Supplementary Appendix B to Dorian et al. “Costeffectiveness of Apixaban versus Current Standard of
Care for Stroke Prevention in Patients with Atrial
Fibrillation -Secondary Analysis of AVERROES (CV185048) to Support Apixaban Cost Effectiveness
Modelling for the Indication of Stroke Prevention in
Atrial Fibrillation”
1
STUDY DESIGN
Study design and data collection associated with AVERROES has been described
previously.1 Seminal results were published by Connolly et al which indicated that
apixaban reduced the risk of stroke or systemic embolism without significantly increasing
the risk of major bleeding or intracranial hemorrhage.2
2
METHODS
AVERROES data were analyzed in post-hoc basis. Annualized events rate and related
hazard ratios were computed for the relevant end-points. Intention to treat (ITT)
principle was used for the analysis of all end-points except the safety end-points which
were based on modified ITT population. Stratified analyses were conducted across
CHADS2 categories.3 All risks were assessed in absolute terms or relative risk was
computed using hazard ratio for the event associated with aspirin versus apixaban. Subgroup analyses were conducted on AVERROES participants who had used previously
used warfarin (VKA) but were not able to stay on the VKA either due to inability to
maintain INR control while on warfarin, experienced either bleeding or non-bleeding
events while on warfarin or other similar reasons described in the AVERROES seminal
publication.2 For the purposes of these analyses, there patients were labeled as warfarinunsuitable population (i.e. proven unsuitable after experiencing warfarin use).
Mortality risk associated with reasons other than stroke, systemic embolism, bleeding and
myocardial infarction was assessed by deleting mortality associated with the above
mentioned causes from all-cause mortality. Absolute mortality risk as well as relative
hazard of mortality with aspirin versus apixaban for causes other than stroke, bleeding
and myocardial infarction was assessed. Apixaban was used as a reference category for
computing hazard ratios (HRs) associated with the above events.
Data were pooled from ARISTOTLE and AVERROES treatment arms to assess
percentage of intracranial hemorrhages manifesting into hemorrhagic stroke as well as
fatality rates associated with intracranial hemorrhages excluding hemorrhagic stroke and
other major bleeds excluding any type of intracranial hemorrhages. For assessing
distribution of hemorrhagic stroke across different levels of stroke severity, events were
pooled across apixaban and aspirin arms due to low absolute event rate in both arms.
All analyses were conducted using SAS 9.2 (SAS Inc, Cary, NC). Since this was
secondary analyses of AVERROES analyses sets carried out in post-hoc manner, please
refer to the Connolly et al for efficacy and safety results obtained based on pre-specified
primary and secondary hypotheses.2
2.1
Risk of Ischemic or Unspecified Stroke by CHADS2
Score
Risk of ischemic or unspecified stroke was assessed at pre-specified CHADS2 categories
of 0-1, 2, 3 as specified in the seminal AVERROES publication.2 As demonstrated in
Table 1, this risk was assessed separately for each treatment arm. Weighted average risk
of ischemic or unspecified stroke was 1.374 and 3.103 for apixaban and aspirin,
respectively, with weights computed based on number of patients in different CHADS2
categories for each treatment arm within AVERROES. When compared to apixaban,
patients treated with aspirin had a greater risk of experiencing ischemic or unspecified
stroke (HR: 2.270, 95% Confidence Interval (CI): 1.590 - 3.230)
Table 1:
CHADS2 Score
Ischemic or Unspecified Stroke Risk by CHADS2 Score
Apixaban
Aspirin
0-1
0.831
1.411
2
1.526
3.363
3
1.957
5.196
Weighted Average
1.374
3.103
2.2
Risk of Experiencing Bleeding or Other Events
Table 2 below describes the absolute event rates (per 100 patient years) and relative risk
(as hazard ratio, HR) of experiencing an event when treated with aspirin versus apixaban.
Table 2:
Absolute and Relative Hazard of Experiencing an Event with
Apixaban versus Aspirin in AVERROES Trial Population
Event
Apixaban
Absolute
Event Rate
Aspirin
Absolute
Event Rate
Hazard Ratio (HR,
95% Confidence
Interval)
Intracranial hemorrhages
0.344
0.348
1.013 (0.439-2.337)
Other major bleeds excluding
intracranial hemorrhages
Clinically-relevant non-major
bleeding
CV hospitalizations unrelated
to stroke or MI
1.066
0.571
0.535 (0.302 - 0.947)
3.113
2.371
0.762 (0.563 - 1.030)
10.460
12.087
1.155 (0.992 - 1.345)
2.3
Hemorrhagic stroke as a part of Intracranial
Hemorrhages
Hemorrhagic strokes comprised 55% of intracranial hemorrhages observed in both
apixaban and aspirin patients. As described in the AVERROES seminal publication,
patients on apixaban had slightly lower risk of experiencing intracranial hemorrhages
(HR: 0.85; 0.38-1.90) well as hemorrhagic stroke (HR: 0.37; 0.24-1.88) versus patients
on aspirin.
2.4
Severity Distribution Associated with Strokes as
Assessed by Modified Rankin Scale (mRS)
Following distribution of stroke severity was observed using modified Rankin Scale
(mRS) at 30-day follow-up post event for apixaban versus aspirin. Patients with mRS
score of 6 represented fatality associated with the stroke event. Stroke severity
distribution associated with ischemic or unspecified stroke by treatment has been
described below in Table 3. For hemorrhagic stroke, events were pooled across apixaban
and aspirin arms due to low absolute event rate in both arms for this analysis (Table 4).
2.4.1
Ischemic or Unspecified Stroke
Table 3:
Stroke Severity Classification Associated with Ischemic or
Unspecified Stroke
mRS classification
Apixaban
n (%)
Aspirin
n (%)
0-2
17 (40%)
35 (36%)
3-4
12 (28%)
37 (38%)
5
5 (12%)
15 (15%)
6
9 (20%)
10 (11%)
2.4.2
Hemorrhagic Stroke
Table 4:
Stroke Severity Classification
Associated with Hemorrhagic Stroke
mRS classification
Apixaban
n
Aspirin
n
Pooled Sample
n (%)
0-2
1
0
1 (7%)
3-4
1
2
3 (20%)
5
0
4
4 (27%)
6
4
3
7 (46%)
2.5
Gastro-intestinal Bleeding Rates as Part of Other Major
Bleeding (Excluding Intracranial Hemorrhages)
Gastro-intestinal bleeding comprised 35% (12 out of 34) and 39% (7 out of 18) of other
major bleeding events (excluding intracranial hemorrhages) for apixaban and aspirin,
respectively.
2.6
Treatment Discontinuation Rates Not Related to
Absorbing States
Treatment discontinuation rate for reasons other than stroke or major bleeding were
higher for aspirin versus that observed for apixaban resulting into greater HR for aspirin
versus apixaban for treatment discontinuations not related to a) stroke or major bleeding
or b) stroke, major bleeding, myocardial infarction or systemic embolism (Table 5).
Table 5:
Treatment Discontinuation Rates Not Related to Absorbing
States
Excluding stroke, major bleeding, myocardial infarction
and systemic embolism
19.012
1.099 (0.972 - 1.241)
537
Aspirin
Apixaban
2.7
495
17.310
1.000 (Reference)
Fatality Rates Associated with Bleeding Episodes
Pooled data analyses, as described in Table 6 below, indicated 13% mortality associated
with ICH that did not manifest into hemorrhagic stroke. Pooled morality rate for OMB
that were not intracranial in nature was 2%.
Table 6:
Pooled Analysis of Fatality Rates Associated with Apixaban
Versus Warfarin or Aspirin Using ARISTOTLE and
AVERROES Data
Trial
Treatment
AVERROES
ARISTOTLE
Average
2.8
Other ICH
OMB
Fatal OMB
n
Fatal Other
ICH
n(%)
n
n(%)
Apixaban
5
1 (20%)
34
1 (3%)
Aspirin
2
1 (50%)
18
1 (6%)
Apixaban
12
2 (17%)
275
6 (2%)
Warfarin
44
4 (9%)
340
7 (25)
63
8 (13%)
667
15 (2%)
Mortality Risk Associated with Causes Other than
Stroke, Systemic Embolism, Major Bleeding or
Myocardial Infarction
Over duration of AVERROES trial, aspirin arm exhibited higher non-stoke, non-SE, nonbleeding and non-MI mortality rate of 3.5935 per 100 patient-years (n= 114) versus
apixaban which had mortality rate of 2.9668 per 100 patient-years (n = 94) thus yielding
a slightly greater HR of 1.212 (95% CI: 0.922 -1.593).
2.9
Absolute Annualized Event Rates in Warfarin-unsuitable
Patients Randomized to Aspirin Arm
Table 7 below describes annualized event rates for various events of interest in warfarin
unsuitable patients randomized to aspirin arm.
Table 7:
Absolute Event Rates in Warfarin-unsuitable Patients
Randomized to Aspirin
Event
Annualized Event Rate
(per 100 patient years)
Ischemic or unspecified stroke
3.453
Intracranial hemorrhages
0.322
Other major bleeds excluding intracranial
hemorrhages
0.887
Clinically-relevant non-major bleeds
2.936
Myocardial infarction
1.110
CV hospitalizations unrelated to stroke or
MI
13.571
REFERENCES
1
Eikelboom JW, O'Donnell M, Yusuf S, et al. Rationale and design of AVERROES:
apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who
have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J
2010;159:348-353
2
Connolly S, Eikelboom J, Joyner C et al. Apixaban in Patients with Atrial Fibrillation.
New Engl J Med, 2011; 364,9:806-17.
3
2011 Writing Group members. 2011 ACCF/AHA/HRS Focused Updated on the
Management of Patients with Atrial Fibrillation (Updating the 2006 Guidelines).
Circulation, 2011;123:104-123.