Rivaroxaban in SPAF - swisscardio.ch · Rivaroxaban in SPAF: Efficacy, safety and cardio-vascular profile Hans Rickli, St.Gallen. ... • Dabigatran and apixaban: evaluated across

Rivaroxaban in SPAF:

Efficacy, safety and cardio-vascular profile

Hans Rickli, St.Gallen

CHADS2 Distribution Across SPAF Trials

• Dabigatran and apixaban: evaluated across a spectrum of stroke risk

categories

• Rivaroxaban: evaluated in patients at high risk of stroke

Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med 2011365:883; Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

CHADS2 Score

%

*CHF or LVEF ≤40%;

#CHF or LVEF ≤35%

With over 11’000 patient-years of exposure, the ROCKET AF trial

provides the largest prospective experience involving high-risk

elderly patients with AF using oral anticoagulation with rivaroxaban

Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med 2011365:883;Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635

Patient Characteristics Across SPAF

Trials

*#

% of Study Patients

#

Characteristic

Rivaroxaban

(N=7,131)

Warfarin

(N=7,133)

CHADS2 score, mean ± SD 3.48 ± 0.94 3.46 ± 0.95

2, n (%) 925 (13.0) 934 (13.1)

3, n (%) 3,058 (42.9) 3,158 (44.3)

4, n (%) 2,092 (29.3) 1,999 (28.0)

5, n (%) 932 (13.1) 881 (12.4)

6, n (%) 123 (1.7) 159 (2.2)

Co-existing conditions, n (%)

Previous stroke/TIA or SE 3,916 (54.9) 3,895 (54.6)

Congestive heart failure 4,467 (62.6) 4,441 (62.3)

Hypertension 6,436 (90.3) 6,474 (90.8)

Diabetes mellitus 2,878 (40.4) 2,817 (39.5)

Previous MI 1,182 (16.6) 1,286 (18.0)

Peripheral vascular disease 401 (5.6) 438 (6.1)

Chronic obstructive pulmonary disease 754 (10.6) 743 (10.4)

CrCl, median (25th, 75th), ml/min 67 (52, 88) 67 (52, 86)

ITT population

Patel MR et al. N Engl J Med 2011;365:883–891

ROCKET AF

Rivaroxaban vs warfarin –Patient characteristics

1 20

5

6

4

3

2

1

0

Warfarin 2.2% events/year

Rivaroxaban 1.7% events/year

20 mg 1x/day

(CrCl 30–49 ml/min: 15 mg 1x/day)

HR=0.79 (0.65–0.95)

p=0.02 (for superiority)

years

n=14'143 (as-treated safety population)

ROCKET AF: Efficacy

Primary endpoint: stroke or systemic embolism

.

RRR: relative risk reduction; HR: Hazard Ratio; NNT = Number Needed to Treat

cu

mu

lati

ve

eve

nt

rate

(%

)

Stroke prevention in non valvular atrial fibrillation. Patel MR. NEJM 2011

Endpoints

Rivaroxaban

(N=7,061)

Warfarin

(N=7,082)

HR

(95% CI)

HR and

95% CIs

n

(% per year)

n

(% per year)

Primary efficacy endpoint 189 (1.7) 243 (2.2) 0.79 (0.65, 0.95)*

All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70,1.03)

Haemorrhagic stroke 29 (0.3) 50 (0.4) 0.59 (0.37,0.93)*

Ischaemic stroke 149 (1.3) 161 (1.4) 0.94 (0.75,1.17)

Unknown stroke type 7 (0.1) 11 (0.1) 0.65 (0.25,1.67)

Non-CNS systemic embolism 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)*

ROCKET AF

Primary efficacy endpoint - components

Safety population – on-treatment analysis

*Statistically significant

0.2 0.5 1 2 5

Favoursrivaroxaban

Favours warfarin


Parameter

Rivaroxaban

(N=7,111)

Warfarin

(N=7,125) HR

(95% CI)

HR and

95% CIsn (% per year) n (% per year)

Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11)

Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20)

Haemoglobin drop

(≥2 g/dl)

305 (2.8) 254 (2.3) 1.22 (1.03,1.44)*

Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)*

Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)*

Intracranial

haemorrhage

55 (0.5) 84 (0.7) 0.67 (0.47,0.93)*

Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)*

Non-major clinically

relevant bleeding

1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13)

ROCKET AF

Rivaroxaban vs warfarin – Results: Safety

Major bleeding from gastrointestinal site (upper, lower and rectal):

rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001*

Safety population – on-treatment analysis. *Statistically significant

0.2 0.5 1 2 5Favours

rivaroxabanFavours warfarin


ROCKET AF: Subanalysis efficacy

Comparison of patients without prior stroke/TIA vs. patients with

prior stroke/TIA

Cu

mu

lati

ve

eve

nt

rate

-s

tro

ke

/SE

(%

)

Months from randomization

0

1

2

3

0

4

5

6

7

306 12 18 24

With prior stroke/TIA: Warfarin

Without prior stroke/TIA: Warfarin

With prior stroke/TIA: Rivaroxaban

Without prior stroke/TIA: Rivaroxaban

Primary efficacy endpoint: Stroke or SE

Intention-to-treat population

Hankey GJ et al. Lancet Neurol 2012;11(4): 315–322

ROCKET AF: Subanalysis secondary prevention – ResultsComparison of patients without prior stroke vs. patients withprior stroke

Endpoint

Without prior stroke or TIA (n=6,729) With prior stroke or TIA (n=7,414)

p-value

Rivaroxaban

Events/yr (nr*)

Warfarin

Events/yr (nr*)

HR

(95% CI)

Rivaroxaban

Events/yr (nr*)

Warfarin

Events/yr (nr*)

HR

(95% CI)

Any stroke or non-CNS

systemic embolism1.09 1.69 0.65 (0.47–0.90) 2.26 2.60 0.87 (0.69–1.10) 0.1477

Any stroke 1.06 1.53 0.69 (0.49–0.97) 2.21 2.37 0.93 (0.73–1.19) 0.1576

Haemorrhagic stroke 0.17 0.41 0.40 (0.19–0.87) 0.35 0.47 0.74 (0.42–1.32) 0.2184

Ischaemic or

unknown stroke0.89 1.11 0.80 (0.55–1.16) 1.86 1.92 0.97 (0.74-1.27) 0.4062

Efficacy endpoints

Safety on-treatment population

* nr=number of events


….these results support the use of rivaroxaban as an alternative to warfarin

for prevention of recurrent as well as initial stroke….

ROCKET AF: Subanalysis SafetyComparison of patients without prior stroke/TIA vs. patients with prior

stroke/TIA

Rivaroxaban

Events/yr (nr*)

Warfarin

Events/yr (nr*)

HR

(95% CI) p-value

Principal safety

bleeding endpoint

16.69 (785)

13.31 (690)

15.19 (743)

13.87 (706)

1.10 (0.99–1.21)

0.96 (0.87–1.07)0.08

Major bleeding4.10 (217)

3.13 (178)

3.69 (203)

3.22 (183)

1.11 (0.92–1.34)

0.97 (0.79–1.19)0.36

Fatal bleeding0.22 (12)

0.26 (15)

0.48 (27)

0.49 (28)

0.46 (0.23–0.90)

0.54 (0.29–1.00)0.74

Intracranial haemorrhage† 0.39 (21)

0.59 (34)

0.68 (38)

0.80 (46)

0.57 (0.34–0.97)

0.74 (0.47–1.15)0.47

Intracerebral haemorrhage‡ 0.24 (13)

0.45 (26)

0.52 (29)

0.54 (31)

0.46 (0.24–0.89)

0.84 (0.50–1.41)0.16

Extracerebral

haemorrhage§

0.18 (10)

0.17 (10)

0.30 (17)

0.35 (20)

0.61 (0.28–1.32)

0.50 (0.23–1.07)0.73

Non-major clinically

relevant bleeding

12.93 (620)

10.78 (565)

11.78 (585)

10.98 (566)

1.10 (0.98–1.23)

0.99 (0.88–1.11)0.20

Safety endpoints


Without prior stroke or TIA

With prior stroke or TIA

* nr=number of events; † 17 intracranial haemorrhages were considered both intracerebral and extracerebral. ‡ Includes intraparenchymal

and intraventricular haemorrhage. One intraparenchymal haemorrhage that occurred with extracerebral haematoma

was classified as traumatic. § Includes subarachnoid haemorrhage, subdural haematoma, and epidural haematoma.


101

Favours warfarin

0.1 0.2 0.5 2 4

Favours rivaroxaban

….equally safe in both subgroups….

ROCKET AF Subanalysis heart failure

Comparison of patients without HF vs. patients with HF

Outcome

Hazard ratio

(95% CI)

p-value

(interaction)

Major or NMCR bleeding1.05 (0.95–1.15)

1.05 (0.93–1.18)0.99

Haemorrhagic stroke0.38 (0.19–0.76)

0.91 (0.48–1.73)0.067

Intracranial haemorrhage0.63 (0.40–1.02)

0.72 (0.44–1.19)0.71

Van Diepen S et al. Circ Heart Fail 2013;6(4): 740–747

Rivaroxaban better Warfarin better

1.00 2.00 4.000.500.25

With HF

Without HF

Safety endpoints by treatment and HF

…. similar treatment-related outcomes in patients with and without

HF and across HF subgroups….

ROCKET AF Subanalysis ischaemic cardiac outcomes:Comparison of pts without MI (83%) vs. patients with MI (17%)

Primary efficacy endpoint: CV death, MI, and UA

Mahaffey KW et al. Eur Heart J 2014 Jan;35(4):233-41

CV

Dea

th, M

I, o

r u

ns

tab

le a

ng

ina

(%

)

Days from randomization

0

3

6

9

0

12

15

18

900180 360 540 720

With prior MI: Warfarin

Without prior MI: Warfarin

With prior MI: Rivaroxaban

Without prior MI: Rivaroxaban


CV=cardiovascular; MI=myocardial infarction; UA=unstable angina

Prior MI was common and associated with substantial risk for

subsequent cardiac events

No significant difference between VKA and rivaroxaban group

ROCKET AF: Subanalysis Type of AF – ResultsHigher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation

All-cause mortality

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0 6 12 18 24 30

Ra

te o

f a

ll-c

au

se

mo

rtali

ty

Months since randomization

Persistent AF

Paroxysmal AF

Adjusted HRparoxysmal (95% CI ) = 0.79 (0.67–0.94)

p=0.048

No. at risk

Persistent 11,485 11,255 10,962 8,113 4,975 2,134

Paroxysmal 2,490 2,451 2,404 1,830 1,216 498

Benjamin A. Steinberg1*, European Heart Journaldoi:10.1093/eurheartj/ehu359

Lip YH, Windecker S et. al EHJ 2014.

Management of pts with PCI and need of anticoagulation in non-

valvular atrial fibrillation

CHA2DS2-VASc < 1 CHA2DS2-VASc > 2

DAPT

IIa C

(N)OAC* +

Clopidogrel

up to 12

months

IIb BSCAD ACS

HAS-BLED < 2

IIa C

(N)OAC* +

DAPT for

(3-)6 months

then

(D)OAC +

SAPT up to

12 months

HAS-BLED > 3

IIa C

(N)OAC* +

DAPT for

1 month, then

(D)OAC +

SAPT (6-)

12 months

Adapted: 2014 ESC/EACTS Guidelines on myocardial Revascularization. European Heart Journal (2014) 35, 2541–2619

Legende:

DAPT: dual antiplatelet therapy (ASS 100mg und Clopidogrel)

SAPT: single antiplatelet therapy (Clopidogrel)

DOAC-dose reduction in pts with Triple-therapy: 2x110mg Dabigatran/d, 15mg Rivaroxaban/d, 2x2.5mg Apixaban/d

SCAD: stable coronary artery disease

All ACS patients -Triple therapy at discharge (ASA and VKA/NOAC and P2Y12 inhibitors) N=48’604

0,0

1,0

2,0

3,0

4,0

5,0

6,0

7,0

% p

atie

nts

Trend: Increased number of patients with triple tx at discharge since 1997

Trends in triple antithrombotic therapy at discharge in ACS patients with atrial fibrillation at admission (n=294)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2010 2011 2012 2013 2014

pat

ien

ts

OAC or NOAC & Prasugrelor Ticagrelor

NOAC & ASA &Clopidogrel

OAC & ASA & Clopidogrel

Increasing rate of Combination of

newer P2Y12 inhibitors together with

OAC

- In hospital bleeding, in hospital-

outcome, at 1 yr?

Increasing rate of triple tx with NOACs

Unpublished data

Open question: Potential Role (Risks and benefits)

of NOACs in ACS

no interaction with (dual) antiplatelet therapy on both efficacy

and bleeding in the AF trials with NOAC

it might be assumed that

the respective advantages of the NOAC over VKA are maintained

in dual or triple therapy.

In addition, there was also no interaction between SAPT vs. DAPT

in the ACS trials with the NOACs apixaban and rivaroxaban

Not enough data of the AMIS-plus population to make any

conclusion – more data needed!

Summary I

• ROCKET provides the largest prospective experience

involving high-risk elderly patients with AF comparing

Warfarin vs. Rivaroxaban

• Efficacy: Significantly fewer cases of haemorrhagic stroke

were observed in patients on rivaroxaban

• Safety: less fatal/intracranial bleedings and more

gastrointestinal bleedings in patients on rivaroxaban

Summary II

• Subanalysis:

– Consistent efficacy and safety of rivaroxaban compared with warfarin in

pts without prior stroke and with prior stroke

– similar treatment-related outcomes in patients with and without HF and

across HF subgroups

– Prior MI was common (17%) and associated with substantial risk for

subsequent cardiac events

– Persistent Afib subgroup associated with higher subsequent all-cause

mortality rate

Summary III

• An increasing number of ACS patients with Afib in Switzerland

gets triple antithrombotic therapy with NOACs

– In contrast of to the guidelines – a substantial number of ACS Afib

patients is treated with Prasugrel or Ticagrelor in combination with

anticoagulation (VKA or NOACs)

• Ongoing Rivaroxan Study (PIONEER-PCI) is addressing the safety

aspects of this clinically important question (PCI in Afib)

Back-up information

ROCKET AF

Rivaroxaban vs warfarin – Patient characteristics

Characteristic

Rivaroxaban

(N=7,131)

Warfarin

(N=7,133)

Age, median (25th, 75th), years 73 (65, 78) 73 (65, 78)

Female, % 39.7 39.7

Body mass index, median, kg/m2 28.3 28.1

Blood pressure, median, mm Hg

Systolic 130 130

Diastolic 80 80

Clinical presentation, n (%)

Type of AF

Persistent 5,786 (81.1) 5,762 (80.8)

Paroxysmal 1,245 (17.5) 1,269 (17.8)

Newly diagnosed/new onset 100 (1.4) 102 (1.4)

Previous ASA use 2,586 (36.3) 2,619 (36.7)

Previous VKA use 4,443 (62.3) 4,461 (62.5)

ITT population


ROCKET AF

Rivaroxaban vs warfarin – Secondary endpoints

Safety population – on-treatment analysis. *Statistically significant

Endpoints

Rivaroxaban

(N=7,061)

Warfarin

(N=7,082)

HR

(95% CI)n (% per year) n (% per year)

Composite of stroke, nonCNS SE,

vascular death

346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)*

Composite of stroke, non-CNS SE,

vascular death and MI

433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)*

Components of major secondary

endpoints

All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03)

Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)*

MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06)

Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10)

All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02)


L.C

H.H

C.0

1.2

015.0

581-D

E/E

N

Low to intermediate

(e.g. HAS-BLED = 0-2)

High

(e.g. HAS-BLED ≥ 3)

CHA2DS2-VASc = 1 CHA2DS2-VASc ≥ 2

Nonvalvular Atrial Fibrillation

0

4 weeks

12 months

6 months

STEP 2 - Bleeding risk

STEP 1 - Stroke risk

STEP 3 - Clinical setting Stable CAD ACS Stable CAD ACS

Lifelong

Stable CAD ACS Stable CAD ACS

Low to intermediate

(e.g. HAS-BLED = 0-2)

High

(e.g. HAS-BLED ≥ 3)

STEP 4 – Antithrombotic therapy

Time from PCI/ACS

A CO

A C

O

A C A or

CO

Dual therapy**

A CO A CO

Triple therapy

A CO

A CO

A CO

Triple or dual

therapy*

A CO

Triple or dual

therapy*

Triple or dual

therapy*

Triple or dual

therapy*

DAPT

DAPT

Dual therapy**

A CO Oral Anticoagulation Aspirin 75-100 mg

daily

Clopidogrel 75 mg

daily

OMonotherapy***

A or

CO

Dual therapy**

A or

CO

Dual therapy**

A or

CO

Dual therapy**

A or

CO

Dual therapy**

A or

C

O

Dual therapy

or

OMonotherapy***

or

A CO

Triple or dual

therapy*

Triple or dual

therapy*

C

Triple therapy

A C

DAPT

or

If PCI is

performed

If PCI is

performedIf PCI is

performed

If PCI is

performed


L.C

H.H

C.0

1.2

015.0

581-D

E/E

N

Consensus recommendation - AF & ASC /

stable CAD

1. In AF patients, stroke risk must be assessed using the

CHA2DS2-VASc score, and bleeding risk using the HAS-BLED

score. (Class I C).

2. Where a NOAC is combined with clopidogrel and/or low-dose

ASA, the lower tested dose for stroke prevention (dabigatran 110

mg b.i.d., rivaroxaban 15 mg qd or apixaban 2.5 mg b.i.d.) may

be considered (Class IIb C).

3. In patients with AF and stable vascular disease the patient

should be managed with OAC alone (i.e. whether NOAC or a

VKA) (Class IIa B).

4. Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor)

should not be part of a triple therapy regimen in patients with AF

(Class III C).


L.C

H.H

C.0

1.2

015.0

581-D

E/E

N

Consensus recommendation - AF & stable CAD

1. Stable CAD and AF at low-bleeding risk (HAS-BLED 0–2)

triple therapy (OAC, ASA 75–100 mg qd, clopidogrel 75 mg qd) for at least 4 weeks

(no longer than 6 months) after PCI (Class IIa C).

followed by dual therapy with OAC (NOAC or VKA) and clopidogrel 75 mg/d (or

ASA 75–100 mg/d) for up to 12 months (Class IIa C).

• CHA2DS2-VASc=1 at low-bleeding risk (HAS-BLED 0–2), DAPT (ASA 75–100 mg

and clopidogrel 75 mg), or dual therapy (OAC: NOAC or VKA) and clopidogrel 75

mg/d should be considered (Class IIa C).

• Dual therapy of OAC (i.e. NOAC or a VKA) and clopidogrel 75 mg/day may be

considered as an alternative to initial triple therapy in selected patients with

CHA2DS2-VASc ≥2 (Class IIb C).

2. Stable CAD and AF at high-bleeding risk (HAS-BLED >3)

triple therapy (OAC, ASA 75–100 mg, clopidogrel 75 mg) or dual therapy consisting

of OAC (NOAC or VKA) and clopidogrel 75 mg/day for 4 weeks

followed by dual therapy with OAC and clopidogrel 75 mg/d (or ASA 75–100 mg/d)

for up to 12 months (Class IIa C).

• CHA2DS2-VASc=1 at high-bleeding risk (HAS-BLED >3)

• DAPT (ASA 75–100 mg and clopidogrel 75 mg/day, or dual therapy consisting of

OAC (NOAC or VKA) and clopidogrel 75 mg/day may be considered (Class IIb C)

for 12 months.


L.C

H.H

C.0

1.2

015.0

581-D

E/E

N

Consensus recommendation - AF & stable CAD

3. Long-term antithrombotic therapy with OAC (NOAC or

VKA) (beyond 12 months) is recommended in all patients

(Class I B).

Combination OAC plus single antiplatelet therapy

(clopidogrel 75 mg/day or ASA 75–100 mg/day)] may be

considered in very selected cases, e.g. stenting of the

left main, proximal left anterior descending, proximal

bifurcation, recurrent MIs, etc. (Class IIb, C).

4. Gastric protection with PPIs should be considered in

patients with OAC plus antiplatelet therapy (Class IIa, C).


ROCKET-AF: WirksamkeitRef.: Fachinformation XARELTO

Documents

Rivaroxaban in SPAF - swisscardio.ch · Rivaroxaban in SPAF: Efficacy, safety and cardio-vascular profile Hans Rickli, St.Gallen. ... • Dabigatran and apixaban: evaluated across