Rivaroxaban Proven Efficacy and

Safety in Patient with Co-Morbid

(Focused in The Elderly and Renal Insufficiency
Patients)

Dr. Yudi Her Oktaviono, Sp. JP

L.ID.MKT.GM.09.2016.1068
2
• It is estimated that 1 in 4 individuals aged 40 years or older will
develop AF1

3
 Thrombus (clot)

1. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046.

2. Decision Resources. Atrial Fibrillation Report. Dec 2008.
3. Go AS, et al. JAMA 2001;285:2370-2375.
 AF-related stroke is preventable
Effect of VKA compared to placebo
2/3 of strokes due to AF are preventable with
appropriate anticoagulant therapy with a Stroke Death
vitamin-K-antagonist (INR 2-3)1

Anticoagulation with a vitamin-K-antagonist

(VKA) is recommended for patients with more
than 1 moderate risk factor2

A meta-analysis of 29 trials in 28,044 patients

showed that adjusted-dose warfarin results in a 67% 26%
reduction in ischaemic stroke and in all-cause
mortality1

1. Hart RG et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-9
v2 December 2010 5
NARROW THERAPEUTIC RANGE WITH VKAs

Ischaemic stroke Intracranial haemorrhage

Events / 1000 patient years

80

60 Target The anticoagulant effect of VKAs

is optimized when therapeutic
INR doses are maintained within a
(2.0–3.0) very narrow range
40

20

0
<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6–4.0 4.1–4.5 >4.5

INR = International normalized ratio; VKA = vitamin K antagonist

Hylek EM, et al. N Eng J Med 2003;349:1019-1026.
v2 December 2010 6
6
Introduction

7
 ROCKET AF
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TH 2018

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 ROCKET AF: Rivaroxaban Effective in a Relatively
High-risk Population of Patients with AF
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 Stroke/systemic

Critical organ events Fatal embolism
bleeding ICH bleeding (PP analysis)

RRR 31% 33% 50% 21%

SCU

Significantly lower event rates

TH 2018 while on rivaroxaban treatment

9 SURABAYA
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UPDATE
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
CHADS2 score patient distribution

ROCKET AF1 RE-LY2 ARISTOTLE3 ENGAGE AF4

rivaroxaban dabigatran apixaban edoxaban

13%

36% 32% 36% 34%

47% 53%

87% 32% 30%

CHADS2 score ≤1 2 3–6

SCU

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;
TH 2018 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.

9 SURABAYA
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UPDATE
Accessed online at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugs
AdvisoryCommittee/UCM420704.pdf
 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 ✓   

AF patients studied in ROCKET AF had higher risk of stroke
than patients in other phase III trials with NOACs
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TH 2018 1. Patel et al, N Engl J Med 2011;365:883–891; 2. Granger et al, N Engl J Med 2011;365:981–992;

9 SURABAYA
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UPDATE
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

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

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

SCU

TH 2018
Per-protocol population

9 SURABAYA
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UPDATE
Patel MR et al. N Engl J Med. 2011;365(10):883-891
 ROCKET AF: rivaroxaban effective in elderly patients (≥75 years)
Elderly

Background/rationale Primary endpoint: Stroke/SE

Warf. ≥75 yrs
◆ Age is a risk factor for stroke and bleeding 6

probability of stroke/SE (%)

Riva. ≥75 yrs 2.85%/yr

Estimated cumulative
5 Warf. <75 yrs 2.29%/yr
Riva. <75 yrs 2.10%/yr
4 2.00%/yr
Results
3
◆ 6,229 patients (44%) were aged ≥75 years
at enrolment 2
HR (95% CI) riva. vs warf.
◆ Higher rates of stroke/SE and bleeding in ≥75 yrs: 0.80 (0.63–1.02)
1
elderly patients than in younger patients <75 yrs: 0.95 (0.76–1.19)
0
◆ Elderly patients had similar rates of efficacy
0 6 12 18 24
and safety outcomes, whether they were
Months since randomization
receiving rivaroxaban or warfarin

Age ≥75 yrs Age <75 yrs p-

(%/yr) (%/yr) value
Riva. Warf. Riva. Warf. (int.)
Conclusion
◆ Results support use of rivaroxaban as an Major bleeding 4.86 4.40 2.69 2.79 0.34
SCU

alternative to warfarin for stroke prevention

in both young and elderly patients with AF Intracerebral
0.66 0.83 0.37 0.68 0.27
haemorrhage
TH 2018

9 SURABAYA
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UPDATE
Halperin JL et al. Circulation. 2014;130:138–146
 ROCKET AF
Subanalysis elderly patients – Results
Primary efficacy endpoint: Stroke and SE
Rivaroxaban
Warfarin
6 6
Estimated cumulative probability

Estimated cumulative probability

2.85%/year
5 Age < 75 years 5 Age ≥ 75 years
HR 0.95 2.10%/year HR 0.80

of stroke/SE (%)
of stroke/SE (%)

4 (95% CI 0.76–1.19) 4 (95% CI 0.63–1.02)

3 3
2.00%/year 2.29%/year
2 2

1 1

0 0
0 6 12 18 24 0 6 12 18 24
Months since randomization Months since randomization
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p-value for interaction= 0.3131

TH 2018

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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
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9 SURABAYA
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UPDATE
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
• 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, supporting rivaroxaban as an
alternative for the elderly
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TH 2018

9 SURABAYA
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UPDATE
Halperin JL et al. Circulation. 2014;130:138–146
 Rivaroxaban in Patients with Non-Valvular
AF and Renal Impairment
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 Metabolism and Elimination of Rivaroxaban
• Approximately 1/3 of the administered rivaroxaban dose
undergoes direct renal excretion as unchanged active drug
• 2/3 undergoes metabolic degradation in the liver
• 50% is eliminated renally
• 50% is eliminated by the faecal route

Routes of elimination of rivaroxaban and excretion of inactive metabolites

~67% rivaroxaban ~33%

Metabolized Renal elimination as
unchanged active drug
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50% of inactive metabolites 50% of inactive metabolites

excreted by hepatobiliary excreted by renal route
TH 2018

9 SURABAYA
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UPDATE
Rivaroxaban SmPC; Kreutz R. Fundam Clin Pharmacol. 2012;26(1):27-32
 Background: AF Patients With Moderate Renal
Impairment
Danish registry2 (N=132,372)
• Every third patient with AF has (~28% of patients received warfarin)
chronic kidney disease (CKD)1
10 Without renal
disease

• Patients with AF and renal 8

Non-end-
stage CKD

Event rate (%/year)

impairment are at higher
risk for bleeding and stroke2 6

• Patient with AF and renal 4

impairment were more often
undertreated with warfarin 2
than those with normal renal
function3 0
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Stroke or Bleeding
thromboembolism
TH 2018

9 SURABAYA
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UPDATE
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: Consistent Efficacy in NVAF Patients
with Moderate Renal Impairment

CrCl 30–49 mL/min

CrCl ≥50 mL/min

0.1 1 10
Favours Favours
SCU

rivaroxaban warfarin

TH 2018
Per-protocol population

9 SURABAYA
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UPDATE
Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
 ROCKET AF: Safety Endpoints in NVAF Patients with
Moderate Renal Impairment
Clinical endpoint CrCl 30–49 mL/min HR (95% CI) p-value
CrCl ≥50 mL/min (interaction)
Clinically relevant 0.98 (0.84–1.14)
bleeding 0.45
1.04 (0.96–1.13)
Major bleeding 0.95 (0.72–1.26)
0.48
1.07 (0.91–1.26)
Critical organ 0.55 (0.30–1.00)
bleeding 0.39
0.74 (0.55–0.99)
Intracranial 0.81 (0.41–1.60)
haemorrhage 0.51
0.62 (0.42–0.92)
Fatal bleeding 0.39 (0.15–0.99)
0.53
0.55 (0.32–0.93)
0.1 1 10
Favours Favours
rivaroxaban warfarin
SCU

Consistent safety profile of rivaroxaban vs. warfarin in NVAF patients with moderate renal
impairment
TH 2018
Based on safety on-treatment population

9 SURABAYA
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UPDATE
Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
 ROCKET AF: Consistent Safety Outcomes in NVAF
Patients With Moderate Renal Impairment
Warfarin
HR 0.55 Rivaroxaban 15 mg OD
(95% CI 0.30–1.00)
1.5 1.4 HR 0.81
(95% CI 0.41–1.60)
HR 0.39
(95% CI 0.15–0.99)
Events (%/year)

0.9
1
0.8
0.7 0.7

0.5
0.3

0
Critical organ bleeding ICH Fatal bleeding
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TH 2018
Safety on-treatment population

9 SURABAYA
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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

Primary safety endpoint

Stroke or SEb (%/year)*

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,

SCU

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

TH 2018
*Primary efficacy endpoint: Composite of all stroke (ischaemic and haemorrhagic) and SE; #Primary safety endpoint: Major or NMCR bleeding.

9 SURABAYA
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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
Dose Adjustments in Eligible AF Patients with ≥1 Risk Factors for Stroke/SE

Rivaroxaban1 Apixaban2
Estimate CrCl Estimate CrCl

<15 ml/min 15–29 ml/min ≥30 ml/min

<15 ml/min 15–49 ml/min* ≥50 ml/min
Check age Check weight Check serum
creatinine
Not
15 mg od 20 mg od ≥80 years ≤60 kg ≥133 µmol/I
recommended

If ≥2 features If ≤1 features

Not 2.5 mg bid 2.5 mg bid 5 mg bid

recommended

Dabigatran3 Edoxaban4
Estimate CrCl Estimate CrCl

<30 ml/min 30–50 ml/min >50 ml/min

<15 ml/min 15–50 ml/min > 50 ml/min
Age >80 years Age Age Age Age >80 years
or on verapamil 75–80 years <75 years 75–80 years or on verapamil
Weight Potent P-gp
Low Low ≤ 60 kg inhibitors
thromboembolic thromboembolic
Contraindicated risk and high risk and high
SCU

bleeding risk bleeding risk Not

30 mg od 30 mg od 30 mg od 60 mg od
recommended
110 mg 110 mg 150 mg 150 mg 110 mg 150 mg 110 mg
bid bid bid bid bid bid bid

TH 2018

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*Rivaroxaban is to be used with caution in patients with CrCl 15–29 mL/min
1. Rivaroxaban SmPC; 2. Apixaban SmPC; 3. Dabigatran SmPC; 4. Edoxaban SmPC
 Renal Outcomes – Individual NOACs
• Comparing each NOAC with warfarin:
• Rivaroxaban and dabigatran were associated with lower risks of ≥30% decline in eGFR and AKI
• Rivaroxaban was also associated with lower risks of doubling of serum creatinine
• Apixaban did not have a statistically significant relationship with any of the renal outcomes
Events per 100 patient-
years
Renal outcomeszz Warfarin* HR (95% CI) HR (95% CI)
‘Rivaroxaban'*
(n=4,185
(n=2,485)
)

≥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)

SCU

0.1 1 10
Favors Favors
TH 2018 ‘Xarelto’ warfarin

9 SURABAYA
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*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
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Adapted from Yao X et al. J Am Coll Cardiol 2017;70:2621–2632
 Conclusions
• Patients with non-valvular AF and renal impairment have higher rates of stroke/SE and
bleeding than those with normal renal function1
• Rivaroxaban is the only novel OAC prospectively studied in phase III with a specific dose
(15 mg OD) in patients with CrCl 30–49 mL/min2
• Efficacy and safety of rivaroxaban 15 mg OD in patients with AF
and moderate renal impairment were consistent with the overall
trial population2
• Rivaroxaban was non-inferior to warfarin for the prevention of stroke/SE
• Critical organ and fatal bleeding were significantly less frequent with rivaroxaban
• Rivaroxaban is approved for stroke prevention in NVAF patients with moderate or
severe* renal impairment (CrCl 15–49 mL/min)3
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TH 2018
*Use with caution in patients with severe renal impairment.

9 SURABAYA
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UPDATE
1. Olesen J et al. N Engl J Med. 2012;367(7):625-635; 2. Fox KA et al. Eur Heart J. 2011;32(19):2387-2394; 3. Rivaroxaban SmPC
SCU

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 Rationale for a Specific Renal Dose of Rivaroxaban in Patients with
CrCl 30–49 mL/min (ROCKET AF)

Plasma concentration (µg/L)

400

CrCl <30 mL/min

Plasma concentration (µg/L)

250 300
CrCl 30–49 mL/min
200 CrCl 50–79 mL/min 200

150 CrCl ≥80 mL/min

100
100

50 0 4 8 12 16 20 24
Time after administration (hours)
0
0 4 8 12 16 20 24 20 mg OD rivaroxaban (CrCl >50 ml/min);
Time after administration (hours) 5th and 95th percentiles ( )
15 mg OD rivaroxaban (CrCl ≤50 ml/min);
5th and 95th percentiles ( )

Simulations in patients with AF showed

Rivaroxaban (10 mg*) exposure is similar exposure between 15 mg OD
increased in renally impaired patients (CrCl 30–49 mL/min) and 20 mg OD
SCU

compared with healthy controls1 (normal/mild renal impairment)2

TH 2018
*Rivaroxaban was given as a single oral dose of 10 mg (two 5 mg tablets).

9 SURABAYA
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UPDATE
1. Kubitza D et al. Br J Clin Pharmacol. 2010;70(5):703-712; 2. Mueck W et al. Clin Pharmacokinet. 2011;50(10):675-686
 LIMITATIONS OF VKA THERAPY
Unpredictable Numerous food–drug
response interactions

VKA therapy has several

Narrow therapeutic Numerous drug–drug
window (INR range 2.0–3.0) limitations that make it interactions
difficult to use in practice

Slow onset/
Warfarin resistance
offset of action

Routine coagulation Frequent dose

monitoring adjustments

INR = International normalized ratio; VKA = vitamin K antagonist

Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137.
Nutescu EA, et al. Cardiol Clin 2008;26:169-187.

30
 Targets for antithrombotic agents in
the coagulation cascade1 Vitamin K antagonists:
Warfarin
Tissue factor/VIIa

X IX

Indirect factor Xa inhibitors:

VIIIa NA
IKa
Direct factor Xa inhibitors:
Va
Apixaban (Not yet approved by BPOM) AT= antithrombin
Rivaroxaban (Not yet approved by BPOM) Xa AT

Direct thrombin inhibitors:

Dabigatran etexilate (Approved by BPOM)
II Thrombin

Anti-platelets:
Aspirin
Clopidogrel
Fibrinogen Fibrin

1Adapted from Turpie AG. Eur Heart J 2008;29 31