meta-analysis of renal function on the safety and efficacy

Accepted Manuscript

Meta-Analysis of Renal Function on the Safety and Efficacy of Novel OralAnticoagulants for Atrial Fibrillation

Freddy Del-Carpio Munoz, MD, MSc, S. Michael Gharacholou, MD, MSc, Thomas M.Munger, MD, Paul A. Friedman, MD, Samuel J. Asirvatham, MD, Douglas L. Packer,MD, Peter A. Noseworthy, MD

PII: S0002-9149(15)02084-6

DOI: 10.1016/j.amjcard.2015.09.046

Reference: AJC 21457

To appear in: The American Journal of Cardiology

Received Date: 14 August 2015

Revised Date: 25 September 2015

Accepted Date: 28 September 2015

Please cite this article as: Del-Carpio Munoz F, Gharacholou SM, Munger TM, Friedman PA, AsirvathamSJ, Packer DL, Noseworthy PA, Meta-Analysis of Renal Function on the Safety and Efficacy of NovelOral Anticoagulants for Atrial Fibrillation, The American Journal of Cardiology (2015), doi: 10.1016/j.amjcard.2015.09.046.

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http://dx.doi.org/10.1016/j.amjcard.2015.09.046

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ACCEPTED MANUSCRIPT1

Meta-Analysis of Renal Function on the Safety and Efficacy of Novel Oral Anticoagulants for

Atrial Fibrillation

Freddy Del-Carpio Munoz, MD, MSc1; S. Michael Gharacholou, MD, MSc

1; Thomas M. Munger,

MD1;Paul A. Friedman, MD

1; Samuel J. Asirvatham, MD

1; Douglas L. Packer, MD

1; Peter A

Noseworthy, MD1,2

(1) Heart Rhythm Section, Cardiovascular Diseases, Mayo Clinic, Rochester MN

(2) Robert D. and Patricia E. Kern Center for Science of Health Care Delivery, Mayo Clinic,

Rochester MN

Address for correspondence:

Freddy Del-Carpio Munoz, MD, MSc

Division of Cardiovascular Diseases, Mayo Clinic College of Medicine

200 First Street SW

Rochester MN, 55905

Tel: 507-266-3564

Fax: 507-284-1732

Email: [email protected]

Running title: NOAC vs. warfarin use for AF in mild or moderate renal dysfunction

Conflicts of interest: None

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Abstract:

Novel oral anticoagulants (NOACs) are safe and effective for the prevention of stroke or systemic

embolism (S/SE) in atrial fibrillation (AF). The efficacy and safety of NOACs compared to warfarin has not

been systematically assessed in subjects with mild or moderate renal dysfunction. We performed a

meta-analysis of the randomized clinical trials that compared efficacy and safety (major bleeding)

outcomes of NOACs compared to warfarin for the treatment of nonvalvular AF and had available data

on renal function. We estimated the pooled relative risk (RR) of S/SE and major bleeding in relation to

renal function (assessed by baseline estimated glomerular filtration rate [eGFR] divided in 3 groups:

normal [eGFR>80 ml/min], mildly impaired [50-80 mL/min], and moderate impairment [<50 mL/min]).

We included 4 randomized clinical trials enrolling a total of 58,338 subjects. The residual risks of S/SE

and major bleeding were higher in subjects with renal impairment compared to normal renal function,

independent of type of anticoagulant therapy. In subjects with normal renal function, no difference in

the risk of S/SE was observed, while the risk of major bleeding was slightly lower for subjects taking

NOACs (RR 0.87; 95% CI 0.76-0.99). In subjects with mild or moderate renal impairment, NOACs were

associated with a reduced risk of S/SE (RR 0.75; 95% CI 0.66-0.85 and RR 0.80; 95% CI 0.68-0.94,

respectively) and major bleeding (RR 0.87; 95% CI 0.79-0.95 and RR 0.80; 95% CI 0.71-0.91, respectively)

compared to warfarin. The pooled analysis for major bleeding demonstrated significant heterogeneity.

In conclusion, the use of NOACs was associated with a reduced risk of S/SE and reduced risk of major

bleeding compared to warfarin in subjects with mild or moderate renal impairment suggesting a

favorable risk profile of these agents in patients with renal disease.

Keywords: Glomerular filtration rate, Novel oral anticoagulant, Warfarin, Stroke, Major bleeding

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Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with five-fold increased

risk of cardioembolic stroke. Warfarin reduces the risk of stroke or systemic embolism (S/SE) by

approximately two-thirds1 and recent large-scale clinical trials have demonstrated that the novel oral

anticoagulants (NOACs) are associated with a similar reduction in stroke with a favorable risk profile2-5

.

Advantages of the NOACs over warfarin include the predictable pharmacokinetics, rapid onset of action,

fewer drug-drug interactions and dietary restrictions, and convenience due to the lack of need for

ongoing monitoring6. Renal impairment is common among patients with atrial fibrillation and has an

important impact on clinical outcomes. Patients with AF and renal dysfunction are at particularly high

risk of thromboembolic complications as well as an increased risk of bleeding7,8

. Each of the NOACs has

some degree of renal metabolism or excretion and their efficacy and safety across the range of mild to

moderate renal impairment have not been fully studied. We performed a systematic review and meta-

analysis of the safety and efficacy of the four FDA-approved NOACs compared to warfarin in nonvalvular

atrial fibrillation in relation to renal function.

Methods

We searched for randomized clinical studies that compared the risk of S/SE events in subjects

with nonvalvular atrial fibrillation randomized to any of four novel oral anticoagulants (dabigatran,

rivaroxaban, apixaban or edoxaban) versus warfarin, and that reported outcomes in relation to renal

function. We searched MEDLINE, EMBASE, Web of Science, and The Cochrane Database. Keywords:

“atrial fibrillation,” “dabigatran,” “rivaroxaban,” “apixaban,” “edoxaban,” “warfarin,” “new oral

anticoagulant,” “oral factor Xa inhibitor,” “oral thrombin inhibitor.” Studies were restricted to English

language in peer-reviewed journals until January 2014. We searched the US Food and Drug

Administration databases (www.fda.gov) to obtain data from the respective drug (NOACs) sponsor’s

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application pursuing FDA approval. Finally, principal investigators and/or sponsors of the trials were also

contacted.

Data were independently reviewed and extracted. Studies considered in the present study were: (1)

randomized clinical trials evaluating the safety and efficacy of any new oral anticoagulant compared to

oral anticoagulation with therapeutic dose-adjusted warfarin, for prevention of S/SE in patients with

non-valvular atrial fibrillation, (2) evaluated renal function at baseline, and (3) reported outcomes in

relation to renal function. For trials reporting more than one publication, data were extracted from the

most complete publication, using the other reports to clarify or complement the information obtained.

To assess the agreement between reviewers for study selection, we used the kappa statistic (kappa =

0.78).

Data included: design, randomization protocol, allocation concealment, number of participants,

mean age, sex, therapeutic interventions, type of drug, duration of treatment, baseline renal function.

Primary efficacy outcome: stroke (ischemic or hemorrhagic) or systemic embolism. Primary safety

outcome: major bleeding as defined by the International Society of Thrombosis and Hemostasis criteria

(bleeding causing a fall in hemoglobin levels of >2 g/dL, bleeding leading to transfusion of > 2 units of

blood, symptomatic bleeding in a critical area [intracranial, intraspinal, intraocular, retroperitoneal,

intrarticular, pericardial, or intramuscular with compartment syndrome]; or bleeding events leading to

death). Secondary outcomes: Total mortality, cardiovascular mortality, ischemic stroke, intracranial

bleeding, gastrointestinal bleeding, and myocardial infarction.

Information about these outcomes was stratified by renal function, according to baseline estimated

Glomerular Filtration Rate (eGFR) using the Cockcroft-Gault formula and classified in the following

groups: eGFR <50 mL/min (moderate renal impairment), eGFR 50-80 mL/min (mild renal impairment),

and eGFR >80 mL/min (normal renal function). Two reviewers independently assessed the quality of the

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included using the checklist of the Cochrane Database of Systematic Reviews that assesses the risk of

bias in sequence generation, allocation concealment, blinding, attrition, selection and other biases.

We calculated pooled relative risks (RRs) and corresponding 95% confidence intervals (CI) for the

primary efficacy (S/SE), safety (major bleeding) and when available for the secondary outcomes in

relation to the three groups according to renal function. When possible we did analysis with the

intention-to-treat population. In the RE-LY study 2 doses of dabigatran were tested, we only included

the higher dose. In the ENGAGE AF-TIMI 48 trial 2 doses of edoxaban were tested we included data from

the higher dose (60mg/30mg). A separate sensitivity analysis was carried out including only factor Xa

inhibitors. Outcomes were then pooled and compared with a fixed effects model (Mantel-Haenszel

method). A value of P<0.05 was considered statistically significant. All analyses were performed using

Review Manager Software (RevMan, version 5.2 from the Cochrane Collaboration). The appropriateness

of pooling data across studies was assessed with the use of Cochran Q and the I2 test for heterogeneity.

Results

Of the 43 full text articles reviewed, 36 articles were excluded (see Study Flow Diagram, figure 1)

and among the excluded studies 3 were randomized studies (1 study was excluded because had no

warfarin comparison group, 1 used different doses of dabigatran, and 1 randomized study was not

blinded and not reporting outcomes in renal function subgroups)9-11

. Six phase II trials were excluded

due to no reporting baseline renal function and/or no outcomes in relation to renal function12-17

. Four

phase III RCTs were included2-5

, information from 3 sub-studies reporting outcomes in relation to renal

function were extracted to complete the information from the primary trials18-20

. Further, data from the

four drugs sponsor’s application to the FDA were reviewed21-24

and used to complement other sources.

All authors of the primary trials and sub-studies were contacted; but were not able to provide more

detailed data about their studies.

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The 4 included studies enrolled a total of 58,076 subjects. Of them 29,066 subjects were

randomized to a NOAC and 29,010 to warfarin. The studies characteristics are listed in Table 1. All 4

trials were phase III randomized, 3 of them (ARISTOTLE4 , ROCKET-AF

3, and ENGAGE-AF TIMI 58

5) were

double blind, double dummy studies. The RELY trial2 had the dabigatran arm blinded and the warfarin

arm unblinded. The RELY and ARISTOTLE studies enrolled subjects with lower risk of stroke (CHADS2

score of 2.1 both), while the ENGAGE-AF TIMI 58 trial enrolled subjects with CHADS2 scores average of

2.8 and the ROCKET AF trial had the highest risk subjects (CHADS2 score of 3.5 with no subjects with

scores of 0 or 1). The number of subjects with previous warfarin use ranged from 50 to 60%. The time in

therapeutic range in the warfarin arms was the lowest in the ROCKET AF trial (mean 58%) and was

similar in the other 3 trials (66-68%). All four studies had small fraction of subjects lost to follow up

(<0.1%). According to the Cochrane Database of Systematic Reviews assessment of the risk of bias, all

four studies were deemed of high quality (Table 2).

As shown in Table 3, the residual risk of S/SE in subjects receiving NOACs ranged from 2.16 % for

subjects with normal renal function to 3.8% for subjects with moderate renal impairment. Compared to

subjects with normal renal function, the odds ratio of residual stroke was 1.3 times (95% CI 1.1-1.5)

higher in subjects with mild renal impairment and 1.79 times (95% CI 1.5-2.2) higher in subjects with

moderate renal impairment. In subjects receiving warfarin the risk of residual S/SE was highest in the

group with moderate renal function; in comparison to subjects with normal renal function, the residual

risk of stroke was higher in subjects with moderate and mild renal impairment.

Similarly, the risk of bleeding was higher in subjects with renal impairment (Table 4). In the

group receiving NOACs, compared with subjects with normal renal function the odds of major bleeding

were higher in subjects with mild or moderate renal impairment. In subjects receiving warfarin we

observed higher risk of major bleeding in subjects with renal impairment.

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In subjects with moderate renal impairment S/SE occurred in 3.8% treated with NOACs and 4.8%

subjects treated with warfarin (Figure 2). The use of NOACs was associated with a significant reduction

of stroke or systemic embolism (RR, 0.79; 95% CI, 0.66-0.94). In subjects with mild renal impairment

S/SE occurred in 2.7% subjects receiving NOACs and in 3.9% subjects taking warfarin; the use of NOACs

was associated with a significant reduction of stroke or systemic embolism (RR, 0.71; 95% CI, 0.62-0.81).

In subjects with normal renal function, there was no difference in the risk of stroke or systemic

embolism between NOACs or warfarin treatment (RR, 0.96; 95% CI, 0.81-1.15). When analyzing the

differences among the groups, the test for interaction was significant (p=0.02) with moderate degree of

heterogeneity among the groups (I2 = 54%).

In subjects with moderate renal, impairment major bleeding occurred in 7.20% of subjects

receiving NOACs and in 8.98% patients receiving warfarin (Figure 3, supplementary figure 1). The use of

NOACs was associated with a significant reduction in the risk of major bleeding compared to warfarin

(RR, 0.80; 95% CI, 0.70-0.91). In subjects with mild renal impairment, major bleeding occurred in 5.66%

patients taking NOACs and in 6.41% subjects taking warfarin. Treatment with NOACs was associated

with a significant reduction of major bleeding compared to the use of warfarin (RR, 0.88; 95% CI, 0.80-

0.97). In subjects with normal renal function, major bleeding occurred in 3.74% subjects taking NOACs

and in 4.35% of patients taking warfarin. The use of NOACs was associated with a significant reduction in

the risk of major bleeding (RR, 0.86; 95% CI, 0.75-0.98). There was significant degree of heterogeneity

(p=0.03).

Data for total mortality in relation to renal function were available from only 2 studies

(Supplementary figure 2): RELY and ARISTOTLE trials. In subjects with moderate renal impairment, the

use of NOACs was not associated with mortality reduction in comparison with the use of warfarin (RR,

1.05; 95% CI, 0.91-1.20). In subjects with moderate renal impairment the use of NOACs was associated

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with a trend to reduced mortality compared to the use of warfarin (RR, 0.89; 95% CI, 0.79-1.01). In

subjects with normal renal function the use of NOACs was also associated with a trend towards less

mortality compared to the use of warfarin (RR, 0.85; 95% CI, 0.73-1.01).

Data for intracranial bleeding were available from 3 trials and only for subjects with moderate

renal impairment and a single group of subjects with mild impairment and normal renal function

(eGFR>50 mL/min) (Supplementary Figure 3). In subjects with moderate renal impairment, intracranial

bleeding occurred in 0.90% subjects taking NOACs and in 1.62% patients taking warfarin. In subjects

with eGFR >50mL/min, intracranial bleeding occurred in 0.58% patients taking NOACs and in 1.15%

patients taking warfarin. Independent of renal function there was a lower risk of intracranial bleeding

associated with the use of NOACs compared to the use of warfarin.

We performed a sensitivity analysis of primary efficacy and safety outcomes in relation to renal

function; including only Factor Xa inhibitors (Supplementary figures 4 and 5). In subjects with moderate

renal impairment the use of Factor Xa inhibitors was associated with a trend to lower risk of S/SE (RR,

0.85; 95% CI, 0.70-1.03), in subjects with mild renal impairment the use of Factor Xa inhibitors was

associated with a significant reduction in the risk of S/SE (RR, 0.71; 95% CI, 0.61-0.83); while in subjects

with normal renal function the use of Factor Xa inhibitors was not associated with a reduction in the

primary efficacy endpoint (RR, 1.02; 95% CI, 0.84-1.24) compared to warfarin. There was a differential

response among the groups (test for interaction p=0.01). Compared to the primary analysis, it seems

apparent that the benefit or lack of, associated with the use of NOACs is not related significantly with

the underlying mechanism of the NOACs.

In terms of major bleeding, in subjects with moderate renal impairment the use of Factor Xa

inhibitors was associated with a significant reduction in the risk of major bleeding (RR, 0.73; 95% CI,

0.62-0.84). In subjects with mild renal impairment the use of Factor Xa inhibitors was associated with a

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reduction of major bleeding compared to warfarin use (RR, 0.87; 95% CI, 0.78-0.98). While in subjects

with normal renal function the use of Factor Xa inhibitors was associated with a trend to less risk of

major bleeding compared to the use of warfarin (RR, 0.86; 95% CI, 0.74-1.00). Similar to the principal

analysis, there was significant heterogeneity in the groups of moderate impairment and normal renal

function.

A funnel plot of the included studies was not informative given the small number of studies

included. Supplementary figure 6 shows the funnel plot S/SE.

Discussion

This meta-analysis of large phase III RCTs demonstrated that in patients with nonvalvular atrial

fibrillation receiving anticoagulation: (1) the residual risks of S/SE and bleeding are higher in subjects

with mild or moderate renal impairment compared to subjects with normal renal function, (2) the risk of

S/SE is lower with the use of NOACs compared to warfarin in subjects with mild or moderate renal

impairment, but that risk is not different in subjects with normal renal function, and (3) the risk of

bleeding is lower with the use of NOACs compared to warfarin, independently of renal function.

Renal impairment is a risk factor for S/SE25

. The present study adds to the body of literature

demonstrating that renal impairment is associated with an increased risk of residual S/SE regardless of

the use of NOACs or warfarin in subjects with nonvalvular AF. Our analysis was unadjusted for other

potential factors known to be associated with higher risk of stroke and renal impairment (older age,

diabetes, hypertension, cardiovascular disease including stroke, and heart failure), which can in part

explain this higher residual S/SE risk.

We found that subjects with mild or moderate renal impairment have less risk of stroke or

systemic embolism when taking NOACs than when taking warfarin, a finding in line with the overall

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effect favoring NOACs over warfarin. For subjects with normal renal function the benefits of NOACs and

warfarin appear to be similar.

The risk of bleeding was higher in subjects with renal impairment compared to subjects with

normal renal function, regardless of the use of NOACs or warfarin. This finding supports previous reports

that renal impairment is a marker of higher risk of bleeding complications26

. Renal impairment is

considered in the bleeding prediction schemes for subjects with AF using anticoagulants (HAS-BLED27

and HEMORR2HAGES28

). As with the residual risk of S/SE, our analysis for bleeding was not adjusted for

other potential factors and a patient-level analysis would better addresses this finding.

In most of the performed comparative analyses there was significant heterogeneity. Regardless

of this heterogeneity, however, all subgroup analyses were in line with the overall trend towards lower

bleeding risk with NOACs compared to warfarin. The overall effect of reduced major bleeding associated

with NOACs compared to warfarin seems to be applicable to all subjects regardless of renal function. No

differential effect was found in relation to different degrees of renal impairment. Potential explanations

for the heterogeneity were not readily identified, but most likely are related to different baseline risk of

bleeding in the populations studied in the four trials.

Our evaluation of secondary outcomes of interest is incomplete. Most secondary outcomes

were not reported in relation to renal function in any published or unpublished articles; and the

sponsors were not able to release that information. For the only two secondary analyses reported, total

mortality was assessed for apixaban and dabigatran and we were not able to show any differential

mortality benefit for NOACs or warfarin in relation to renal function. For intracranial bleeding our

analysis reported on dabigatran, rivaroxaban, and edoxaban; in relation to moderate renal impairment

and a group including subjects with normal and mild renal impairment. It appears that there is no

differential effect between the two groups.

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Analysis of the benefits and risks of the use of factor Xa inhibitors versus warfarin yielded similar

results compared to the primary analysis. Coincidentally, two of the potential factors to explain

heterogeneity of drug characteristics were accomplished with this sensitivity analysis, since dabigatran is

the one NOAC with the highest degree of renal excretion (80%) and it is the only direct thrombin

inhibitor. Compared to the primary analysis, there were only minor differences in the effect size for S/SE

prevention in the group of moderate renal impairment and similar effect sizes in the group of mild

impairment and normal renal function.

Our study has several limitations. First subgroup analysis according to renal function was not

pre-determined and no hypothesis was specified in all the studies included. This is a study-level sub-

group meta-analysis; therefore we could not perform further analyses for other clinical characteristics.

Renal function was assessed at baseline using the Cockcroft-Gault equation, a formula that is not

recommended by the US Renal Data System (USRDS). Even further, the accepted classification of chronic

renal disease based on GFR uses different cutoffs to classify renal impairment from the one used in the

landmark clinical trials. Therefore, there exists the possibility for misclassification of the severity of renal

impairment. Renal function was uniformly assessed by the same method in all studies included. This

meta-analysis included four large RCTs on NOACs and excluded all phase II RCTs due to not reporting

outcomes in relation to renal function. Because these phase II trials had short follow-up, relatively small

sample sizes, and small number of efficacy and safety events, we believe that the final pooled analysis

would not have changed by including these studies. However our analysis has several strengths. The

number of events in each subgroup was large and this analysis represents the largest subgroup analysis

performed on this topic. Our meta-analysis specified a prior hypothesis. Our findings are consistent with

previous evidence that subjects with renal impairment are at higher risk of stroke and bleeding. Finally

there are plausible biological mechanisms to explain the higher risk of stroke. Our data collection was as

complete as possible and included FDA drug sponsor’s applications.

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23. Apixaban Medical Review Application Number: 202155. FDA Center for Drug Evaluation and


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2015;http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206316Orig1Orig2s000TOC.cfm.

25. Banerjee A, Fauchier L, Vourc'h P, Andres CR, Taillandier S, Halimi JM, Lip GY. Renal impairment and

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Figure 1. Flow diagram of the clinical trial selection process.

Figure 2. Risk of stroke or systemic embolism and use of novel oral anticoagulants versus warfarin in

atrial fibrillation in relation to renal function.

Figure 3. Risk of major bleeding and use of novel oral anticoagulants versus warfarin in relation to renal

function.

Supplementary Figure 1. Risk of major bleeding and the use of novel oral anticoagulants versus warfarin

in relation to renal function. Analysis using a random-effects model.

Supplementary Figure 2. Total mortality and the use of novel oral anticoagulants versus warfarin in atrial

fibrillation in relation to renal function.

Supplementary Figure 3. Risk of intracranial bleeding and the use of novel oral anticoagulants versus

warfarin in atrial fibrillation in relation to renal function.

Supplementary Figure 4. Sensitivity analysis of the risk of stroke and peripheral embolism and the use of

factor Xa inhibitors versus warfarin in atrial fibrillation in relation to renal function.

Supplementary Figure 5. Sensitivity analysis of the risk of major bleeding and the use of factor Xa

inhibitors versus warfarin in atrial fibrillation in relation to renal function.

Supplementary Figure 6. Funnel plot showing risk of publication bias for stroke or systemic embolism in

relation to renal function.

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Table 1: Relevant Characteristics of Included Clinical Studies.

RE-LY2, 19

ROCKET-AF3,

18

ARISTOTLE4, 20

ENGAGE-AF TIMI 485

Dabi

150

Warf Riva Warf Apixa Warf Edo

60

Warf

Study design RCT phase

III,

unblinded

warfarin

RCT phase III,

double blind,

double

dummy

RCT phase III,

double blind,

double dummy

RCT phase III, double

blind, double dummy

Population NVAF and

≥1 risk

factor

(stroke or

TIA, CHF,

age >75yo

or 65-74 yo

+ DM or

HTN or CAD

NVAF, CHADS

score ≥2

NVAF, ≥1 risk

factor (age ≥75 y,

stroke or TIA,

CHF, DM, HTN

NVAF, CHADS ≥ 2

Number of

randomized

subjects

6076 6022 7131 7133 9120 9081 7035 7036

CHADS2 2.2 2.1 3.5 3.5 2.1 2.1 2.8 2.8

0-1 32% 31% 0 0 34% 34% <1% <1%

2 35% 37% 13% 13% 36% 36% 46% 47%

3-6 33% 32% 87% 87% 30% 30% 54% 53%

Age 71 (mean) 73 (median) 70 (median) 72 (median)

Women 37% 37% 40% 40% 36% 35% 39% 38%

Previous warfarin

use

50% 49% 62% 63% 57% 57% 59% 59%

Concomitant

Aspirin use

39% 41% 36% 37% 31% 31% 29% 30%

Median follow-up

(years)

2.0 1.9 1.8 2.8

Warfarin group

time in therapeutic

range

67 (54-78) 58 (43-71) 66 (52-77) 68 (57-77)

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Table 2. Risk of bias in accordance to the Cochrane Database of Systematic Reviews.

Random

sequence

generation

(selection

bias)

Allocation

concealment

(selection

bias)

Blinding of

participants

and

personnel

(performance

bias)

Blinding of

outcome

assessment

(detection

bias)

Incomplete

outcome

data

(attrition

bias)

Selective

reporting

(reporting

bias)

Other

bias

RE-LY Low Low Unclear Low Low Low Low

ROCKET-AF Low Low Low Low Low Low Low

ARISTOTLE Low Low Low Low Low Low Low

ENGAGE

AF-TIMI 48

Low Low Low Low Low Low Low

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Table 3: Residual risk of stroke in relation to renal function.

Stroke or

Systemic

Embolism

Risk of

Stroke

Odds

Ratio

95% CI P value

NOACs

• Normal Renal

Function

229/10,603 2.16% Ref Ref NA

• Mild Renal

Impairment

352/12,952 2.72% 1.27* 1.07-1.5 <0.01

• Moderate

Renal

Impairment

210/5,511 3.81% 1.79* 1.48-2.17 <0.001

Warfarin

• Normal Renal

Function

235/10,515 2.23% Ref Ref NA

• Mild Renal

Impairment

505/13,098 3.86% 1.75* 1.50-2.06 <0.0001

• Moderate

Renal

Impairment

261/5,397 4.84% 2.22* 1.86-2.66 <0.0001

(*) Compared to normal renal function.

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Table 4: Risk of bleeding in relation to renal function.

Major

Bleeding

Risk of

Major

Bleed

Odds

Ratio

95% CI P value

NOACs

• Normal Renal

Function

397/10,606 3.74% Ref Ref NA

• Mild Renal

Impairment

734/12,957 5.66% 1.54* 1.36-

1.75

<0.0001

• Moderate

Renal

Impairment

397/5,514 7.20% 2.00* 1.73-

2.30

<0.0001

Warfarin

• Normal Renal

Function

457/10,512 4.35% Ref Ref NA

• Mild Renal

Impairment

840/13,096 6.41% 1.51* 1.34-

1.70

<0.0001

• Moderate

Renal

Impairment

486/5,411 8.98% 2.17* 1.90-

2.48

<0.0001

(*) Compared to normal renal function.

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meta-analysis of renal function on the safety and efficacy

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