Correspondence
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Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014; 383: 955–62. Wieloch M, Sjalander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011; 32: 2282–89. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvular atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472. Lane DA, Lip GY. Quality of anticoagulation control in atrial fibrillation. Lancet 2010; 376: 935–37. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011; 123: 2562–70.
Although new oral anticoagulants (NOACs) showed a favourable risk-benefit profile for treatment of atrial fibrillation,1 it is questionable whether they should be recommended in unselected elderly patients in primary care. Many patients with atrial fibrillation using oral anticoagulants do not meet the eligibility criteria of trials that showed effectiveness and safety of these drugs. In a case-control study, 2 40% of users of vitamin K antagonists presenting with bleeding had one or more exclusion criteria for these trials. This might also apply to NOACs, especially in elderly people. Several factors, such as interactions with concomitant medication, worsening of renal function, and reduced patient compliance in daily care compared with research context might affect the blood level of NOACs. In the absence of regular monitoring of coagulation, which is routine in patients using vitamin K antagonists, any deviation beyond the therapeutic range will not be noticed. This might expose patients to inadequate protection against strokes or increased risk of harm. A recent observational study3 reported that dabigatran might be as effective 24
and safe in daily practice and research context. However, since the study was not randomised, confounding by indication might have biased these results. Therefore, we would recommend that NOACs should only be prescribed in patients younger than 80 years with few comorbidities, good renal function (glomerular filtration rate >50 mL/min), and good expected drug adherence. 4 According to principles of shared decision making, primary care physicians could discuss the benefits and harms of antithrombotic management options with their patients. We declare no competing interests.
*Wim Opstelten, Maureen van den Donk, Ton Kuijpers, Jako S Burgers [email protected] Dutch College of General Practitioners, 3502 GE, Utrecht, Netherlands 1
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3
4
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014; 383: 955–62. Levi M, Hovingh GK, Cannegieter SC, Vermeulen M, Buller HR, Rosendaal FR. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 2008; 111: 4471–76. Larsen TB, Rasmussen LH, Skjoth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation. J Am Coll Cardiol 2013; 61: 2264–73. van den Donk M, Opstelten W. Important changes in the Dutch College of General Practitioners (NHG) practice guideline ‘Atrial fibrillation’: revised practice guideline issued (in Dutch). Ned Tijdschr Geneeskd 2013; 157: A6697.
Christian Ruff and colleagues’ meta-analysis 1 reports substantial reductions in stroke and all-cause mortality by use of the new oral anticoagulants (NOACs) compared with warfarin for atrial fibrillation, justifying their increasing use, but also the unequivocal increased risk of gastrointestinal bleeding. Furthermore, the trials included patients with a presumed low risk
of gastrointestinal complications and therefore the true risk might be greater outside the clinical trial setting. Prothrombotic agents such as activated factor VII and activated prothrombin complex concentrate can be used to reduce bleeding by globally increasing thrombin generation but they do not reverse the effects of NOACs2 and therefore the traditional approach of rapid reversal of anticoagulation and then prompt endoscopy after gastrointestinal bleeding 3 with warfarin is not possible because of the lack of an antidote for NOACs. This raises challenges and uncertainties as to the optimal endoscopic timing and management of patients anticoagulated with NOACs who bleed because of tissue friability associated with endotherapy. Since prevention is better than cure, more work is needed to understand whether coprescription of proton-pump inhibitors with NOACs might be gastroprotective. In the interim, we urge clinicians to exercise caution in prescribing NOACs as an alternative to warfarin in patients with risk factors for gastrointestinal bleeding including those with previous peptic ulcer disease, chronic renal failure, and liver cirrhosis. We declare no competing interests.
*Michael J R Desborough, Vipul Jairath [email protected] John Radcliffe Hospital, Oxford OX3 9DU, UK 1
2
3
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–62. Schulman S, Ritchie B, Goy JK, Nahirniak S, Almutawa M, Ghanny S. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol 2014; 164: 308–10. Barkun AN, Bardou M, Kulpers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010; 152: 101–13.
www.thelancet.com Vol 384 July 5, 2014
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Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014; 383: 955–62. Wieloch M, Sjalander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011; 32: 2282–89. Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvular atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472. Lane DA, Lip GY. Quality of anticoagulation control in atrial fibrillation. Lancet 2010; 376: 935–37. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011; 123: 2562–70.
Although new oral anticoagulants (NOACs) showed a favourable risk-benefit profile for treatment of atrial fibrillation,1 it is questionable whether they should be recommended in unselected elderly patients in primary care. Many patients with atrial fibrillation using oral anticoagulants do not meet the eligibility criteria of trials that showed effectiveness and safety of these drugs. In a case-control study, 2 40% of users of vitamin K antagonists presenting with bleeding had one or more exclusion criteria for these trials. This might also apply to NOACs, especially in elderly people. Several factors, such as interactions with concomitant medication, worsening of renal function, and reduced patient compliance in daily care compared with research context might affect the blood level of NOACs. In the absence of regular monitoring of coagulation, which is routine in patients using vitamin K antagonists, any deviation beyond the therapeutic range will not be noticed. This might expose patients to inadequate protection against strokes or increased risk of harm. A recent observational study3 reported that dabigatran might be as effective 24
and safe in daily practice and research context. However, since the study was not randomised, confounding by indication might have biased these results. Therefore, we would recommend that NOACs should only be prescribed in patients younger than 80 years with few comorbidities, good renal function (glomerular filtration rate >50 mL/min), and good expected drug adherence. 4 According to principles of shared decision making, primary care physicians could discuss the benefits and harms of antithrombotic management options with their patients. We declare no competing interests.
*Wim Opstelten, Maureen van den Donk, Ton Kuijpers, Jako S Burgers [email protected] Dutch College of General Practitioners, 3502 GE, Utrecht, Netherlands 1
2
3
4
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2014; 383: 955–62. Levi M, Hovingh GK, Cannegieter SC, Vermeulen M, Buller HR, Rosendaal FR. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 2008; 111: 4471–76. Larsen TB, Rasmussen LH, Skjoth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation. J Am Coll Cardiol 2013; 61: 2264–73. van den Donk M, Opstelten W. Important changes in the Dutch College of General Practitioners (NHG) practice guideline ‘Atrial fibrillation’: revised practice guideline issued (in Dutch). Ned Tijdschr Geneeskd 2013; 157: A6697.
Christian Ruff and colleagues’ meta-analysis 1 reports substantial reductions in stroke and all-cause mortality by use of the new oral anticoagulants (NOACs) compared with warfarin for atrial fibrillation, justifying their increasing use, but also the unequivocal increased risk of gastrointestinal bleeding. Furthermore, the trials included patients with a presumed low risk
of gastrointestinal complications and therefore the true risk might be greater outside the clinical trial setting. Prothrombotic agents such as activated factor VII and activated prothrombin complex concentrate can be used to reduce bleeding by globally increasing thrombin generation but they do not reverse the effects of NOACs2 and therefore the traditional approach of rapid reversal of anticoagulation and then prompt endoscopy after gastrointestinal bleeding 3 with warfarin is not possible because of the lack of an antidote for NOACs. This raises challenges and uncertainties as to the optimal endoscopic timing and management of patients anticoagulated with NOACs who bleed because of tissue friability associated with endotherapy. Since prevention is better than cure, more work is needed to understand whether coprescription of proton-pump inhibitors with NOACs might be gastroprotective. In the interim, we urge clinicians to exercise caution in prescribing NOACs as an alternative to warfarin in patients with risk factors for gastrointestinal bleeding including those with previous peptic ulcer disease, chronic renal failure, and liver cirrhosis. We declare no competing interests.
*Michael J R Desborough, Vipul Jairath [email protected] John Radcliffe Hospital, Oxford OX3 9DU, UK 1
2
3
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955–62. Schulman S, Ritchie B, Goy JK, Nahirniak S, Almutawa M, Ghanny S. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol 2014; 164: 308–10. Barkun AN, Bardou M, Kulpers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010; 152: 101–13.
www.thelancet.com Vol 384 July 5, 2014
