- Email: [email protected]
Direct oral anticoagulants and gastroenterologists
Comment
Direct oral anticoagulants are marketed worldwide and extensively prescribed. They are subdivided by mode of action into a direct thrombin inhibitor, dabigatran, and direct factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban. Their efficacy and safety compared with traditional anticoagulants have been the focus of several publications. Indeed, many systematic reviews and meta-analyses (including network meta-analyses) have been published, as described in a critical review.1 Although most direct oral anticoagulants are not prescribed by gastroenterologists, knowledge about them is important because gastroenterologists treat patients taking these drugs who present with gastrointestinal bleeding and other non-bleeding gastrointestinal adverse events such as gastro-oesophageal reflux disease and dyspepsia. Gastroenterologists who perform invasive diagnostic and therapeutic procedures such as endoscopy on patients taking direct oral anticoagulants must have expertise in the use of these drugs during the periprocedural period. The risk of gastrointestinal bleeding with direct oral anticoagulants compared with traditional anticoagulant therapies has been assessed in two conventional meta-analyses,2,3 but their conclusions were not consistent. One of the reasons for this discrepancy might be the heterogeneity between included studies in terms of drugs, doses, period of observation, and enrolled patients. For instance, the dose of rivaroxaban approved in Japan (15 mg per day) is lower than that used in Europe and North America (20 mg per day). As such, synthesis of data from Japanese trials might have diluted the risk of rivaroxaban reported by one of the meta-analyses.3 Nevertheless, because real-world data for direct oral anticoagulants are published every year, an updated meta-analysis is welcome if it provides new insights on the basis of accumulating data, with a versatile analytical method like network meta-analysis. In The Lancet Gastroenterology & Hepatology, Nick Burr and colleagues4 report the results of a network meta-analysis of a large dataset assessing the risk of gastrointestinal bleeding with the use of direct oral anticoagulants. Network meta-analysis enables comparison between therapies in the absence of a direct head-to-head study.5 For example, the result of network meta-analysis as presented by a league table will offer an
easy way to understand the rank order to judge benefit or hazard of treatments. The investigators’ conclusions for major gastrointestinal bleeding seem to stand midway between the two previous meta-analyses: direct oral anticoagulants were not associated with an increased risk of major gastrointestinal bleeding compared with warfarin or low-molecular-weight heparin, and although factor Xa inhibitors were associated with fewer gastrointestinal bleeding events, these results were not statistically significant. In a sensitivity analysis that compared each individual direct oral anticoagulant, edoxaban was associated with a significantly reduced risk of major gastrointestinal bleeding compared with dabigatran. The investigators also did a network meta-analysis of all severities of gastrointestinal bleeding with a limited dataset, which is more clinically relevant for gastroenterologists, and found that a similar rank order was maintained. Thus, this updated meta-analysis incorporating real-world data provides useful information for gastroenterologists about the risk of gastrointestinal bleeding with direct oral anticoagulants. However, we need to be cautious of accepting the investigators’ conclusions; some reports have raised concerns about the credibility of the data in the pivotal clinical trials.6,7 When interpreting network meta-analyses, one of the concerns is whether treatment effect modifiers are properly adjusted for, because collections of a wide range of reports increase heterogeneity in many important elements that can skew the risk and benefit.1 Unfortunately, adjustment for treatment effect modifiers was incomplete because of a lack of essential information, as acknowledged by the investigators. Another method of adjustment is the use of subgroup analyses, some of which were done by Burr and colleagues (eg, indications for anticoagulation), but results of these subgroup analyses were similar to the main analysis, suggesting that treatment effect modifiers such as indication were unlikely to have affected the results. This network meta-analysis did not address nonbleeding gastrointestinal adverse events that might compromise adherence to direct oral anticoagulants. During low-dose aspirin therapy, adherence is a crucial factor, for which co-administration of proton pump inhibitors is helpful to prevent gastrointestinal events.8
www.thelancet.com/gastrohep Published online November 15, 2016 http://dx.doi.org/10.1016/S2468-1253(16)30178-9
Marc Phares/Science Photo Library
Direct oral anticoagulants and gastroenterologists
Lancet Gastroenterol Hepatol 2016 Published Online November 15, 2016 http://dx.doi.org/10.1016/ S2468-1253(16)30178-9 See Online/Articles http://dx.doi.org/10.1016/ S2468-1253(16)30162-5
1
Comment
Among the direct oral anticoagulants, dabigatran is known to increase dyspeptic symptoms, and it would be useful to investigate whether proton pump inhibitors can reduce such symptoms and contribute to increased adherence. As for gastrointestinal bleeding with direct oral anticoagulants, conflicting data on the preventive effect of proton pump inhibitors have been reported.9,10 To resolve this issue, the effects of proton pump inhibitors in preventing gastrointestinal bleeding or non-bleeding gastrointestinal adverse events should be tested by prospective controlled studies. Furthermore, because antidotes for direct oral anticoagulants in patients presenting with gastrointestinal bleeding are now available,11 management guidelines considering the risk and benefit of antidotes should be established. Gastroenterologists need to have solid evidence on the best timing to re-start direct oral anticoagulants following gastrointestinal bleeding or major interventions. Gastroenterologists have obligations to investigate the unexplored issues of direct oral anticoagulants to increase patient safety. Kentaro Sugano
I have received lecture fees from Takeda Pharmaceutical Company. 1
2
3
4
5
6 7 8 9
10
11
Cope S, Clemens A, Hammès F, Noack H, Jansen JP. Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials. Value Health 2015; 18: 234–49. Holster L, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013; 145: 105–12. Caldeira D, Barra M, Ferreira A, et al. Systematic review with meta-analysis: the risk of major gastrointestinal bleeding with non-vitamin K antagonist oral anticoagulants. Aliment Pharmacol Ther 2015; 42: 1239–49. Burr N, Lummis K, Sood R, Kane JS, Corp A, Subramanian V. Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2016; published online Nov 15. http://dx.doi.org/10.1016/S24681253(16)30162-5. Greco T, Biondi-Zoccai G, Saleh O, et al. The attractiveness of network meta-analysis: a comprehensive systematic and narrative review. Heart Lung Vessel 2015; 7: 133–42. Cohen D. Concerns over data in the key dabigatran trial. BMJ 2014; 349: g4747. Fleming TR, Emerson SS. Evaluating rivaroxaban for novalvular atrial fibrillation—regulatory considerations. N Engl J Med 2011; 365: 1557–59. Sugano K. Prevention of upper gastrointestinal ulcer and complications in low-dose aspirin users. Curr Pharm Des 2015; 21: 5082–88. Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015; 350: h1857. Chan EW, Lau WC, Leung WK, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology 2015; 149: 586–95. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol 2015; 35: 1736–45.
Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan [email protected]
2
www.thelancet.com/gastrohep Published online November 15, 2016 http://dx.doi.org/10.1016/S2468-1253(16)30178-9
Direct oral anticoagulants are marketed worldwide and extensively prescribed. They are subdivided by mode of action into a direct thrombin inhibitor, dabigatran, and direct factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban. Their efficacy and safety compared with traditional anticoagulants have been the focus of several publications. Indeed, many systematic reviews and meta-analyses (including network meta-analyses) have been published, as described in a critical review.1 Although most direct oral anticoagulants are not prescribed by gastroenterologists, knowledge about them is important because gastroenterologists treat patients taking these drugs who present with gastrointestinal bleeding and other non-bleeding gastrointestinal adverse events such as gastro-oesophageal reflux disease and dyspepsia. Gastroenterologists who perform invasive diagnostic and therapeutic procedures such as endoscopy on patients taking direct oral anticoagulants must have expertise in the use of these drugs during the periprocedural period. The risk of gastrointestinal bleeding with direct oral anticoagulants compared with traditional anticoagulant therapies has been assessed in two conventional meta-analyses,2,3 but their conclusions were not consistent. One of the reasons for this discrepancy might be the heterogeneity between included studies in terms of drugs, doses, period of observation, and enrolled patients. For instance, the dose of rivaroxaban approved in Japan (15 mg per day) is lower than that used in Europe and North America (20 mg per day). As such, synthesis of data from Japanese trials might have diluted the risk of rivaroxaban reported by one of the meta-analyses.3 Nevertheless, because real-world data for direct oral anticoagulants are published every year, an updated meta-analysis is welcome if it provides new insights on the basis of accumulating data, with a versatile analytical method like network meta-analysis. In The Lancet Gastroenterology & Hepatology, Nick Burr and colleagues4 report the results of a network meta-analysis of a large dataset assessing the risk of gastrointestinal bleeding with the use of direct oral anticoagulants. Network meta-analysis enables comparison between therapies in the absence of a direct head-to-head study.5 For example, the result of network meta-analysis as presented by a league table will offer an
easy way to understand the rank order to judge benefit or hazard of treatments. The investigators’ conclusions for major gastrointestinal bleeding seem to stand midway between the two previous meta-analyses: direct oral anticoagulants were not associated with an increased risk of major gastrointestinal bleeding compared with warfarin or low-molecular-weight heparin, and although factor Xa inhibitors were associated with fewer gastrointestinal bleeding events, these results were not statistically significant. In a sensitivity analysis that compared each individual direct oral anticoagulant, edoxaban was associated with a significantly reduced risk of major gastrointestinal bleeding compared with dabigatran. The investigators also did a network meta-analysis of all severities of gastrointestinal bleeding with a limited dataset, which is more clinically relevant for gastroenterologists, and found that a similar rank order was maintained. Thus, this updated meta-analysis incorporating real-world data provides useful information for gastroenterologists about the risk of gastrointestinal bleeding with direct oral anticoagulants. However, we need to be cautious of accepting the investigators’ conclusions; some reports have raised concerns about the credibility of the data in the pivotal clinical trials.6,7 When interpreting network meta-analyses, one of the concerns is whether treatment effect modifiers are properly adjusted for, because collections of a wide range of reports increase heterogeneity in many important elements that can skew the risk and benefit.1 Unfortunately, adjustment for treatment effect modifiers was incomplete because of a lack of essential information, as acknowledged by the investigators. Another method of adjustment is the use of subgroup analyses, some of which were done by Burr and colleagues (eg, indications for anticoagulation), but results of these subgroup analyses were similar to the main analysis, suggesting that treatment effect modifiers such as indication were unlikely to have affected the results. This network meta-analysis did not address nonbleeding gastrointestinal adverse events that might compromise adherence to direct oral anticoagulants. During low-dose aspirin therapy, adherence is a crucial factor, for which co-administration of proton pump inhibitors is helpful to prevent gastrointestinal events.8
www.thelancet.com/gastrohep Published online November 15, 2016 http://dx.doi.org/10.1016/S2468-1253(16)30178-9
Marc Phares/Science Photo Library
Direct oral anticoagulants and gastroenterologists
Lancet Gastroenterol Hepatol 2016 Published Online November 15, 2016 http://dx.doi.org/10.1016/ S2468-1253(16)30178-9 See Online/Articles http://dx.doi.org/10.1016/ S2468-1253(16)30162-5
1
Comment
Among the direct oral anticoagulants, dabigatran is known to increase dyspeptic symptoms, and it would be useful to investigate whether proton pump inhibitors can reduce such symptoms and contribute to increased adherence. As for gastrointestinal bleeding with direct oral anticoagulants, conflicting data on the preventive effect of proton pump inhibitors have been reported.9,10 To resolve this issue, the effects of proton pump inhibitors in preventing gastrointestinal bleeding or non-bleeding gastrointestinal adverse events should be tested by prospective controlled studies. Furthermore, because antidotes for direct oral anticoagulants in patients presenting with gastrointestinal bleeding are now available,11 management guidelines considering the risk and benefit of antidotes should be established. Gastroenterologists need to have solid evidence on the best timing to re-start direct oral anticoagulants following gastrointestinal bleeding or major interventions. Gastroenterologists have obligations to investigate the unexplored issues of direct oral anticoagulants to increase patient safety. Kentaro Sugano
I have received lecture fees from Takeda Pharmaceutical Company. 1
2
3
4
5
6 7 8 9
10
11
Cope S, Clemens A, Hammès F, Noack H, Jansen JP. Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials. Value Health 2015; 18: 234–49. Holster L, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013; 145: 105–12. Caldeira D, Barra M, Ferreira A, et al. Systematic review with meta-analysis: the risk of major gastrointestinal bleeding with non-vitamin K antagonist oral anticoagulants. Aliment Pharmacol Ther 2015; 42: 1239–49. Burr N, Lummis K, Sood R, Kane JS, Corp A, Subramanian V. Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2016; published online Nov 15. http://dx.doi.org/10.1016/S24681253(16)30162-5. Greco T, Biondi-Zoccai G, Saleh O, et al. The attractiveness of network meta-analysis: a comprehensive systematic and narrative review. Heart Lung Vessel 2015; 7: 133–42. Cohen D. Concerns over data in the key dabigatran trial. BMJ 2014; 349: g4747. Fleming TR, Emerson SS. Evaluating rivaroxaban for novalvular atrial fibrillation—regulatory considerations. N Engl J Med 2011; 365: 1557–59. Sugano K. Prevention of upper gastrointestinal ulcer and complications in low-dose aspirin users. Curr Pharm Des 2015; 21: 5082–88. Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015; 350: h1857. Chan EW, Lau WC, Leung WK, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology 2015; 149: 586–95. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol 2015; 35: 1736–45.
Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan [email protected]
2
www.thelancet.com/gastrohep Published online November 15, 2016 http://dx.doi.org/10.1016/S2468-1253(16)30178-9