Download Study Overview - Clinical Trial Results

Efficacy and Safety of Apixaban Compared
with Warfarin According to Patient Risk of
Stroke and Bleeding in Atrial Fibrillation
Presented by Renato D. Lopes, MD, PhD,
Duke Clinical Research Institute, Duke University, USA
for the ARISTOTLE investigators.
Disclosures for Renato D. Lopes
Institutional research grants from:
Bristol-Myers Squibb
Advisory board or consultancy for:
Boehringer Ingelheim and Bristol-Myers Squibb
Background
• Warfarin is very effective at preventing stroke in patients with atrial
fibrillation (AF), but it has several limitations.
• The need to assure optimal benefit given the known bleeding risks of
warfarin has led to the development of risk scores for
thromboembolism and bleeding in patients with AF.
• Scores are important tools to predict the risk of stroke and bleeding in
patients with AF and to inform decisions regarding the use of
antithrombotic therapy.
• The value of these scores in guiding decision making in patients with
AF receiving apixaban, a novel oral factor Xa inhibitor, is uncertain.
Atrial Fibrillation with at Least One
Additional Risk Factor for Stroke
Inclusion risk factors
 Age ≥ 75 years
 Prior stroke, TIA or SE
 HF or LVEF ≤ 40%
 Diabetes mellitus
 Hypertension
Randomize
double blind,
double dummy
(n = 18,201)
Exclusion
 Mechanical prosthetic valve
 Severe renal insufficiency
 Need for aspirin plus
thienopyridine
Apixaban 5 mg oral twice daily
Warfarin
(2.5 mg BID in selected patients)
(target INR 2-3)
Warfarin/warfarin placebo adjusted by INR/sham INR
based on encrypted point-of-care testing device
Primary outcome: stroke or systemic embolism
Main Trial Results
Stroke or systemic embolism
ISTH major bleeding
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P=0.011
31% RRR
Apixaban 327 patients, 2.13% per year
Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.60–0.80); P<0.001
Median TTR 66%
Objectives
We conducted this analysis of the ARISTOTLE population to assess
the efficacy and safety of apixaban compared with warfarin according to
CHADS2 and HAS-BLED scores in patients with AF.
• Pre-specified outcomes:
– Stroke or systemic embolism (primary efficacy outcome).
– ISTH Major bleeding (primary safety outcome).
– Mortality.
• Post-hoc explored outcomes:
– Intracranial bleeding.
– Net clinical benefit (the composite of stroke, systemic embolism, major
bleeding, and all-cause mortality).
Methods
The efficacy, safety, and balance of efficacy and safety of apixaban and
warfarin were compared across patient risk categories classified by:
1.CHADS2 (low risk: 0-1, medium risk: 2, high risk: ≥3) and
2.HAS-BLED (low risk: 0-1, medium risk: 2, high risk: ≥3) scores.
CHADS2
Risk factors
History of CHF
Hypertension
Age ≥75 years
Diabetes mellitus
Previous stroke, TIA, or
systemic embolism
HAS-BLED
+1
+1
+1
+1
+2
Risk factors
Hypertension
+1
(systolic BP >160 mm Hg)
Abnormal renal function (dialysis, transplant, serum Cr ≥200
+1
µmol/L [2.6 mg/dL])
Abnormal liver function (chronic hepatic disease, bilirubin
+1
>2×ULN, AST/ALT/ALP >3×ULN)
History of stroke
History of bleeding
Labile INR
+1
+1
+1
(INR <2 or >3 among patients on warfarin before randomization)
Elderly (age >65 years)
Use of antiplatelets, NSAIDs, or anti-inflammatory
medications
Drug and/or alcohol abuse
+1
+1
+1
Statistical Analysis
• Efficacy analyses included all randomized patients (18201 subjects).
• The analyses of bleeding events included all patients who received at
least one dose of study drug (18140 subjects).
• Analyses based on interactions between treatment and categories of
CHADS2 and HAS-BLED were performed using a Cox proportional
hazards model.
Baseline Characteristics
CHADS2 0–1
(N=6183)
67·0 (60, 71)
30·3
CHADS2 2
(N=6516)
71·0 (63, 77)
36·1
CHADS2 ≥3
(N=5502)
75·0 (67, 79)
39·7
82·7
17·3
58·1
85·7
14·2
55·6
85·7
14·3
57·9
Age ≥75 yrs
9·3
36·1
50·1
Prior stroke, TIA, or SE
0·6
4·7
58·0
Heart failure or reduced LVEF
8·4
36·0
48·6
Diabetes
3·2
28·0
45·9
Hypertension requiring treatment
77·3
91·7
93·8
Normal >80 mL/min
52·8
40·9
29·0
Mild impairment
38·7
41·1
45·8
Moderate impairment
7·7
16·2
22·0
Severe impairment
0·4
1·3
2·9
Age, yrs, median (25th, 75th)
Female, %
Type of AF, %
Persistent or permanent
Paroxysmal
Prior use of vitamin K antagonist, %
Qualifying risk factors, %
Renal function, %
Correlation between CHADS2 and
HAS-BLED scores
HAS-BLED
CHADS2
Total
0–1
2
≥3
0–1
2980
(43)
2142
(32)
1061
(23)
6183
(34)
2
2621
(38)
2549
(38)
1346
(30)
6516
(36)
≥3
1275
(19)
2091
(31)
2136
(47)
5502
(30)
Total
6876
(38)
6782
(37)
4543
(25)
18201
(100)
Data presented at number (%).
Stroke/Systemic Embolism
ISTH Major Bleeding
Intracranial Bleeding
All-cause Mortality
Net Clinical Benefit:
Stroke, Systemic Embolism, Major Bleeding,
or All-cause Mortality
Limitations
• The absence of patients with CHADS2 score of 0 does not
permit an assessment of the benefit / risk profile of
apixaban in this low-risk group of patients with AF.
• We calculated labile INR based on one single INR value
among warfarin-experienced patients at baseline and this
is different from how labile INR was initially described (TTR
less than 60%).
• Our results were derived from a large clinical trial
population that differs from an unselected clinical patient
population.
Conclusion
• The benefits of apixaban compared with warfarin in
reducing stroke or systemic embolism, all-cause mortality,
and causing less bleeding are consistent across AF
patients with a wide range of stroke and bleeding risks as
assessed by the CHADS2 and HAS-BLED scores.
• Patients with AF and at the highest risk of bleeding may
have the greatest reduction (both relative and absolute) in
intracranial bleeding with apixaban as compared with
warfarin.
Thank you