New oral anticoagulants in patients with atrial fibrillation – Authors'reply

Abstract

Claudia Stöllberger and Josef Finsterer, and Rahman Shah and colleagues raise important comments about how international normalised ratio (INR) management affected our analyses.1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar Stöllberger and Finsterer specifically ask about the measures taken by the data safety monitoring committees to improve INR control. It is important to point out that these trials were done in about 50 countries, across six continents. The median combined time in therapeutic range (TTR) for all four trials was a respectable 65% (IQR 51–76), which compares very favourably with the most recent estimate of the quality of INR management in the USA (average TTR 53·7%).2Dlott JS George RA Huang X et al.National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation.Circulation. 2014; 129: 1407-1414Crossref PubMed Scopus (115) Google Scholar They also raise the relevant question of whether the benefit of new oral anticoagulants compared with warfarin was dependent on how well warfarin was managed. While acknowledging the limitations of using centre-based TTR (cTTR) pointed out by Shah and colleagues (it is the only INR metric available for the trials), in our meta-analysis we examined a cTTR threshold of 66% and found that the reduction in stroke or systemic embolism compared with warfarin was not dependent on how well warfarin was managed. However, an even more pronounced relative reduction in bleeding with new oral anticoagulants seems to take place in patients who have difficulty maintaining a therapeutic INR. As Shah and colleagues point out, we did not report the effect of cTTR on intracranial haemorrhage and mortality because we only had cTTR and outcome data for the primary efficacy (stroke or systemic embolism) and safety (major bleeding) endpoints.Stöllberger and Finsterer, and Wim Opstelten and colleagues address the important topic of anticoagulation in the elderly patients because they are a susceptible subgroup at high risk of both stroke and bleeding complications. We do, however, disagree with Opstelten and colleagues' broad recommendation to only prescribe new oral anticoagulants to patients younger than 80 years. The median age across the trials was 72 years with about 40% of patients aged 75 years or older. In our meta-analysis,1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar we compared outcomes in patients aged 75 years or older with those younger than 75 years and found that the efficacy and safety of new oral anticoagulants was consistent irrespective of age. We agree with Stöllberger and Finsterer that it would be interesting to look specifically at the data stratified by age older than 80 years and younger than 80 years in addition to older than 75 years and younger than 75 years, but unfortunately these data are not publicly available for all the trials and therefore it was not possible for us to include these data in our analyses.We agree with Michael Desborough and Vipul Jairath's caution in using new oral anticoagulants in patients at increased risk for gastrointestinal bleeding because we noted a 25% increased risk compared with warfarin. Finally, definitions of all outcomes, including gastrointestinal bleeding, can be found in the primary publication for each of the respective trials.3Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8692) Google Scholar, 4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6997) Google Scholar, 5Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6507) Google Scholar, 6Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus Warfarin in Patients with Atrial Fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3430) Google ScholarStöllberger and Finsterer, also ask how patients were treated in the analysis if they discontinued study prematurely. The numbers they report are actually for patients who discontinued study drug and not who prematurely discontinued the study. In our meta-analysis,1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar all events were included regardless of whether they occurred while patients were taking study drug or after an interruption.Regarding dose adjustment, and specifically if patients in the ROCKET AF trial4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6997) Google Scholar were included in the analysis if their dose was reduced from rivaroxaban 20 mg once daily to 15 mg once daily; there were also dose reductions in both ARISTOTLE5Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6507) Google Scholar (apixaban 5 mg twice daily to 2·5 mg twice daily) and ENGAGE AF-TIMI 48 trials6Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus Warfarin in Patients with Atrial Fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3430) Google Scholar (high-dose regimen: edoxaban 60 mg once daily to 30 mg once daily; low dose regimen: edoxaban 30 mg once daily to 15 mg once daily). All patients, irrespective of dose reduction, were included in our analyses.We agree with Shah and colleagues that in addition to assessing the efficacy and safety of these new agents (the primary purpose of our meta-analysis), further work needs to be done to understand the cost implications that incorporates both the increased cost of the drug as well as the potential cost savings due to prevention of stroke and serious bleeding and avoidance of the need for INR measurements.CTR has served as a consultant and has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Myers Squibb. RPG has served as a consultant and has received honoraria from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Sanofi, and received grant support from Daiichi Sankyo, Johnson & Johnson, and Merck. EB has recieved grants and personal fees for lectures from Daiichi Sankyo; grants from Duke University, AstraZeneca, Merck, and GlaxoSmithKline; uncompensated personal fees for consultancy from Merck; personal fees for consultancies from Genyzme, Medicines Co, and Sanofi-Aventis; uncompensated personal fees for lectures from Merck; and personal fees for lectures from Menarini International and Medscape outside the submitted work. EMA has received a research grant from Daiichi Sankyo. Claudia Stöllberger and Josef Finsterer, and Rahman Shah and colleagues raise important comments about how international normalised ratio (INR) management affected our analyses.1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar Stöllberger and Finsterer specifically ask about the measures taken by the data safety monitoring committees to improve INR control. It is important to point out that these trials were done in about 50 countries, across six continents. The median combined time in therapeutic range (TTR) for all four trials was a respectable 65% (IQR 51–76), which compares very favourably with the most recent estimate of the quality of INR management in the USA (average TTR 53·7%).2Dlott JS George RA Huang X et al.National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation.Circulation. 2014; 129: 1407-1414Crossref PubMed Scopus (115) Google Scholar They also raise the relevant question of whether the benefit of new oral anticoagulants compared with warfarin was dependent on how well warfarin was managed. While acknowledging the limitations of using centre-based TTR (cTTR) pointed out by Shah and colleagues (it is the only INR metric available for the trials), in our meta-analysis we examined a cTTR threshold of 66% and found that the reduction in stroke or systemic embolism compared with warfarin was not dependent on how well warfarin was managed. However, an even more pronounced relative reduction in bleeding with new oral anticoagulants seems to take place in patients who have difficulty maintaining a therapeutic INR. As Shah and colleagues point out, we did not report the effect of cTTR on intracranial haemorrhage and mortality because we only had cTTR and outcome data for the primary efficacy (stroke or systemic embolism) and safety (major bleeding) endpoints. Stöllberger and Finsterer, and Wim Opstelten and colleagues address the important topic of anticoagulation in the elderly patients because they are a susceptible subgroup at high risk of both stroke and bleeding complications. We do, however, disagree with Opstelten and colleagues' broad recommendation to only prescribe new oral anticoagulants to patients younger than 80 years. The median age across the trials was 72 years with about 40% of patients aged 75 years or older. In our meta-analysis,1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar we compared outcomes in patients aged 75 years or older with those younger than 75 years and found that the efficacy and safety of new oral anticoagulants was consistent irrespective of age. We agree with Stöllberger and Finsterer that it would be interesting to look specifically at the data stratified by age older than 80 years and younger than 80 years in addition to older than 75 years and younger than 75 years, but unfortunately these data are not publicly available for all the trials and therefore it was not possible for us to include these data in our analyses. We agree with Michael Desborough and Vipul Jairath's caution in using new oral anticoagulants in patients at increased risk for gastrointestinal bleeding because we noted a 25% increased risk compared with warfarin. Finally, definitions of all outcomes, including gastrointestinal bleeding, can be found in the primary publication for each of the respective trials.3Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8692) Google Scholar, 4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6997) Google Scholar, 5Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6507) Google Scholar, 6Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus Warfarin in Patients with Atrial Fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3430) Google Scholar Stöllberger and Finsterer, also ask how patients were treated in the analysis if they discontinued study prematurely. The numbers they report are actually for patients who discontinued study drug and not who prematurely discontinued the study. In our meta-analysis,1Ruff 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: 955-962Summary Full Text Full Text PDF PubMed Scopus (3219) Google Scholar all events were included regardless of whether they occurred while patients were taking study drug or after an interruption. Regarding dose adjustment, and specifically if patients in the ROCKET AF trial4Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (6997) Google Scholar were included in the analysis if their dose was reduced from rivaroxaban 20 mg once daily to 15 mg once daily; there were also dose reductions in both ARISTOTLE5Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6507) Google Scholar (apixaban 5 mg twice daily to 2·5 mg twice daily) and ENGAGE AF-TIMI 48 trials6Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus Warfarin in Patients with Atrial Fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3430) Google Scholar (high-dose regimen: edoxaban 60 mg once daily to 30 mg once daily; low dose regimen: edoxaban 30 mg once daily to 15 mg once daily). All patients, irrespective of dose reduction, were included in our analyses. We agree with Shah and colleagues that in addition to assessing the efficacy and safety of these new agents (the primary purpose of our meta-analysis), further work needs to be done to understand the cost implications that incorporates both the increased cost of the drug as well as the potential cost savings due to prevention of stroke and serious bleeding and avoidance of the need for INR measurements. CTR has served as a consultant and has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Myers Squibb. RPG has served as a consultant and has received honoraria from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Sanofi, and received grant support from Daiichi Sankyo, Johnson & Johnson, and Merck. EB has recieved grants and personal fees for lectures from Daiichi Sankyo; grants from Duke University, AstraZeneca, Merck, and GlaxoSmithKline; uncompensated personal fees for consultancy from Merck; personal fees for consultancies from Genyzme, Medicines Co, and Sanofi-Aventis; uncompensated personal fees for lectures from Merck; and personal fees for lectures from Menarini International and Medscape outside the submitted work. EMA has received a research grant from Daiichi Sankyo. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trialsThis meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Full-Text PDF New oral anticoagulants in patients with atrial fibrillationChristian Ruff and colleagues' meta-analysis (March 15, p 955)1 raises several questions. When calculating the numbers of outcome events on the basis of event rates, sample size, and duration of follow-up, how were patients who discontinued the study prematurely considered? The rates of discontinuation in the new-oral-anticoagulant (NOAC)-investigating studies were 34% with edoxaban, 17–21% with dabigatran at 2 years, 22–24% with rivaroxaban and 25–28% with apixaban.2–5 Since rates of discontinuation were higher in patients randomised to dabigatran or rivaroxaban than to warfarin, patients treated with warfarin might have been exposed to anticoagulant therapy longer and thus might have had a higher frequency of cerebral haemorrhages. Full-Text PDF New oral anticoagulants in patients with atrial fibrillationFrom a meta-analysis of four studies, Christian Ruff and colleagues1 concluded that use of new oral anticoagulants (NOACs) in patients with atrial fibrillation results in a decreased incidence of stroke and mortality when compared with warfarin. However, the mean time in therapeutic range (TTR) was less than 65% in the warfarin group (table).1 A recent registry study2 reported a TTR of more than 75% with warfarin, indicating that medical care in these randomised trials was disappointing. In patients with atrial fibrillation, a 10% increase in the time spent out of the therapeutic range is associated with substantial increased risks of ischaemic stroke, other thromboembolic events, and mortality. Full-Text PDF New oral anticoagulants in patients with atrial fibrillationAlthough 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. Full-Text PDF New oral anticoagulants in patients with atrial fibrillationChristian Ruff and colleagues' meta-analysis1 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. Full-Text PDF