REVIEWS
Beyond Warfarin: A Patient-Centered Approach to Selecting Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation Keval K. Patel, MD1, Ali A. Mehdirad, MD2, Michael J. Lim, MD2, Scott W. Ferreira, MD2, Peter C. Mikolajczak, MD2, Joshua M. Stolker, MD2* 1
Department of Internal Medicine, Saint Louis University, St. Louis, Missouri; 2Center for Comprehensive Cardiovascular Care, Saint Louis University, St. Louis, Missouri.
BACKGROUND: Warfarin reduces stroke in patients with atrial fibrillation. However, its narrow therapeutic index and need for chronic monitoring are barriers to its optimal utilization in many patients. The recent introduction of 3 novel oral anticoagulants (NOACs), as alternatives to warfarin, may change the eligibility and management of patients with nonvalvular atrial fibrillation (NVAF) who require systemic anticoagulation. PURPOSE: To summarize contemporary indications for anticoagulation in NVAF, and to help provide patientcentered clinical decision making for selecting warfarin or 1 of the NOACs (dabigatran, rivaroxaban, apixaban) based on randomized trials and mechanistic data for each drug. DATA SOURCES AND STUDY SELECTION: The primary clinical outcome trials of warfarin and the NOACs, pharmacologic studies, and briefing documents from the US Food and Drug Administration were reviewed.
Approximately 2.3 million people in the United States and 4.5 million people in Europe have atrial fibrillation (AF), with an increase in prevalence with age to 8% among patients aged 80 years and older.1 The most feared and potentially preventable complications of AF are stroke or systemic thromboembolism, and stroke in particular is increased approximately 5-fold in patients with nonvalvular atrial fibrillation (NVAF).2 For over 50 years, warfarin and similar vitamin K antagonists have been the principal anticoagulants used for preventing stroke in NVAF, with consistent reductions in systemic thromboembolic events when compared with placebo or aspirin.2,3 However, because of its narrow therapeutic window and related management difficulties (ie, frequent monitoring of international normalized ratio [INR] levels, dietary and medication restrictions, interindividual variability in dosing), many patients with NVAF do not receive warfarin or are inadequately treated.4
*Address for correspondence and reprint requests: Joshua M. Stolker, MD, Saint Louis University, 3635 Vista Avenue, St. Louis, MO 63110; Telephone: 314-577-8877; Fax: 314-577-8861; E-mail: [email protected] Additional Supporting Information may be found in the online version of this article. Received: November 22, 2013; Accepted: March 2, 2014 2014 Society of Hospital Medicine DOI 10.1002/jhm.2201 Published online in Wiley Online Library (Wileyonlinelibrary.com).
400
An Official Publication of the Society of Hospital Medicine
DATA EXTRACTION AND DATA SYNTHESIS: In randomized trials, NOACs were consistently noninferior to warfarin for reducing stroke or systemic embolism in patients with NVAF, with reductions in intracranial bleeding as well. However, NOACs have several important drug-drug interactions, exclusion criteria for specific patient subgroups (eg, severe renal disease), and each medication may have a different impact on other clinical outcomes such as myocardial infarction or gastrointestinal bleeding. Benefits of the new drugs are particularly pronounced when international normalized ratio levels on warfarin are labile. CONCLUSIONS: Warfarin continues to play an important role in the prevention of stroke or systemic embolism in NVAF. Among selected patients, the use of NOACs provides equal or superior benefit, without the need for chronic anticoagulation monitoring or ongoing dose titration. Journal of Hospital C 2014 Society of Hospital Medicine Medicine 2014;9:400–406. V
In response to the need for antithrombotic agents with better efficacy, patient tolerance, and convenience, the US Food and Drug Administration (FDA) recently approved 3 novel oral anticoagulants (NOACs) as alternatives to warfarin for NVAF: dabigatran, rivaroxaban, and apixaban. In this review, we evaluated the pharmacologic properties and clinical studies of these NOACs, including the continued role of warfarin in many patients requiring systemic anticoagulation, to guide practicing clinicians in providing individualized, patient-centered care to each of their patients with NVAF.
PHARMACOLOGY Mechanisms of Action Whereas warfarin inhibits the formation of multiple vitamin K-dependent coagulation factors (II, VII, IX, and X),5 the NOACs are competitive and reversible inhibitors of more distal targets in the coagulation pathway. Dabigatran is a direct thrombin inhibitor, whereas rivaroxaban and apixaban directly inhibit factor Xa, ultimately resulting in the inhibition of fibrin formation and thrombosis. Clinical Pathways and Drug Interactions Key aspects of the pharmacokinetic profiles of the 3 NOACs are summarized in Table 1. In addition to these baseline properties of each medication, drug interactions play an important role in the effectiveness Journal of Hospital Medicine Vol 9 | No 6 | June 2014
Novel Anticoagulants in Atrial Fibrillation
TABLE 1. Pharmacologic Properties of the Three
Novel Oral Anticoagulant Medications Characteristic
Target Reversible binding Half-life, h Time to peak serum concentration, h Protein binding, % Renal excretion, % Primary hepatic clearance pathway
Dabigatran
Rivaroxaban
Apixaban
Factor IIa Yes 12–17 1–3 35 80 Does not interact with CYP enzymes
Factor Xa Yes 5–9 2–4 92–95 66 CYP-3A4
Factor Xa Yes 8–15 3–4 87 25–27 CYP-3A4
NOTE: Abbreviations: CYP, cytochrome P450.
and potential toxicities of the NOACs. For example, dabigatran is almost exclusively excreted via glomerular filtration, resulting in a terminal half-life of 12 to 17 hours in normal volunteers and a significantly higher half-life in moderate and severe renal dysfunction (18 and 27 hours, respectively). In phase II and III trials, there was a 30% decrease in bioavailability when dabigatran was administered with pantoprazole, but no comparable effect was noted when coadministered with histamine receptor blockers like ranitidine.6 In addition, although dabigatran has no significant interaction with hepatic P450 enzymes, its prodrug is excreted by the intestinal efflux transporter p-glycoprotein. As a result, dabigatran’s bioavailability is increased by coadministration with potent p-glycoprotein inhibitors such as dronedarone, amiodarone, verapamil, diltiazem, or ketoconazole.6,7 According to FDA labeling, the only drug contraindicated with concomitant dabigatran administration is rifampin, which reduces serum concentration of dabigatran by 66%. Unlike dabigatran, the absorption of rivaroxaban has significant variability between individuals, but the bioavailability of the 20-mg dose increases by 39% and is significantly less variable when taken with food.8 Phase I studies of rivaroxaban demonstrated that elderly patients had 50% higher serum concentrations when compared with younger patients.7,9 Also of note, rivaroxaban has 50% higher bioavailability in Japanese patients as compared with other ethnicities, including Chinese ethnicity, resulting in higher exposure to the drug and potentially explaining higher bleeding rates in Japan when using this drug.9 The primary mechanisms for metabolism of rivaroxaban are the CYP-3A4 and CYP-2C8 pathways in the liver,10 so other drugs metabolized through these pathways (eg, azole antifungals, protease inhibitors, clarithromycin) may have significant drug-drug interactions. Like the other NOACs, apixaban achieves its maximal concentration within 3 to 4 hours,11 and like rivaroxaban, apixaban is metabolized by the CYP3A4 hepatic pathway. However, apixaban does not induce or inhibit hepatic cytochrome P450 (CYP) An Official Publication of the Society of Hospital Medicine
| Patel et al
enzymes, so the potential for drug-drug interactions is considered minimal.12 Important exceptions include coadministration with ketoconazole or clarithromycin, each of which increases the bioavailability of apixaban up to 1.5-fold, so a dose reduction to 2.5 mg twice-daily (BID) is recommended.11
CLINICAL STUDIES Randomized trials evaluating warfarin against placebo or aspirin for NVAF have spanned more than 3 decades, encompassing a variety of study designs, patient populations, and analytic techniques.2,3 Despite differences between trials, these studies have provided the framework for contemporary AF management, with consistent reductions in thromboembolic events with systemic anticoagulation, most notably among patients with multiple risk factors for stroke. Current professional guidelines recommend risk assessment of patients with NVAF, using the CHADS2 (1 point each for Congestive heart failure, Hypertension, Age 75 years, Diabetes, and 2 points for prior Stroke) or similar risk scores, to identify patients most likely to benefit from systemic anticoagulation.1,13 As a result of this extensive background literature, the 3 NOACs have primarily been evaluated against warfarin (instead of aspirin or placebo) as potential alternatives for reducing thromboembolic events in patients with NVAF. The 1 exception is a prematurely terminated trial of apixaban in warfarin-ineligible patients with NVAF, in which apixaban reduced stroke or systemic embolism by 55% compared with aspirin after only 1.1 years of follow-up, with no significant difference in major bleeding.14
Pivotal Clinical Trials The 3 principal trials evaluating the NOACs against warfarin for NVAF are summarized in Table 2. In the Randomized Evaluation of Long-term anticoagulation Therapy (RE-LY) trial, dabigatran was compared with warfarin in 18,113 patients recruited from 951 clinical centers in 44 countries using a noninferiority study design.15 Two different doses of dabigatran were studied, but only the 150-mg BID dose was approved by the FDA. As a result, only the findings from the clinically approved 150-mg dose are summarized in this review. Although RE-LY was considered a semiblinded randomized trial, patients enrolled in the warfarin control arm underwent regular INR surveillance by their treating physicians, leaving the trial open to potential reporting biases. The authors tried to minimize bias by providing a standardized protocol for INR management, and by assigning 2 independent investigators blinded to the treatment assignments to adjudicate each event. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study involved 14,264 Journal of Hospital Medicine Vol 9 | No 6 | June 2014
401
Patel et al |
Novel Anticoagulants in Atrial Fibrillation
TABLE 2. Design of the Three Pivotal Trials Evaluating the Novel Oral Anticoagulants Versus Warfarin in Nonvalvular Atrial Fibrillation Characteristic
RE-LY
Drug Dosing
Dabigatran 150 mg BID (110 mg BID also tested)
Total population Randomization Primary analytic approach Primary efficacy end point Primary safety end point Key inclusion criteria Documented atrial fibrillation
ROCKET-AF
ARISTOTLE
18,113 Semiblinded Noninferiority, intention-to-treat Stroke or systemic embolism Major bleeding
Rivaroxaban 20 mg daily (15 mg for creatinine clearance 30–49 mL/min) 14,264 Double blinded Noninferiority, both intention-to-treat and on-treatment Stroke or systemic embolism Major and clinically relevant nonmajor bleeding
Apixaban 5 mg BID (2.5 mg for patients at higher risk of bleeding)* 18,201 Double blinded Noninferiority, intention-to-treat Stroke or systemic embolism Major bleeding
At screening or within 6 months
Within 30 days prior to randomization and within past year
1
2
At least 2 episodes recorded 2 weeks apart in past year 1
Any hemodynamically relevant or prosthetic valve
Severe mitral stenosis or any mechanical prosthetic valve
Stroke Bleeding
Severe 6 months or mild/moderate 14 days Surgery 30 days, gastrointestinal bleed 12 months, any prior intracranial bleed, severe hypertension
Renal
Creatinine clearance 30–50 mL/min 64%).24 In the same analysis of variability within the RE-LY trial, center-specific TTRs demonstrated higher rates of cardiovascular events and major bleeds in centers with TTR 68%, rivaroxaban was associated with higher rates of stroke and systemic embolism, and in the US subgroup (where TTR was 64%), rivaroxaban had a Journal of Hospital Medicine Vol 9 | No 6 | June 2014
403
Patel et al |
Novel Anticoagulants in Atrial Fibrillation
TABLE 4. Clinical Outcomes in the Three Pivotal Trials of Novel Oral Anticoagulant Therapies RE-LY
Clinical Outcome
Stroke or systemic embolism Any stroke Ischemic Hemorrhagic Myocardial infarction All-cause mortality Major bleeds Intracranial Gastrointestinal
ROCKET-AF
Dabigatran, 150 mg BID, %/y
Warfarin, %/y
Hazard Ratio
1.11 1.01 0.92 0.10 0.74 3.64 3.11 0.30 1.51
1.69 1.57 1.20 0.38 0.53 4.13 3.36 0.74 1.02
0.66 0.64 0.76 0.26 1.38 0.88 0.93 0.40 1.50
P Value*
ARISTOTLE
Rivaroxaban, 20 mg QD, No./100 Patient-Years
Warfarin, No./100 Patient-Years
Hazard Ratio
2.1 1.65 1.34 0.26 0.91 1.87 3.6 0.5 3.15†
2.4 1.96 1.42 0.44 1.12 2.21 3.4 0.7 2.16†
0.88 0.85 0.94 0.59 0.81 0.85 1.04 0.67 —
Beyond Warfarin: A Patient-Centered Approach to Selecting Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation Keval K. Patel, MD1, Ali A. Mehdirad, MD2, Michael J. Lim, MD2, Scott W. Ferreira, MD2, Peter C. Mikolajczak, MD2, Joshua M. Stolker, MD2* 1
Department of Internal Medicine, Saint Louis University, St. Louis, Missouri; 2Center for Comprehensive Cardiovascular Care, Saint Louis University, St. Louis, Missouri.
BACKGROUND: Warfarin reduces stroke in patients with atrial fibrillation. However, its narrow therapeutic index and need for chronic monitoring are barriers to its optimal utilization in many patients. The recent introduction of 3 novel oral anticoagulants (NOACs), as alternatives to warfarin, may change the eligibility and management of patients with nonvalvular atrial fibrillation (NVAF) who require systemic anticoagulation. PURPOSE: To summarize contemporary indications for anticoagulation in NVAF, and to help provide patientcentered clinical decision making for selecting warfarin or 1 of the NOACs (dabigatran, rivaroxaban, apixaban) based on randomized trials and mechanistic data for each drug. DATA SOURCES AND STUDY SELECTION: The primary clinical outcome trials of warfarin and the NOACs, pharmacologic studies, and briefing documents from the US Food and Drug Administration were reviewed.
Approximately 2.3 million people in the United States and 4.5 million people in Europe have atrial fibrillation (AF), with an increase in prevalence with age to 8% among patients aged 80 years and older.1 The most feared and potentially preventable complications of AF are stroke or systemic thromboembolism, and stroke in particular is increased approximately 5-fold in patients with nonvalvular atrial fibrillation (NVAF).2 For over 50 years, warfarin and similar vitamin K antagonists have been the principal anticoagulants used for preventing stroke in NVAF, with consistent reductions in systemic thromboembolic events when compared with placebo or aspirin.2,3 However, because of its narrow therapeutic window and related management difficulties (ie, frequent monitoring of international normalized ratio [INR] levels, dietary and medication restrictions, interindividual variability in dosing), many patients with NVAF do not receive warfarin or are inadequately treated.4
*Address for correspondence and reprint requests: Joshua M. Stolker, MD, Saint Louis University, 3635 Vista Avenue, St. Louis, MO 63110; Telephone: 314-577-8877; Fax: 314-577-8861; E-mail: [email protected] Additional Supporting Information may be found in the online version of this article. Received: November 22, 2013; Accepted: March 2, 2014 2014 Society of Hospital Medicine DOI 10.1002/jhm.2201 Published online in Wiley Online Library (Wileyonlinelibrary.com).
400
An Official Publication of the Society of Hospital Medicine
DATA EXTRACTION AND DATA SYNTHESIS: In randomized trials, NOACs were consistently noninferior to warfarin for reducing stroke or systemic embolism in patients with NVAF, with reductions in intracranial bleeding as well. However, NOACs have several important drug-drug interactions, exclusion criteria for specific patient subgroups (eg, severe renal disease), and each medication may have a different impact on other clinical outcomes such as myocardial infarction or gastrointestinal bleeding. Benefits of the new drugs are particularly pronounced when international normalized ratio levels on warfarin are labile. CONCLUSIONS: Warfarin continues to play an important role in the prevention of stroke or systemic embolism in NVAF. Among selected patients, the use of NOACs provides equal or superior benefit, without the need for chronic anticoagulation monitoring or ongoing dose titration. Journal of Hospital C 2014 Society of Hospital Medicine Medicine 2014;9:400–406. V
In response to the need for antithrombotic agents with better efficacy, patient tolerance, and convenience, the US Food and Drug Administration (FDA) recently approved 3 novel oral anticoagulants (NOACs) as alternatives to warfarin for NVAF: dabigatran, rivaroxaban, and apixaban. In this review, we evaluated the pharmacologic properties and clinical studies of these NOACs, including the continued role of warfarin in many patients requiring systemic anticoagulation, to guide practicing clinicians in providing individualized, patient-centered care to each of their patients with NVAF.
PHARMACOLOGY Mechanisms of Action Whereas warfarin inhibits the formation of multiple vitamin K-dependent coagulation factors (II, VII, IX, and X),5 the NOACs are competitive and reversible inhibitors of more distal targets in the coagulation pathway. Dabigatran is a direct thrombin inhibitor, whereas rivaroxaban and apixaban directly inhibit factor Xa, ultimately resulting in the inhibition of fibrin formation and thrombosis. Clinical Pathways and Drug Interactions Key aspects of the pharmacokinetic profiles of the 3 NOACs are summarized in Table 1. In addition to these baseline properties of each medication, drug interactions play an important role in the effectiveness Journal of Hospital Medicine Vol 9 | No 6 | June 2014
Novel Anticoagulants in Atrial Fibrillation
TABLE 1. Pharmacologic Properties of the Three
Novel Oral Anticoagulant Medications Characteristic
Target Reversible binding Half-life, h Time to peak serum concentration, h Protein binding, % Renal excretion, % Primary hepatic clearance pathway
Dabigatran
Rivaroxaban
Apixaban
Factor IIa Yes 12–17 1–3 35 80 Does not interact with CYP enzymes
Factor Xa Yes 5–9 2–4 92–95 66 CYP-3A4
Factor Xa Yes 8–15 3–4 87 25–27 CYP-3A4
NOTE: Abbreviations: CYP, cytochrome P450.
and potential toxicities of the NOACs. For example, dabigatran is almost exclusively excreted via glomerular filtration, resulting in a terminal half-life of 12 to 17 hours in normal volunteers and a significantly higher half-life in moderate and severe renal dysfunction (18 and 27 hours, respectively). In phase II and III trials, there was a 30% decrease in bioavailability when dabigatran was administered with pantoprazole, but no comparable effect was noted when coadministered with histamine receptor blockers like ranitidine.6 In addition, although dabigatran has no significant interaction with hepatic P450 enzymes, its prodrug is excreted by the intestinal efflux transporter p-glycoprotein. As a result, dabigatran’s bioavailability is increased by coadministration with potent p-glycoprotein inhibitors such as dronedarone, amiodarone, verapamil, diltiazem, or ketoconazole.6,7 According to FDA labeling, the only drug contraindicated with concomitant dabigatran administration is rifampin, which reduces serum concentration of dabigatran by 66%. Unlike dabigatran, the absorption of rivaroxaban has significant variability between individuals, but the bioavailability of the 20-mg dose increases by 39% and is significantly less variable when taken with food.8 Phase I studies of rivaroxaban demonstrated that elderly patients had 50% higher serum concentrations when compared with younger patients.7,9 Also of note, rivaroxaban has 50% higher bioavailability in Japanese patients as compared with other ethnicities, including Chinese ethnicity, resulting in higher exposure to the drug and potentially explaining higher bleeding rates in Japan when using this drug.9 The primary mechanisms for metabolism of rivaroxaban are the CYP-3A4 and CYP-2C8 pathways in the liver,10 so other drugs metabolized through these pathways (eg, azole antifungals, protease inhibitors, clarithromycin) may have significant drug-drug interactions. Like the other NOACs, apixaban achieves its maximal concentration within 3 to 4 hours,11 and like rivaroxaban, apixaban is metabolized by the CYP3A4 hepatic pathway. However, apixaban does not induce or inhibit hepatic cytochrome P450 (CYP) An Official Publication of the Society of Hospital Medicine
| Patel et al
enzymes, so the potential for drug-drug interactions is considered minimal.12 Important exceptions include coadministration with ketoconazole or clarithromycin, each of which increases the bioavailability of apixaban up to 1.5-fold, so a dose reduction to 2.5 mg twice-daily (BID) is recommended.11
CLINICAL STUDIES Randomized trials evaluating warfarin against placebo or aspirin for NVAF have spanned more than 3 decades, encompassing a variety of study designs, patient populations, and analytic techniques.2,3 Despite differences between trials, these studies have provided the framework for contemporary AF management, with consistent reductions in thromboembolic events with systemic anticoagulation, most notably among patients with multiple risk factors for stroke. Current professional guidelines recommend risk assessment of patients with NVAF, using the CHADS2 (1 point each for Congestive heart failure, Hypertension, Age 75 years, Diabetes, and 2 points for prior Stroke) or similar risk scores, to identify patients most likely to benefit from systemic anticoagulation.1,13 As a result of this extensive background literature, the 3 NOACs have primarily been evaluated against warfarin (instead of aspirin or placebo) as potential alternatives for reducing thromboembolic events in patients with NVAF. The 1 exception is a prematurely terminated trial of apixaban in warfarin-ineligible patients with NVAF, in which apixaban reduced stroke or systemic embolism by 55% compared with aspirin after only 1.1 years of follow-up, with no significant difference in major bleeding.14
Pivotal Clinical Trials The 3 principal trials evaluating the NOACs against warfarin for NVAF are summarized in Table 2. In the Randomized Evaluation of Long-term anticoagulation Therapy (RE-LY) trial, dabigatran was compared with warfarin in 18,113 patients recruited from 951 clinical centers in 44 countries using a noninferiority study design.15 Two different doses of dabigatran were studied, but only the 150-mg BID dose was approved by the FDA. As a result, only the findings from the clinically approved 150-mg dose are summarized in this review. Although RE-LY was considered a semiblinded randomized trial, patients enrolled in the warfarin control arm underwent regular INR surveillance by their treating physicians, leaving the trial open to potential reporting biases. The authors tried to minimize bias by providing a standardized protocol for INR management, and by assigning 2 independent investigators blinded to the treatment assignments to adjudicate each event. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study involved 14,264 Journal of Hospital Medicine Vol 9 | No 6 | June 2014
401
Patel et al |
Novel Anticoagulants in Atrial Fibrillation
TABLE 2. Design of the Three Pivotal Trials Evaluating the Novel Oral Anticoagulants Versus Warfarin in Nonvalvular Atrial Fibrillation Characteristic
RE-LY
Drug Dosing
Dabigatran 150 mg BID (110 mg BID also tested)
Total population Randomization Primary analytic approach Primary efficacy end point Primary safety end point Key inclusion criteria Documented atrial fibrillation
ROCKET-AF
ARISTOTLE
18,113 Semiblinded Noninferiority, intention-to-treat Stroke or systemic embolism Major bleeding
Rivaroxaban 20 mg daily (15 mg for creatinine clearance 30–49 mL/min) 14,264 Double blinded Noninferiority, both intention-to-treat and on-treatment Stroke or systemic embolism Major and clinically relevant nonmajor bleeding
Apixaban 5 mg BID (2.5 mg for patients at higher risk of bleeding)* 18,201 Double blinded Noninferiority, intention-to-treat Stroke or systemic embolism Major bleeding
At screening or within 6 months
Within 30 days prior to randomization and within past year
1
2
At least 2 episodes recorded 2 weeks apart in past year 1
Any hemodynamically relevant or prosthetic valve
Severe mitral stenosis or any mechanical prosthetic valve
Stroke Bleeding
Severe 6 months or mild/moderate 14 days Surgery 30 days, gastrointestinal bleed 12 months, any prior intracranial bleed, severe hypertension
Renal
Creatinine clearance 30–50 mL/min 64%).24 In the same analysis of variability within the RE-LY trial, center-specific TTRs demonstrated higher rates of cardiovascular events and major bleeds in centers with TTR 68%, rivaroxaban was associated with higher rates of stroke and systemic embolism, and in the US subgroup (where TTR was 64%), rivaroxaban had a Journal of Hospital Medicine Vol 9 | No 6 | June 2014
403
Patel et al |
Novel Anticoagulants in Atrial Fibrillation
TABLE 4. Clinical Outcomes in the Three Pivotal Trials of Novel Oral Anticoagulant Therapies RE-LY
Clinical Outcome
Stroke or systemic embolism Any stroke Ischemic Hemorrhagic Myocardial infarction All-cause mortality Major bleeds Intracranial Gastrointestinal
ROCKET-AF
Dabigatran, 150 mg BID, %/y
Warfarin, %/y
Hazard Ratio
1.11 1.01 0.92 0.10 0.74 3.64 3.11 0.30 1.51
1.69 1.57 1.20 0.38 0.53 4.13 3.36 0.74 1.02
0.66 0.64 0.76 0.26 1.38 0.88 0.93 0.40 1.50
P Value*
ARISTOTLE
Rivaroxaban, 20 mg QD, No./100 Patient-Years
Warfarin, No./100 Patient-Years
Hazard Ratio
2.1 1.65 1.34 0.26 0.91 1.87 3.6 0.5 3.15†
2.4 1.96 1.42 0.44 1.12 2.21 3.4 0.7 2.16†
0.88 0.85 0.94 0.59 0.81 0.85 1.04 0.67 —
