Walking the Tightrope Between Suppressing Ischemia and Minimizing Bleeding∗

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 9, NO. 14, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2016.05.044

EDITORIAL COMMENT

Walking the Tightrope Between Suppressing Ischemia and Minimizing Bleeding* Robert J. Applegate, MD

I

n today’s practice a growing emphasis has been

Implantation) trial randomized 604 patients to 6

placed on the risk of bleeding arising from thera-

weeks versus 6 months of TAT after PCI with drug-

pies

and

eluting stents (DES), achieved by discontinuing clo-

ischemic events after percutaneous coronary inter-

pidogrel at these time points (1). The primary study

vention (PCI), particularly in patients requiring

endpoint was a composite of death, myocardial

concomitant oral anticoagulant therapy (OAC). In an

infarction (MI), definite stent thrombosis, stroke or

ideal world reduction of both thrombosis and

Thrombolysis In Myocardial Infarction (TIMI) major

ischemic risks would be achieved with minimal

bleeding. At 9 months, the primary composite

bleeding and with a single medication. Currently,

endpoint occurred in 9.8% of patients treated with

however, dual-antiplatelet therapy (DAPT) is needed

6 weeks of TAT, and in 8.8% of those receiving

aimed

at

suppressing

thrombotic

for patients undergoing stenting, and is superior to

6 months of TAT (hazard ratio [HR]: 1.14; 95% confi-

anticoagulation for this indication, and OAC is

dence interval [CI]: 0.68 to 1.91; p ¼ 0.63). Secondary

needed to reduce the thrombotic risk from conditions

endpoints of thrombotic and ischemic events, and

such as atrial fibrillation and mechanical heart valves,

bleeding, were also similar for the 2 groups. The au-

whereas DAPT or a P2Y12 inhibitor is not as effective.

thors concluded that the shorter duration of TAT was

Because the need for OAC in patients undergoing

not superior to 6 months of TAT. However, many

stent placement is not infrequent, the need for triple

have interpreted this study to indicate that short term

anticoagulant therapy (TAT) (i.e., DAPT and OAC) is

TAT is preferable to longer term TAT, particularly in

common. Unfortunately, these patients are exposed

patients at high risk for bleeding. Taking a somewhat

to a higher bleeding risk as a result of the combina-

different approach, the WOEST (What is the Optimal

tion therapy that often makes optimal management

Antiplatelet and Anticoagulant Therapy in Patients

challenging. At the end of the day, the clinician is

with Oral Anticoagulation and Coronary Stenting)

forced to walk a tightrope between the need to reduce

trial evaluated the impact of omitting aspirin in pa-

thrombosis and ischemia while minimizing bleeding

tients requiring antithrombotic therapy after stent

risk in patients requiring TAT. However, there are

placement and compared OAC plus clopidogrel ther-

only limited randomized clinical data to guide

apy to TAT (2). The primary study endpoint was any

decision making in these patients.

bleeding to 1 year after PCI, which occurred in 19.4%

The ISAR-TRIPLE (Triple Therapy in Patients on Oral

Anticoagulation

after

Drug

Eluting

Stent

of OAC plus clopidogrel patients (n ¼ 279), and 44.6% of TAT patients (HR: 0.36; 95% CI: 0.26 to 0.50; p < 0.001). A composite ischemic endpoint of death, MI, stroke, target revascularization, and stent throm-

*Editorials published in JACC: Cardiovascular Interventions reflect the

bosis occurred in 11.1% of double therapy and 17.6%

views of the authors and do not necessarily represent the views of JACC:

of TAT (HR: 0.56; 95% CI: 0.35 to 0.91; p ¼ 0.025).

Cardiovascular Interventions or the American College of Cardiology. From the Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina. Dr. Applegate has reported

The reduction in both bleeding and ischemic events in the WOEST trial was somewhat unanticipated, given

that he has no relationships relevant to the contents of this paper to

the belief that DAPT is necessary in the first month

disclose.

after stenting and in light of the results of the

Applegate

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 14, 2016 JULY 25, 2016:1484–6

Bleeding Versus Ischemia

ISAR-TRIPLE trial (i.e., no difference in bleeding).

practice, the clinician is often faced with substantial

Nonetheless, these results are intriguing. However,

gaps in knowledge when trying to decide on optimal

they also point out how much there is to learn about

therapy in any single patient. The findings from the

identifying the most important factors influencing

Bern PCI registry support the strategy of limiting TAT

thrombotic, ischemic as well as bleeding events in pa-

to 1 month in patients with high bleeding risk who

tients requiring TAT. Current guidelines recommend

require OAC after coronary stenting: bleeding com-

minimizing the duration of TAT in patients requiring

parable to a more prolonged period of TAT (although

DAPT for stents and concomitant OAC but the optimal

in patients at lower risk of bleeding) without an in-

duration and combination of TAT remains unclear.

crease in ischemic events. However, given the

SEE PAGE 1473

observational nature of these findings these results should be viewed as hypothesis generating, as

In this issue of JACC: Cardiovascular Interventions,

acknowledged by the authors. In addition to the

Koskinas et al. (3) provide observations from the Bern

nonrandomized nature of the study there are a couple

PCI registry of prospectively collected clinical out-

of aspects of the study that merit discussion and may

comes data on 8,772 consecutive patients undergoing

have an impact on the ability to generalize these ob-

PCI. A total of 568 of these patients had an indication

servations. First, cessation of TAT was most often

for OAC, and these investigators stratified clinical

achieved by discontinuing the P2Y 12 inhibitor in both

outcomes by duration of TAT: 43% were discharged

groups (85% in the short TAT group, 92% in the longer

on a regimen of 1 month of TAT and 57% on a regimen

TAT group) (L. Raber, personal communication, May

of more than 1 month of TAT (median 3 months). The

2016), similar to the ISAR-TRIPLE trial. This is an

primary endpoint was a composite of cardiac death,

important point as there are insufficient data to date

MI, stroke, definite stent thrombosis or TIMI major

indicating whether or not cessation of aspirin or a

bleeding within 1 year of follow-up. As the authors

P2Y 12 inhibitor is the optimal strategy in patients

describe, this “natural dichotomization” was a result

receiving DES requiring concomitant OAC therapy.

of following clinical guidelines and practice in which

Moreover, it is not clear that outcomes in patients

higher bleeding risk patients were treated with

receiving the newer P2Y 12 inhibitors ticagrelor or

shorter duration of TAT. This contention is supported

prasugrel would be similar to those in patients

by the clinical baseline characteristics of the patients

receiving clopidogrel requiring OAC therapy. Only

receiving 1 month of TAT: they were more commonly

limited data are available indicating that use of pra-

female, had higher HAS-BLED scores (hypertension,

sugrel as part of TAT is associated with a higher

abnormal liver or renal function, stroke or thrombo-

bleeding risk. Second, there were disparities of use of

embolism, bleeding history, elderly >age 65, drug

DES versus BMS between the 2 groups with BMS and

consumption, or alcohol abuse), and less often

standalone percutaneous coronary angioplasty used

received a DES. In multivariable analyses the com-

in 50% of 1 month TAT patients, but in only 9.3% of

posite primary endpoint occurred in 9.5% of 1 month

longer TAT patients. Additionally, there was a sub-

TAT patients, and in 12.9% of longer TAT patients

stantial difference in the type of DES used between

(HR: 1.007; 95% CI: 0.56 to 2.06; p ¼ 0.84). The sec-

the 2 groups. Whether or not these disparities had an

ondary composite ischemic endpoint (cardiac death,

impact on the study observations is unclear but it

MI, stroke or definite stent thrombosis) between the

certainly gives one pause in attempting to translate

2 groups was similar with a HR of 1.12 (95% CI: 0.55

the findings beyond the study population.

to 2.29; p ¼ 0.76), as was the composite secondary

Clinical investigation of the optimal approach to

bleeding endpoint (Bleeding Academic Research

the patient requiring both DAPT and OAC is compli-

Consortium bleeding $3, or TIMI major bleeding; HR:

cated by many factors, including the nonuniform

0.62; 95% CI: 0.21 to 1.80; p ¼ 0.37). These results

distribution of ischemic risk after stenting, as well as

were consistent in stratified analysis in patients with

an uncertain effect of the type and intensity of anti-

acute coronary syndrome (ACS) (vs. non-ACS) as well

coagulation on the bleeding risk. The risk of stent

as those undergoing PCI with DES (vs. BMS). The

thrombosis and ischemic events post-PCI is highest in

authors concluded that 1 month of TAT, used prefer-

the first month after PCI, and is strongly influenced

entially in patients with higher estimated bleeding

by clinical presentation. Patients with ST-segment

risk, was associated with similar net clinical outcomes

elevation MI have substantially higher early stent

compared with longer TAT durations, up to 1 year of

thrombosis rates than patients with stable ischemic

clinical follow-up.

heart disease. Moreover, the complexity of coronary

Although adequately powered randomized clinical

disease, stent type, and comorbid illnesses also in-

trials provide the strongest data to help shape

fluence the risk of stent thrombosis and these affects

1485

1486

Applegate

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 14, 2016 JULY 25, 2016:1484–6

Bleeding Versus Ischemia

may not be simply additive. In contrast, the risk of

fibrillation who under coronary stenting will be ran-

thrombotic events such as stroke in patients with

domized to 1 of 2 “dual therapy” arms: 110 mg of

atrial fibrillation, as well as the bleeding risk in pa-

dabigatran etexilate bid and clopidogrel or ticagrelor,

tients requiring OAC is more consistent across time.

or 150 mg dabigatran etexilate bid and clopidogrel or

Use of OAC carries with it a cumulative risk deter-

ticagrelor, and compared to “triple therapy” with a

mined by the duration of the need for, and intensity,

VKA, 100 mg aspirin, and clopidogrel or ticagrelor (5).

of anticoagulant therapy. The use of novel oral anti-

Although the trial results are greatly anticipated, it is

coagulant agents introduces yet another variable in

unlikely that either 1 or both of these trials will

this complex milieu. With such a complex interaction

address all of the issues outlined previously that

of the risk of thrombotic and ischemic events, as well

affect ischemic and bleeding rates in patients

as that of bleeding, it is not surprising that identifying

requiring both DAPT and OAC.

the definitive duration of optimal TAT in patients requiring both OAC and DAPT has been uncertain.

At the end of the day, the type, and duration, of OAC and antiplatelet therapy needs to be individu-

Two large randomized clinical trials are now

alized, recognizing the differential impact of clinical

enrolling patients to help shed light on the optimal

presentation leading to coronary intervention, the

duration, and combination of antiplatelet and OAC to

bleeding risk of the patient, and the intensity and

be used in patients requiring TAT. In the PIONEER

need of OAC. The results of the Bern PCI registry

AF-PCI (A Study Exploring Two Strategies of Rivar-

should provide some comfort to practitioners that in

oxaban [JNJ39039039; BAY-59-7939] and One of Oral

patients identified at the time of a coronary inter-

Vitamin K Antagonist in Patients With Atrial Fibril-

vention to have a higher than normal bleeding risk,

lation Who Undergo Percutaneous Coronary Inter-

a shorter duration of triple therapy can be safely

vention) trial (NCT01830543) the safety and efficacy

considered, although the exact duration of which

of 2 rivaroxaban (RIV) treatment strategies and 1

remains to be determined. As more data similar to

vitamin K antagonist (VKA) strategy will be assessed

that provided by the Bern PCI registry are available,

in 2,100 patients with nonvalvular atrial fibrillation

the tightrope that the clinician walks between

who undergo coronary stenting: 15 mg of RIV and

reducing bleeding while minimizing ischemic events

clopidogrel (or other P2Y 12 inhibitor) for 12 months

in patients who require both DAPT and OAC should

without aspirin; 2.5 mg twice daily (bid) RIV, 81 mg

get wider (more confidence) and lower to the ground

aspirin, and 1, 6, or 12 months of a P2Y12 inhibitor; and

(softer fall).

dose-adjusted International Normalized Ratio (2 to 3 target) with VKA, and DAPT for 1, 6, or 12 months (4).

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

In the REDUAL-PCI (Evaluation of Dual Therapy with

Robert J. Applegate, Section of Cardiovascular Medi-

Dabigatran vs Triple Therapy with Warfarin in Pa-

cine, Wake Forest School of Medicine, Medical Center

tients with AF that undergo a PCI with Stenting) study

Boulevard, Winston-Salem, North Carolina 27157-

(NCT02164864) 2,500 patients with nonvalvular atrial

1045. E-mail: [email protected].

REFERENCES 1. 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: 1619–29.

3. Koskinas KC, Räber L, Zanchin T, et al. Duration of triple antithrombotic therapy and outcomes among patients undergoing percutaneous coronary intervention. J Am Coll Cardiol Intv 2016;9: 1473–83.

2. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention:

4. Gibson CM, Mehran R, Bode C, et al. An openlabel, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin k antagonist

An open-label, randomised, controlled trial. Lancet 2013;381:1107–15.

treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary

intervention (PIONEER AF-PCI). Am Heart J 2015; 169:472–8.e5. 5. Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (REDUAL-PCI). Available at: https://clinicaltrials.gov/ct2/show/ NCT02164864. Accessed May 17, 2016.

KEY WORDS bleeding, ischemia, triple anticoagulation