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Bioresorbable polymer stents for high-risk coronary artery disease patients Evaluating new evidence on small vessel disease from the BIO-RESORT trial

IntroductionOver the last decade, the technology of intravascular stents has evolved into three main classes following disappointing results with the fully bioresorbable stent scaffold. These are bare metal stents, durable polymer drug-eluting stents (DP-DESs) and hybrid biodegradable polymer drug-eluting stents (BP-DESs). In the BP-DES class, results are influenced by factors such as differences in thickness of stent struts, attributes of the biodegradable polymer (duration of degradation, situation on stent), and the selected antiproliferative agent and its release kinetics.1

Increasingly, patients with diabetes and small-vessel disease and those at high bleeding risk are set to benefit further as data emerge on the advantages of the newer-generation BP-DESs in these high-risk patients requiring percutaneous coronary intervention (PCI). Results from clinical trials of differing stent types are presented in this review and illustrate the benefits of these new technologies.

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KEY MESSAGES

• Newer-generation BP-DESs have been shown to be non-inferior to contemporary thicker-strut second-generation DP-DESs in treating all-comer patients

• Newer-generation BP-DESs improve long-term, five-year clinical outcomes for coronary artery disease (CAD) in comparison with second-generation DP-DESs

• In small-vessel lesions, biodegradable ultra-thin-strut sirolimus-eluting stents (Orsiro-SES) showed fewer repeated target lesion revascularisations and stent thrombosis than durable thin-strut zotarolimus-eluting stents.

The BIO-RESORT and BIOFLOW-V trials of BP-DESs vs DP-DESs in CADMore than 3000 patients with obstruc-tive CAD were randomly assigned (1:1:1) in the BIO-RESORT trial to the ultra-thin-strut bioresorbable sirolimus-elut-ing stent, Orsiro-SES; a very thin-strut bioresorbable everolimus-eluting stent, Synergy-EES; or a previous-generation

zotarolimus-eluting durable stent, Resolute Integrity-ZES (Table 1). The pri-mary endpoint was a composite of safety (cardiac death or target vessel-related myocardial infarction (MI)) and efficacy (target lesion revascularisation (TLR)) at 12 months of follow-up.

Table 1. Attributes of stents used in the BIO-RESORT trial

Type of stent Uncoated strut Coated strut Coating type

Orsiro-SES* 60µm (≤3.00mm)(ultra-thin)

71µm Asymmetrical

Synergy-EES 74µm (≤3.00mm)(very thin)

78µm Abluminal

Resolute Integrity-ZES 91µm(thin)

102µm Conformal

All DESs were available in 2.25-4.00mm + lengths of 8-40mm* click here to view attributes of Orsiro-SES

In this assessor- and patient-blinded eval-uation of outcomes at one year, both the ultra-thin and very thin-strut DESs (with dissimilar biodegradable polymer coat-ings eluting either everolimus or siroli-mus) were shown to be non-inferior to the durable polymer stent in treating all-comer patients, with a high proportion (70%) of these patients presenting with

acute coronary syndromes (ACSs).2 In another large clinical outcome trial,

the BIOFLOW-V trial3 of the ultra-thin Orsiro bioresorbable stent versus contem-porary second-generation durable stents, the Orsiro stent was shown to be superior at reducing target lesion failure (TLF) over a five-year period, driven by less tar-get-vessel MI (Figure 1).

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Bioresorbable polymer stents for high-risk coronary artery disease patients

While five-year results from the BIO-RESORT trial are not yet available, three-year results in prespecified subgroups

have just been released and are yielding important new insights.

BIO-RESORT outcomes in small coronary vessels at three yearsTreatment of lesions in small vessels is associated with worse clinical outcomes. In the DUTCH-PEERS randomised trial, an evaluation of the size of treated vessels that resulted in increased TLF showed that the threshold of <2.5mm is a suitable point to identify small target-vessel size that will contribute to higher TLF rates.4

The Small Vessel Subgroup analy-sis of the BIO-RESORT trial used this

reference size in its assessor- and patient-blinded evaluation (Figure 2).5 Patients with small-vessel disease included in the sub-study were aged 34-70 years with a mean age of 64 years. Two-thirds pre-sented with ACS, 30% of the population were women and 20% had diabetes. Most patients presented with complex target lesions (Table 2).

Ultra-thin 2nd Generation

Study Events N Events N RR (95% CI) Weight (D+L)

Orsiro

0.1 101

BIOFLOW II 0 298 0 154 0.52 (0.01, 26.04) 1.91

BIOFLOW V 4 884 3 450 0.68 (0.15, 3.03) 13.11

BIORESORT 4 1169 3 1173 1.34 (0.30, 5.98) 13.11

BIOSCIENCE 9 1 063 4 1056 2.24 (0.69, 7.26) 21.18

ORIENT 0 250 0 122 0.49 (0.01, 24.59) 1.91

PRISON IV 1 165 1 165 1.00 (0.06, 15.99) 3.82

SORT OUT VII 5 1261 15 1264 0.33 (0.12, 0.92) 28.69

D+L Subtotal (I-squared=6.5%. p=0.378) 0.81 (0.43, 1.53) 83.74

I-V Subtotal 0.80 (0.44, 1.45)

MiStentDESSOLVE-III 3 703 5 695 0.59 (0.14, 2.48) 14.34

D+L Subtotal (I-squared=NA. p=NA) 0.59 (0.14, 2.48) 14.34

I-V Subtotal 0.59 (0.14, 2.48)

BioMimemerit-V 0.51 (0.01, 25.49) 1.91

D+L Subtotal (I-squared=NA. p=NA) 0.51 (0.01, 25.49) 1.91

I-V Subtotal 0.51 (0.01, 25.49)

All StentsD+L Subtotal (I-squared=0.0%. p=0.580) 0.76 (0.44, 1.31) 100.00

I-V Overall 0.76 (0.44, 1.31)

Figure 1. Newer-generation ultra-thin-strut DESs versus older second-generation thicker-strut DESs

DESs: drug-eluting stents; D+L: Dersimonian and Laird random-effects model; I-V: inverse variance fixed effect model; RR: relative risk. Definite stent thrombosis. Trials are stratified by the type of ultra-thin-strut DES. Data are for one-year outcomes

Favours Ultra-thin Favours 2nd Generation

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Table 2. Baseline lesion characteristics

Orsiro(n=636)

Synergy(n=581)

Resolute Integrity(n=602)

p-valueOrsiro vs. Resolute Integrity

p-valueSynergy vs. Resolute Integrity

ACC-AHA lesion class

A, No. (%) 42/633 (6.6) 34/581 (5.9) 40/600 (6.7) 0.01 0.20

B1, No. (%) 139/633 (22.0) 148//581 (25.5) 180/600 (30.0) –

B2/C (complex lesion), No. (%) 452 (71.4) 399 (68.7) 380 *63.3) 0.002 0.05

Chronic total occlusion, No. (%) 24 (3.8) 21 (3.6) 26 (4.3) 0.63 0.54

In-stent restenosis, No. (%) 3 (0.5) 12 (2.1) 13 (2.2) 0.009 0.91

Severe calcification, No. (%) 113 (17.8) 111 (19.1) 126 (20.9) 0.16 0.43

Bifurcated lesion, No. (%) 222 (34.9) 206 (35.5) 205 (34.1) 0.75 0.61

Left main stem lesion, No. (%) 5 (0.8) 10 (1.7) 7 (1.2) 0.50 0.42

Lesion length, mean (SD) mm 16.61±10.07 16.50±11.26 16.16±11.11 0.46 0.61

Reference vessel diameter, mean (SD), mm

2.11±0.28 2.12±0.28 2.11±0.28 0.83 0.61

Total stent length, mean (SD), mm 28.2±17.7 27.4±18.0 28.3±19.5 0.89 0.40

Number of stents per lesion, mean (SD)

1.4±0.7 1.3±0.7 1.4±0.7 0.42 0.10

Predilation performed, No. (%) 516 (81.1) 479 (82.4) 491 (81.6) 0.85 0.69

Postdilation performed, No. (%) 428 (67.3) 433 (74.5) 418 (69.4) 0.42 0.05

Figure 2. Small vessel subgroup analysis – study overview5

1506 of 3514 patients 4 centers in Netherlands

1 : 1 : 1 randomization

Resolute Integrityn=485

Synergyn=496

Orsiron=525

Principal InvestigatorsProf. Clemens von Birgelen, Thoraxcentrum Twente, Netherlands

DesignSmall Vessel, defined as vessels with a reference diameter <2.5mm subgroup analysis of a large scale, all-corners, multi-centre, assessor and patient-blinded, randomised, non-inferiority trial.

Clinical Endpoint• Target Lesion Failure (TLF), defined as the composite

of: Cardiac Death, Target Vessel Myocardial Infaction (TV-MI) and clinically-driven Target Lesion Revascularisation (CD-TLR)

• Stent Thrombosis (ST)36-month clinical follow-up

24-month clinical follow-up

24-month clinical follow-up

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Bioresorbable polymer stents for high-risk coronary artery disease patients

During three years of follow-up, there was a significantly lower incidence of TLF in patients treated with the ultra-thin-strut DES (Orsiro) compared to those treated with the thin-strut DES (Resolute Integrity-ZES); this difference

emerged during the second year of fol-low-up (Figure 3).5 Stent thrombosis rates were also lower when ultra-thin stents were used in these smaller vessels (Figure 4); as was TLR, with 60% lower rates at three years (Figure 5).5

Figure 4. Small-vessel subgroup stent thrombosis (ST) rates at three years5,6

Dual antiplatelet therapy was discontinued at 12 months per protocol. Stent thrombosis was classified according to the Academic Research Consortium definitions.6

Definite/probable ST Definite ST

P=0.16 P=0.21P=0.97 P=0.72

Orsiro Synergy Resolute Integrity

0.6%0.4%

1.5%

1.1%

1.5%

0.8%

Figure 3. Small-vessel subgroup Target Lesion Failure (TLF) and components at three years5

Log rank: P=0.08, HR 0.68 (95% CI: 0.44–1.05)Log rank: P=0.72, HR 0.93 (95% CI: 0.62–1.39)In

cide

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of t

arge

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failu

re (%

) 12

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8

6

4

2

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Time after initial procedure (days)

0 180 360 540 720 900 1080

Orsiro Synergy Resolute Integrity

10.0%

9.5%

7.0%

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Bioresorbable polymer stents for high-risk coronary artery disease patients

DeNovo Medica

@deNovoMedica

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

Published by

70 Arlington Street, Everglen, Cape Town, 7550Tel: (021) 976 0485 I info@denovomedica.com

deNovo MedicaReg: 2012/216456/07

The BIO-RESORT trial and patients at high bleeding risk A substantial portion of PCI patients are at high bleeding risk and also have an increased risk of ischaemic events. Theoretically, BP-DESs should offer these patients better outcomes with reduced inflammation and better healing rates, but to date no unequivocal benefit of BP-DESs over contemporary DP-DESs has been shown. For this reason, there is special interest in the recent evaluation of patients at high bleeding risk as a sub-group within the BIO-RESORT trial.

In this evaluation, patients were classi-fied as being at high bleeding risk if they:1. Were older than 75 years2. Were users of anticoagulation therapy 3. Had a haemoglobin level of <6.8mmol/l 4. Had a platelet count of <100 000/mm3

5. Had previous gastrointestinal bleeding or stroke, or intracranial bleeding

6. Had renal insufficiency requiring dial-ysis or were current users of non-ste-roidal anti-inflammatory drugs.

In the first year of follow-up, the primary endpoint of target-vessel failure occurred in 6.5% of patients treated with BP-DESs compared to 7.3% treated with DP-DESs. This overall reduction was not statisti-cally significant. The event rates in the BIO-RESORT high-bleeding-risk group was shown to be lower than in other tri-als such as the ZEUS trial, which used early-generation DP-DESs.7 Also, differ-ing dual antiplatelet therapy duration in these trials may have played a role in the reduced event rate.

At the forthcoming 2019 ESC Congress, further long-term results from the BIO-RESORT series will be announced.

ReferencesClick on reference to access the scientific article1. Kutcher MA. Biodegradable-polymer drug-eluting stents

platforms. JACC Cardiovascular Intervention 2018; 11(10): 1003-1004. DOI: 10.1016/j.jcin.2018.04.025

2. Von Birgelen C, Kok MM, van der Heijden LC, et al. Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in all-comers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial. Lancet 2016; 388(10060): 2607-2617.

3. Bangalore S, Toklu B, Patel N, et al. Newer-generation ultrathin strut drug-eluting stents versus second-generation thicker strut drug-eluting stents for coronary artery disease. Circulation 2018; 138(20): 2216-2226.

4. Van der Heijden LC, Kok MM, Danse PW, et al. Small-vessel treatment from contemporary newer-generation drug-eluting coronary stents in all-comers: Insights from

2-year DUTCH PEERS (TWENTE II) randomized trial. Am Heart J 2016; 176: 28-35.

5. Buiten RA, Ploumen EH, Zocca P, et al. Outcomes in patients treated with thin-strut, very thin-strut or ultrathin-strut drug eluting stents in small coronary vessels. JAMA Cardiology. May 2019. DOI:10.1001/jamacardio.2019.1776

6. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115(17): 2344-2351.

7. Ariotti S, Adamo M, Costa F, et al. Is bare metal stent implantation still justifiable in high bleeding risk patients undergoing coronary intervention?: A pre-specified analysis from the ZEUS trial. JACC Cardiovasc Interv 2016; 9: 426-436.

This CPD-accredited programme was written for deNovo Medica byJulia AalbersBSc (Hons) Pharmacology

Figure 5. Target Lesion Revascularisation (TLR) at three years5

60% lower rate of TLR at 3 years compared to Resolute Integrity 2.1% vs. 5.3% p=0.009

Cum

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TLR

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Orsiro Synergy Resolute Integrity

5.3%

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