October 2017 HEARTBEAT - sjhg.org · HEARTBEAT A Publication of South Jersey Heart Group October...

HEARTBEATA Publication of South Jersey Heart Group

October 2017

Managing Patients with AF and PCI

Patients with atrial fibrillation (AF), who meet the

indication for oral anticoagulation (Table 1) and have

concomitant coronary artery disease (CAD), with an

indication for percutaneous coronary intervention

(PCI—usually a drug eluting stent [DES])—meaning it’s

necessary to use dual anti-platelet therapy, or DAPT—

continue to pose an important clinical challenge

for physicians.

Table 1 — Stroke Risk: CHA2DS2 VASc Score

Congestive heart failure: 1 point

Hypertension: 1 point

Age: 65-74 =1 point; >75=2 points

Diabetes: 1 point

Stroke or TIA: 2 points

VAScular disease: 1 point (PAD, CAD,

Carotid vasc dx or aortic plaque)

Female sex: 1 point

Oral anticoagulant (OAC) treatment should be

considered for men with a risk score of 1 and

strongly recommended for all with a score of 2.1

Balancing antithrombotic therapy with bleeding risk

(Table 2) is a major issue in cardiovascular medicine,

but is an especially thorny problem in patients with

AF who undergo coronary stenting. Approximately

6–8% of patients undergoing PCI have an indication for

long-term oral anticoagulants (OACs) due to various

conditions such as AF, mechanical heart valves or venous

thromboembolism. Compared with OAC therapy alone,

the addition of DAPT to OAC therapy results in at least

a two- to three-fold increase in bleeding complications.2

Clinicians are frequently left wondering which

combination and duration of the following drugs

provides the greatest efficacy along with the lowest risk

for bleeding: aspirin, clopidogrel, ticagrelor (Brilinta), a

direct-acting oral anticoagulant (DOAC), or warfarin.

Table 2 — Bleeding Risk: HAS-BLED Score

� Abnormal renal function: dialysis; SCr > 2

� Hypertension: SBP > 160mmHg

� Abnormal liver function: cirrhosis or LFT > 3x ULN

� History of major bleed: any cause

� History of alcohol ingestion: > 8 drinks/week

� Currently taking NSAIDS or anti -platelet drug

� History of labile INR: < 60% TTR

� Age > 65; 2 points for age > 75

� Frequent falls

Two or more points indicates high risk.

Thrombocardiology—New Frontiers

Heartbeat Newsletter October 2017_Heartbeat June 10/13/17 8:59 AM

Contemporary Strategy

There is a contemporary strategy among physicians

for patients with AF and CAD to use “triple therapy”

(aspirin, clopidogrel and oral anticoagulation with

warfarin) for a short period of time following PCI,

then drop the aspirin and use only clopidogrel and oral

warfarin for the duration of the required antiplatelet

therapy. Data supports the use of triple therapy for a

shortened duration.3

Until recently, “triple therapy”—a combination of dual

antiplatelet therapy (aspirin plus a P2Y12 inhibitor) and

a vitamin-K antagonist (warfarin)—was preferred.

Although “all bases were covered” with this strategy

(i.e., thrombin and platelet inhibition), the combination

of these agents resulted in significantly higher rates

of bleeding compared to the individual components

of treatment, especially among the elderly and others

with unfavorable profiles (Table 3). Newer strategies

have emerged to help reduce this risk.

Table 3 — Unfavorable Patient Profile for OAC & DAPT

� Short life expectancy

� Ongoing malignancy

� Poor expected adherence

� Poor mental status

� End stage kidney disease

� Advanced age

� Prior major bleeding/prior hemorrhagic stroke

� Chronic alcohol abuse

� Anemia

� Clinically significant bleeding on DAPT

WOEST

Among these is the strategy investigated in the WOEST

trial, published in 2013, in which aspirin is dropped

and platelet inhibition is achieved using mono-therapy

with a P2Y12 inhibitor plus an OAC after PCI.4 Study

authors, writing in the Lancet, concluded, “Use of

clopidogrel without aspirin was associated with a

significant reduction in bleeding complications and

no increase in the rate of thrombotic or ischemic

events.” An important caveat about the study is that use

of radial access was low, which may have artificially

inflated the rates of bleeding in the triple therapy arm.

Less Aspirin

This decreased risk was kind of anticipated, as

discontinuation of any antiplatelet agent at one year

after stenting is encouraged in stabilized, event-free

patients based on studies demonstrating that OACs

alone are superior to aspirin post-acute coronary

syndrome (ACS), and OAC plus aspirin may not be

more protective, but associated with excess bleeding.5

Another recent large observational study showed that

the primary prevention of myocardial infarction (MI)

and stroke in patients with AF is better with warfarin

alone as compared to aspirin alone and dual therapy.6

Today, many patients with AF take direct-acting oral

anticoagulants (DOACs), which were not included in

these studies. However, in the studies comparing

warfarin to DOACs, the observed MI rates were the

same. So, it was very reasonable to assume that the

results would be similar with the DOACs.

“Not a commandment. Just a suggestion.”


The COMPASS trial showed that rivaroxaban plus

aspirin was better than aspirin alone for secondary

prevention and showed that rivaroxaban alone was

equal to aspirin for secondary prevention, although

both arms had increased bleeding.7 We believe COMPASS

supports our thesis, that it’s safe to delete aspirin in

stable CAD patients with AF who are taking DOACs to

decrease stroke risk as they also decrease ischemic risk.

PIONEER AF-PCI

This trial, published in 2016, is the first to use one of the

DOACs instead of warfarin for OAC therapy in patients

with AF and PCI.8 Patients (2,124) were randomly

assigned to low-dose rivaroxaban (Xarelto) [15 mg once

daily] with a P2Y12 inhibitor for 12 months (group 1);

very-low-dose rivaroxaban (2.5 mg twice daily) plus

DAPT for one, six or 12 months (group 2); and standard

therapy with warfarin plus DAPT for one, six and 12

months (group 3). The safety data in the rivaroxaban

groups appeared promising, with a significant reduction

in bleeding.

Unfortunately, even though efficacy rates were similar

with regard to thrombotic and ischemic events, the

observed broad confidence intervals don’t allow surety

regarding efficacy. Additionally, the 2.5 mg dose is not

available to us and the 15 mg dose is only recommended

for AF when creatinine clearance in less than 50 mL/min.

RE-DUAL Deals Another Blow to Triple Therapy

The RE-DUAL PCI trial, presented in August at the

European Society of Cardiology Congress 2017,

randomized 2,725 patients with AF who had undergone

PCI to triple therapy with warfarin, plus a P2Y12 inhibitor

(clopidogrel or ticagrelor) and aspirin (for 1 [bare-metal

stent {BMS}] to 3 [drug-eluting stent {DES}] months)

or to dual therapy with one of two doses of dabigatran

plus a P2Y12 inhibitor in a paired fashion with triple

therapy.9 Notably, only the 150 mg dose of dabigatran is

approved in the U.S. for treatment of patients with AF.

Similar to PIONEER, the primary endpoint here concerned

bleeding alone—time to first major or clinically relevant

bleeding event. Ischemic and thromboembolic events were

analyzed as a secondary endpoint using a non-inferiority

design, as a composite of all-cause death, MI, stroke,

systemic embolism or unplanned revascularization.

The findings of RE-DUAL PCI concluded that “triple

therapy” (option A) resulted in the highest rate of

major or clinically relevant non-major bleeding (26.9% vs

the 110 mg dual therapy group [option B]) and 20.2%

in the 150 mg dual therapy group (option C). Both dual

therapy options met the non-inferiority endpoint for

bleeding compared to warfarin and the 110 mg option

was also significant for superiority. Most of the benefit

(decreased bleeding) is from removing aspirin. There

was a huge difference in the Kaplan Meier curves within

the first three months, but then continuous divergence

of the curves.

This argues for the case of dabigatran, that there is less

bleeding over time even after aspirin has been stopped in

all groups.

The trial also reported that the incidence of the composite

secondary efficacy endpoint of thromboembolic events

(MI, stroke or systemic embolism), death or unplanned

revascularization was non-inferior in the triple therapy


arm (13.4%) compared with a composite of the dual

therapy arms (13.7%). The authors concluded that dual

antithrombotic therapy with either of the two doses of

dabigatran conferred lower bleeding risk compared to

triple therapy with warfarin, and was non-inferior

regarding the risk of ischemic and thromboembolic

events—offering the best balance of safety and efficacy.

Dr. Christopher Cannon, the lead author, during a

discussion of the results at the ESC, noted that the

ongoing AUGUSTUS trial using apixaban vs. warfarin

and aspirin vs. no aspirin will better tease out the relative

contributions of omitting aspirin with DOACs. These

results won’t be available for at least another year.

Is This the Beginning of the End of Full-DoseTriple Therapy with Warfarin?

The main results of the RE-DUAL PCI trial should come

as no surprise. After all, this study was sponsored by the

company that manufactures dabigatran, (Boehringer

Ingelheim), and was designed as a safety trial. The

“dual-therapy” groups included only the two dosing

regimens with dabigatran, with no “WOEST-like” arm

with warfarin. The triple-therapy arm was destined to

lose out regarding bleeding, with full-dose warfarin

acting as a strawman of sorts. So why should clinicians

pay attention to these results, and what can clinicians

learn to improve practice?

First, this is a confirmation and reminder that triple

therapy is associated with strikingly high rates of

clinically evident bleeding. Fully one-quarter of patients

in the triple therapy group exhibited some clinically

evident bleeding, and nearly 4% experienced major

bleeding. RE-DUAL used the contemporary abbreviated

version of triple therapy: stopping aspirin after one month

for BMS and after three months for DES. Basically, this

trial compared dual therapy using a DOAC with three

months of triple therapy (in the majority who received

DES) followed by dual therapy with warfarin, and still

showed a significant increased bleeding risk.

More difficult is the interpretation of the ischemic and

thrombotic events in the trial, which were relegated to

secondary endpoints. RE-DUAL was underpowered to

study low-frequency events, including the feared

complication of stent thrombosis. Yet, as in the similarly

underpowered PIONEER and WOEST trials, there was

not even a signal or trend suggesting increased risk with a

DOAC-based dual-therapy regimen. This leaves room for

individualization of therapy, balancing a patient’s specific

risk profiles for thrombotic vs. bleeding outcomes. There

remain patients with elevated thrombotic risk (based on

clinical presentation and stent anatomy—Table 3) for

whom triple therapy still may be the favored approach.

Table 4 — High-Risk Features of Stent-Driven Ischemic Events

� Prior stent thrombosis on adequate tx

� Stenting of last remaining patent coronary artery

� Diffuse multi-vessel disease especially in DM

� Chronic kidney disease (CrCl < 60mL/min)

� At least 3 stents implanted; at least 3 lesions tx

� Bifurcation with 2 stents implanted

� Total stent length > 60mm

� Treatment of chronic total occlusion

However, for most patients with AF after PCI, a dual

antithrombotic regimen with a DOAC and a P2Y12 “It was green when I went through.”


Guest Editors: Adam Levine, DO, FACC, FACAI

Howard M Weinberg, DO, FACC

Mario L Maiese, DO, FACC, FACOI Associate Professor of Medicine,

Rowan SOM Email: [email protected]

Sign up to receive Heartbeats online: www.sjhg.org

Heartbeat is a South Jersey Heart Group publicationin conjunction with Lourdes Cardiology Services.

What You Need to Know

Combination antithrombotic treatment increases risk of

bleeding, and this risk should be estimated and discussed

with patients to guide treatment.

In most patients with independent indications for both

antiplatelet and OAC therapy, the pathophysiology will

intersect and combination antithrombotic may not

be necessary.

When co-prescribing, check that the patient is not on

other medications that increase bleeding risk further (e.g.

non-steroidal anti-inflammatory drugs or amiodarone

with DOACs) and consider addition of PPIs.

inhibitor should be considered a viable option for a

year, then just the DOAC without a P2Y12 inhibitor

or aspirin as we no longer need to treat the stent. We

are now interested in prevention of ischemic events

(usually from a non-stent involved vessel) and stroke

prevention from AF.

Conclusions

Importantly, HAS-BLED draws attention to the reversible

bleeding risk factors to be addressed by the clinician

during the follow-up. Risk is not static, and particularly

for bleeding, many risk factors can be modified. Hence, a

high risk of bleeding (e.g. HAS-BLED score ≥3) is not a

reason to withhold OAC; instead, such patients should

be monitored more closely and definitely started on a

proton pump inhibitor (PPI).

The following is our strategy to avoid bleeding

complications in patients with AF and need for PCI along

with an algorithm from the 2017 European Society of

Cardiology, “Focused update on dual antiplatelet therapy

in coronary artery disease.”10

1. Assess ischemic and bleeding risks using validated risk

predictors (e.g. CHA2@DS2@ Vasc), HAS-BLED with

a focus on modifiable risk factors.

2. Keep triple therapy duration as short as possible.

3. Consider dual therapy after PCI in AF (OAC and

clopidogrel) instead of triple therapy.

4. Consider the use of DOACs instead of warfarin.

5. Consider target INR in lower part of recommended

target range (2-2.5) and maximize time in therapeutic

range (> 65-70%) when warfarin is used.

6. Clopidogrel is the P2Y12 inhibitor of choice.

7. Use low-dose aspirin (81 mg).

8. Routine use of PPIs (pantoprazole is our favorite

because of the least interaction with clopidogrel).

9. Long-term antithrombotic therapy (after one year) is

not necessary with OAC to decrease ischemic risk.

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7

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Table 5 — Patients with an Indication for OAC Undergoing PCI


1600 Haddon AvenueCamden, NJ 08103

Our Lady of LourdesMedical Center

NON-PROFIT ORGU.S. POSTAGE

PAIDPERMIT #36BELLMAWRNJ 08031

References

1 Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of AF developed in collaboration with EACTS: The Task Force for the Management of AF of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke Organisation (ESO). Eur Heart J Aug 27 . 2016 [Epub ahead of print]

2 Dans AL, Yusuf S, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127: 634 – 640.

3 Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE Trial. J Am Coll Cardiol 2015; 65: 1619-1629.

4 Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial (WOEST). Lancet 2013; 381: 1107-1115.

5 Lamberts M, Gislason GH, Lip GY, Lassen JF, Olesen JB, Mikkelsen AP, Sorensen R, Kober L, Torp-Pedersen C, Hansen ML. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation 2014; 129 : 1577-1585.

6 Lee CJ, Pallisgaard JL, Olesen JB, et al. Antithrombotic therapy and first myocardial infarction in patients with atrial fibrillation. J Am Coll Cardiol 2017; 69: 2901-2909.

7 Eikelboan JW, Connolly SJ, et al, and Yusef S for the COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J MedAugust 27 2017 ;377:1319-1330; Online First at NEJM.org DOI: 10.1056/NEJMoa1709118.

8 Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI (PIONEER). N Engl J Med 2016; 375: 2423-2434.

9 Cannon CP, Bhatt DL, et al. for the RE-DUAL PCI Steering Committee and Investigators. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med August 27 2017; Online First at NEJM.org DOI: 10.1056/NEJMoa1708454.

10 Valgimigli M, Bueno H, Byrne R A et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2017; DOI:10.1093/eurheartj/ehx419. Article


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