JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 7, NO. 10, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jcin.2014.07.006

EDITORIAL COMMENT

Shifting the Focus to Recurrences So Good We Can Afford it or Too Bad We Cannot Avoid it?* Marco Valgimigli, MD, PHD

perseverare

capability to minimize late loss and as such poten-

diabolicum. (To err is human, but to

tially compromise stent coverage. Inflammation was

persist in the error is diabolical.)

also noted in experimental animal models. In the

Errare

T

umano

est,

sed

—Seneca (1) he threat of early (i.e., within the first 30 days) stent thrombosis (ST) has accompanied percutaneous coronary intervention

since the early days of stent intervention. The initial attempts to mitigate that risk with aspirin, a single antiplatelet therapy, in conjunction with parenteral and oral anticoagulant medications, paved the way to the dual-antiplatelet therapy (DAPT) regimen consisting in a P2Y 12 inhibitor and aspirin, an irreversible cyclooxygenase-1 inhibitor (2,3). Because the vast majority of ST cases were noted to occur within the first

weeks after stent implantation, an arbitrary 30-day to 6-week duration of DAPT has been investigated and a 30-day duration of therapy has become the standard of care approach after uncoated stent implantation. Yet proper stent expansion was also acknowledged in these early days as a key factor to minimize the risk of stent reocclusion (4), and optimal stent expansion in some DAPT studies even a prerequisite for patients’ eligibility (2,3). The advent of the first-generation drug-eluting stent (DES) has triggered renewed interest in reassessing optimal DAPT duration after stent placement. DES per se have been initially regarded more as thrombogenic devices. This was due to their intrinsic

pivotal studies designed for stent approval, DAPT was recommended for 2 (5) or 3 (6) months after sirolimuseluting stent placement or 6 months (7) after paclitaxel-eluting stent placement. No safety issues were noted early on up to at least 1 year compared with the uncoated stents. After several anecdotal observations that firstgeneration DES were associated with the occurrence of very late ST, an entity that was at that time hardly

known

to

exist

after

bare-metal

stents

(BMS), the community reacted by endorsing a longterm, or even an indefinite, DAPT regimen after DES implantation. An extraordinary amount of scientific scrutiny has been devoted to the safety profile of first-generation DES (Figure 1). There has been not 1 single randomized, controlled study or meta-analysis of randomized studies showing that the risk of early, including either acute or subacute, as well as late (from 30 days to 1 year) ST is higher after first-generation DES compared with BMS (8). Some meta-analyses have actually provided evidence that the risk of ST within the first year may be lower after first-generation DES compared with BMS (9). On the other hand, undoubtedly, first-generation DES were consistently shown later to be associated with a 4- to 5-fold higher risk of very late (i.e., after the first year) ST compared with BMS (8,9). This

*Editorials published in the JACC: Cardiovascular Interventions reflect the

observation corroborated the perception of increased

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

thrombogenicity of DES compared with BMS and

Cardiovascular Interventions or the American College of Cardiology.

fueled the “longer the better” notion for DAPT dura-

From Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands.

tion in DES-treated patients (10).

Dr. Valgimigli has received honoraria for lectures from, is on the Advisory

First-generation DES have been entirely replaced

Board of, and has received research grants from AstraZeneca, Medtronic,

by newer generation devices. Emerging evidence of

Terumo, and The Medicines Company; has received honoraria for lectures from; and is on the Advisory Board of St. Jude, Abbott Vascular, and CID

superior safety with respect to ST and target vessel

Vascular.

myocardial infarction has been generated for some of

Valgimigli

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 10, 2014 OCTOBER 2014:1114–6

Shifting the Focus to Recurrences

the newly introduced devices compared with firstgeneration DES (11–13). Importantly, most of these second-generation stents were approved in noninferiority trials compared with first-generation DES. Therefore, few

studies have directly compared

second-generation DES with BMS. There is a growing literature suggesting that at least some secondgeneration devices may be safer not only when compared with first-generation but also with the corresponding BMS counterparts (13–15). Still, the last chapter of the first-generation DES saga needs to be written, including answering the question of how long will the enhanced risk of ST remain such after implantation as well as identifying how to best treat patients presenting with ST. Unlike the vast amount of rigorous statistics

F I G U R E 1 PubMed Citations for Stent Thrombosis

generated on the incidence and distribution of ST

The number of PubMed citations stratified by the year of publication using the

events over time after first-generation devices, the

search term “stent thrombosis.”

complete absence of randomized data to inform on the best management strategy for patients presenting with ST is notable. observation

SEE PAGE 1105

carries

important

implications

with

respect to the duration of secondary preventive

In this issue of JACC: Cardiovascular Interventions, Armstrong et al. (16) report on a combined retrospective and prospective observational California registry of angiographic definite ST at 5 academic

measures in this relatively small yet challenging patient population. Two procedural and 1 post-procedural management strategies deserve specific comments.

hospitals from 2005 to 2013. The entry criterion was

At the time of the index ST event, intravascular

the occurrence of a definite ST, which was observed

ultrasound was used in w1 in every 4 patients. Given

in 221 patients of an unknown number of patients at

the well-known capability of intravascular ultrasound

risk. With the important caveat of not knowing the

to shed new light on the reasons underlying an ST

exact timing of first ST event after the index proce-

event, including undersizing, malapposition, and re-

dure for each stent type, 104 (47%) patients had

sidual untreated vessel dissection, I tend to believe

received a first-generation DES, 51 (23%) a BMS, and

that an intravascular imaging modality should be

19 (9%) a second-generation DES. After a median

offered to all patients experiencing this catastrophic

follow-up of 3.3 years, definite or probable recurrent

scenario. Importantly, large proximal vessel diameter

ST (rST) developed in 29 patients, whereas 19 pre-

and initial ST at bifurcation were identified as inde-

sented with angiographic definite rST.

pendent rSTs. These findings emphasize the need for

The cumulative hazard ratio of definite or probable

optimal stent deployment and apposition as a key

rST was 16% at 1 year and 24% at 5 years. The

procedural factor to mitigate the risk of recurrences.

cumulative hazard ratio of angiographic definite rST

These observations are consistent with the Dutch

was 11% at 1 year and 20% at 5 years. Taken together,

stent thrombosis registry that showed undersizing to

these findings confirm the high risk of ST recurrences

be among the most important predictors of ST, sec-

after the occurrence of the first ST and call for dedi-

ond only to clopidogrel discontinuation within the

cated treatment protocols for patients presenting

first 30 days (17). A second remarkable procedural aspect is that >1

with ST. A

second

key

piece

of

information

that

is

patient in every 2 underwent restenting in the

conveyed by this important analysis is that the risk

setting of the first ST event. New stent deploy-

of recurrence is highest in the first few months after

ment was not identified as a predictor of rST in

the first event, but it does not abate entirely over

this registry. Yet, given the relatively low number of

time. This study suggests that w50% of events are

recurrent ST events, caution should be used in in-

clustered within the first year after reintervention,

terpreting current findings, especially considering

whereas the remaining 50% of events occur from

that the reasons for restenting were not collected. It

the second to the fifth year of follow-up. This

is noteworthy that 2 independent studies previously

1115

1116

Valgimigli

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 7, NO. 10, 2014 OCTOBER 2014:1114–6

Shifting the Focus to Recurrences

suggested an association between restenting and

compared with clopidogrel. Hence, the use of clopi-

mortality after the first ST event (17,18). While

dogrel after ST cannot be regarded as an effective

acknowledging that only a prospective, randomized,

treatment option. Considering the long-term risk of

controlled trial could conclusively ascertain the risk-

recurrence after the first ST, it may be reasonable in

benefit ratio of restenting, based on available retro-

this highly selected high-risk patient population to

spective data (17,18), additional stent implantation

make any effort to maintain DAPT in the very long

in the setting of ST should probably be restricted to a

term, if tolerated.

bailout strategy. Because stent underexpansion or

Finally, all attempts should be made to retrieve

undersizing is known to frequently contribute to

any possible driver of ST, including inspection of the

ST, optimal, ideally imaging-guided, further expan-

index procedure and careful assessment of a patient’s

sion of the originally implanted stent should most

history, focusing on compliance with antiplatelet

likely be the goal of reintervention beyond vessel

therapy and appraisal of possible triggers, which also

recanalization.

comprise prothrombotic morbidity and concomitant

The majority of patients were discharged on

medications.

aspirin and clopidogrel in this registry. This reflects

If ST avoidance is the mind-set of every interven-

the limited availability of more potent and consistent

tional cardiologist during every stent procedure,

P2Y 12 inhibitors during the study period. Both pra-

prevention

sugrel and ticagrelor have been shown to be associ-

commitment from all potential stakeholders.

of

recurrences

requires

even

more

ated with a significant reduction of definite and definite or probable ST compared with clopidogrel

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

(19,20). Moreover, both studies indicated that the

Marco Valgimigli, Thoraxcenter, Ba 587, Erasmus Medical

number of recurrent events is also significantly

Center, ’s-Gravendijkwal 230, 3015 CE Rotterdam, the

decreased by treatment with ticagrelor or prasugrel

Netherlands. E-mail: [email protected].

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16. Armstrong EJ, Sab S, Singh GD, et al. Predictors and outcomes of recurrent stent thrombosis: results from a multicenter registry. J Am Coll Cardiol Intv 2014;7:1105–13. 17. van Werkum JW, Heestermans AA, de Korte FI, et al. Long-term clinical outcome after a first angiographically confirmed coronary stent thrombosis: an analysis of 431 cases. Circulation 2009;119:828–34. 18. Burzotta F, Parma A, Pristipino C, et al. Angiographic and clinical outcome of invasively managed patients with thrombosed coronary bare metal or drug-eluting stents: the OPTIMIST study. Eur Heart J 2008;29:3011–21. 19. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357: 2001–15. 20. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–57.

14. Sabate M, Brugaletta S, Cequier A, et al. The EXAMINATION Trial (Everolimus-Eluting Stents

KEY WORDS intravascular imaging, myocardial

Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction): 2-year results from a

infarction, recurrent stent thrombosis, stent, stent thrombosis, thrombectomy