the novel oral anticoagulant used with ORs of 0.31 (95% CI 0.01–7.69) for edoxaban, 1.23 (95% CI 0.56–2.73) for apixaban, 1.48 (95% CI 1.21–1.82) for rivaroxaban and 1.58 (95% CI 1.29–1.93) for dabigatran. Other smaller studies focusing on single agents, have similarly demonstrated an increased risk of gastrointestinal bleeding associated with novel anticoagulants.1,7 Hernandez and colleagues6 examined the risk of all types of bleeding in patients with atrial fibrillation treated with dabigatran or warfarin. Pharmacy and medical claims data from a 5% random sample of Medicare bene ficiaries were used as the basis of this retro spective cohort study. Patients with newly diagnosed atrial fibrillation from 1 October 2010 to 31 October 2011 and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis were included in the analysis. Patients were followed up until anticoagulants were discontinued or changed, death occurred, or until 31 December 2011. Bleeding events were categorized as major or minor and by anatomical site. Major bleed ing events included intracranial haemor rhage, haemoperitoneum and inpatient or emergency department stays for haematuria or gastrointestinal or other haemorrhage. The investigators also used propensity matching in an attempt to balance underlying patient characteristics in the two groups (that is, patients on dabigatran or
warfarin). The risk of bleeding was also investigated in four subgroups of high-risk patients: those ≥75 years; African Americans; those with chronic kidney disease; and those with >7 concomitant comorbidities. Importantly, dabigatran was associated with a reduced risk of intracranial haemor rhage compared with warfarin (HR = 0.32; 95% CI 0.20–0.50), presumably owing to a reduction in atrial fibrillation mediated central nervous system embolization and haemorrhage. Dabigatran was also associ ated with an overall higher risk of bleeding than warfarin, with HRs of 1.30 (95% CI 1.20–1.41) for any bleeding event, 1.58 (95% CI 1.36–1.83) for major bleeding and 1.85 (95% CI 1.64–2.07) for gastrointesti nal bleeding. The risk of bleeding was also increased in patients taking antiplatelet agents compared with those taking warfa rin. Dabigatran was consistently associated with an increased risk of major bleed ing with gastrointestinal haemorrhage by far the most common type of bleeding identified. The risk of major bleeding asso ciated with dabigatran was especially high for African Americans and patients with chronic kidney disease. The authors con cluded that before more evidence is avail able, dabigatran should be prescribed with caution, especially in high-risk patients. There are many important limitations associated with the study. First, the study was retrospective and so ascertainment bias is an important potential confound ing issue. Second, no information was provided about the severity of gastrointestinal bleed ing and we do not know in how many patients gastrointestinal bleeding directly
Krishna Kumar/Hermera/Thinkstock/Modified by NPG
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2015 Macmillan Publishers Limited. All rights reserved
VOLUME 12 | MARCH 2015
NEWS & VIEWS contributed to an adverse outcome, includ ing death (in fact, the study did not report on death at all). In addition, follow-up was fairly short (only a maximum 14 months), which means that the authors could not evaluate important clinical outcomes; a short follow-up also precluded the evalu ation of the risk-benefit ratios of warfarin and dabigatran. The study lacked detailed laboratory data, for example serum creati nine levels; therefore, limiting the ability to more carefully perform propensity matching and to take into account whether bleeding events increased because of failure to adjust the dabigatran dose according to renal function.
‘‘
…before more evidence is available, dabigatran should be prescribed with caution…
’’
Despite the study’s limitations, the find ings from Hernandez et al.6 and data from other studies clearly indicates that the risk of gastrointestinal bleeding is increased in patients who use dabigatran and the other new oral anticoagulants. Further, the evi dence indicates that when these oral anti coagulants are used in combination with antiplatelet agents, the risk of gastrointes tinal bleeding is even greater.7–9 Although the risk of gastrointestinal bleeding associ ated with these combinations of agents is offset by their protective effect linked to cardiovascular disease, the window between benefit and risk is extremely narrow. Given that the use of anticoagulants and antiplatelet agents is beneficial in patients with cardiovascular disease their use will continue and probably proliferate. Thus in practice, patients will continue to have gastrointestinal bleeding when taking them. In what position does this dilemma leave the clinician? From my clinical expe rience, the following concepts are critical to consider. First, bleeding is a result of under lying gastrointestinal tract lesions and the anticoagulant or antiplatelet agents them selves do not cause bleeding, but rather they exacerbate it.10 Second, the use of dabigatran,
MARCH 2015 | VOLUME 12
other anticoagulants (novel and traditional) and/or antiplatelet agents in patients with cardiovascular disease should be individu alized and managed in a collaborative team approach—typically including a primary care physician and cardiologist. A gastro enterologist should become part of the team if there is a past history of gastro—intestinal disease or bleeding. Third, medications that increase the risk of gastrointestinal bleeding should be used in the lowest dose possible; this concept is especially true for the use of aspirin, which should be used at a maximum of 81 mg. Finally, PPIs should typically be used in patients at high risk of gastro intestinal bleeding including the following: those with a prior history of gastrointestinal bleeding or upper gastrointestinal mucosal injury; patients over 65 years; patients with multiple comorbidities; or patients prescribed aspirin, thienopyridine anti platelet agents, or NSAIDs concomitantly with anticoagulants. Several important points should be considered when managing patients with gastrointestinal bleeding whilst taking anti coagulants. Most gastrointestinal bleeding can be controlled by an expert and attentive gastroenterology team and indeed these patients should be managed by those with experience in gastrointestinal bleeding. In patients with clinically meaningful gastro intestinal bleeding, endoscopy should be performed early in an attempt not only to clearly identify the source of bleeding, but also to aggressively deploy mechanical methods to stop bleeding. Anticoagulant reversal agents might need to be used, but these drugs should be used only after con sultation with both the physician prescribing the anticoagulant and/or antiplatelet agent, and an expert in coagulation management. In conclusion, in patients with atrial fibrillation, dabigatran seems to substan tially increase the risk of gastrointestinal bleeding compared with warfarin. The risk is even greater when anticoagulants (includ ing novel agents such as dabigatran and traditional agents) and antiplatelet drugs are used concomitantly. As it is clear that the use of all of these agents will continue
to proliferate in patients with cardiovascular disease, it is important for practitioners to be familiar with the gastrointestinal bleed ing risks and the appropriate management of patients once bleeding has commenced. Department of Internal Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, MSC 623, Charleston, SC 29425, USA.
[email protected] Competing interests The author declares no competing interests. 1.
Harper, P., Young, L. & Merriman, E. Bleeding risk with dabigatran in the frail elderly. N. Engl. J. Med. 366, 864–866 (2012). 2. Southworth, M. R., Reichman, M. E. & Unger, E. F. Dabigatran and postmarketing reports of bleeding. N. Engl. J. Med. 368, 1272–1274 (2013). 3. Larsen, T. B. et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J. Am. Coll. Cardiol. 61, 2264–2273 (2013). 4. Sipahi, I., Celik, S. & Tozun, N. A comparison of results of the US food and drug administration’s mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran. JAMA Intern. Med. 174, 150–151 (2014). 5. Holster, I. L., Valkhoff, V. E., Kuipers, E. J. & Tjwa, E. T. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 145, 105–112 (2013). 6. Hernandez, I., Baik, S. H., Piñera, A. & Zhang, Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern. Med. http://dx.doi.org/ 10.1001/jamainternmed.2014.5398. 7. Komócsi, A., Vorobcsuk, A., Kehl, D. & Aradi, D. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials. Arch. Intern. Med. 172, 1537–1545 (2012). 8. Abraham, N. S. et al. Risk of lower and upper gastrointestinal bleeding, transfusions, and hospitalizations with complex antithrombotic therapy in elderly patients. Circulation 128, 1869–1877 (2013). 9. Lamberts, M. et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study. Ann. Intern. Med. 161, 690–698 (2014). 10. Greenberg, P. D., Cello, J. P. & Rockey, D. C. Asymptomatic chronic gastrointestinal blood loss in patients taking aspirin or warfarin for cardiovascular disease. Am. J. Med. 100, 598–604 (1996).
www.nature.com/nrgastro © 2015 Macmillan Publishers Limited. All rights reserved
