The
n e w e ng l a n d j o u r na l
of
m e dic i n e
C or r e sp ondence
Point-of-Care Warfarin Monitoring in the ROCKET AF Trial To the Editor: In 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), investigators found that rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation.1 In December 2014, four years after completion of the trial, the Food and Drug Administration (FDA) issued a recall notice for a medical device correction of the Alere INRatio Monitor System (formally known as the Hemosense INRatio device). The recall correction notice was issued because the FDA-approved and European Conformity (CE)–marked wholeblood, point-of-care device may provide an international normalized ratio (INR) result that is lower than an automated, plasma-based laboratory INR in patients with certain specific medical conditions. These conditions include abnormal hematocrit levels, conditions associated with raised fibrinogen levels, and bleeding or unusual bruising (see a description of conditions and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).2 In October 2015, the ROCKET AF executive committee was notified that the device that was used in the trial was included in this FDA recall correction notice. To understand the effect of possible device malfunction leading to lower INR values and inappropriately high doses of warfarin and bleeding, we conducted a series of post hoc analyses of the ROCKET AF data. Two physicians who were unaware of studygroup assignments reviewed baseline medical history and adverse events identified during trial follow-up for all patients enrolled in the trial for any of the conditions cited in the recall (Table S2 in the Supplementary Appendix). Patients with central laboratory evidence of hematocrit values
of less than 30% or more than 55% were also identified. We categorized the entire trial population according to whether patients had any recall condition or no recall condition and then compared efficacy and safety outcomes of patients receiving rivaroxaban with those receiving warfarin within these subgroups. Details regarding the study methods are provided in the Supplementary Appendix. In the primary analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in the overall trial population (as-treated population) and in patients with no recall conditions. In a subsequent analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in patients with any recall condition (Fig. 1). We also performed a sensitivity analysis in which patients with possible acuteonset recall conditions (e.g., an acute infection) were included in the subgroup of patients with no recall condition until the time of onset of the acute condition (Table S1 in the Supplementary Appendix). In addition, we evaluated the primary efficacy end point in the intention-to-treat and per-protocol populations to present results consistent with those in the primary trial report. Of the total safety population of 14,236 patients, 8942 (63%) had no recall condition and 5294 (37%) had a recall condition. Both types of patients were equally distributed between the warfarin and rivaroxaban groups (Table S2 in the Supplementary Appendix). Patients without recall conditions were younger than those with recall conditions (72 years vs. 74 years) and were more likely to have a history of stroke or transient is chemic attack (57% vs. 51%), less likely to have diabetes (39% vs. 42%), and less likely to have been treated with a vitamin K antagonist before study entry (60% vs. 66%) (Table S3 in the Supplemen-
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1
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
A Efficacy Outcomes
Rivaroxaban
Warfarin
no. of events per 100 person-yr (no. of events)
Stroke or embolism: intention-to-treat patients/study period All patients No condition Any condition Stroke or embolism: per-protocol patients/as-treated All patients No condition Any condition Stroke or embolism: safety patients/ as-treated All patients No condition Any condition Death: safety patients/as-treated All patients No condition Any condition Vascular death: safety patients/as-treated All patients No condition Any condition
P Value for Interaction
Hazard Ratio (95% CI)
0.75 2.12 (269) 2.26 (174) 1.91 (95)
2.42 (306) 2.52 (196) 2.26 (110)
0.88 (0.75–1.03) 0.89 (0.73–1.10) 0.84 (0.64–1.11)
1.71 (188) 1.96 (129) 1.35 (59)
2.16 (241) 2.30 (157) 1.93 (84)
0.79 (0.66–0.96) 0.85 (0.67–1.07) 0.70 (0.50–0.97)
1.70 (189) 1.93 (129) 1.35 (60)
2.15 (243) 2.29 (158) 1.93 (85)
0.79 (0.65–0.95) 0.84 (0.66–1.06) 0.70 (0.50–0.97)
1.87 (208) 2.06 (138) 1.58 (70)
2.21 (250) 2.23 (154) 2.18 (96)
0.85 (0.70–1.02) 0.92 (0.73–1.16) 0.72 (0.53–0.98)
1.53 (170) 1.75 (117) 1.19 (53)
1.71 (193) 1.80 (124) 1.56 (69)
0.89 (0.73–1.10) 0.97 (0.75–1.25) 0.76 (0.53–1.09)
0.25
0.50
1.00
Rivaroxaban Better
2.00
Rivaroxaban
Warfarin
0.39
0.22
0.28
4.00
Warfarin Better
B Safety Outcomes
0.36
P Value for Interaction
Hazard Ratio (95% CI)
no. of events per 100 person-yr (no. of events) Major or NMCR bleeding All patients No condition Any condition NMCR bleeding All patients No condition Any condition Major bleeding All patients No condition Any condition Fatal bleeding All patients No condition Any condition Critical organ bleeding All patients No condition Any condition Decrease in hemoglobin All patients No condition Any condition Transfusion All patients No condition Any condition Intracerebral hemorrhage All patients No condition Any condition Gastrointestinal bleeding All patients No condition Any condition
14.92 (1475) 11.36 (702) 20.84 (773)
14.52 (1449) 11.42 (718) 19.78 (731)
1.03 (0.96–1.11) 0.99 (0.90–1.10) 1.06 (0.96–1.17)
11.81 (1185) 9.38 (585) 15.78 (600)
11.37 (1151) 8.88 (563) 15.55 (588)
1.04 (0.96–1.13) 1.06 (0.94–1.19) 1.02 (0.91–1.14)
3.60 (395) 2.34 (156) 5.53 (239)
3.45 (386) 2.68 (184) 4.69 (202)
1.04 (0.90–1.20) 0.87 (0.70–1.08) 1.18 (0.98–1.42)
0.24 (27) 0.22 (15) 0.27 (12)
0.48 (55) 0.52 (36) 0.43 (19)
0.50 (0.31–0.79) 0.43 (0.23–0.78) 0.62 (0.30–1.29)
0.82 (91) 0.71 (48) 0.97 (43)
1.18 (133) 1.17 (81) 1.18 (52)
0.69 (0.53–0.91) 0.61 (0.42–0.87) 0.82 (0.55–1.22)
2.77 (305) 1.68 (112) 4.44 (193)
2.26 (254) 1.63 (112) 3.27 (142)
1.22 (1.03–1.44) 1.03 (0.79–1.33) 1.36 (1.09–1.69)
1.65 (183) 0.88 (59) 2.82 (124)
1.32 (149) 0.84 (58) 2.08 (91)
1.25 (1.01–1.55) 1.04 (0.73–1.50) 1.36 (1.04–1.78)
0.49 (55) 0.46 (31) 0.54 (24)
0.74 (84) 0.88 (61) 0.52 (23)
0.67 (0.47–0.93) 0.52 (0.34–0.80) 1.03 (0.58–1.83)
2.00 (221) 1.19 (80) 3.22 (141)
1.24 (140) 0.81 (56) 1.92 (84)
1.61 (1.30–1.99) 1.47 (1.04–2.06) 1.68 (1.28–2.20) 0.25
0.50
1.00
Rivaroxaban Better
2
n engl j med
2.00
4.00
Warfarin Better
nejm.org
The New England Journal of Medicine Downloaded from nejm.org on February 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.
0.39
0.68
0.04
0.42
0.28
0.11
0.26
0.06
0.54
Correspondence
sistent with the reported results of the overall trial (Table S8 in the Supplementary Appendix). Among patients with any recall condition, the bleeding rate was higher in both the rivaroxaban and warfarin groups. Furthermore, among patients with any recall condition, there was a trend toward a higher relative risk of major bleeding with rivaroxaban than with warfarin, a trend that was not seen among patients with no recall condition (P = 0.04 for interaction) (Fig. 1). This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial. The results of the additional sensitivity analyses are consistent with those already reported for the primary efficacy and safety end points in patients with or without recall conditions (Tables S9 and S10 in the Supplementary Appendix) and for key secondary efficacy and safety end points (Fig. S1 in the Supplementary Appendix). These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial. Manesh R. Patel, M.D. tary Appendix). The characteristics of the pa- Anne S. Hellkamp, M.S. tients were similar in the rivaroxaban group and Duke Clinical Research Institute the warfarin group in the subgroups with and Durham, NC manesh.patel@duke.edu without recall conditions (Tables S4 and S5 in Keith A. A. Fox, M.B., Ch.B. the Supplementary Appendix). University of Edinburgh The main trial results for the primary efficacy Edinburgh, United Kingdom and safety end points of the overall ROCKET AF for the ROCKET AF Executive trial population have been reported previously1 Committee and Investigators and are provided in Table S6 in the SupplemenA complete list of ROCKET AF executive committee members tary Appendix. The results of the primary analy- and investigators is provided in the Supplementary Appendix, sis of efficacy and safety outcomes in the sub- available at NEJM.org. Supported by the Duke Clinical Research Institute. group of patients with no recall conditions are Disclosure forms provided by the authors are available with shown in Table S7 in the Supplementary Appen- the full text of this letter at NEJM.org. dix. These results are consistent with those of This letter was published on February 3, 2016, at NEJM.org. the overall trial population in showing the noninferiority of rivaroxaban versus warfarin for 1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus preventing stroke and systemic embolism, with warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-91. similar rates of overall bleeding and lower rates 2. Food and Drug Administration. Alere INRatio2 PT/INR of fatal and intracranial bleeding among pa- Professional Test Strips: recall — higher INR when performed tients treated with rivaroxaban but a higher rate by central laboratory. December 5, 2014 (http://www.fda.gov/ Safety/MedWatch/SafetyInformation/ of gastrointestinal bleeding. SafetyAlertsforHumanMedicalProducts/ucm396324.htm). The primary efficacy and safety findings in DOI: 10.1056/NEJMc1515842 patients with any recall condition are also con- Correspondence Copyright © 2016 Massachusetts Medical Society. Figure 1 (facing page). Subgroup Analyses of Efficacy and Safety Outcomes. Shown are efficacy events in all patients who underwent randomization (Panel A) and safety events in all patients who received at least one dose of study drug (Panel B), according to the subgroup for their recall condition among patients receiving rivaroxaban or warfarin (primary analysis). The main trial results are listed under “all patients,” patients with any condition (chronic inflammation, acute inflammation, or hematocrit out of range) at any time are listed under “any condition,” and patients without any of these conditions at any time are listed under “no condition.” In Panel A, all patients who underwent randomization are included in the intention-to-treat analysis; all patients who underwent randomization and received at least one dose of a study drug are included in the safety analysis. Included in the per-protocol analysis are all patients who received at least one dose of study drug and had no major protocol violations. The study period extended from randomization until the last contact with a patient or site notification of the end of the study, whichever was first, regardless of study-drug exposure. For the as-treated population, the study period extended from the administration of the first dose of a study drug until the last dose plus 2 days. All analyses omit 93 patients from one site that had a Good Clinical Practice violation. In Panel B, all analyses were performed in the safety cohort. Events are counted from the administration of the first dose of a study drug until the administration of the last dose plus 2 days. NMCR denotes nonmajor, clinically relevant.
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on February 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.
3
n e w e ng l a n d j o u r na l
of
m e dic i n e
C or r e sp ondence
Point-of-Care Warfarin Monitoring in the ROCKET AF Trial To the Editor: In 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), investigators found that rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation.1 In December 2014, four years after completion of the trial, the Food and Drug Administration (FDA) issued a recall notice for a medical device correction of the Alere INRatio Monitor System (formally known as the Hemosense INRatio device). The recall correction notice was issued because the FDA-approved and European Conformity (CE)–marked wholeblood, point-of-care device may provide an international normalized ratio (INR) result that is lower than an automated, plasma-based laboratory INR in patients with certain specific medical conditions. These conditions include abnormal hematocrit levels, conditions associated with raised fibrinogen levels, and bleeding or unusual bruising (see a description of conditions and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).2 In October 2015, the ROCKET AF executive committee was notified that the device that was used in the trial was included in this FDA recall correction notice. To understand the effect of possible device malfunction leading to lower INR values and inappropriately high doses of warfarin and bleeding, we conducted a series of post hoc analyses of the ROCKET AF data. Two physicians who were unaware of studygroup assignments reviewed baseline medical history and adverse events identified during trial follow-up for all patients enrolled in the trial for any of the conditions cited in the recall (Table S2 in the Supplementary Appendix). Patients with central laboratory evidence of hematocrit values
of less than 30% or more than 55% were also identified. We categorized the entire trial population according to whether patients had any recall condition or no recall condition and then compared efficacy and safety outcomes of patients receiving rivaroxaban with those receiving warfarin within these subgroups. Details regarding the study methods are provided in the Supplementary Appendix. In the primary analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in the overall trial population (as-treated population) and in patients with no recall conditions. In a subsequent analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in patients with any recall condition (Fig. 1). We also performed a sensitivity analysis in which patients with possible acuteonset recall conditions (e.g., an acute infection) were included in the subgroup of patients with no recall condition until the time of onset of the acute condition (Table S1 in the Supplementary Appendix). In addition, we evaluated the primary efficacy end point in the intention-to-treat and per-protocol populations to present results consistent with those in the primary trial report. Of the total safety population of 14,236 patients, 8942 (63%) had no recall condition and 5294 (37%) had a recall condition. Both types of patients were equally distributed between the warfarin and rivaroxaban groups (Table S2 in the Supplementary Appendix). Patients without recall conditions were younger than those with recall conditions (72 years vs. 74 years) and were more likely to have a history of stroke or transient is chemic attack (57% vs. 51%), less likely to have diabetes (39% vs. 42%), and less likely to have been treated with a vitamin K antagonist before study entry (60% vs. 66%) (Table S3 in the Supplemen-
n engl j med nejm.org
The New England Journal of Medicine Downloaded from nejm.org on February 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.
1
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
A Efficacy Outcomes
Rivaroxaban
Warfarin
no. of events per 100 person-yr (no. of events)
Stroke or embolism: intention-to-treat patients/study period All patients No condition Any condition Stroke or embolism: per-protocol patients/as-treated All patients No condition Any condition Stroke or embolism: safety patients/ as-treated All patients No condition Any condition Death: safety patients/as-treated All patients No condition Any condition Vascular death: safety patients/as-treated All patients No condition Any condition
P Value for Interaction
Hazard Ratio (95% CI)
0.75 2.12 (269) 2.26 (174) 1.91 (95)
2.42 (306) 2.52 (196) 2.26 (110)
0.88 (0.75–1.03) 0.89 (0.73–1.10) 0.84 (0.64–1.11)
1.71 (188) 1.96 (129) 1.35 (59)
2.16 (241) 2.30 (157) 1.93 (84)
0.79 (0.66–0.96) 0.85 (0.67–1.07) 0.70 (0.50–0.97)
1.70 (189) 1.93 (129) 1.35 (60)
2.15 (243) 2.29 (158) 1.93 (85)
0.79 (0.65–0.95) 0.84 (0.66–1.06) 0.70 (0.50–0.97)
1.87 (208) 2.06 (138) 1.58 (70)
2.21 (250) 2.23 (154) 2.18 (96)
0.85 (0.70–1.02) 0.92 (0.73–1.16) 0.72 (0.53–0.98)
1.53 (170) 1.75 (117) 1.19 (53)
1.71 (193) 1.80 (124) 1.56 (69)
0.89 (0.73–1.10) 0.97 (0.75–1.25) 0.76 (0.53–1.09)
0.25
0.50
1.00
Rivaroxaban Better
2.00
Rivaroxaban
Warfarin
0.39
0.22
0.28
4.00
Warfarin Better
B Safety Outcomes
0.36
P Value for Interaction
Hazard Ratio (95% CI)
no. of events per 100 person-yr (no. of events) Major or NMCR bleeding All patients No condition Any condition NMCR bleeding All patients No condition Any condition Major bleeding All patients No condition Any condition Fatal bleeding All patients No condition Any condition Critical organ bleeding All patients No condition Any condition Decrease in hemoglobin All patients No condition Any condition Transfusion All patients No condition Any condition Intracerebral hemorrhage All patients No condition Any condition Gastrointestinal bleeding All patients No condition Any condition
14.92 (1475) 11.36 (702) 20.84 (773)
14.52 (1449) 11.42 (718) 19.78 (731)
1.03 (0.96–1.11) 0.99 (0.90–1.10) 1.06 (0.96–1.17)
11.81 (1185) 9.38 (585) 15.78 (600)
11.37 (1151) 8.88 (563) 15.55 (588)
1.04 (0.96–1.13) 1.06 (0.94–1.19) 1.02 (0.91–1.14)
3.60 (395) 2.34 (156) 5.53 (239)
3.45 (386) 2.68 (184) 4.69 (202)
1.04 (0.90–1.20) 0.87 (0.70–1.08) 1.18 (0.98–1.42)
0.24 (27) 0.22 (15) 0.27 (12)
0.48 (55) 0.52 (36) 0.43 (19)
0.50 (0.31–0.79) 0.43 (0.23–0.78) 0.62 (0.30–1.29)
0.82 (91) 0.71 (48) 0.97 (43)
1.18 (133) 1.17 (81) 1.18 (52)
0.69 (0.53–0.91) 0.61 (0.42–0.87) 0.82 (0.55–1.22)
2.77 (305) 1.68 (112) 4.44 (193)
2.26 (254) 1.63 (112) 3.27 (142)
1.22 (1.03–1.44) 1.03 (0.79–1.33) 1.36 (1.09–1.69)
1.65 (183) 0.88 (59) 2.82 (124)
1.32 (149) 0.84 (58) 2.08 (91)
1.25 (1.01–1.55) 1.04 (0.73–1.50) 1.36 (1.04–1.78)
0.49 (55) 0.46 (31) 0.54 (24)
0.74 (84) 0.88 (61) 0.52 (23)
0.67 (0.47–0.93) 0.52 (0.34–0.80) 1.03 (0.58–1.83)
2.00 (221) 1.19 (80) 3.22 (141)
1.24 (140) 0.81 (56) 1.92 (84)
1.61 (1.30–1.99) 1.47 (1.04–2.06) 1.68 (1.28–2.20) 0.25
0.50
1.00
Rivaroxaban Better
2
n engl j med
2.00
4.00
Warfarin Better
nejm.org
The New England Journal of Medicine Downloaded from nejm.org on February 6, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.
0.39
0.68
0.04
0.42
0.28
0.11
0.26
0.06
0.54
Correspondence
sistent with the reported results of the overall trial (Table S8 in the Supplementary Appendix). Among patients with any recall condition, the bleeding rate was higher in both the rivaroxaban and warfarin groups. Furthermore, among patients with any recall condition, there was a trend toward a higher relative risk of major bleeding with rivaroxaban than with warfarin, a trend that was not seen among patients with no recall condition (P = 0.04 for interaction) (Fig. 1). This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial. The results of the additional sensitivity analyses are consistent with those already reported for the primary efficacy and safety end points in patients with or without recall conditions (Tables S9 and S10 in the Supplementary Appendix) and for key secondary efficacy and safety end points (Fig. S1 in the Supplementary Appendix). These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial. Manesh R. Patel, M.D. tary Appendix). The characteristics of the pa- Anne S. Hellkamp, M.S. tients were similar in the rivaroxaban group and Duke Clinical Research Institute the warfarin group in the subgroups with and Durham, NC manesh.patel@duke.edu without recall conditions (Tables S4 and S5 in Keith A. A. Fox, M.B., Ch.B. the Supplementary Appendix). University of Edinburgh The main trial results for the primary efficacy Edinburgh, United Kingdom and safety end points of the overall ROCKET AF for the ROCKET AF Executive trial population have been reported previously1 Committee and Investigators and are provided in Table S6 in the SupplemenA complete list of ROCKET AF executive committee members tary Appendix. The results of the primary analy- and investigators is provided in the Supplementary Appendix, sis of efficacy and safety outcomes in the sub- available at NEJM.org. Supported by the Duke Clinical Research Institute. group of patients with no recall conditions are Disclosure forms provided by the authors are available with shown in Table S7 in the Supplementary Appen- the full text of this letter at NEJM.org. dix. These results are consistent with those of This letter was published on February 3, 2016, at NEJM.org. the overall trial population in showing the noninferiority of rivaroxaban versus warfarin for 1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus preventing stroke and systemic embolism, with warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-91. similar rates of overall bleeding and lower rates 2. Food and Drug Administration. Alere INRatio2 PT/INR of fatal and intracranial bleeding among pa- Professional Test Strips: recall — higher INR when performed tients treated with rivaroxaban but a higher rate by central laboratory. December 5, 2014 (http://www.fda.gov/ Safety/MedWatch/SafetyInformation/ of gastrointestinal bleeding. SafetyAlertsforHumanMedicalProducts/ucm396324.htm). The primary efficacy and safety findings in DOI: 10.1056/NEJMc1515842 patients with any recall condition are also con- Correspondence Copyright © 2016 Massachusetts Medical Society. Figure 1 (facing page). Subgroup Analyses of Efficacy and Safety Outcomes. Shown are efficacy events in all patients who underwent randomization (Panel A) and safety events in all patients who received at least one dose of study drug (Panel B), according to the subgroup for their recall condition among patients receiving rivaroxaban or warfarin (primary analysis). The main trial results are listed under “all patients,” patients with any condition (chronic inflammation, acute inflammation, or hematocrit out of range) at any time are listed under “any condition,” and patients without any of these conditions at any time are listed under “no condition.” In Panel A, all patients who underwent randomization are included in the intention-to-treat analysis; all patients who underwent randomization and received at least one dose of a study drug are included in the safety analysis. Included in the per-protocol analysis are all patients who received at least one dose of study drug and had no major protocol violations. The study period extended from randomization until the last contact with a patient or site notification of the end of the study, whichever was first, regardless of study-drug exposure. For the as-treated population, the study period extended from the administration of the first dose of a study drug until the last dose plus 2 days. All analyses omit 93 patients from one site that had a Good Clinical Practice violation. In Panel B, all analyses were performed in the safety cohort. Events are counted from the administration of the first dose of a study drug until the administration of the last dose plus 2 days. NMCR denotes nonmajor, clinically relevant.
n engl j med nejm.org
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3
