Triple Antithrombotic Therapyin Cardiac Patients

Elizaveta P. Panchenko, MD,PhDCardiology Research and Production Center

MoscowRussian Federation

September 17, 2014

DisclosuresConsultancy fees or honoraria from

SANOFI, Takeda-NYCOMED, Boehringer Ingelheim,Pfizer, Bristol-Myers Squibb, Bayer, Lilly, AstraZeneca, GlaxoSmithKline, MEDICINES

Triple antithrombotic therapy

1. Aspirin 2. Р2Y12 antagonists: clopidogrel, prasugrel,

ticagrelor3. Oral anticoagulants: vitamin K antagonists,

dabigatran, apixaban, rivaroxaban

Cardiac Patients Who Need Triple Antithrombotic Therapy

Patients with indications for long anticoagulant therapy: atrial fibrillation, venous thromboembolism, mechanical valve surgery, thrombosis of left ventricle

If they have acute coronary syndrom (ACS)If they need elective PCI because of angina

pectoris

1. Analysis of 261 consecutive pts with AF undergoing CAG: The rate of CAD – 34% The need of PCI /CABG – 21%

2. The frequency of AF (Meta-analysis 120 566 pts from 10 clinical trials)

- in pts with STEMI – 8% - in pts with NSTE-ACS - 6,4%

3. 2-21% of pts with ACS have AF

1-Kralev et al., PLoSOne.2011;6:e24964.2-Lopes et al. Heart.2008;94:867-873.

3-Schmitt et al., EHJ.2009; 30:1038-104

COEXISTENCE OF CORONARY ARTERY DISEASE AND ATRIAL FIBRILLATION

BOTH DISEASES DEMAND ANTITHROMBOTIC THERAPY

Acute Coronary Syndrome

•Aspirin (forever)•Р2Y12 inhibitor: Clopidogrel, Prasugrel, Ticagrelor (12 months)

Atrial Fibrillation• Warfarin• Dabigatran• Rivaroxaban• Apixaban• Aspirin• Aspirin+Clopidogrel

Dual antiplatelet therapy Anticoagulant

Bleedings worsen the outcomes in patients receiving the antithrombotic therapy

Achilles' heel

BLEEDINGS SIGNIFICANTLY INCREASE THE RISK OF DEATH

OASIS-5 dataset

What do we know about the frequency of bleedings in patients

with antithrombotic therapy?

Major Bleedings In AF Patients Receiving Antithrombotic Therapy

Aspirin Aspirin + Clopidogrel Warfarin1,3%(ACTIVE-A)

1,2%(AVERROES)2,0% (ACTIVE-W) 1,5-3,0%

Randomized trials

ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS IN PATIENTS WITH ATRIAL FIBRILLATION

Antithrombotic therapy HR 95% CIWarfarin 2,08 1,95-2,23Clopidogrel 1,57 1,37-1,81Aspirin 1,25 1,17-1,34Aspirin + Clopidogrel 1,68 1,44-1,97Warfarin+Aspirin 2,87 2,58-3,19Warfarin+Clopidogrel 2,74 2,14-3,51Warfarin+Aspirin+Clopidogrel 3,75 2,7-5,19

70,760 patients with AF (UKGPRD registry) 1993-2008 years follow up 10,850 patients had bleedings during follow up

Fatal and nonfatal bleedings* according to antithrombotic regimen in time periods following inclusion (Denmark register)

Lamberts M et al. Circulation. 2012;126:1185-1193

11480 pts with AF and MI/PCI between 2000-2009y. Mean age -75,6 y. Male -60,9%

*- reguiring hospitalisation

Triple-22,6%

VKA+ ASP/CLOPI - 20,3%

VKA

HOW TO MINIMIZE THE RISK OF BLEEDINGS?

1. To decrease the number of antithrombotic drugs

What do we know about efficacy and safety of antiplatelet drugs in prevention of

stroke in AF patients?

ASPIRIN IS SUPERIOR TO PLACEBO

STROKE PREVENTION IN ATRIAL FIBRILLATION

Major bleedings

Major Fatal0

60

120

180

240251

42

162

27

Clopi+Asp Pl+Asp

ОР (95%CI)1,56 (0.96-2.53)

р=0,07

%

RR (95%CI)1,57 (1.29-1,92)

р<0,001

2,0%

1,3%

0,2%0,3%

RR11%

р=0,01

RR28%

р<0,001

RR22%

р=0,08

%

7,554 pts with AF, those didn’t wish or couldn’t intake warfarin

33 countries, follow-up – 3,6 years

ASP+CLOPI are superior to ASP,

STROKE PREVENTION IN AF PATIENTSACTIVE-A

but induce more bleedings…

Connolly et all, N Engl J Med 2009;360:2066-78.

WARFARIN IS SUPERIOR TO ASPIRIN

STROKE PREVENTION IN ATRIAL FIBRILLATION

VKA therapy is more effective than aspirin, relative risk reduction of stroke/SE on warfarin is 39%

In AF patients with high risk of stroke/SE (>6% per year) RRR is more higher - 50%

The ACTIVE Writing Group Lancet 2006; 367:1903-12

Stroke + SE +MI +CVD

Warfarin is superior to CLOPI+ASP

WarfarinWarfarin

Clopi+AspClopi+Asp

STROKE PREVENTION IN ATRIAL FIBRILLATIONACTIVE-W

Ха

Thrombin

Rivaroxaban

Apixaban

Dabigatran

Edoxaban

Fibrin

The NOACs fall into two classes: the oral direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

In contrast to VKAs, which block the formation of multiple active vitamin K dependent coagulation factors (factors II,VII,IX and X), NOACs target selectively the individual step in coagulation cascade

VKA

VKAVKA

VKA

Apixaban is Superior to Aspirin

AVERROES

Stroke or Systemic Embolism Major Bleeding

Cum

ulati

ve H

azar

d

STROKE PREVENTION IN ATRIAL FIBRILLATION

5,599 pts with AF at increased risk of stroke to whom VKA therapy was unsuitable Randomization Apixaban 5mg twice daily or Aspirin 81-324 mg per day Mean follow up period 1,1 year

All NOACs have demonstrated non-inferiority compare to warfarin with better safety by consistently limiting the number of ICH

Guideline now recommends them as broadly preferable to VKA in the vast majority of patients with NVAF

What do we know about efficacy and safety of warfarin in patients survived

acute coronary syndrome?

Warfarin (INR 2,0-2,5) in addition to Aspirin 80 mg per day the risk of cardio-vascular events (ASPECT-2, OASIS-2, WARIS-II), the risk of re-occlusion of IRA in patients with MI and thrombolysis (APRICOT-2) no increase of major bleeding (ASPECT-2, OASIS-2)

Warfarin (INR 2,8-3,2) is superior to Aspirin 80 mg the risk of cardio-vascular events (ASPECT-2, WARIS-II)

WARFARIN in Patients Survived Acute Coronary Syndrome Conservative strategy of treatment, before

«clopidogrel era»

Major bleeding

WARIS II WARIS II WARIS II CURE

Aspirin Aspirin + Warfarin (INR 2,2)

Warfarin (INR 2,8)

Aspirin + Clopidogrel

0,15% per year

0,52% per year

0,58% per year

3,6% per 9 months

WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM

• WARFARIN +ASPIRIN are better than ASPIRIN in prevention of recurrent events,

• moreover, benefits are more than risk of bleeding in patients with medium and low bleeding risk (WARIS-2)

CONSERVATIVE STATEGY

HOW TO MINIMIZE THE RISK OF BLEEDINGS?

1.To decrease the number of antithrombotic drugs

2.To choose the optimal combination of anticoagulant (VKA or novel oral anticoagulant) and antiplatelet drugs (aspirin or clopidogrel or aspirin+clopidogrel)

Is it suitable to withdraw aspirin from triple therapy (asp+clopi+VKA)

in patients after PCI?

Incidence of any bleedingCumulative incidence of death, MI, Stroke, TVR and stent thrombosis

W JM Dewilde et al., for the WOEST study investigators www.thelancet.com http://dx.dol.org/10/1016/S0140-6736(12)62177-1

Clopidogrel+VKA versus Clopidogrel+VKA+Aspirin in PCI Patients An open-labelled, multicentred, randomised, controlled trial 573 on VKA were enrolled, 279 pts assigned double therapy and 284 assigned triple therapy Indication for oral anticoagulation (AF-67%, Mechanical valve-11%, Other.-20%) ACS-25-30%; EF-13-15%; Radial access-25-27%

ESC, Hotline III, Munchen, August 28th, 2012

age75

male

t0acs

oacind3cat

des

Overall

FALSE

TRUE

no

yes

no

yes

AF/AFlut

Mechanical valve

Other

No

DES

200

79

50

234

195

86

162

25

47

90

194

284

194

82

65

214

207

69

164

24

48

94

184

279

0.9157

0.8217

0.721

0.1116

0.7761

0.7894

Factor

Age

Gender

ACS

IndicationOAC

Stenttype

Overall

Subgroup

<75 years

>75 years

female

male

no

yes

AF/AFlut

MechanicalvalveOther

BMS

DES

Triple

79

200

50

234

195

86

162

25

47

90

194

284

VKA+Clopi

82

194

65

214

207

69

164

24

48

94

184

279

P-value for interaction

0.9157

0.8217

0.7210

0.1116

0.7761

0.7894

double therapy better <=> triple therapy better0.1 0.4 1

Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis)

WOEST

HR

All-Cause Mortality

Days

Cu

mu

lati

ve

in

cid

en

ce

of

de

ath

0 30 60 90 120 180 270 365

0 %

2.5 %

5 %

7.5 %

284 281 280 280 279 277 270 252n at risk: 279 278 276 276 276 275 274 256

6.4%

2.6%

HR=0.39 95%CI[0.16-0.93]

p=0.027

Triple therapy groupDouble therapy group

WOEST

ESC, Hotline III, Munchen, August 28th, 2012

WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM

WOEST • WARFARIN + CLOPIDOGREL

are better than WARFARIN +ASPIRIN +CLOPIDOGREL in the frequency of bleeding complications and similar in the rate of thrombotic events

PCI TREATMENT

What about adding novel oral anticoagulant to dual antiplatelet therapy

in patients survived acute coronary syndrome?

Apixaban with Antiplatelet therapy after Acute Coronary Syndrome (APPRAISE-2)

Probability of TIMI major bleedingProbability of CVD/MI/Stroke

Randomized, double-blind controlled clinical trial comparing apixaban, at dose of 5 mg twice daiy with placebo in addition to standard antiplatelet therapy in pts with a recent ACS and at least 2 additional RF for recurrent ischemic events

Probability of major and clinically relevant minor bleedings

Dabigatran vs. placebo in ACS patients with dual antiplatelet therapy

A randomized, double-blind, phase II trial

Dabigatran, in a dose dependent manner, increases bleeding events during dual antiplatelet therapy

98,7% -intake aspirin92,6% -intake clopidogrel

This dose is less than dose for patients with

AF

BLEEDINGS 2,5 twice daily

N=5114

PlaceboN=5113

TIMI major not associated with CABG

65 (1,8%) 19 (0,6%)

TIMI minor 32 (0,9%) 20 (0,5%)

Intracranial 14 (0,4%) 5 (0,2%)

Fatal 6 (0,1%) 9 (0,2%)

Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51)

Double-blind, placebo-controlled trial Patients with recent ACS, n=15526 (Api 2,5mg twice daily or Api 5 mg twice daily or placebo) Mean follow-up - 13 months Primary efficacy end point – CVD/MI/Stroke

In pts with recent ACS Riva reduced risk of death from cardiovascular causes, MI or stroke. Riva increased the risk of major bleeding and intracranial hemorrhage but not the risk of

fatal bleeding

NEW ORAL ANTICOAGULANTS AS COMPONENTS OF TRIPLE THERAPY

18,113 pts with AF in RELY 6,952 pts (38,4%) also received an

antiplatelet therapy during the study 5,789 pts on aspirin alone 351 pts on clopidogrel alone 812 pts on both drugs

Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in RELY Trial

WARF D-150 D-1100 +1 +2 0 +1 +2 0 +1 +2

Major bleeding rate (%/year)

Concomitant antiplatelet drugs appeared to increase the risk of major bleedings in RELY with no advantage of dabigatran over warfarin

These recent recommendations are based on expert consensus and observational trials and many questions do remain

unanswered…

GENERAL RECOMMENDATIONS Class Level

1. In AF patients stroke risk must be assessed using the CHA2DS2VASc score, and bleeding risk assessed using the HAS-BLED score. Risk stratification must be performed at regular intervals.a) HAS-BLED score should be used to identify and correct potentially reversible bleeding risk factorsb) GRACE score should be used to stratify ACS risk

I C

2. If VKA is used good quality anticoagulation control is recommended with TTR>70%

I A

3. When VKA is given in combination with clopidogrel and/or aspirin target INR 2,0-2,5

IIa C

4. Where a NOAC is used in combination with clopidogrel and/or low dose aspirin, the lower tested dose for stroke prevention in AF may be considered (dabi- 110mg b.I.d., riva- 15mg o.d., api-2,5 mg b.i.d.)

IIb C

5. In pts with AF and stable vascular disease (free from any acute ischaemic event or repeat revascularization >1 year) the patient should be managed with OAC alone (whether NOAC or VKA)

IIa B

6. Radial access should be considered as the default for CAG/PCI to minimize the risk of access related bleeding depending on operator expertise and preference

IIa C

7. New generation DES may be preferred over BMS in pts at low risk of bleeding (HAS-BLED 0-2)

IIb C

8. Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of triple therapy in pts with AF

III C

SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF

*- Dual therapy with OAC+Clopi may be considered in selected pts**- Asp may be considered in pts on dual therapy***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF

*- Dual therapy with OAC+Clopi may be considered in selected pts**- Asp may be considered in pts on dual therapy***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

NOAC trials are ongoing

The period of triple therapy should be as short as possible The duration of triple therapy depends on a number of considerations: acute

or elective PCI, HAS-BLED score, type of stent with preference for new generation of DES or BMS

Use aspirin in low doses: 75-100 mg daily Use clopidogrel as preferred P2Y12 inhibitor to more potent ticagrelor or

prasugrel OAC – well-controlled adjusted dose warfarin (INR 2,0-2,5; TTR>70%) or NOAC Use BMS*, thus minimizing the duration of triple therapy Use the radial approach thus minimizing the risk of bleeding at the access site

The optimal NOAC regimen for patients with AF and ACS or undergoing PCI has not been addressed by RCT

* - It is uncertain whether BMS use requires a shorter duration of dual therapy than new generation DES. New data on dual therapy cessation shows no difference between BMS and DES, especially with new generation stents.

CONCLUSIONS

PHARMACOLOGY OF THE NOVEL ANTICOAGULANTS

Is it always necessary to avoid aspirin from the combinatory therapy?