- Email: [email protected]
New anticoagulants in atrial fibrillation management
Thrombosis Research 131, Suppl. 1 (2013) S63–S66
New anticoagulants in atrial fibrillation management Sam Schulman * Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada, and Karolinska Institute, Stockholm, Sweden
A R T I C L E Keywords: Atrial fibrillation Stroke Major bleeding Oral anticoagulants
I N F O
A B S T R A C T Three new oral anticoagulants have been evaluated in large registration trials and are now available in many jurisdictions for patients with atrial fibrillation. Questions arise whether these drugs are equally effective and safe for all patients. Now when we are moving away from decades with only one orally available drug for anticoagulation there is opportunity to tailor the therapy according to patient characteristics and preferences. This review addresses the interaction of various patient characteristics with the treatment and what features can assist the physician in the choice of anticoagulant for the individual patient. © 2013 Elsevier Ltd. All rights reserved.
Introduction Stroke prophylaxis in atrial fibrillation (SPAF) is the most important indication for anticoagulant therapy in view of the large number of patients, the serious consequences of a stroke for the individual and the heavy burden on society. Since 2009 three large phase III trials comparing dabigatran, rivaroxaban and apixaban with warfarin have been published [1–3] and a fourth trial on betrixaban is close to completion. Overall, non-inferiority was demonstrated for efficacy in stroke prevention compared to warfarin and there were fewer intracranial bleeding events will all new anticoagulants. There were also specific advantages for some drugs or regimens regarding reduction of ischemic stroke (dabigatran 150 mg) [1], reduction of major bleeding (dabigatran 110 mg, apixaban) [1] and reduced mortality (apixaban, although of same magnitude as with the other drugs). We are thus moving from an era with only a coumarin derivative available to an interesting choice between several orally available alternatives. The eliminated need for frequent laboratory monitoring and adjustment of doses with the new anticoagulants makes them very attractive. Yet, convenience is not the priority for all patients. Some prefer drugs with optimum safety or longest experience. There are also physicians that have demonstrated hesitation prescribing the new drugs based on lack of established routines for management in emergency situations [4,5]. The use of these new anticoagulants in elderly patients has been questioned, partly due to their decreasing renal function and thereby inability to efficiently eliminate drugs that depend on renal excretion [6]. Careful analysis of data from subpopulations and of outcomes in patients with bleeding, trauma or surgery will be required to inform recommendations on optimal management.
* Corresponding author: Sam Schulman, MD, PhD, Thrombosis Service, HHSGeneral Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. Tel.: +1 905-5270271, ext 44479; fax: +1 905-5211551. E-mail address: [email protected] (S. Schulman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
This review will address some of the questions regarding choice of anticoagulant for different subpopulations. General patient characteristics None of the trials showed any significant interaction between sex and treatment effect although for dabigatran at 150 mg twice daily versus warfarin there was a more favourable risk difference for females (−0.89%) than for males (−0.39%), although not statistically significant [1]. Interestingly, there was a similar trend in the study on treatment of venous thromboembolism, using the same dabigatran regimen with a risk difference for females of −0.4% and for males of +0.7%, although in this case for the outcome of recurrent venous thromboembolism. One could speculate that these differential effects are related to the lower body weight in females. The risk for major bleeding was almost identical in males and females in all studies although for apixaban there is a trend to less major bleeding (versus warfarin) in females (P = 0.08) [1–3,7]. Gastrointestinal bleeding was more common on rivaroxaban than on warfarin but this harm was seen less in females [3]. With increasing age there seems to be an increased effect of the new anticoagulants versus warfarin (Table 1). The exception is dabigatran 150 mg, which was significantly better than warfarin for any age group. The interactions are, however, not statistically significant. For major bleeding the intriguing pattern is that for dabigatran the benefit is the greatest for younger patients, whereas for both factor Xa inhibitors there is a trend towards reduced risk in comparison with warfarin for older patients. In the case of dabigatran it is the extracranial major bleeds that increase more than for patients on warfarin, whereas dabigatran provides a consistent reduction of intracranial hemorrhages for all ages [7]. The interaction between age and major bleeding and for extracranial bleeding is statistically significant for dabigatran. Ethnicity or race is defined differently between studies and is often by the discretion of the investigator. There is in all studies a trend to better effect of the new anticoagulants in Asians and
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Table 1 Hazard ratios for the primary efficacy outcome (stroke and systemic embolism) and for major bleeding versus warfarin according to age group. Dabigatran 110 mg (95% CI)
Dabigatran 150 mg (95% CI)
Primary efficacy <65 years 65 to <75 years ≥75 years
1.10 (0.64–1.87) 0.87 (0.62–1.20) 0.88 (0.66–1.17)
0.51 (0.26–0.98) 0.68 (0.47–0.96) 0.67 (0.49–0.90)
Major bleeding <65 years 65 to <75 years ≥75 years
0.33 (0.19–0.59) 0.70 (0.56–0.89) 1.01 (0.83–1.23)
0.36 (0.21–0.62) 0.80 (0.64–1.00) 1.18 (0.98–1.43)
Rivaroxaban (95% CI)
0.95 (0.76–1.19) 0.8 (0.63–1.02)
0.91 (0.7–1.19) 0.67 (0.51–0.88)
Apixaban † (95% CI) 1.16 (0.77–1.75) 0.73 (0.54–0.97) 0.72 (0.53–0.96) 0.77 (0.54–1.10) 0.71 (0.56–0.91) 0.66 (0.53–0.81)
CI, confidence interval. † The data for apixaban are odds ratios (95% CI), based on calculation from the event rates provided in [2], and they appear visually identical to the forest plot in the original article.
when specified by region, in Asia or Asia–Pacific. This is most likely related to the fact that control of warfarin is less tight in this region of the world with lower mean International Normalized Ratio (INR) and lower proportion time in therapeutic range. Fortunately, the relative increase in effect in Asians is not mirrored by any decrease in safety, as reported for rivaroxaban and apixaban [2,3]. Co-morbid conditions Renal dysfunction The renal function decreases with age and regulatory authorities have recommended assessment of this function for new anticoagulants initially and then annually [8]. Dabigatran is the drug that is most dependent on the renal function for its elimination although currently none of the new anticoagulants are approved for a creatinine clearance below 30 mL/min in Europe or Canada. In the United States the drug was, however approved at a reduced dose of 75 mg twice daily for creatinine clearance down to 15 mL/min, based on pharmacokinetic modelling but despite the fact that this dose had not been investigated in clinical trials. The dose of rivaroxaban was reduced by 25% (from 20 to 15 mg/day) in patients with a creatinine clearance of 30–49 mL/min [3]. In the trial with apixaban patients with a creatinine clearance down to 25 mL/min were included and there was a lower dose regimen (2.5 mg bid instead of 5 mg bid) for patients fulfilling 2 of the conditions: (1) age ≥80 years, (2) weight ≤60 kg, and (3) creatinine ≥133 μmol/L [2]. Only 137 patients with a creatinine clearance <30 mL/min ended up receiving apixaban, which makes it hard to draw any conclusions regarding efficacy and safety for patients with severe renal failure. The risk for major bleeding increased with decreasing renal function. For dabigatran 110 mg the annual event rate was 1.53%, 2.89% and 5.29% for creatinine clearance ≥80, 50–79 and <50 mL/ min, respectively, and for the 150 mg dose the corresponding event rates were 2.09%, 3.33% and 5.44%, respectively [7]. For rivaroxaban the event rate was 3.39% for a clearance ≥50 mL/min and 4.49% for clearance 30–49 mL/min, despite the reduction in dose [3]. Finally for apixaban the event rate was 1.5%, 2.5% and 3.2% for normal
renal function, mild or moderate-severe impairment, respectively and there was a significant interaction between renal function and treatment (P = 0.03) [2]. In all studies there was a similar pattern for the patients allocated to warfarin. Nevertheless, Eikelboom et al found a significant interaction only between age and bleeding and thus not between renal function and bleeding [7]. In the rivaroxaban study there was again not any significant interaction between creatinine clearance and major bleeding, whereas in the apixaban study the P-value was 0.03 [2]. It is obviously quite plausible that the renal function depends to a large extent on age, which would be the independent risk factor. CHADS2 score The patients in these studies were risk stratified using the CHADS2 score REF. In the dabigatran and apixaban trials patients with a score of 1 or higher were eligible for inclusion, whereas in the rivaroxaban trial only those with CHADS2 of 2 or higher were included. It has been discussed whether that could have influenced the results of the trials, since rivaroxaban did not show superiority over warfarin in the intention to treat analysis, whereas dabigatran 150 mg and apixaban did. The hazard ratios for stroke or systemic embolism did, however, not appear to change with increasing CHADS2 score (Table 2) [2,3,9]. The only subset with a possible, although not significant, decrease in effect compared to warfarin was the small CHADS2 score = 6 – group with 11 events in 122 patients on rivaroxaban (9.0%) versus 9 in 156 on warfarin (5.8%; hazard ratio 1.49; 95% confidence interval [CI], 0.62–3.59). There was no significant interaction between CHADS2 score and treatment on the effect or risk of major bleeding for any of the drugs [2,3,9]. Antiplatelet therapy Concomitant antiplatelet therapy is sometimes required when the patient has active coronary artery disease or had a stent inserted. In the study on dabigatran in atrial fibrillation 20% of the patients had concomitant aspirin [1]. In the rivaroxaban study with generally sicker patients included than in the studies on the other
Table 2 Hazard ratios for primary efficacy outcome (stroke and systemic embolism) versus warfarin according to CHADS2 score. CHADS2 score
Dabigatran 110 mg (95% CI)
Dabigatran 150 mg (95% CI)
Rivaroxaban (95% CI)
Apixaban † (95% CI)
1 2 3 4 5 6
0.98 (0.63–1.51) 1.06 (0.74–1.52)
0.61 (0.37–0.99) 0.61 (0.40–0.92)
0.86 (0.57–1.29) 0.90 (0.65–1.23)
0.78 (0.58–1.04) *
0.69 (0.51–0.93) *
Excluded 0.85 (0.52–1.38) 0.76 (0.57–1.01) 0.95 (0.72–1.24) 0.88 (0.58–1.34) 1.49 (0.62–3.59)
0.70 (0.53–0.91) *
CHADS2 assigns 1 point each for a history of Congestive heart failure, Hypertension, Age 75 years or older, and Diabetes mellitus and 2 points for a history of Stroke or transient ischemic attack; CI, confidence interval. * Hazard ratio for CHADS2 ≥3. † The data for apixaban are odds ratios (95% CI), based on calculation from the event rates provided in [2], and they appear visually identical to the forest plot in the original article.
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new anticoagulants, 35% took aspirin during the study [3]. There was no interaction between aspirin and concomitant treatment with an anticoagulant in the dabigatran study [1]. Diabetes In the study with apixaban the advantage of reduced major bleeding compared to warfarin was only seen in patients without diabetes (1.9% versus 3.1%) and not at all in patients with diabetes (3.0% versus 3.1%; P = 0.003 for interaction) [2]. Choice of drug Patients already on warfarin For patients doing well on warfarin, i.e. no major complications and a time in therapeutic range of 65% or higher, there is probably little or nothing to gain regarding efficacy by switching a new anticoagulant. In a substudy of the dabigatran trial the study sites with a mean time in therapeutic range above 65% for the warfarin group, the confidence intervals of the hazard ratios for any combination of efficacy parameters always included the line of unity [10]. The risk of intracranial hemorrhage was, however, reduced by 61–65% with dabigatran even in comparison with well-managed warfarin, whereas the risk of major gastrointestinal hemorrhage was increased by 200–226%. In absolute numbers this translates into 45–48 fewer intracranial hemorrhages and 102–129 more major gastrointestinal hemorrhages per 10,000 treated patients per year. From a convenience aspect these stable patients on warfarin would have blood tests once a year instead of once a month. Ultimately, this discussion needs to be held openly with the patient to identify the preferences of the patient and any reimbursement issues. In many jurisdictions the public reimbursement for new anticoagulants excludes patients who are doing well on warfarin. Patients with a history of intracranial hemorrhage and thereby increased risk for recurrent hemorrhage in this location will hopefully do better on the new anticoagulants, although this requires confirmation. Conversely, patients with pathology in the gastrointestinal canal and particularly in the distal part where the active new anticoagulants seem to be concentrated [11], may do better remaining on warfarin. The patients on warfarin with time in therapeutic range below 65% can be roughly split into two categories. • Patients who are likely to benefit from a switch: Patients who are adhering to their test interval schedule but still are unable to get the INRs to stabilize. Specific causes such as pronounced variations in dietary habits or intermittent intake of acetaminophen/paracetamol exceeding 1 g/day should first be identified and corrected. In addition, patients who have an identifiable cause for INR instability, which is difficult to correct, e.g., frequent infections requiring antibiotic treatment. • Patient who might have less stroke protection from a switch: Patients demonstrating evidence of poor adherence, e.g., not following instructions regarding test intervals or who admit to frequent missed doses or are likely to do this due to substance abuse. If these patients are switched to a new, non-monitored anticoagulant there is a clear risk that they will have therapeutic effect during a smaller proportion of the time than with warfarin. New patients on anticoagulation Here it will first of all be a question of reimbursement. If the patient is not covered the choice is usually to try warfarin first and review after approximately 3 months. It is difficult to judge the chances for long-term stability earlier than that. If the patient
Fig. 1. Hazard ratios (or for dabigatran risk reductions) and 95% confidence intervals for the primary efficacy outcome (horizontal lines) and for major bleeding (vertical lines) in comparison with warfarin. D150, dabigatran 150 mg bid; D110, dabigatran 110 mg bid; R, rivaroxaban 20 mg daily; A, apixaban 5 mg bid; SE, systemic embolism.
is covered for a new anticoagulant it is good practice to inform the patient of the nature of the two types of treatments with their advantages and drawbacks. Some patients will, perhaps surprisingly, ask for warfarin for a number of reasons. They may have a close relative (spouse) doing well on warfarin, or have a compulsive obsessive trait with satisfaction from being well monitored. The patient could have suffered previous gastrointestinal hemorrhages and wishes to avoid additional events or he/she may feel very uncomfortable with a new drug. An illustration of how irrational and strong the sentiments can be is the patients that will never take warfarin “because it is rat poison” but they will take Coumadin® despite the additional charge and my information that the chemical substance is the same. The preferences of the patients are clearly influenced by the way the data is presented to them and it is only fair to try and present the facts as objectively as possible. Decision tools for patients are under evaluation. Which new anticoagulant should be preferred? It is possible to describe and compare the main efficacy and safety characteristics in one picture (Fig. 1). From this illustration it seems as if apixaban provides the best combination of safety and efficacy. It is important to note that these are not head-to-head comparisons between the new anticoagulants. There are several other outcomes of interest and it is not possible to combine all in a single expression. The all-cause mortality was significantly reduced only by apixaban but the absolute risk reduction was approximately 10% for all new anticoagulants. Dabigatran 150 mg was the only regimen that reduced the risk for ischemic stroke significantly [1]. Conversely, in a meta-analysis of many studies on different indications there was an increase of myocardial infarctions with dabigatran [12] but in the atrial fibrillation population this difference was not statistically significant [13]. It was not possible to predict this risk from the patient’s history of coronary artery disease. Although a twice-daily regimen is feasible for most patients, who with the diagnosis of atrial fibrillation are not uncommonly on a twice-daily treatment with a beta-blocker, it does not work well for others. It is recommended to take dabigatran with food and approximately every 12 hours, which may not be compatible with the lifestyle of some individuals. In that case rivaroxaban will provide the most feasible alternative. Based on the data presented initially in this article and from the aspect of bleeding risk, dabigatran appears safer in younger patients
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and rivaroxaban perhaps in older patients. Apixaban seems safer in patients without diabetes. Areas of uncertainty Several questions remain to be answered such as what is the therapeutic range for the new anticoagulants with suitable tests (diluted thrombin time for dabigatran, standardized factor Xa for rivaroxaban and apixaban) to measure the effect? What is the optimal management in case of requirement for rapid reversal of the anticoagulant effect? When can these drugs be safely resumed after major surgery or procedures with a high risk of bleeding? How can we optimize adherence when the treatment is no longer monitored? Are these drugs as effective in patients who also have cancer? Studies are already being performed to answer most of these questions. Conclusions Of the various patient characteristics age seems to be the most important predictor for bleeding on dabigatran, and diabetes for bleeding on apixaban. There were no characteristics that interacted with the treatment regarding efficacy and importantly, the degree of stroke prevention does not depend on the CHADS2 score. The choice of anticoagulants is soon between 4 different drugs and a careful review of the patient together with an open discussion, addressing patient preferences is strongly recommended for patients starting on the treatment. For patients already on warfarin it is also crucial to review benefits, possible disadvantages, preferences and expectations before switching to a new anticoagulant. The new drugs have different characteristics, which may matter for some patients in tailoring the optimal individual anticoagulant regimen. Although the large studies have been performed and are yielding a large number of secondary publications, there is room for many new research projects focusing on questions that the registration studies were not designed to answer. Conflict of interest statement The author has received honoraria for work in study-related committees from Boehringer Ingelheim and Bayer Healthcare.
References [1] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [2] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. [3] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883– 91. [4] Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med 2011;365:2039–40. [5] Radecki RP. Dabigatran: uncharted waters and potential harms. Ann Intern Med 2012;157:66–8. [6] Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012;366:864–6. [7] Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial. Circulation 2011;123:2363–72. [8] U.S. Food and Drug Administration. FDA Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate). 2011. [9] Oldgren J, Alings M, Darius H, Diener HC, Eikelboom J, Ezekowitz MD, et al. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Ann Intern Med 2011;155:660–7. [10] Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975–83. [11] Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386–99. [12] Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of non-inferiority randomized controlled trials. Arch Intern Med 2012;172:397–402. [13] Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012;125:669–76.
New anticoagulants in atrial fibrillation management Sam Schulman * Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada, and Karolinska Institute, Stockholm, Sweden
A R T I C L E Keywords: Atrial fibrillation Stroke Major bleeding Oral anticoagulants
I N F O
A B S T R A C T Three new oral anticoagulants have been evaluated in large registration trials and are now available in many jurisdictions for patients with atrial fibrillation. Questions arise whether these drugs are equally effective and safe for all patients. Now when we are moving away from decades with only one orally available drug for anticoagulation there is opportunity to tailor the therapy according to patient characteristics and preferences. This review addresses the interaction of various patient characteristics with the treatment and what features can assist the physician in the choice of anticoagulant for the individual patient. © 2013 Elsevier Ltd. All rights reserved.
Introduction Stroke prophylaxis in atrial fibrillation (SPAF) is the most important indication for anticoagulant therapy in view of the large number of patients, the serious consequences of a stroke for the individual and the heavy burden on society. Since 2009 three large phase III trials comparing dabigatran, rivaroxaban and apixaban with warfarin have been published [1–3] and a fourth trial on betrixaban is close to completion. Overall, non-inferiority was demonstrated for efficacy in stroke prevention compared to warfarin and there were fewer intracranial bleeding events will all new anticoagulants. There were also specific advantages for some drugs or regimens regarding reduction of ischemic stroke (dabigatran 150 mg) [1], reduction of major bleeding (dabigatran 110 mg, apixaban) [1] and reduced mortality (apixaban, although of same magnitude as with the other drugs). We are thus moving from an era with only a coumarin derivative available to an interesting choice between several orally available alternatives. The eliminated need for frequent laboratory monitoring and adjustment of doses with the new anticoagulants makes them very attractive. Yet, convenience is not the priority for all patients. Some prefer drugs with optimum safety or longest experience. There are also physicians that have demonstrated hesitation prescribing the new drugs based on lack of established routines for management in emergency situations [4,5]. The use of these new anticoagulants in elderly patients has been questioned, partly due to their decreasing renal function and thereby inability to efficiently eliminate drugs that depend on renal excretion [6]. Careful analysis of data from subpopulations and of outcomes in patients with bleeding, trauma or surgery will be required to inform recommendations on optimal management.
* Corresponding author: Sam Schulman, MD, PhD, Thrombosis Service, HHSGeneral Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. Tel.: +1 905-5270271, ext 44479; fax: +1 905-5211551. E-mail address: [email protected] (S. Schulman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
This review will address some of the questions regarding choice of anticoagulant for different subpopulations. General patient characteristics None of the trials showed any significant interaction between sex and treatment effect although for dabigatran at 150 mg twice daily versus warfarin there was a more favourable risk difference for females (−0.89%) than for males (−0.39%), although not statistically significant [1]. Interestingly, there was a similar trend in the study on treatment of venous thromboembolism, using the same dabigatran regimen with a risk difference for females of −0.4% and for males of +0.7%, although in this case for the outcome of recurrent venous thromboembolism. One could speculate that these differential effects are related to the lower body weight in females. The risk for major bleeding was almost identical in males and females in all studies although for apixaban there is a trend to less major bleeding (versus warfarin) in females (P = 0.08) [1–3,7]. Gastrointestinal bleeding was more common on rivaroxaban than on warfarin but this harm was seen less in females [3]. With increasing age there seems to be an increased effect of the new anticoagulants versus warfarin (Table 1). The exception is dabigatran 150 mg, which was significantly better than warfarin for any age group. The interactions are, however, not statistically significant. For major bleeding the intriguing pattern is that for dabigatran the benefit is the greatest for younger patients, whereas for both factor Xa inhibitors there is a trend towards reduced risk in comparison with warfarin for older patients. In the case of dabigatran it is the extracranial major bleeds that increase more than for patients on warfarin, whereas dabigatran provides a consistent reduction of intracranial hemorrhages for all ages [7]. The interaction between age and major bleeding and for extracranial bleeding is statistically significant for dabigatran. Ethnicity or race is defined differently between studies and is often by the discretion of the investigator. There is in all studies a trend to better effect of the new anticoagulants in Asians and
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Table 1 Hazard ratios for the primary efficacy outcome (stroke and systemic embolism) and for major bleeding versus warfarin according to age group. Dabigatran 110 mg (95% CI)
Dabigatran 150 mg (95% CI)
Primary efficacy <65 years 65 to <75 years ≥75 years
1.10 (0.64–1.87) 0.87 (0.62–1.20) 0.88 (0.66–1.17)
0.51 (0.26–0.98) 0.68 (0.47–0.96) 0.67 (0.49–0.90)
Major bleeding <65 years 65 to <75 years ≥75 years
0.33 (0.19–0.59) 0.70 (0.56–0.89) 1.01 (0.83–1.23)
0.36 (0.21–0.62) 0.80 (0.64–1.00) 1.18 (0.98–1.43)
Rivaroxaban (95% CI)
0.95 (0.76–1.19) 0.8 (0.63–1.02)
0.91 (0.7–1.19) 0.67 (0.51–0.88)
Apixaban † (95% CI) 1.16 (0.77–1.75) 0.73 (0.54–0.97) 0.72 (0.53–0.96) 0.77 (0.54–1.10) 0.71 (0.56–0.91) 0.66 (0.53–0.81)
CI, confidence interval. † The data for apixaban are odds ratios (95% CI), based on calculation from the event rates provided in [2], and they appear visually identical to the forest plot in the original article.
when specified by region, in Asia or Asia–Pacific. This is most likely related to the fact that control of warfarin is less tight in this region of the world with lower mean International Normalized Ratio (INR) and lower proportion time in therapeutic range. Fortunately, the relative increase in effect in Asians is not mirrored by any decrease in safety, as reported for rivaroxaban and apixaban [2,3]. Co-morbid conditions Renal dysfunction The renal function decreases with age and regulatory authorities have recommended assessment of this function for new anticoagulants initially and then annually [8]. Dabigatran is the drug that is most dependent on the renal function for its elimination although currently none of the new anticoagulants are approved for a creatinine clearance below 30 mL/min in Europe or Canada. In the United States the drug was, however approved at a reduced dose of 75 mg twice daily for creatinine clearance down to 15 mL/min, based on pharmacokinetic modelling but despite the fact that this dose had not been investigated in clinical trials. The dose of rivaroxaban was reduced by 25% (from 20 to 15 mg/day) in patients with a creatinine clearance of 30–49 mL/min [3]. In the trial with apixaban patients with a creatinine clearance down to 25 mL/min were included and there was a lower dose regimen (2.5 mg bid instead of 5 mg bid) for patients fulfilling 2 of the conditions: (1) age ≥80 years, (2) weight ≤60 kg, and (3) creatinine ≥133 μmol/L [2]. Only 137 patients with a creatinine clearance <30 mL/min ended up receiving apixaban, which makes it hard to draw any conclusions regarding efficacy and safety for patients with severe renal failure. The risk for major bleeding increased with decreasing renal function. For dabigatran 110 mg the annual event rate was 1.53%, 2.89% and 5.29% for creatinine clearance ≥80, 50–79 and <50 mL/ min, respectively, and for the 150 mg dose the corresponding event rates were 2.09%, 3.33% and 5.44%, respectively [7]. For rivaroxaban the event rate was 3.39% for a clearance ≥50 mL/min and 4.49% for clearance 30–49 mL/min, despite the reduction in dose [3]. Finally for apixaban the event rate was 1.5%, 2.5% and 3.2% for normal
renal function, mild or moderate-severe impairment, respectively and there was a significant interaction between renal function and treatment (P = 0.03) [2]. In all studies there was a similar pattern for the patients allocated to warfarin. Nevertheless, Eikelboom et al found a significant interaction only between age and bleeding and thus not between renal function and bleeding [7]. In the rivaroxaban study there was again not any significant interaction between creatinine clearance and major bleeding, whereas in the apixaban study the P-value was 0.03 [2]. It is obviously quite plausible that the renal function depends to a large extent on age, which would be the independent risk factor. CHADS2 score The patients in these studies were risk stratified using the CHADS2 score REF. In the dabigatran and apixaban trials patients with a score of 1 or higher were eligible for inclusion, whereas in the rivaroxaban trial only those with CHADS2 of 2 or higher were included. It has been discussed whether that could have influenced the results of the trials, since rivaroxaban did not show superiority over warfarin in the intention to treat analysis, whereas dabigatran 150 mg and apixaban did. The hazard ratios for stroke or systemic embolism did, however, not appear to change with increasing CHADS2 score (Table 2) [2,3,9]. The only subset with a possible, although not significant, decrease in effect compared to warfarin was the small CHADS2 score = 6 – group with 11 events in 122 patients on rivaroxaban (9.0%) versus 9 in 156 on warfarin (5.8%; hazard ratio 1.49; 95% confidence interval [CI], 0.62–3.59). There was no significant interaction between CHADS2 score and treatment on the effect or risk of major bleeding for any of the drugs [2,3,9]. Antiplatelet therapy Concomitant antiplatelet therapy is sometimes required when the patient has active coronary artery disease or had a stent inserted. In the study on dabigatran in atrial fibrillation 20% of the patients had concomitant aspirin [1]. In the rivaroxaban study with generally sicker patients included than in the studies on the other
Table 2 Hazard ratios for primary efficacy outcome (stroke and systemic embolism) versus warfarin according to CHADS2 score. CHADS2 score
Dabigatran 110 mg (95% CI)
Dabigatran 150 mg (95% CI)
Rivaroxaban (95% CI)
Apixaban † (95% CI)
1 2 3 4 5 6
0.98 (0.63–1.51) 1.06 (0.74–1.52)
0.61 (0.37–0.99) 0.61 (0.40–0.92)
0.86 (0.57–1.29) 0.90 (0.65–1.23)
0.78 (0.58–1.04) *
0.69 (0.51–0.93) *
Excluded 0.85 (0.52–1.38) 0.76 (0.57–1.01) 0.95 (0.72–1.24) 0.88 (0.58–1.34) 1.49 (0.62–3.59)
0.70 (0.53–0.91) *
CHADS2 assigns 1 point each for a history of Congestive heart failure, Hypertension, Age 75 years or older, and Diabetes mellitus and 2 points for a history of Stroke or transient ischemic attack; CI, confidence interval. * Hazard ratio for CHADS2 ≥3. † The data for apixaban are odds ratios (95% CI), based on calculation from the event rates provided in [2], and they appear visually identical to the forest plot in the original article.
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new anticoagulants, 35% took aspirin during the study [3]. There was no interaction between aspirin and concomitant treatment with an anticoagulant in the dabigatran study [1]. Diabetes In the study with apixaban the advantage of reduced major bleeding compared to warfarin was only seen in patients without diabetes (1.9% versus 3.1%) and not at all in patients with diabetes (3.0% versus 3.1%; P = 0.003 for interaction) [2]. Choice of drug Patients already on warfarin For patients doing well on warfarin, i.e. no major complications and a time in therapeutic range of 65% or higher, there is probably little or nothing to gain regarding efficacy by switching a new anticoagulant. In a substudy of the dabigatran trial the study sites with a mean time in therapeutic range above 65% for the warfarin group, the confidence intervals of the hazard ratios for any combination of efficacy parameters always included the line of unity [10]. The risk of intracranial hemorrhage was, however, reduced by 61–65% with dabigatran even in comparison with well-managed warfarin, whereas the risk of major gastrointestinal hemorrhage was increased by 200–226%. In absolute numbers this translates into 45–48 fewer intracranial hemorrhages and 102–129 more major gastrointestinal hemorrhages per 10,000 treated patients per year. From a convenience aspect these stable patients on warfarin would have blood tests once a year instead of once a month. Ultimately, this discussion needs to be held openly with the patient to identify the preferences of the patient and any reimbursement issues. In many jurisdictions the public reimbursement for new anticoagulants excludes patients who are doing well on warfarin. Patients with a history of intracranial hemorrhage and thereby increased risk for recurrent hemorrhage in this location will hopefully do better on the new anticoagulants, although this requires confirmation. Conversely, patients with pathology in the gastrointestinal canal and particularly in the distal part where the active new anticoagulants seem to be concentrated [11], may do better remaining on warfarin. The patients on warfarin with time in therapeutic range below 65% can be roughly split into two categories. • Patients who are likely to benefit from a switch: Patients who are adhering to their test interval schedule but still are unable to get the INRs to stabilize. Specific causes such as pronounced variations in dietary habits or intermittent intake of acetaminophen/paracetamol exceeding 1 g/day should first be identified and corrected. In addition, patients who have an identifiable cause for INR instability, which is difficult to correct, e.g., frequent infections requiring antibiotic treatment. • Patient who might have less stroke protection from a switch: Patients demonstrating evidence of poor adherence, e.g., not following instructions regarding test intervals or who admit to frequent missed doses or are likely to do this due to substance abuse. If these patients are switched to a new, non-monitored anticoagulant there is a clear risk that they will have therapeutic effect during a smaller proportion of the time than with warfarin. New patients on anticoagulation Here it will first of all be a question of reimbursement. If the patient is not covered the choice is usually to try warfarin first and review after approximately 3 months. It is difficult to judge the chances for long-term stability earlier than that. If the patient
Fig. 1. Hazard ratios (or for dabigatran risk reductions) and 95% confidence intervals for the primary efficacy outcome (horizontal lines) and for major bleeding (vertical lines) in comparison with warfarin. D150, dabigatran 150 mg bid; D110, dabigatran 110 mg bid; R, rivaroxaban 20 mg daily; A, apixaban 5 mg bid; SE, systemic embolism.
is covered for a new anticoagulant it is good practice to inform the patient of the nature of the two types of treatments with their advantages and drawbacks. Some patients will, perhaps surprisingly, ask for warfarin for a number of reasons. They may have a close relative (spouse) doing well on warfarin, or have a compulsive obsessive trait with satisfaction from being well monitored. The patient could have suffered previous gastrointestinal hemorrhages and wishes to avoid additional events or he/she may feel very uncomfortable with a new drug. An illustration of how irrational and strong the sentiments can be is the patients that will never take warfarin “because it is rat poison” but they will take Coumadin® despite the additional charge and my information that the chemical substance is the same. The preferences of the patients are clearly influenced by the way the data is presented to them and it is only fair to try and present the facts as objectively as possible. Decision tools for patients are under evaluation. Which new anticoagulant should be preferred? It is possible to describe and compare the main efficacy and safety characteristics in one picture (Fig. 1). From this illustration it seems as if apixaban provides the best combination of safety and efficacy. It is important to note that these are not head-to-head comparisons between the new anticoagulants. There are several other outcomes of interest and it is not possible to combine all in a single expression. The all-cause mortality was significantly reduced only by apixaban but the absolute risk reduction was approximately 10% for all new anticoagulants. Dabigatran 150 mg was the only regimen that reduced the risk for ischemic stroke significantly [1]. Conversely, in a meta-analysis of many studies on different indications there was an increase of myocardial infarctions with dabigatran [12] but in the atrial fibrillation population this difference was not statistically significant [13]. It was not possible to predict this risk from the patient’s history of coronary artery disease. Although a twice-daily regimen is feasible for most patients, who with the diagnosis of atrial fibrillation are not uncommonly on a twice-daily treatment with a beta-blocker, it does not work well for others. It is recommended to take dabigatran with food and approximately every 12 hours, which may not be compatible with the lifestyle of some individuals. In that case rivaroxaban will provide the most feasible alternative. Based on the data presented initially in this article and from the aspect of bleeding risk, dabigatran appears safer in younger patients
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and rivaroxaban perhaps in older patients. Apixaban seems safer in patients without diabetes. Areas of uncertainty Several questions remain to be answered such as what is the therapeutic range for the new anticoagulants with suitable tests (diluted thrombin time for dabigatran, standardized factor Xa for rivaroxaban and apixaban) to measure the effect? What is the optimal management in case of requirement for rapid reversal of the anticoagulant effect? When can these drugs be safely resumed after major surgery or procedures with a high risk of bleeding? How can we optimize adherence when the treatment is no longer monitored? Are these drugs as effective in patients who also have cancer? Studies are already being performed to answer most of these questions. Conclusions Of the various patient characteristics age seems to be the most important predictor for bleeding on dabigatran, and diabetes for bleeding on apixaban. There were no characteristics that interacted with the treatment regarding efficacy and importantly, the degree of stroke prevention does not depend on the CHADS2 score. The choice of anticoagulants is soon between 4 different drugs and a careful review of the patient together with an open discussion, addressing patient preferences is strongly recommended for patients starting on the treatment. For patients already on warfarin it is also crucial to review benefits, possible disadvantages, preferences and expectations before switching to a new anticoagulant. The new drugs have different characteristics, which may matter for some patients in tailoring the optimal individual anticoagulant regimen. Although the large studies have been performed and are yielding a large number of secondary publications, there is room for many new research projects focusing on questions that the registration studies were not designed to answer. Conflict of interest statement The author has received honoraria for work in study-related committees from Boehringer Ingelheim and Bayer Healthcare.
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