Management

of Stroke Prevention in Atrial

Fibrillation Patient with Multimorbid:
Focus on Elderly and Renal Impairment Patient

Erika Maharani
Sardjito General Hospital
Yogyakarta
Outline

• Burden and Management of Atrial Fibrillation

• The goal of OAC therapy
• Rivaroxaban in a Relatively High-risk Population of Patients with AF
• Rivaroxaban in Patients with Non-Valvular AF and Elderly
• Rivaroxaban in Patients with Non-Valvular AF and Renal Impairment
• Conclusion
Atrial Fibrillation is The Most Common
Sustained Arrhythmia
 The Five Domain of Integrated AF Management

ESC Guideline 2016

Management of Atrial Fibrillation

Atrial Sinus
Fibrillation Rhythm

ESC Guideline 2016

 Stroke and Atrial Fibrillation

Affected
portion of the
brain Stroke is the leading complication of
Atrial Fibrillation
– 5-fold increase in stroke risk
Thrombus (clot) – AF doubles the risk of stroke when
adjusted for other risk factors
– Risk persists in asymptomatic/
paroxysmal AF

TIA = transient ischaemic attack

Savelieva I et al. Ann Med 2007;39:371–91;
Hart RG et al. J Am Coll Cardiol 2000;35:183–7;
 CHA2DS2-VASc score
CHA2DS 2-VASc risk factor Points

Congestive heart failure +1

Signs/symptoms of heart failure or objective evidence of reduced left-ventricular ejection fraction

Hypertension
Resting blood pressure >140/90 mmHg on at least two occasions or current antihypertensive +1
treatment
Age 75 years or older +2

Diabetes mellitus +1
Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycaemic agent and/or insulin

Previous stroke, transient ischaemic attack, or thromboembolism +2

Vascular disease +1
Previous myocardial infarction, peripheral artery disease, or aortic plaque
Age 65–74 years +1
Sex category (female) +1

Low risk, 0; moderate risk, 1; high risk, ≥ 2

Stroke Prevention in Atrial Fibrillation

ESC Guideline 2016

European Society of Cardiology Guideline 2016

Oral Anticoagulant

Vitamin K antagonis Novel Oral Anti Coagulant

(warfarin) (NOAC)

Factor Xa Inhibitors
Direct Thrombin Inhibitors
(RIVAROXABAN,
(Dabigatran)
Apixaban, Edoxaban)
ROCKET AF : Rivaroxaban Effective in a
Relatively High-risk Population of Patients with AF
ROCKET AF: Rivaroxaban Effective in a Relatively
High-risk Population of Patients with AF (N= 14,264)
Mean CHADS2 score: 3.5

Double-blind, double-dummy Rivaroxaban: non-inferior to warfarin

international study of AF patients HR=0.79 (95% CI 0.66–0.96); p<0.001 (non-inferiority)
with two or more risk factors for
stroke Similar rates of major bleeding: significantly lower rate of
critical bleeding events with rivaroxaban

Rivaroxaban 20 mg od Rivaroxaban 15 mg od
Prospectively tested (and approved)
Consistent benefits across all
dose in patients with moderate renal
subgroups
impairment

Significant reduction in critical bleeding events

Critical organ Fatal Stroke/systemic embolism
bleeding ICH bleeding (PP analysis)

RRR 31% 33% 50% 21%

Significantly lower event rates

while on rivaroxaban treatment
Patel MR et al, N Engl J Med 2011;365:883–891 (ITT analysis)
AF Patients in ROCKET AF Had a Higher Risk of
Stroke than Patients in Other Phase III Trials

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Connolly SJ et al, N Engl J Med 2009;361:1139–1151;
3. Granger CB et al, N Engl J Med 2011;365:981–992; 4. FDA Briefing Information for the Cardiovascular and Renal
Drugs Advisory Committee.
 Comparing Phase III Trials: There Are
Differences in Patient Characteristics
ROCKET AF1 ARISTOTLE2 ENGAGE AF3 RE-LY4,5
(n=14,264) (n=18,201) (n=21,105) (n=18,113)
Mean CHADS2 score 3.5 2.1 2.8 2.1

C CHF 62% 35% 57% 32%

H Hypertension 91% 87% 94% 79%

A Age ≥75 years 43% 31% 40% 40%

D Diabetes mellitus 40% 25% 36% 23%

S2 Prior stroke or TIA 55% 19% 28% 20%

Moderate renal impairment 21% 15% 19% 19%

Specific dose studied

prospectively ü û û û
AF patients studied in ROCKET AF had higher risk of stroke
than patients in other phase III trials with NOACs
1. Patel et al, N Engl J Med 2011;365:883–891; 2. Granger et al, N Engl J Med 2011;365:981–992;
3. Giugliano et al, N Engl J Med 2013; 369; 2093–2104; 4. Connolly et al, N Engl J Med 2009;361:1139–1151; 5.
Eikelboom et al, Circulation 2011;123:2363–2372
 ROCKET AF: Consistent Benefit Across Different
Co-morbidities for the Challenging AF Patients

• Primary Efficacy Endpoint: Stroke/SE (n=14,171)

Comorbidity / Patient HR
risk factor (%) (95% CI)
C CHF 62 0.91 (0.74–1.13)
H Hypertension 91 0.87 (0.73–1.03)
A Elderly ≥ 75 years 43 0.80 (0.63–1.02)
D Diabetes 40 0.74 (0.54–1.01)
S2 Prior stroke or TIA 55 0.94 (0.77–1.16)
Mean CHADS2 Score 3.5
0.1 1 1.5 2.0
Favours Favours
rivaroxaban warfarin

Per-protocol population
Patel MR et al. N Engl J Med. 2011;365(10):883-891
Rivaroxaban in Patients with Non-Valvular AF
and Elderly
 ROCKET AF
Subanalysis elderly patients – Rationale

• To determine the efficacy and safety of rivaroxaban compared

with warfarin among elderly AF patients (≥ 75 years) compared
with patients < 75 years
• Age is a risk factor for stroke and bleeding
• 6,229 patients (44%) aged ≥ 75 years with AF and ≥ 2 stroke risk
factors
• Median age 79 vs. 66 years
• Mean CHADS2-Score 3.7 vs. 3.3
• Female 46% vs. 35%
• Prior stroke/TIA or SE 42% vs. 65%

SE=systemic embolism
Halperin JL et al. Circulation. 2014;130:138–146
ROCKET AF Subanalysis
Rivaroxaban effective in elderly patients (≥75 years)

Background/rationale
u Age is a risk factor for stroke and bleeding

Results
u 6,229 patients (44%) were aged ≥75 years at enrolment
u Higher rates of stroke/SE and bleeding in elderly patients than in younger
patients
u Elderly patients had similar rates of efficacy and safety outcomes, whether they
were receiving rivaroxaban or warfarin

Conclusion
u Results support use of rivaroxaban as an alternative to warfarin for stroke
prevention in both young and elderly patients with AF

Halperin JL et al. Circulation. 2014;130:138–146

ROCKET AF
Subanalysis elderly patients – Results

Primary efficacy endpoint by age

Warfarin
Rivaroxaban
3.0 2.85
Estimated cumulative probability

2.5 2.29
2.10 2.0
of stroke/SE (%/year)

2.0

1.5

1.0

0.5

0
< 75 years ≥ 75 years
p-value for interaction=0.313
ITT population
Halperin JL et al. Circulation. 2014;130:138–146
 ROCKET AF
Subanalysis elderly patients – Results

Net clinical benefit vs. warfarin in older and younger patients

Rivaroxaban Warfarin Hazard ratio p-value

Events (%/year) Events (%/year) (95% CI) (interaction)
Stroke + SE (n=14,171) 0.313
≥ 75 years 125 (2.29) 154 (2.85) 0.80 (0.63–1.02)
< 75 years 144 (2.00) 152 (2.10) 0.95 (0.76–1.19)
MB (n=14,236) 0.336
≥ 75 years 223 (4.86) 204 (4.40) 1.11 (0.92–1.34)
< 75 years 172 (2.69) 182 (2.79) 0.96 (0.78–1.19)
Haemorrhagic stroke (n=14,171) 0.365
≥ 75 years 19 (0.34) 27 (0.49) 0.70 (0.39–1.26)
< 75 years 14 (0.19) 30 (0.41) 0.47 (0.25–0.88)

0.25 0.5 1 2
Rivaroxaban better Warfarin better

MB=major bleeding; SE=systemic embolism

Halperin JL et al. Circulation. 2014;130:138–146
 ROCKET AF
Subanalysis elderly patients – Conclusion

• Compared with younger participants, elderly patients had

• higher rates of stroke and SE
• higher rates of major bleeding
• similar rates of haemorrhagic stroke
• The overall relative effects of rivaroxaban vs. warfarin were
consistent among elderly (and younger) patients for both efficacy
and safety
• In elderly patients with non-valvular AF at medium to high risk of
stroke, rivaroxaban is as effective as warfarin

Halperin JL et al. Circulation. 2014;130:138–146

Rivaroxaban in Patients with Non-Valvular AF
and Renal Impairment
 Routes of Elimination of Rivaroxaban And
Excretion of Inactive Metabolites

~67% Rivaroxaban ~33%

Metabolized Renal elimination as
unchanged active drug

50% of inactive 50% of inactive

metabolites excreted by metabolites excreted by
hepatobiliary renal route

Rivaroxaban SmPC; Kreutz R. Fundam Clin Pharmacol. 2012;26(1):27-32

Background: AF Patients With Moderate
Renal Impairment
Danish registry2 (N=132,372)
(~28% of patients received warfarin)
• Every third patient with AF has 10
chronic kidney disease (CKD)1
• Patients with AF and renal 8

Event rate (%/year)

impairment are at higher
risk for bleeding and stroke2 6 Without renal
disease
Non-end-
• Patient with AF and renal stage CKD
4
impairment were more often
undertreated with warfarin
2
than those with normal renal
function3
0
Stroke or Bleeding
thromboembolism

1. Hart RG et al. Can J Cardiol. 2013;23:S71-S78; 2. Olesen JB et al. N Engl J Med. 2012;367(7):625-35;
3. Capodanno D et al. Circulation 2012;125(21):2649-2661
 ROCKET AF: Primary Efficacy Endpoint in Patients with
Moderate Renal Impairment

Primary efficacy endpoint: Stroke/SE

HR 0.86
(95% CI 0.63–1.17)
4
3.44
2.95 HR 0.89
Events (%/year)

3 (95% CI 0.73–1.08)
2.16 Warfarin
1.92
2 Rivaroxaban

0
30–49 ≥ 50
CrCl (mL/min)

Consistent efficacy of rivaroxaban vs. warfarin in NVAF patients with moderate renal
impairment
Intention-to-treat population
Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
ROCKET AF: Consistent Safety Outcomes in NVAF
Patients With Moderate Renal Impairment

HR 0.55 Warfarin
(95% CI 0.30–1.00) Rivaroxaban 15 mg OD
1.5 1.4
HR 0.81
(95% CI 0.41–1.60) HR 0.39
Events (%/year)

1 (95% CI 0.15–0.99)
0.9
0.8 0.7
0.7

0.5
0.3

0
Critical organ bleeding ICH Fatal bleeding

Safety on-treatment population

Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
 ROCKET AF: Consistent Results in NVAF Patients
With Moderate Renal Impairment
Efficacy1 Safety1
ITT analysis Safety on-treatment analysis

20 18.3
4 17.8
3.4
Stroke or SEb (%/year)*

Primary safety endpoint

3.0 15
3

(%/year)#
2 10

1 5

0 0
Warfarin Rivaroxaban Warfarin Rivaroxaban
15 mg OD 15 mg OD

Rivaroxaban, the only novel OAC with a prospectively tested,

specific renal dose in patients with moderate renal impairment (CrCl 30–49 mL/min)2

*Primary efficacy endpoint: Composite of all stroke (ischaemic and haemorrhagic) and SE; #Primary safety endpoint: Major or NMCR bleeding.
Fox KA et al. Eur Heart J. 2011;32(19):2387-2394; Patel MR et al. N Engl J Med. 2011;365(10):883-891
Rivaroxaban is the Only NOAC with a Prospectively Tested
Specific Renal Once-Daily Dose
Rivaroxaban is the Only NOAC with a Prospectively Tested
Specific Renal Once-Daily Dose
 Renal Outcomes – Individual NOACs

Events per 100 patient-years

Renal outcomes HR (95% CI) HR (95% CI)

‘Rivaroxaban'* Warfarin *
(n=2,485) (n=4,185)

≥30% decline in eGFR 15.10 20.64 0.73 (0.62–0.87)

Doubling of serum
1.47 3.26 0.46 (0.28–0.75)
creatinine
AKI 7.63 11.15 0.69 (0.57–0.84)

Kidney failure 0.80 1.28 0.63 (0.35–1.15)

0.1 1 10
Favors Favors
‘Xarelto’ warfarin
*weighted event rates per 100 patient-years.
Yao et al., JACC Nov 2017, 70 (21) 2621-2632; DOI: 10.1016/j.jacc.2017.09.1087
 Renal Outcomes Associated with The Different
OACs: Possible Mechanisms and Outcomes

Adapted from Yao X et al. J Am Coll Cardiol 2017;70:2621–2632

Conclusions

• Atrial fibrillation remains one of the major causes of stroke, heart

failure, sudden death, and cardiovascular morbidity in the world.
• Patients with non-valvular AF elderly and renal impairment have
higher rates of stroke/SE and bleeding
• Results support use of rivaroxaban as an alternative to warfarin for
stroke prevention in both young and elderly patients with AF
• Efficacy and safety of rivaroxaban 15 mg OD in patients with AF
and moderate renal impairment were consistent with the overall
trial population
Thank You