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STATE-OF-THE-ART REVIEW

Antiplatelet Therapy After Implantationof Bioresorbable Vascular ScaffoldsA Review of the Published Data, Practical Recommendations,and Future Directions

Davide Capodanno, MD, PHD,a Dominick J. Angiolillo, MD, PHDb

ABSTRACT

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The introduction of bioresorbable vascular scaffolds (BVS) for clinical use has raised a number of questions on whether

current dual-antiplatelet therapy (DAPT) recommendations after drug-eluting stent (DES) implantation, mostly deriving

from data on second-generation DES, are also applicable to this completely different technology. This article aims to

review the technical shortcomings of BVS—the most extensively studied fully bioresorbable coronary stent—and its

contemporary rates of scaffold thrombosis, with a focus on recommendations for DAPT duration. (J Am Coll Cardiol Intv

2017;10:425–37) © 2017 by the American College of Cardiology Foundation.

I n patients undergoing percutaneous coronaryintervention (PCI), dual-antiplatelet therapy(DAPT), consisting in the combination of aspirin

and a P2Y12 inhibitor, is the cornerstone of treat-ment to prevent ischemic events, including stentthrombosis (1,2). Currently, 3 oral P2Y12 inhibitors(clopidogrel, prasugrel, and ticagrelor) are approvedfor clinical use in patients undergoing PCI (1–3). Clo-pidogrel is the only agent indicated for patientswith stable coronary artery disease undergoingPCI, whereas all 3 agents are indicated for patientswho undergo PCI within the context of an acute cor-onary syndrome (ACS), with prasugrel and ticagrelorbeing preferable options in the absence of contrain-dications (1,2).

Transition to newer drug-eluting stents (DES) withthinner struts and biocompatible or biodegradablepolymers has sensibly reduced the risk of stentthrombosis compared with first-generation DES (4).

m the aFerrarotto Hospital, University of Catania, Catania, Italy; and

ksonville, Jacksonville, Florida. Dr. Capodanno has received consulting f

dicines Company, Abbott Vascular, AstraZeneca, Cordis, Bristol-Myers Squ

s or honoraria from Amgen, Bayer, Sanofi, Eli Lilly, Daiichi-Sankyo, Th

scular, Pfizer, and PLx Pharma; has received payment for participation in re

dical; and has received institutional grant support from Amgen, GlaxoS

mpany, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc.

nuscript received September 23, 2016; revised manuscript received Nove

In parallel with the improved safety profile of DES,recommendations on intensity and duration of DAPThave also evolved (1,2). However, the introduction ofbioresorbable vascular scaffolds (BVS) (Absorb GT1,Abbott Vascular, Santa Clara, California) in the marketnow raises a number of questions on whether currentDAPT recommendations after DES implantation,mostly deriving from data on second-generation DES,are also applicable to a completely different tech-nology. This article aims to review the technicalshortcomings of BVS—the most extensively studiedfully bioresorbable coronary stent—and its contem-porary rates of scaffold thrombosis (ScT), with a focuson recommendations for DAPT duration.

DAPT DURATION: CURRENT GUIDELINES

The 2016 focused updated guidelines on duration ofDAPT from the American College of Cardiology (ACC)/

the bUniversity of Florida College of Medicine-

ees or honoraria from Eli Lilly, Daiichi-Sankyo, The

ibb, and Bayer. Dr. Angiolillo has received consulting

e Medicines Company, AstraZeneca, Merck, Abbott

view activities from Johnson & Johnson and St. Jude

mithKline, Eli Lilly, Daiichi-Sankyo, The Medicines

, Novartis, CSL Behring, and Gilead.

mber 15, 2016, accepted December 15, 2016.

TABLE 1 Summary of Current A

Duration of Dual-Antiplatelet Th

Population

Acute coronarysyndrome (BMSor DES)

At least 1

Shorter (C(Classbe co

Stable ischemiaand BMS

At least 1

>1 month

Stable ischemiaand DES

At least 6

>6 mont

HBR: 3 m

Secondaryprevention

Prior MI (be rea

Adapted with permission from WindeckMontalescot et al. (56), Levine et al. (64

ACC ¼ American College of CardioloDES ¼ drug-eluting stent(s); ESC ¼ Euroinfarction.

ABBR EV I A T I ON S

AND ACRONYMS

ACC = American College of

Cardiology

ACS = acute coronary

syndrome(s)

AHA = American Heart

Association

BVS = bioresorbable vascular

scaffold

DAPT = dual-antiplatelet

therapy

DES = drug-eluting stent(s)

EES = everolimus-eluting

stent(s)

ESC = European Society of

Cardiology

MI = myocardial infarction

PCI = percutaneous coronary

intervention

PLLA = poly-L-lactide

ScT = scaffold thrombosis

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American Heart Association (AHA) recom-mend patients who receive DES in thecontext of elective PCI to be prescribed atleast 6 months of DAPT (Class I), with anoption to prolong up to 12 months if theyhave no significant overt bleeding while onDAPT and no high bleeding risk (Class IIb) (2).In cases where a DES is placed in the contextof an ACS, DAPT is required for 12 months(Class I), with an option to discontinue before12 months if the risk of morbidity frombleeding outweighs the anticipated benefit(Class IIa), and to prolong >12 months inpatients with no significant overt bleedingwhile on DAPT and no high bleeding risk(Class IIb) (5). Similarly, in the 2014 guide-lines on myocardial revascularization fromthe European Society of Cardiology (ESC),DAPT is indicated for 6 months after DESimplantation, with consideration on extend-ing DAPT beyond 6 months (Class IIb) in pa-tients at high ischemic risk and low bleeding

risk, or shortening below 6 months in patients at highbleeding risk (Class IIb) (1). DAPT duration should be12 months after an ACS, regardless of whether a DES isimplanted or not, with an option to prolong beyond 12months for selected patients after careful assessmentof ischemic and bleeding risks (Class IIb), or toshorten (i.e., 3 to 6 months) in patients deemed athigh bleeding risk (Class IIb) (6). Thus, a general andconsistent message from the ACC/AHA and ESC

CC/AHA and ESC Guidelines Recommendations for

erapy

ACC/AHA ESC

2 months (Class I-BR) Maximum of 12 months(Class I-A)

lass IIb-C-LD) or longerIIb-ASR) durations maynsidered

Shorter or longer durationsmay be considered(Class IIb-A)

month (Class I-A) At least 1 month (Class I-A)

if no HBR (Class IIb-A)

months (Class I-B-NR)

hs if no HBR (Class IIb-A) 6 months (Class I-B)

onths (Class IIb-C-LD)

1–3 years), no HBR: maysonable (Class IIb-A)

Selected patients at highischemic risk

er et al. (1), Levine et al. (2), Amsterdam et al. (5), Roffi et al. (6),), and Smith et al. (65).

gy; AHA ¼ American Heart Association; BMS ¼ bare-metal stent(s);pean Society of Cardiology; HBR ¼ high bleeding risk; MI ¼ myocardial

guidelines is that DAPT duration should be individ-ualized (Table 1). Although the default approach is torecommend DAPT for 6 months in the context ofelective PCI and 12 months after an ACS, consider-ations on extending or shortening DAPT rely on pa-tients’ individual ischemic and bleeding risk profiles.

BVS: FEATURES AND IMPLICATIONS

The Absorb BVS is made of a semicrystalline poly-L-lactide (PLLA) scaffold with a poly-D,L-lactidecoating that controls the release of everolimus(100 mg/cm2 of scaffold). Both PLLA (backbone) andpoly-D,L-lactide (coating) are fully bioresorbable anddegrade to lactic acid in about 2 to 4 years. Due to thelower tensile strength and stiffness of PLLA comparedwith metal, the struts of BVS need to be ticker thanthose of DES (i.e., w150 mm, with a strut width of 188to 213 mm depending on size) for the scaffold toguarantee the same vessel support (7). This is animportant difference, because the struts of contem-porary second-generation DES are now as thin as60 to 90 mm, a feature that might factor considerablyon the lower thrombogenicity observed comparedwith first-generation DES (4). The impact of thickerstruts on thrombus formation is obviously enhancedin conditions were layering is necessary (i.e., thepoint of overlap between 2 scaffolds). Indeed, over-lapping struts tend to heal slower than nonoverlap-ping struts at 28 days in animal models (8). Inaddition, the PLLA nature of BVS limits their abilityto be extended >0.7 mm above the nominal size. Thishas implications in terms of sizing and implantationtechnique to prevent fracture, underexpansion, orincomplete apposition (9). Although fracture andunderexpansion are known determinants of devicethrombosis, incomplete scaffold apposition is asso-ciated with delayed healing, another potential trigger(10). Dismantling of BVS at sites without completeendothelialization, leading to floating struts intothe lumen, has been also suggested to serve as anidus for thrombus formation (11). Finally, in ran-domized comparisons versus everolimus-elutingstents (EES), BVS were found to achieve less acutegain and a smaller minimal lumen diameter,which may reflect a tendency toward greater recoil(12–15).

ScT: THE DIMENSION OF THE PROBLEM

INCIDENCE AND TEMPORAL DISTRIBUTION. In ameta-analysis by Lipinski et al. (16), encompassing8,183 patients from 26 studies, definite or probableacute ScT occurred in 0.3%, and subacute ScT

FIGURE 1 Scaffold Thrombosis Rates and Potential Related Mechanisms at Different Time Intervals

Data are shown on the basis of the meta-analysis of Collet et al. (20). Data are shown as event rates and 95% confidence intervals.

DAPT ¼ dual-antiplatelet therapy.

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occurred in 0.6%. These figures reflect a lowerrisk than that reported in the GHOST-EU (Gaugingcoronary Healing with biOresorbable ScaffoldingplaTforms in Europe) registry, an earlier Europeanmulticenter registry of 1,189 all-comers patientswhere definite or probable ScT was 1.5% at 30 days(17). Conversely, the estimates from Lipinski et al. (16)are consistent with those of a prior meta-analysis byIshibashi et al. (18), encompassing 4,309 patients from18 studies (including the GHOST-EU registry), wherethe weighted rates of acute and subacute definite orprobable ScT were 0.2% and 0.6%, respectively.Similarly, in a patient-level meta-analysis of theABSORB II, ABSORB III, ABSORB CHINA, and ABSORBJAPAN trials from Stone et al. (19), the risk of ScT was0.9% at 30 days. The largest systematic review andmeta-analysis conducted so far on the topic of ScT byCollet et al. (20), encompassing 16,380 patients and256 definite or probable ScT events from 59 studies,reported slightly higher rates of both acute (0.5%) andsubacute (1.0%) ScT than those noted in previous

meta-analyses (Figure 1). As far as late ScT is con-cerned, Stone et al. (19) reported a cumulativeincidence of 0.4% between 30 days and 1 year,which is slightly lower than the 0.7% reported byCollet et al. (20).

Despite BVS being a relatively novel technology,multiple cases of very late ScT have been alreadydescribed in the published data, with the latest case sofar reported at 44 months, when an advanced stage ofscaffold resorption is presumed (11) (Figure 2).Because these cases are typically anecdotal and do notbelong to series with a clear denominator and long-term follow-up available for the vast majority of pa-tients, a fair assessment of the incidence of very lateScT is problematic. Yet, it appears increasinglyevident that this outcome is not zeroed after 1 year, atleast within the timeframe when the device is not fullyresorbed. In 2 registries of BVS, collecting 14 and 42cases of ScT, respectively, the timing of ScT wasevenly distributed from early (43% to 50% of cases) tolate (26% to 36% of cases) and very late (21% to 24% of

FIGURE 2 Published Case Reports of Very Late Scaffold Thrombosis

Time and most likely explanations are reported. DAPT ¼ dual-antiplatelet therapy.

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cases) (21,22). In the ABSORB II and ABSORB JAPANtrials, the rates of very late ScT between 1 and 2 yearswere 0.6% and 1.6%, respectively (23,24). In the studyby Collet et al. (20), a meta-analysis of 2,622 patientsfrom 10 studies with at least 2 years of follow-upavailable concluded that the incidence of very lateScT is 1.0% (Figure 1). The 3-year outcomes of ABSORBII have also been recently reported, with a 2.8% inci-dence of definite or probable ScT, which represents a1.3% absolute increase between 2 and 3 years (25).

CLINICAL CONSEQUENCES. Similar to DES throm-bosis, ScT generally presents with death or ACS.In a series from Puricel et al. (22), the clinical conse-quences of ScT were cardiac death in 14%, ST-segment elevation myocardial infarction (MI) in52%, and non–ST-segment elevation ACS in 22%. Of10 spontaneous MI at 3 years in the BVS group of theABSORB II trial, 9 were due to ScT (8 definite and1 probable, all presenting with ST-segment elevationMI), and 1 patient with definite ScT died (25).

RELATIVE RISK VERSUS DES. In the patient-levelmeta-analysis of the 4 ABSORB trials from Stone et al.(19) there were nonsignificant increases in both earlyand late ScT. In addition, the study level meta-analysisfromCassese et al. (26), including 3,738 patients from 6randomized trials of BVS versus EES, showed anincreased risk of subacute ScT. In a network meta-analysis of 147 trials from Kang et al. (4), BVS wereassociatedwith an increased risk of ScT comparedwithEES and other second-generation DES at 1 year. Allthe available meta-analyses, including the 1 fromLipinski et al. (16), concur that the overall risk of defi-nite or probable ScT is approximately 2-fold comparedwith that of EES. Notably, during the follow-up be-tween 1 and 2 years of the ABSORB II and ABSORBJAPAN trials, no cases of stent thrombosis weredetected in the EES group (vs. 0.6% and 1.6% in pa-tients treated with BVS, respectively, as noted previ-ously) (23,24). Finally, in the ABSORB II trial, definiteor probable ScT significantly increased compared withEES thrombosis at 3 years (3% vs. 0%; p ¼ 0.03) (25).

FIGURE 3 Minimum Dual-Antiplatelet Therapy Duration as Mandated by Study Protocol in Pivotal and Upcoming Bioresorbable Vascular Scaffolds Trials

A minimum of 12 months of dual-antiplatelet therapy is mandated by the protocol of all trials of bioresorbable vascular scaffolds designed after the pivotal ABSORB FIM

and ABSORB II. AIDA ¼ Amsterdam Investigator-initiateD Absorb strategy all-comers; EU ¼ European; FIM ¼ first-in-man; PCI ¼ percutaneous coronary intervention;

RCT ¼ randomized controlled trial; US ¼ American.

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MECHANISMS AND DETERMINANTS. In the meta-analysis from Lipinski et al. (16), ScT was more likelyto occur in patients with ACS. Similarly, in the meta-analysis from Ishibashi et al. (18), the weighted ratesof ScT were 0.9% and 2.2% in patients with stablecoronary artery disease and ACS, respectively. Indeed,early neointimal growth and strut coverage arereduced following ACS in patients receiving BVS (27).In the patient-level meta-analysis from Stone et al.(19), 1-year device thrombosis was independentlyassociated with diabetes mellitus, small vessels, andB2/C lesions according to the ACC/AHA classification.This analysis was not specific to BVS, because theanalyzed cohort included also patients randomized toEES. Conversely, in the study from Puricel et al. (22),left ventricular ejection fraction and treatment ofostial lesions were independently associated with ScTin BVS-treated patients at a median of 485 days. In thesame study, angiographic predictors of ScT were post-

procedural minimum lumen diameter, pre- and post-procedural reference vessel diameter, maximumfootprint (i.e., the percentage of the vascular circum-ference occupied by struts at the level of the minimumlumen diameter), and residual scaled stenosis (i.e.,the residual stenosis corrected by the nominal diam-eter of the BVS) (22). An in-depth angiographic andoptical coherence tomography analysis of 14 patientswith ScT from Karanasos et al. (21) suggested thatsuboptimal implantation with incomplete lesioncoverage, underexpansion, and malapposition com-prises the main etiology for both early and late ScT. Alikely role for technical factors in the onset of earlyand late ScT is consistent with the observation that aBVS-specific implantation protocol was associatedwith a significant reduction in ScT in the study fromPuricel et al. (22).

Population-based studies of very late ScT arecurrently limited by the lack of large series with

TABLE 2 Event Rates and Adherence to Dual-Antiplatelet Therapy in Randomized Studies of BVS

ABSORB II (23,25,43) ABSORB CHINA (14) ABSORB JAPAN (13,24) ABSORB III (15)

BVS EES BVS EES BVS EES BVS EES

Patients 335 166 241 239 266 134 1322 686

On P2Y12 inhibitors

1-yr follow-up 83.0% 83.0% 98.7% 99.2% 97.0% 97.3% 94.4% 95.0%

2-yr follow-up 36.2% 34.3% NR NR 52.3% 50.7% — —

3-yr follow-up 31.0% 30.0% — — — — — —

Definite or probable device thrombosis

1-yr follow-up 0.9% 0.0% 0.4% 0.0% 1.5% 1.5% 1.5% 0.7%

2-yr follow-up 1.5% 0.0% 0.8% 0.0% 3.1% 1.5% — —

3-yr follow-up 2.8% 0.0% — — — — — —

ARR 1–2 yr follow-up þ0.6% 0.0% þ0.4% 0.0% þ1.6% 0.0% — —

ARR 2–3 yr follow-up þ1.3% 0.0% — — — — — —

ARR ¼ absolute risk difference; BVS ¼ bioresorbable vascular scaffold; EES ¼ everolimus-eluting stent(s); NR ¼ not reported.

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sufficient follow-up. In a recent univariate analysis ofthe BVS-EXPAND registry (N ¼ 249), the followingcharacteristics tended to be associated with $3 timesincreased risk of ScT at a median follow-up of 622days: >65 years of age, long lesions, calcified lesion,and reference vessel diameter #2.5 mm (28). Mostlikely causes of very late ScT identified by the authorsof published case reports were incomplete tissuecoverage, recoil, intraluminal scaffold dismantling,and DAPT discontinuation (Figure 2) (11,29–39). Basedon the intracoronary imaging and histopathologicalanalysis of 4 cases, Raber et al. (11) suggested scaffolddiscontinuity and restenosis during the resorptionprocess to act as key determinants of very late ScT.Non–signal-attenuating zones around struts, alsoknown as peristrut low-intensity areas, which arethought to represent a surrogate marker of edema,have been identified by optical coherence tomogra-phy in patients with very late ScT. Whether thisphenomenon is innocent during the resorption phaseor the expression of underlying inflammation, trig-gering thrombosis, is unknown (40).

In summary, the available evidence suggests thatmost mechanisms of ScT are similar to those of DESthrombosis, with the possible exception of late scaf-fold dismantling (41). These factors include a numberof clinical (i.e., diabetes mellitus), angiographic (i.e.,small vessels), and technical (i.e., underexpansionand malapposition) challenges. Delayed endotheliza-tion, which tends to be more frequent when struts arethicker (42), and DAPT discontinuation have been alsodescribed as primary or secondary triggers of late andvery late ScT. Overall, these considerations outline theimportance of careful implantation techniques whenBVS are considered (i.e., with adequate pre-dilation,sizing and post-dilation) (9), but also suggest that

some patients may experience an extended period ofvulnerability for thrombotic events.

DAPT REGIMENS IN LANDMARK AND

UPCOMING STUDIES OF BVS

Figure 3 depicts the minimum duration of DAPTmandated by the protocol of landmark and upcomingtrials of BVS. The most recent trials mandated aminimum DAPT duration of 12 months, reflecting ashift toward the understanding that BVS behavedifferently than second-generation DES with regardto thrombotic complications, and require more anti-platelet protection. Notably, the protocol of theABSORB II trial mandated a minimum DAPT durationof 6 months, but 83% of patients were still on DAPT at1 year, 36% at 2 years, and 31% at 3 years, suggestingcautionary preventive use of DAPT by the study in-vestigators (23,25,43) (Table 2). Notably, all patientswho experienced late or very late ScT in the ABSORBII trial were not on DAPT. Conversely, no cases of ScToccurred in the 63 patients who never interruptedDAPT up to 3 years (25).

CONSIDERATIONS ON DAPT DURATION

AFTER BVS IMPLANTATION

The challenge of BVS is to deliver a bioresorbabledevice with a similar technical performance than thatof conventional metallic DES. To this aim, thickerstent struts are necessary, which approximate thebulky sizes of first-generation DES. Therefore, it is notsurprising that the rates of ScT reported so far in thepublished data are higher than those commonly re-ported for second-generation DES. Thicker strutsgenerate more injury at the time of implantation and

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tend to heal slowly. In addition, thick struts areassociated with high endothelial shear stress on top ofthem, which promotes platelet activation and releaseof adenosine diphosphate and thromboxane A2,2 potent platelet agonists (Central Illustration) (41).Conversely, recirculation zones with low endothelialshear stress downstream of the strut increase the localconcentration of activated platelets and attenuate theproduction of antithrombotic factors, including nitricoxide and prostacyclin (Central Illustration) (41). Thisis in line with a pilot pharmacodynamic investigationsuggesting increased platelet reactivity in patientswho received at least 1 BVS compared with controlsubjects (44), whereas another investigation failed toprove a relationship between the extent of blood-to-BVS total surface area and on-treatment plateletreactivity (45). Taken together, the previouslymentioned factors favor platelet aggregation andthrombus formation. Moreover, despite the struts ofBVS being thicker, their plastic nature leads to a lowerluminal gain and a smaller post-procedure minimallumen diameter compared with DES. Importantly,early ScT, which occurs at a time when DAPT is inplace in virtually all patients, is mostly related toprocedure-related factors. Similar to DES, the leadingmorphological substrate of acute and subacute BVSthrombosis appears to be suboptimal implantation(i.e., underexpansion, acute malapposition). There-fore, the importance of optimal sizing and implanta-tion techniques cannot be overlooked particularlywith BVS.

The previously mentioned considerations on ScThave important implications for antiplatelet treat-ment regimens to be considered in patients under-going BVS implantation. In the first 30 days afterimplantation, some centers advocate the use of pra-sugrel or ticagrelor not only in ACS, but also in thecontext of PCI for stable coronary artery disease,followed by switch to clopidogrel after 30 days (9).The rationale for this so-called “de-escalationstrategy” in stable coronary artery disease settingsstands on the notion that thrombosis rates are highestin the first month and reduce over time; moreover,patients who are more prone to receive BVS aretypically young (9), thereby being less exposed to therisk of bleeding complications associated with morepotent P2Y12 receptor inhibitors. Prasugrel and tica-grelor achieve more prompt and potent platelet in-hibition and are associated with reduced rates ofstent thrombosis (46,47). Therefore, these agents maybe of potential benefit in situations at early highthrombotic risk, including in patients undergoingelective PCI, particularly if not pre-treated with aP2Y12 receptor inhibitor (48–50). Importantly, given

the current controversies surrounding the benefitsassociated with upstream use of a P2Y12 receptor in-hibitor, a considerable number of patients undergo-ing PCI are not pre-treated with a P2Y12 receptorinhibitor, particularly in the United States (51–55).Guidelines for stable coronary artery disease from theESC do not recommend (Class III) pre-treatment ofpatients with stable angina when the coronary anat-omy is not known (56), whereas pre-treatment may beconsidered in patients with high probability for sig-nificant coronary artery disease referred to PCI (1).Although ESC guidelines on stable coronary arterydisease provide a Class IIb recommendation for theuse of prasugrel or ticagrelor in high-risk situations ofelective stenting (i.e., left main stenting, high risk ofstent thrombosis, diabetes) (56), it should be notedthat the use of prasugrel and ticagrelor in stable cor-onary artery disease is currently off-label. Moreover,whether this strategy can effectively and safely bluntthe rates of acute and subacute ScT compared withusual care warrants dedicated investigations. Evenamong patients presenting with an ACS, a consider-able number of patients are not pre-treated with aP2Y12 receptor inhibitor, and most recent guidelineupdates are neutral on the optimal approach for thesepatients. (5,6). In light of these findings in clinicalpractice, the ongoing ABSORB IV trial (NCT02173379)requires that an intravenous antiplatelet agent (eithera glycoprotein IIb/IIIa inhibitor or cangrelor) be usedfor all patients with ACS with positive cardiac bio-markers being randomized who have not been pre-treated with a P2Y12 receptor inhibitor. In patientswith ACS, prasugrel or ticagrelor should be preferredover clopidogrel (1,2).

On the basis of the previously mentioned obser-vations, and consistent with a recent survey of 152expert BVS operators (57), a 6-month DAPT durationcannot be presently recommended for patients whoreceive BVS. The risk of 1-year thrombosis was 2-foldhigher with BVS than second-generation DES in ran-domized trials where the protocol-mandated DAPTduration was 12 months. It is unknown if shorterduration of DAPT would have yielded different ef-fects, but it is likely that the risk of late thrombosiswould have been higher. Current guideline recom-mendations across both sides of the Atlantic arealigned in recommending more than 6 months ofDAPT for patients at high ischemic risk (1,2). Patientswho receive BVS might fall into this category whilethe device is not fully resorbed. The risk of bleedingneeds of course to be taken into consideration, whichleads to the simple consequence that those patientswho cannot comply with a 12-month DAPT regimenshould not receive BVS; similar considerations should

CENTRAL ILLUSTRATION Impact of Strut Thickness of Thrombogenicity

Capodanno, D. et al. J Am Coll Cardiol Intv. 2017;10(5):425–37.

(Top) Thick, rectangular struts of bioresorbable vascular scaffolds (BVS) may promote thrombogenicity. High endothelial shear stress on top of struts

activates platelets to release adenosine diphosphate (ADP) and thromboxane A2 (TXA2), 2 potent platelet aggregation promoters. Recirculation zones

with low endothelial shear stress downstream of the strut increase local concentration of activated platelets, retard re-endothelialization, and attenuate

the production of natural antagonists of von Willebrand factor (vWF), fibrinogen, and prothrombin. (Bottom) Thin, circular struts of second-generation

drug-eluting stents (DES) retain physiologic endothelial shear stress, which favors platelet quiescence on top of struts and enhances re-

endothelialization and production of antithrombotic factors downstream of struts (i.e., nitric oxide [NO], prostacyclin [PGI2], tissue plasminogen activator

[tPA]).

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be made for patients who for socioeconomic reasonscannot comply with a 12-month DAPT regimen.

There have been reports of very late events withBVS after initial mechanical dismantling of the device,and cases of very late BVS thrombosis have been

described in the 2-year report of the ABSORB JAPANtrial (24) and the 2- and 3-year reports of the ABSORB IItrial (23–25). Very late ScT has been observed in thepresence of regional suboptimal flow conditions (i.e.,persistent and acquired malapposition, strut

TABLE 3 Key Considerations on Bioresorbable

Vascular Scaffolds

The putative long-term benefit of bioresorbable vascular scaffoldsshould be weighted against the adverse safety signals emerging inrecent studies and meta-analyses with respect to scaffoldthrombosis.

Device iterations and technological advancements are expected toreduce the current rate of scaffold thrombosis.

Operators should strictly adhere to the manufacturer’s instructions foruse, in particular with regard to patient and lesion characteristicsas well as implantation techniques, when using bioresorbablevascular scaffolds, to optimize outcomes.

Dual-antiplatelet therapy remains the cornerstone of pharmacologicalprevention of scaffold thrombosis. Patients who cannot tolerate aprolonged period of dual-antiplatelet therapy are not idealcandidates for bioresorbable vascular scaffold implantation.

Gaps in platelet inhibition reflect potential windows of vulnerabilityand should be therefore avoided in patients who undergoimplantation of bioresorbable vascular scaffolds.

It may be advisable to prolong the duration of dual-antiplatelettherapy duration beyond 12 months in patients who have receivedbioresorbable vascular scaffolds and have not experiencedbleeding complications.

Whether better implantation strategies or different or newergeneration bioresorbable devices can improve the outcomes ofbioresorbable vascular scaffolds warrants specific investigations.

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discontinuity) and delayed healing, and in some re-ported cases was triggered by DAPT discontinuation.This evidence may suggest the need for prolongingDAPT beyond 12 months in patients who receive BVS,particularly when multiple devices are implanted or inthe presence of overlapping points where 2 layers ofstruts further increase the tendency to thrombus for-mation for the mechanisms described previously. Alarge-scale randomized study showed that prolongingDAPT up to 30 months reduces significantly the risk ofstent thrombosis, which is particularly true for first-generation DES (58). In view of the similar risk pro-file of BVS compared with first-generation DES, asdiscussed previously, a 24- to 30-month regimencould be considered in selected patients with multipleimplanted BVS and low risk of bleeding.

PRACTICAL RECOMMENDATIONS

ScT prevention begins with patient selection andoptimal stent implantation (Table 3). An expertconsensus document recently summarized recom-mended technical steps for PCI with BVS, andincluded numerous patient- and lesion-specific con-siderations (9). The device manufacturer has alsorecently endorsed an approach called PSP (pre-dilation, sizing, post-dilation) consisting of: 1) vesselpre-dilation with a 1:1 balloon-to-artery ratio usinga noncompliant balloon (or plaque-modificationdevices if needed) targeting full balloon expansionand residual 20% to 40% stenosis in 2 orthogonalviews; 2) scaffold selection for the best fit, considering

intravascular imaging or quantitative coronaryangiography to assist vessel sizing (avoiding implan-tation in vessels with a reference vessel diameterof <2.5 mm and >3.75 mm); and 3) high-pressure post-dilation with a noncompliant balloon up to 0.5 mmabove nominal scaffold diameter, targeting a <10%final residual stenosis in 2 orthogonal views, andensuring full strut apposition. Notably, in theABSORB II trial, a minority of patients adhered tothese criteria, which further underscores scaffold im-plantation as an area of improvement to amelioratecurrent rates of ScT (25). Operators with less experi-ence in implanting BVS should approach simpler le-sions. Overlaps should be absent or minimal, andtreatment of bifurcation lesions with 2 scaffolds isgenerally not recommended. Patients who are unlikelyto comply with prolonged DAPT or are at high risk ofbleeding should not receive BVS (Table 3). The lattermay include patients on oral anticoagulant drugs,where the combination with antiplatelet therapies(aspirin or clopidogrel) may increase the risk of majorhemorrhages (59).

In patients with ACS who are not pre-treated withP2Y12 inhibitors, it is not unreasonable to consider theuse of an intravenous agent (either a glycoprotein IIb/IIIa inhibitor or cangrelor). This should particularly bethe case in patients with ST-segment elevation MI orthose exposed to morphine who experience a delay inantiplatelet effects, primarily due to impaired drugabsorption, including with the use of the newer gen-eration P2Y12 receptor inhibitors, which may require4 to 6 h to exert their full antiplatelet effects (60–63).Patients with ACS should preferably use prasugrel orticagrelor over clopidogrel. In patients with stablecoronary artery disease, whereas clopidogrel is thetreatment of choice, it is not unreasonable to considerthe use of prasugrel or ticagrelor for the first 30 days,particularly if patients have not been pre-treated witha P2Y12 receptor inhibitor and if they are at higherthrombotic risk. After BVS implantation, DAPT shouldbe continued for at least 12 months, with an option toprolong up to 24 and beyond in selected patientsand lesions (i.e., patients with ACC/AHA B2/C lesions,>1 BVS implanted on lesions of any ACC/AHA type, orin presence of any other unfavorable clinical, angio-graphic and procedural characteristic) if no signifi-cant bleeding issues arise during the first year(Figure 4, Table 3).

FUTURE PERSPECTIVES

The landscape of scaffold technologies is rapidlyevolving. The announced next generation of theAbsorb BVS is expected to feature thinner struts

FIGURE 4 Treatment Algorithm for Duration of DAPT in Patients Undergoing PCI With BVS

Clopidogrel is the only currently used P2Y12 inhibitor studied in patients with stable ischemic heart disease (SIHD) undergoing percutaneous coronary

intervention (PCI). Considerations on a more intense regiment of dual-antiplatelet therapy (DAPT) in patients with SIHD (i.e., prasugrel or ticagrelor in

combination with aspirin [ASA] for 1 month, followed by de-escalation to regular DAPT with clopidogrel and ASA) may prevail in patients at high risk of

thrombosis, but such a recommendation is currently off-label. Arrows at the bottom of the figure denote that the optimal duration of prolonged DAPT

after bioresorbable vascular scaffold (BVS) implantation is not established. *Simple procedures include 1 BVS implanted in American College of

Cardiology (ACC)/American Heart Association (AHA) A/B1 lesions. #Complex procedures include 1 BVS implanted in ACC/AHA B2/C lesions, >1 BVS

implanted on lesions of any ACC/AHA type, or any other unfavorable clinical, angiographic, and procedural characteristics. §Considerations on the use of

ASA in combination with prasugrel or ticagrelor for the initial 30 days, followed by switch to ASA and clopidogrel, may prevail on the basis of the

individual risks of ischemia and bleeding. HBR ¼ high bleeding risk; mo ¼ months; NSTE-ACS ¼ non–ST-segment elevation acute coronary syndrome;

STEMI ¼ ST-segment elevation myocardial infarction.

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(w100 mm), a larger expansion limit ($0.75 mm overnominal), a broader pressure working range and afaster reabsorption time (data onfile, Abbott Vascular).The 2 other scaffolds available in the European market(DESsolve, Elixir Medical Corportation, Sunnyvale,California; and Magmaris, Biotronik, Berlin, Germany)

are expected to disappear in about 12 months, whichgenerates reasonable expectations on how this is goingto impact on the rates of very late ScT comparedwith first-generation BVS. The DESsolve device hasself-correcting properties, which may reduce therisk of incomplete apposition, and the Magmaris

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device—being metallic—has greater tensile strengthand ductility. These factors may contribute to bluntthe rates of early and late thrombosis noted with BVS,although no robust clinical data currently support thisconcept. Similarly, several other companies havelaunched ambitious clinical programs for their manu-factured scaffold device. There is expectation that thecurrent drawbacks of BVS may be solved in the nearfuture by the next device iterations, resembling theprogress that many current technologies haveencountered over time in the history of interventionalcardiology. It should be also noted that there is now amore comprehensive understanding and experiencewith BVS implantation compared with few yearsago, which is also expected to factor into a reductionin early and late ScT. These ameliorations willlikely have an impact on recommendations for DAPTduration, which are reasonably conservative at thepresent stage. With numerous trials dedicated toinvestigating the correct DAPT duration after DESimplantation, it is warranted that similar designsare conceived for studies encompassing patientstreated with bioresorbable scaffolds. One such study,targeting a 2,000 patient sample size, is underway(NCT02939872).

There is an emerging interest in understanding therole of optical coherence tomography for guiding theduration of DAPT. Theoretically, patients with allstruts embedded into a layer of neointima are lessexposed to the risk of ScT due to protection fromscaffold dismantling and blood-to-strut surface con-tact. However, routine follow-up of bioresorbablescaffolds by invasive intravascular imaging cannot bepresently recommended, due to its uncertain clinicalimpact. Studies are currently ongoing to define

whether DAPT duration may be tailored by usingfollow-up optical coherence tomography after DESimplantation (NCT01219894, NCT01752894). Simi-larly, there is no evidence to suggest that plateletfunction testing is effective in guiding the decision-making process with respect to DAPT in the settingof PCI with DES or bioresorbable scaffolds, androutine platelet function testing is contraindicated(1). However, according to guidelines, such assess-ments may be considered in specific high-risk situa-tions, a consideration that could apply to a proportionof patients treated with bioresorbable scaffolds (1).

CONCLUSIONS

Current guideline recommendations for DAPT dura-tion after implantation of DES should not be extendedtout court to BVS, which feature important differentcharacteristics and risk profile. This review makes acase for the development of BVS-specific recommen-dations in future DAPT guidelines, with the sugges-tion of indicating a default 12-month DAPT regimenand the option for an extended >12-month regimen inselected patients with multiple BVS implanted and atlow bleeding risk. These recommendations would belevel of evidence “C” due to the lack of randomizeddata and studies specifically designed to address theoptimal duration of DAPT after BVS implantation,which are urgently necessary.

ADDRESS FOR CORRESPONDENCE: Dr. Dominick J.Angiolillo, University of Florida College ofMedicine-Jacksonville, 655 West 8th Street,Jacksonville, Florida 32209. E-mail: dominick.angiolillo@jax.ufl.edu.

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KEY WORDS bioresorbable vascularscaffolds, dual-antiplatelet therapy