Percutaneous coronary interventions
from various perspectives
PERCUTANEOUS CORONARY INTERVENTIONS
FROM VARIOUS PERSPECTIVES
COLOFON
Lay-out: Ridderprint B.V. | www.ridderprint.nl Cover Design T.B. Kok
Printed by: Ridderprint B.V. | www.ridderprint.nl ISBN: 978-90-365-4671-3
This thesis is part of the Health Sciences Series of the Health Technology and Services Department, University of Twente, Enschede, the Netherlands: HSS 18-25. ISSN: 1878-4968.
©2018 Marlies M. Kok
All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior permission of the author.
Financial support by the Dutch Heart Foundation for publication of this thesis is gratefully acknowledged.
Additional financial support for printing this thesis was kindly provided by: Stichting Kwaliteitsverbetering Cardiologie, Lide Jannink Stichting KNMG district Twente, Stichting Thoraxcentrum Twente, Medical School Twente.
PERCUTANEOUS CORONARY INTERVENTIONS
FROM VARIOUS PERSPECTIVES
DISSERTATION to obtain
the degree of doctor at the University of Twente on the authority of the rector magnificus,
Prof. dr. T.T.M. Palstra,
on account of the decision of the graduation committee, to be publicly defended
on Thursday 13 December 2018 at 14.45
by
Marlies Melanie Kok
Born on 13 October 1988 In Zevenaar, the Netherlands
This dissertation has been approved by the promotors: Prof. dr. C. von Birgelen
Members of the committee Chairman/Secretary
Prof. dr. Th. A.J. Toonen University of Twente, Enschede Promotor
Prof. dr. C. von Birgelen University of Twente, Enschede Co-promotor
Dr. C. J.M. Doggen University of Twente, Enschede Other members
Prof. dr. J.G. Grandjean University of Twente, Enschede Prof. dr. R.H. Geelkerken University of Twente, Enschede Prof. dr. R. J. de Winter University of Amsterdam, Amsterdam Prof. dr. J.C.A. Hoorntje University of Maastricht, Maastricht Prof. dr. A.H.E.M. Maas Radboud University, Nijmegen Prof. dr. P.W. Serruys Imperial College, London, UK
TABLE OF CONTENTS
Chapter 1 General Introduction and Outline of the Thesis
PART I. Clinical outcome of newer-generation drug-eluting stents
Chapter 2 Three-year safety and efficacy of treating all-comers with newer-generation Resolute Integrity or Promus Element stents in the randomized DUTCH PEERS (TWENTE II) Trial.
EuroIntervention 2017;12:2128-31
Chapter 3 Five-year outcome following randomized treatment of all-comers with zotarolimus-eluting Resolute Integrity and everolimus-eluting Promus Element coronary stents: Final report of the DUTCH PEERS (TWENTE II) Trial.
J Am Coll Cardiol Intv 2018;11:462-469
Chapter 4 Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): A three-arm, randomized, non-inferiority trial.
Lancet 2016;388:2607-17
Chapter 5 Two-year clinical outcome of all-comers treated with three highly dissimilar contemporary coronary drug-eluting stents in the randomized BIO-RESORT trial.
EuroIntervention 2018; Oct 12;14:e1049-e1056
Chapter 6 Bioresorbable coated Orsiro versus durable polymer-coated Resolute Onyx stents (BIONYX): Rationale and design of the randomized TWENTE IV multicenter trial.
American Heart Journal 2018;198:25-32
Chapter 7 Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt-chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomized non-inferiority trial. Lancet 2018;392:1235-45 11 23 25 35 51 85 105 121
Chapter 8 Clinical outcome after percutaneous coronary intervention with the COMBO stent versus Resolute Integrity and Promus Element stent: A propensity matched analysis.
EuroIntervention 2017;13:1202-1209
PART II. Diabetes, known, new or borderline
Impact on clinical outcome after coronary intervention
Chapter 9 “Silent” diabetes and clinical outcome after treatment with contemporary drug-eluting stents:
The BIO-RESORT Silent Diabetes Study. J Am Coll Cardiol Intv 2018;11:448-59
Chapter 10 Prediabetes and its impact on clinical outcome after coronary intervention in a broad patient population.
EuroIntervention 2018; Oct 12;14:e1049-e1056
PART III Sex-related differences in patients with obstructive coronary
artery disease
Chapter 11 Sex differences in chest pain after implantation of newer-generation coronary drug-eluting stents: A patient-level pooled analysis from the TWENTE and DUTCH PEERS Trials.
J Am Coll Cardiol Intv 2016;2: 553-561
Chapter 12 Impact of sex on recurrent chest pain, emergency room visits, repeat coronary angiography, and clinical endpoints two years after treatment with contemporary stents: from the BIO-RESORT trial. Submitted
PART IV Patient preferences in interventional cariology
Chapter 13 Patient preference regarding assessment of clinical follow-up after percutaneous coronary intervention: the PAPAYA study.
EuroIntervention 2016;11:1487-1494. 151 173 175 201 223 225 245 267 269
Chapter 14 Patient preference for radial versus femoral vascular access for elective coronary procedures: the PREVAS study.
Catheter Cardiovasc Interv 2018;91:17-24.
Chapter 15 Are component endpoints equal? A preference study into the practice of composite endpoints in clinical trials.
Health Expectations 2018; Aug 14: doi:10.1111/hex.12798
PART V General discussion and future perspectives
Chapter 16 General discussion and Future Perspectives Chapter 17 Summary and Conclusion
Nederlandse Samenvatting Chapter 18 Appendices List of Publications Dankwoord Curriculum Vitae 287 309 329 331 341 348 355 356 360 364
CHAPTER
GENERAL INTRODUCTION
OUTLINE OF THE THESIS
12 | CHAPTER 1
GENERAL INTRODUCTION
Coronary artery disease and its percutaneous treatment
Coronary artery disease is the result of plaque formation within the vessel wall of an artery, known as atherosclerosis, which leads to obstruction of blood flow causing insufficient oxygen supply to the myocardium.1 To restore myocardial perfusion, different percutaneous treatment strategies have been developed as an alternative to surgery with coronary artery bypass grafting (CABG).2 After the invention of balloon angioplasty by Andre Grüntzig in 1974, in which an inflatable balloon on the tip of a catheter was used to dilate obstructions in the coronary vessels, the rapidly evolving field of interventional cardiology took flight.3-12 To overcome re-narrowing of the artery over time coronary stents were developed, leading to less restenosis in the bare-metal stent era.4,5 The downside of these new devices were acute obstructions caused by thrombus formation in the metallic stent occurring shortly after implantation.6,7 Stent designs were altered adding a coating which released antiproliferative drugs in the coronary artery to solve this problem.8 These first generation drug-eluting stents (DES) showed less short term complications such as in-stent thrombosis, as compared to their predecessor the bare-metal stents.9,13 However, there remained a higher risk of late and very late stent thrombosis with these DES due to delayed endothelialization.14,15 Newer-generation drug-eluting stents were developed with novel stent coatings which were more biocompatible, reducing the inflammatory response of the vessel wall and thereby the risk of stent thrombosis.16-18 Coatings releasing drugs were altered so they would be resorbed completely, combining the short-term advantages of the drug-eluting stents with the long-term benefits of a bare-metal stents.19-22 Further advancements consisted of minimizing the strut thickness without compromising the radial strength of the stent, which resulted in ‘very thin strut’ stents with biodegradable polymers that were non-inferior to durable polymer stents with thin struts.21-25 Although clinical event rates have decreased tremendously with these contemporary drug-eluting stents in broad all-comer patient populations, specific subsets of patients remain at an increased risk of adverse events, which warrants further investigations. To level the playing field, it is important to know which patients are at a high risk, how they can be detected at an early stage, and what can be done to improve their outcome.
Diabetes
Diabetes mellitus (DM) is the most common metabolic disorder worldwide. The global incidence and prevalence of DM is rapidly increasing in both developed and developing countries, with the number of patients with DM expected to exceed 592 million worldwide by 2035.26 Compared to patients without diabetes, people with DM are between two
1
GENERAL INTRODUCTION | 13and four times more likely to have cardiovascular disease, which is why an increasing proportion of patients referred for percutaneous coronary intervention (PCI) with stent implantation is diabetic.27,28
Screening for diabetes mellitus can be performed by different approaches. Traditionally, the diagnosis of diabetes or prediabetes –an early stage of diabetes– is made based on increased fasting plasma glucose (FPG) levels or oral glucose tolerance testing (OGTT) or elevated glycated hemoglobin (HbA1c).29-31 Despite major advances in PCI and the development of newer generation drug-eluting stents and improvements in medical therapy, studies have continued to consistently show a trend toward more frequent major adverse cardiovascular events in patients with DM compared to non-DM patients.32 Whilst refinements in stent design have significantly improved outcomes in non-DM patients; with lower rates of target vessel revascularization, cardiac mortality and rates of stent thrombosis in the general population of patients undergoing coronary stenting, such improvements have not been transferred to DM patients thus far.33,34 A specific concern is the number of patients that have undetected and thus untreated (silent) diabetes, which may lead to more cardiovascular complications, and patients with an abnormal glucose metabolism that does not meet the criteria of diabetes.35 This last state, often referred to as prediabetes, is becoming more present in patients presenting with coronary artery disease requiring revascularisation, while there is still a lack of data on the potential relevance of pre-diabetes and silent diabetes in patients with proven obstructive coronary disease. Men and women
Coronary artery disease has traditionally been seen as a men’s disease.36 Evaluation of women with symptoms suggestive for myocardial ischemia is hampered by a definition of ‘typical angina’ derived largely from male study populations.37 During the last decade increasing evidence shows that there are in fact many differences between men and women presenting with ischemic heart disease: not only in symptoms at presentation to the emergency room, but also in pathophysiological differences of their coronary artery disease.38,39 Women tend to have smaller coronary arteries, making revascularisation procedures more difficult or sometimes even impossible.40 Furthermore, hormonal changes throughout a women’s life may contribute to development of microvascular disease, which is characterised by thickening of the vessel wall and sclerosis, which may contribute to their recurring chest pain, even after revascularisation of the epicardial coronary arteries.41-43 The difference in microvascular disease as a mechanism of ischemia appears to be reflected in the fact that women more often experience persistent chest pain and chest pain at rest.43,44 Since the introduction of drug-eluting stents in the clinical arena, little attention has been paid to the assessment of residual symptoms after percutaneous coronary interventions (PCI). Recurring chest pain can cause distress
14 | CHAPTER 1
leading to revisits to the emergency room, hospitalizations and excessive diagnostic testing.45 More research that takes the differences between both sexes into account is needed to optimize symptom recognition and response to treatment.46
Involving the patient
Clinical studies in interventional cardiology assessing the impact of coronary revasculation therapies mainly focus on short or long-term failure of treatment measured by ‘hard’ clinical events such as death, major stroke, repeat revascularisation or myocardial infarcation, frequently combined in a composite endpoint. This approach assumes that all underlying adverse events are of equal value.47,48 The studies are designed by clinicians and researchers without involvement of patients; however, previous research has shown that patient and physician’s perspectives are often different.49 In the current ‘era of patient-centered care’ a trend is evolving toward shared decision-making, in which a more systematic involvement of the patient’s values and preferences is desirable.50 Patient reported outcome data are becoming more frequently an object of clinical trials, and research has provided several decision support tools that help clinicians and patients deliberate about treatment options. Nevertheless, systematic assessment and involvement of patient preferences in interventional cardiology remains scarce.
Objectives
In this thesis percutaneous coronary interventions are assessed from different perspectives: the interventional cardiologist’s, the patient’s and the researcher’s perspective.
From the interventional cardiologist’s perspective, we investigated several contemporary DES and assessed their safety and efficacy on the short and long-term, in broad patient populations. We focused on the prevalence and diagnosis of diabetes and prediabetes and the impact on clinical outcome after PCI.
We investigated the sex-related differences in patients with coronary artery disease, specifically potential differences in adverse events and the presence of residual chest pain after PCI and its impact on patients’ daily life.
Further, we studied the role of the patients in research and daily clinical care, in terms of patients’ preferences for follow-up assessment, shared decision making and preference for vascular access in PCI. Finally, we studied patients’ perspectives regarding composite endpoints and the utility patients put on possible adverse outcomes of revascularization procedures.
1
GENERAL INTRODUCTION | 15OUTLINE OF THIS THESIS
The general introduction describes the development of drug-eluting stents in broad patient populations, elaborates on specific subsets at higher risk such as patients with (pre-)diabetes and women, and provides the background of the importance of patient’s involvement and their preferences.
Part I focusses on the clinical outcome of newer-generation drug-eluting stents in investigator initiated prospective all-comer trials.
Chapter 2 and Chapter 3 start to describe the long-term follow-up of the randomized DUTCH PEERS (TWENTE II) trial, in which to newer-generation DES are compared: the zotarolimus-eluting Resolute Integrity and the everolimus-eluting Promus Element stents.
Chapter 4 provides the one-year clinical outcome of the three-arm, randomized, multicenter BIO-RESORT (TWENTE III) trial, comparing three contemporary drug-eluting stents in 3514 patients, treated with either a durable polymer coated stent (Resolute Integrity) or bioresorbable polymer coated stent (Orsiro or Synergy).
Chapter 5 describes the two-year results of the BIO-RESORT trial and reports safety and efficacy beyond the primary endpoint, after the resorption of the biodegradable coatings of Orsiro and Synergy stent is completed.
Chapter 6 describes the rationale and design of the BIONYX (TWENTE IV) trial, an investigator-initiated, multicenter, international study in which a randomized comparison is performed of a thin composite wire strut, durable polymer-coated stent (Resolute Onyx) versus an ultrathin cobalt-chromium strut, bioresorbable polymer-coated stent (Orsiro). Chapter 7 assesses the primary outcome of the BIONYX trial.
Chapter 8 reports a patient level pooled analysis aiming to compare the results of the newer-generation drug-eluting stents with the dual-therapy COMBO stent. A propensity matched analysis was performed of clinical outcomes after PCI with the COMBO stent versus the Resolute Integrity or Promus Element stents.
Part II elaborates on the clinical outcome after PCI in patients with disturbed glucose metabolism.
Chapter 9 describes the BIO-RESORT Silent Diabetes Study, in which a subset of 988 patients without previously known diabetes underwent oral glucose tolerance testing in combination with an assessment of glycosylated hemoglobin and fasting glucose to
16 | CHAPTER 1
assess the prevalence of silent diabetes and pre-diabetes and its potential impact on clinical outcome after PCI.
Chapter 10 provides the outcome data of all the patients of the BIO-RESORT trial of whom glucose metabolic states were known solely based on glycosylated hemoglobin or fasting plasma glucose, to assess the relation between pre-diabetes and one-year outcome after PCI.
Part III focusses on the differences between men and women who underwent PCI.
Chapter 11 evaluates residual chest pain after PCI with newer-generation DES in men and women, treated in the TWENTE and DUTCH PEERS trials.
Chapter 12 investigates potential differences between women and men in chest pain, repeat coronary angiography, and clinical outcome up to two years after PCI with contemporary DES in the BIO-RESORT trial.
Part IV adresses research that is focused on patient preferences in cardiovascular medicine.
Chapter 13 reports the PAPAYA study in which patient preference regarding assessment of clinical follow-up after PCI was reported.
Chapter 14 elaborates on patient preference for radial versus femoral vascular access in elective percutaneous coronary procedures from the PREVAS trial.
Chapter 15 reports the PRECORE preference study, assessing the practice of composite endpoints in clinical trials and whether patients consider all component clinical endpoints equal.
Part V summarizes the results of this thesis and the discusision.
Chapter 16 contains the general discussion of the observed findings in perspective of our current knowledge. In addition, recommendations for future investigations are proposed.
1
GENERAL INTRODUCTION | 17REFERENCES
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18 | CHAPTER 1
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21. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with bioadbsorbably polymer- versus durable polymer-based drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol 2014;63:299-307.
22. von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet. 2014;383:413-23. 23. Smits PC, Hofma S, Togni M, et al. Abluminal biodegradable polymer biolimus-eluting stent
versus durable polymer everolimus-eluting stent (COMPARE II): a randomised, controlled, non-inferiority trial. Lancet 2013;381:651–60.
24. Raungaard B, Jensen LO, Tilsted HH, et al. Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial. Lancet 2015;385:1527–35.
25. de Winter RJ, Katagiri Y, Asano T, et al. A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial. Lancet. 2018;391:431-440.
26. Guariguata L. Whiting DR, Hambleton I. Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49.
27. Aronson D, Rayfiel E. Diabetes and obesity. Atherosclerosis and Coronary Artery Disease 1996;327-359.
28. Kedhi E, Généreux P, Palmerini T, et al. Impact of coronary lesion complexity on drug-eluting stent outcomes in patients with and without diabetes mellitus: analysis from 18 pooled randomized trials. J Am Coll Cardiol 2014;63:2111–8.
29. Ryden L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology(ESC) and developed in collaboration with the European Association for the Study of Diabetes(EASD). Eur Heart J 2013;34:3035-87.
30. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;27:S81-90.
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32. Tada T, Kimura T, Morimoto T et al. Comparison of three-year clinical outcomes after sirolimus-eluting stent implantation among insulin-treated diabetic, non-insulin-treated diabetic, and non-diabetic patients form j-Cypher registry. Am J Cardiol 2011;107:1155-62.
33. Stone GW, Kedhi E, Kereiakes DJ, et al. Differential clinical responses to everolimus-eluting and Paclitaxel-eluting stents in patients with and without diabetes mellitus. Circulation 2011;124:893-900.
34. Bangalore S, Kumar S, Fusaro M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomised trials. BMJ 2012;345:e5170.
35. Rydén L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2013;34:3035-87.
36. Wenger N. Women and coronary heart disease: a century after Herrick. Understudied, underdiagnosed, and undertreated. Circulation 2012;126:604-611.
37. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med 1996;16:1311-5.
38. Canto JG, Goldberg RJ, Hand MM, et al. Symptom presentation of women with acute coronary syndromes: myth vs reality. Arch Intern Med. 2007;167:2405-13.
39. Yahagi K, Davis HR, Arbustini E, Virmani R. Sex differences in coronary artery disease: pathological observations. Atherosclerosis 2015;239:260-7.
40. Jaworski R, Jankowska EA, Ponikowski P, et al. Costs of management of patients with coronary artery disease in Poland: the multicenter RECENT study. Pol Arch Med Wewn 2012;122:599– 607.
41. Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA 2005;293:477–84.
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45. Shaw LJ, Bairey Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the national institutes of health – National Heart, Lung, and Blood Institute – sponsored women’s ischemia syndrome evaluation (WISE). Circulation 2006;114:894-904.
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47. Ferreira-González I, Permanyer-Miralda G, Domingo-Salvany A, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786.
48. Borm GF, Teerenstra S, Zielhuis GA. Objective and perspective determine the choice of composite endpoint. J Clin Epidemiol. 2008;61:99-101.
49. Stolker JM, Spertus JA, Cohen DJ, et al. Re-thinking composite endpoints in clinical trials: insights from patients and trialists. Circulation 2014;130:1254-1261.
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1
GENERAL INTRODUCTION | 21CLINICAL OUTCOME OF
NEWER-GENERATION DRUG-ELUTING STENTS
Conflicts of interest statement
CvB was consultant to Boston Scientific and Medtronic; he received lecture fees from AstraZeneca and Biotronik. The institution has received research grants, provided by AstraZeneca, Biotronik, Boston Scientific, and Medtronic.
THREE-YEAR SAFETY AND EFFICACY OF
TREATING ALL-COMERS WITH
NEWER-GENERATION RESOLUTE INTEGRITY
OR PROMUS ELEMENT STENTS IN THE
RANDOMIZED DUTCH PEERS (TWENTE II) TRIAL
CHAPTER
2
Liefke C. van der Heijden, Marlies M. Kok, Marije M. Löwik, Peter W. Danse, Gillian A.J. Jessurun, Raymond W.M. Hautvast,
K. Gert van Houwelingen, Martin G. Stoel, Marc Hartmann, Gerard C.M. Linssen, Carine J.M. Doggen,
Clemens von Birgelen
26 | CHAPTER 2
ABSTRACT
Aim: The aim of this report was to assess the three-year safety and efficacy of implanting newer-generation Resolute Integrity zotarolimus-eluting stents (ZES) versus Promus Element everolimus-eluting stents (EES) in all-comers.
Methods and results: In the randomised, multicentre, investigator-initiated DUTCH PEERS trial, a total of 1,811 all-comers were 1:1 randomly assigned to treatment with ZES versus EES. A total of 1,293 patients (72%) were treated for complex lesions and 455 patients (25%) were treated for multiple lesions. The primary endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel-related myocardial infarction or target vessel revascularisation. Adverse clinical events were independently adjudicated. Three-year follow-up data were obtained in 1,807 patients (99.8%, four withdrawals). Both the ZES and EES groups, showed favourable outcomes with a similar incidence of TVF (10.7% vs. 10.3%; PLog-rank=0.77) and the individual components thereof: cardiac death (3.2% vs. 3.1%; PLog-rank=0.87), target vessel-related myocardial infarction (2.8% vs. 2.2%; PLog-rank=0.44) and target vessel revascularisation (6.0% vs. 6.2%; PLog-rank=0.87). In addition, the incidence of definite-or-probable stent thrombosis was similar for patients treated with ZES versus EES (1.4% vs. 1.1%; PLog-rank=0.66).
Conclusion: The safety and efficacy of treating all-comers with newer-generation Resolute Integrity and Promus Element stents was found to be extended up to three years.
2
THREE-YEAR OUTCOME DUTCH PEERS TRIAL | 27INTRODUCTION
Newer-generation metallic drug-eluting stents (DES), such as the cobalt-chromium-based Resolute Integrity zotarolimus-eluting stent (ZES) (Medtronic, Minneapolis, MN, USA) and the platinum chromium-based Promus Element everolimus-eluting stent (EES) (Boston Scientific, Marlborough, MA, USA), have stent designs that were developed to facilitate deliverability and further improve DES apposition.1,2 Both DES were compared for the first time in the randomised DUTCH PEERS trial, which was also the first trial ever to investigate Resolute Integrity. In 1,811 all-comers, this study demonstrated non-inferiority of the ZES versus the EES at 12-month follow-up.1 Long-term data from the DUTCH PEERS trial are of interest, as certain between-stent differences may only be discovered after years. We therefore assessed the three-year clinical outcome of percutaneous coronary interventions in the two DES arms.
METHODS
The design of the study, definitions of clinical endpoints and characteristics of patients, lesions and procedures of the multicentre, patient-blinded, investigator-initiated, 1:1 randomised DUTCH PEERS (TWENTE II) trial (ClinicalTrials.gov NCT01331707) have been reported previously.1 DUTCH PEERS enrolled 1,811 patients with any type of clinical syndrome, including 20.4% of patients with ST-elevation myocardial infarction (MI), 24.7% with non-ST-elevation MI and 71.7% with complex coronary lesions.1 The external CRO Diagram (Zwolle, the Netherlands) monitored clinical outcome in 10% of randomly selected patients and organised the adjudication of adverse events by an independent clinical events committee for both two- and three-year follow-up. The DUTCH PEERS trial complied with the Declaration of Helsinki and was approved by the Medical Ethics Committee Twente and the institutional review boards of all participating centers. All patients provided written informed consent. Clinical endpoints were defined according to the Academic Research Consortium (ARC), including the addendum on MI.3,4 Primary endpoint was target vessel failure (TVF) at one year, a composite of cardiac death, target vessel-related MI and clinically-indicated target vessel revascularisation. P-values and confidence intervals were two-sided and p-values <0.05 were considered significant. Statistics were performed as previously reported,4 using SPSS, Version 22.0 (IBM Corp. Armonk, NY, USA).
RESULTS
Three-year follow-up was obtained from 1,807 patients (99.8%; four consent withdrawals). Patients treated with Resolute Integrity ZES (n=906) and Promus Element EES (n=905) showed favourable outcomes with similar TVF rates (10.7% vs. 10.3%; PLog-rank=0.77) (Table
28 | CHAPTER 2
1, Figure 1). The incidence of the individual components of TVF was similar for both DES: cardiac death (3.2% vs. 3.1%; PLog-rank=0.87); target vessel-related MI (2.8% vs. 2.2%; P Log-rank=0.44); and target vessel revascularisation (6.0% vs. 6.2%; PLog-rank=0.87) (Table 1, Figure 1). At three-year follow-up, 6.1% of patients treated with Resolute Integrity ZES and 7.1% of patients treated with Promus Element ZES were on dual antiplatelet therapy.
Figure 1. Kaplan-Meier curves for target vessel failure and individual components.
A) Target vessel failure. B) Cardiac death. C) Target vessel-related myocardial infarction. D) Target vessel revascularisation. Patients treated with Resolute Integrity (yellow) versus PROMUS Element stents (grey).
2
THREE-YEAR OUTCOME DUTCH PEERS TRIAL | 2930 | CHAPTER 2
Figure 2. Kaplan-Meier curve for stent thrombosis. Patients treated with Resolute Integrity (yellow) versus PROMUS Element stents (grey).
Dual antiplatelet therapy means acetylsalicylic acid plus P2Y12 receptor antagonist.
As shown in Table 1 and Figure 2, the rates of defi nite and defi nite-or-probable stent thrombosis were low for patients treated with Resolute Integrity ZES and Promus Element EES (1.0% vs. 0.9%; PLog-rank=0.80 and 1.4% vs. 1.1%; PLog-rank=0.66, respectively). Due to an apparent dissimilarity between the Resolute Integrity ZES and Promus Element EES groups in the course of their time-to-event curves for defi nite or probable stent thrombosis (catch-up after >1 year vs. main increase within fi rst 12 months) (Figure 2), we performed post hoc a landmark analysis at 12-month follow-up. Defi nite or probable stent thrombosis occurred during the fi rst year in 0.6% vs. 0.9% (PLog-rank=0.41) of patients and during the second plus third years in 0.8% vs. 0.2% (PLog-rank=0.09) of patients.
DISCUSSION
The current study reports the three-year clinical outcome of the DUTCH PEERS trial, which is the fi rst randomised study to compare Resolute Integrity ZES versus Promus Element EES in all-comers.1 Patients of both stent arms had similar and relatively low rates of the main clinical endpoint TVF (10.7% vs. 10.3%), and the incidence of defi nite or probable stent thrombosis was low and comparable (1.4% vs. 1.1%).
Our fi ndings corroborate with the results of previous randomised studies, that compared the predecessors of these newer-generation DES in broad patient populations.5,6 Long-term outcome data about Resolute Integrity ZES and Promus Element EES in all-comers are scarce. The only randomised trial other than DUTCH PEERS that studied Resolute
2
THREE-YEAR OUTCOME DUTCH PEERS TRIAL | 31T able 1. Clinical out come at 3-y ear f ollo w-up of all-comer patients tr eat ed with Resolut e I n te g rit y ZES v ersus P
romus Element EES.
Outc ome a t 3 y ears Outc ome diff er enc e betw een 1 and 3 y ears Resolute Integrity ZES P romus Elemen t EES Hazar d r a tio (95% CI) PL o g-r ank Resolute Integrity ZES P romus Elemen t EES Diff e renc e (95%-CI) p -v alue Death (an y) 48 (5.3) 43 (4.8) 1.13 (0.75 – 1.70) 0.57 26 (2.9) 31 (3.5) -0.5 (-2.2 – 1.1) 0.53 C a rdiac death 29 (3.2) 28 (3.1) 1.04 (0.62 – 1.76) 0.87 14 (1.6) 18 (2.0) -0.4 (-1.7 – 0.8) 0.50 Ta rget v essel m y ocar dial infar c tion 25 (2.8) 20 (2.2) 1.26 (0.70 – 2.26) 0.44 5 (0.6) 8 (0.9) -0.3 (-1.1 – 0.5) 0.42 Clinically-indicat ed tar get v essel re vascularisation 53 (6.0) 55 (6.2) 0.97 (0.67 – 1.41) 0.87 29 (3.4) 29 (3.3) 0.0 (-1.7 – 1.7) 0.98 Clinically-indicat ed tar get lesion re vascularisation 42 (4.7) 39 (4.4) 1.09 (0.70 – 1.68) 0.71 22 (2.5) 19 (2.2) 0.4 (-1.1 – 1.8) 0.61 Ta rget v essel failur e 96 (10.7) 93 (10.3) 1.04 (0.79 – 1.39) 0.77 41 (4.9) 46 (5.4) -0.5 (-2.6 – 1.6) 0.63 Ta
rget lesion failur
e 88 (9.7) 81 (8.9) 1.10 (0.82 – 1.49) 0.53 37 (4.4) 40 (4.6) -0.3 (-2.2 – 1.7) 0.79 M ajor adv erse car diac ev ents 106 (11.7) 103 (11.4) 1.04 (0.79 – 1.37) 0.77 48 (5.7) 59 (6.9) -1.2 (-3.5 – 1.1) 0.31 P a tient-orient ed c omposit e endpoint 148 (16.4) 154 (17.0) 0.97 (0.77 – 1.21) 0.76 66 (8.0) 80 (9.6) -1.6 (-4.3 – 1.1) 0.25 Definit e -or-pr obable st ent thr ombosis 12 (1.4) 10 (1.1) 1.21 (0.52 – 2.79) 0.66 7 (0.8) 2 (0.2) 0.6 (-0.1 – 1.2) 0.11 Definit e st ent thr ombosis 9 (1.0) 8 (0.9) 1.13 (0.44 – 2.93) 0.80 6 (0.7) 2 (0.2) 0.5 (-0.2 – 1.1) 0.18 V alues ar
e n (%). *Definitions of clinical endpoints ha
v e been r epor ted pr eviously . CI: c onfidenc e int e rv al
32 | CHAPTER 2
Integrity in all-comers is the SORT OUT VI study2, but definite long-term results of that study have not yet been published. In addition, the PLATINUM trial is the only randomised trial that has published three-year folup data on the use of Promus Element in low-to-moderate risk patients (e..g. ≤2 de novo lesions in vessels ≥2.5mm), showing similar safety and efficacy for both Promus Element and Xience V (Abbott Vascular, Santa Clara, CA, USA).7 Our current three-year follow-up data support these favourable findings in a broader, greatly unrestricted patient population.
As the present study was not powered to assess between-group differences in secondary clinical endpoints, these findings should be considered hypothesis-generating. CONCLUSION
The safety and efficacy of treating all-comers with newer-generation Resolute Integrity and Promus Element stents in the randomised DUTCH PEERS trial was extended up to three years.
IMPACT ON DAILY PRACTICE
The three-year results of the DUTCH PEERS trial are the first long-term data in all-comers from a randomised comparison of the newer-generation Resolute Integrity ZES and the Promus Element EES, two stents that are often used in routine clinical practice. The consistently low rates of adverse clinical events, such as target vessel myocardial infarction, target vessel revascularisation and definite or probable stent thrombosis, provide a strong signal of sustained safety and efficacy of both metallic drug-eluting stents in this broad patient population. These long-term outcome data fill a gap in the literature and might in the future be useful for interpreting long-term data following broader applications of bioresorbable scaffolds.
Funding
This investigator-initiated study was supported equally by Boston Scientific and Medtronic.
2
THREE-YEAR OUTCOME DUTCH PEERS TRIAL | 33REFERENCES
1. von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet 2014;383:413-23. 2. Raungaard B, Okkels Jensen L, Tilsted HH, et al. Zotarolimus-eluting durable-polymer-coated
stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial. Lancet 2015;385:1527-35.
3. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.
4. Vranckx P, Cutlip DE, Mehran R, Kint PP, Silber S, Windecker S, Serruys PW. Myocardial infarction adjudication in contemporary all-comer stent trials: balancing sensitivity and specificity: addendum to the historical MI definititons used in stent studies. EuroIntervention 2010;5:871-4.
5. Iqbal J, Serruys PW, Silber S, et al. Comparison of zotarolimus- and everolimus-eluting coronary stents: final 5-year report of the RESOLUTE all-comers trial. Circ Cardiovasc Interv 2015;8:e002230.
6. Lowik MM, Lam MK, Sen H, et al. Safety of second-generation drug-eluting stents three years after randomised use in the TWENTE trial. EuroIntervention 2015;10:1276-9.
7. Meredith IT, Teirstein PS, Bouchard A, et al. Three-year results comparing platinum-chromium PROMUS element and cobalt-chromium XIENCE V everolimus-eluting stents in de novo coronary artery narrowing (from the PLATINUM trial). Am J Cardiol 2014;113:117-23.
Conflicts of interest statement
CvB was consultant to Boston Scientific and Medtronic; he received lecture fees from AstraZeneca and Biotronik. The institution has received research grants, provided by AstraZeneca, Biotronik, Boston Scientific, and Medtronic. All other authors declare that they have no conflict of interest.
FIVE-YEAR OUTCOME FOLLOWING
RANDOMIZED TREATMENT
OF ALL-COMERS WITH ZOTAROLIMUS-ELUTING
RESOLUTE INTEGRITY AND
EVEROLIMUS-ELUTING PROMUS ELEMENT
CORONARY STENTS:
FINAL REPORT OF THE DUTCH PEERS
(TWENTE II) TRIAL
CHAPTER
3
Paolo Zocca, Marlies M. Kok, Kenneth Tandjung, Peter W. Danse, Gillian A.J. Jesserun, Raymond W.M. Hautvast, K. Gert van Houwelingen, Martin G. Stoel, Alexander R. Schramm,
R.Melvyn Tjon-Joe-Gin, Frits H.A.F. de Man, Marc Hartmann, J.(Hans) W. Louwerenburg, Gerard C.M. Linssen, Marije M. Löwik,
Carine J.M. Doggen, Clemens von Birgelen
36 | CHAPTER 3
ABSTRACT
Objectives: The study sought to evaluate for the first time the 5-year outcomes after treating an all-comers population with newer-generation cobalt chromium-based Resolute Integrity zotarolimus-eluting stents (ZES) (Medtronic, Santa Rosa, California) versus platinum chromium-based PROMUS Element everolimus eluting stents (EES) (Boston Scientific, Natick, Massachusetts).
Background: The DUTCH PEERS (TWENTE II) (DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity: TWENTE II) trial is a randomized, multicenter, single-blinded, investigator-initiated all-comers trial that found at its main analysis similar 1-year safety and efficacy for both drug-eluting stents. It is the first randomized trial ever to investigate the Resolute Integrity ZES and the first trial to compare both devices. Methods: In total, 1,811 patients were 1:1 randomized to ZES versus EES. We performed a pre-specified assessment of the 5-year clinical outcomes in terms of safety and efficacy. The main endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel–related myocardial infarction, or target vessel revascularization. Secondary endpoints included the individual components of TVF, and stent thrombosis. The study was independently monitored, and adverse clinical events were independently adjudicated.
Results: Five -year clinical follow-up data was available in 1,798 (99.3%) patients. The ZES and EES groups showed favorable outcomes, with similar 5-year incidence of TVF (13.2% vs. 14.2%; plog-rank = 0.62) and its individual components: cardiac death (4.5% vs. 4.9%; plog-rank = 0.69), target vessel–related myocardial infarction (3.1% vs. 2.6%; plog-rank = 0.47), and target vessel revascularization (7.6% vs. 8.6%; plog-rank= 0.46). The 5-year incidence of definite or probable stent thrombosis was similar (1.5% vs. 1.3%; plog-rank = 0.83)
Conclusion: At 5-year follow-up, the Resolute Integrity ZES and PROMUS Element EES showed similar and sustained results in terms of safety and efficacy for treating a broad population of all-comers.
3
FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 37INTRODUCTION
Second-generation metallic drug-eluting stents (DES) have resolved the issue of late and very late coronary stent thrombosis, which occurred with first generation DES in the late post- implantation period, by improvements in stent design and polymer coatings, and the use of newer antiproliferative drugs (1). The cobalt-chromium–based Resolute Integrity zotarolimus-eluting stent (ZES) (Medtronic, Santa Rosa, California) and the platinum chromium-based PROMUS Element everolimus-eluting stent (EES) (Boston Scientific, Natick, Massachusetts) are examples of newer- generation DES that were developed to facilitate deliverability and improve DES apposition while maintaining the same durable polymer coatings and antiproliferative drugs as used in the second- generation DES (2– 4). Both DES were compared for the first time in the randomized DUTCH PEERS (DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity) trial, which demonstrated in 1,811 all-comer patients noninferiority of ZES versus EES for the primary endpoint target vessel failure (TVF) at 1-year follow-up (6.1% vs. 5.2%; noninferiority p = 0.006) (2).
Long-term data from comparative clinical DES trials are of significant interest as certain between-stent differences, such as late restenosis and very late stent thrombosis, may only be discovered after several years. However, published reports of long-term clinical outcome data are limited and not yet available for the 2 aforementioned DES. In this final report of the DUTCH PEERS trial we present the 5-year assessment of safety and efficacy of treating a broad population of all-comers by percutaneous coronary interventions (PCIs) with these newer-generation DES.
METHODS
Study design and patient populations
The design of the DUTCH PEERS trial has previously been reported (5). In short, this multicenter, patient- blinded, investigator-initiated, randomized clinical trial (NCT01331707) enrolled 1,811 patients between November 2010 and May 2012 at 4 PCI centers in the Netherlands (Thoraxcentrum Twente, Enschede; Rijnstate Hospital, Arnhem; Treant Zorg-groep, Emmen; Alkmaar Medical Center, Alkmaar). Patients 18 years of age and older and capable of providing informed consent with an indication for PCI with DES were randomized in a 1:1 fashion for treatment with Resolute Integrity ZES or PROMUS Element EES. Exclusion criteria were limited and all coronary syndromes, de novo and restenotic lesions, and coronary artery or bypass stenosis were permitted. There was no limit for lesion length, reference size, or number of lesions to be treated (2). Generally, dual antiplatelet therapy consisted of aspirin and clopidogrel and was prescribed in patients without anticoagulation therapy for 1 year. In patients on oral
38 | CHAPTER 3
anticoagulation, triple therapy was generally prescribed for 1 to 3 months, followed by a period with clopidogrel as a single antiplatelet agent. The contract research organization CardioResearch Enschede (Enschede, the Netherlands) coordinated the trial and data management. Follow-up data were obtained by the treating physician or cardiologist or dedicated research nurses every 12 months during routine visits to outpatient clinics (if they coincided with the time of follow-up) or by telephone call or medical questionnaire. Clinical outcome monitoring and event adjudication was performed by the independent external CRO Diagram (Zwolle, the Netherlands). The DUTCH PEERS trial complied with the CONSORT 2010 statement (6) and the Declaration of Helsinki, and was approved by the Medical Ethics Committee Twente and the institutional review boards of all participating centers. All patients provided written informed consent. The clinical outcome of the DUTCH PEERS trial has not been reported beyond the 3-year follow-up (7). [FIGURE 1]
Figure 1. Study flow chart
ZES= zotarolimus-eluting stent. EES= everolimus-eluting stent
Clinical endpoints
Clinical endpoints were defined according to the Academic Research Consortium, including the addendum on definition of myocardial infarction (MI) (8,9). The main endpoint was TVF at 5-year follow-up, a composite of cardiac death, target vessel-related MI or clinically indicated target vessel revascularization. Pre-specified secondary endpoints included the individual components of TVF, all-cause mortality, and definite or probable stent thrombosis. Further composite clinical endpoints were: target lesion failure (TLF) (cardiac death, any MI which was not clearly attributable to a nontarget vessel, or clinically indicated target lesion revascularization), major adverse cardiac events (MACE) (all-cause death, any MI, emergent coronary artery bypass surgery, or repeat clinically indicated target lesion revascularization), and a more global
patient-3
FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 39oriented composite endpoint (all-cause death, any MI, or any coronary revascularization). Besides this, we assessed very late clinical adverse events in all patients who had stents implanted with longitudinal stent deformation during the index procedure (2). Of all cases of longitudinal stent deformation, 6 of 9 (66.7%) cases were detected by angiography (i.e., no intracoronary imaging modalities were used) by the operator whereas all 9 cases were detected post-procedurally by the analysts. All stent deformations were located in the proximal stent entrance; additional proximal stents were implanted in 7 of 9 (77.8%) cases and post-dilation was per- formed in 8 of 9 (88.9%) cases. Death was regarded as cardiac unless an unequivocal noncardiac cause could be established. MI was defined by creatine kinase concentrations of more than double the upper limit of normal with raised confirmatory cardiac biomarkers. Revascularization procedures were regarded as clinically indicated if the angiographic diameter stenosis of the then treated lesion was 50% or more in the presence of ischemic signs or symptoms, or if the diameter stenosis was 70% or more irrespective of ischemic signs or symptoms (9).
Statistical analyses
Categorical variables were assessed with the chi-square test, whereas continuous variables were assessed with the Student t test or the Wilcoxon rank sum test, as appropriate. The time to clinical endpoints was assessed by Kaplan- Meier analyses and the log-rank test was applied to compare groups. Hazard ratios were calculated using Cox proportional hazards regression analysis. The p values and confidence intervals were 2-sided and p values < 0.05 were considered significant. Further details on statistical methods have been reported previously (2). SPSS version 22.0 (IBM Corporation, Armonk, New York) was used.
RESULTS
Out of all 1,811 patients, 5-year clinical follow-up data were available in 1,798 patients (99.3% follow-up: 3 patients were lost to follow-up and 10 withdrew consent) (Figure 1). As previously reported, there were no differences in baseline clinical and lesion characteristics between patients randomized to treatment with ZES versus EES (Table 1) (2). In both groups, large proportions of patients with acute MI presentation (46.5% vs. 43.7%) were included. Target lesion and interventional characteristics were also similar for both groups, including high rates of complex coronary lesions (American College of Cardiology/American Heart Association class B2 or C: 65.8% vs. 65.6%), with the only exception of more frequent stent post- dilation in EES (73.6% vs. 78.9%; p = 0.002) (Table 2). This is probably related to the excellent radiographic visibility of the PROMUS Element EES and has been reported in other trials (4). At discharge, most patients (99%) were treated with antiplatelet therapy that included aspirin and clopidogrel; only 18 (1%)
40 | CHAPTER 3
Table 1. Baseline demographics
Resolute Integrity ZES PROMUS Element EES p value N=906 N=905 Age (years) 63.9 ± 10.6 63.9 ± 11.0 0.97 Men 665 (73.4) 657 (72.6) 0.70 Body-mass index (kg/m2)* 28.1 ± 4.8 27.8 ± 4.6 0.39
Diabetes Mellitus (any) 167 (18.4) 157 (17.3) 0.55
Chronic renal failure† 35 (3.9) 28 (3.1) 0.37
Arterial hypertension 500 (55.2) 484 (53.5) 0.47
Hypercholesterolemia 418 (46.1) 430 (47.5) 0.56
Current smoker‡ 213 (23.6) 231 (25.5) 0.32
Family history of coronary artery disease§ 452 (50.1) 451 (49.9) 0.98
Previous myocardial infarction 207 (22.8) 190 (21.0) 0.34
Previous percutaneous coronary intervention 182 (20.1) 167 (18.5) 0.38
Previous coronary bypass surgery 84 (9.3) 89 (9.8) 0.68
Clinical syndrome at presentation Stable angina
Unstable angina
Non-ST-elevation myocardial infarction ST-elevation myocardial infarction
372 (41.1) 113 (12.5) 246 (27.2) 175 (19.3) 377 (41.7) 132 (14.6) 201 (22.2) 195 (21.5) 0.07
Acute coronary syndrome (any) 534 (58.9) 528 (58.3) 0.80
Left ventricular ejection fraction <30% 15 (1.7) 13 (1.4) 0.71
De-novo coronary lesions only 817 (90.2) 810 (89.5) 0.64
At least one chronic total occlusion 38 (4.2) 38 (4.2) 0.99
At least one bifurcation 244 (26.9) 221 (24.4) 0.22
At least one in-stent restenosis 27 (3.0) 28 (3.1) 0.89
At least one small-vessel (RVD <2.75 mm) 551 (60.8) 517 (57.1) 0.11
At least one lesion length > 27 mm 161 (17.8) 157 (17.3) 0.81
Glycoprotein IIb/IIIa antagonist 262 (28.9) 259 (28.6) 0.89
Number of lesions treated per patient One Two Three or more 668 (73.7) 191 (21.1) 47 (5.2) 668 (76.0) 182 (20.1) 35 (3.9) 0.32
Values are n (%) or mean ± SD. *Data from 721 patients in the ZES group and 703 patients in the EES group. †Chronic renal failure defined by serum creatinine level ≥130 μmol/L. ‡Data from 903 patients in the ZES group and 905 patients in the EES group. §Data from 903 patients in the ZES group and 902 patients in the EES group. ZES: zotarolimus-eluting stent. EES: everolimus-eluting stent. RVD: reference vessel diameter.
3
FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 41patients received prasugrel and 3 (<1%) patients received ticagrelor in addition to aspirin. Information regarding medication use at 5-year follow-up was available in $93.9% of all patients. In both DES groups, there was no statistically significant difference in the use of aspirin (78.7% vs. 81.3%; p = 0.17), P2Y12 receptor inhibitors (12.1% vs. 10.2%; p = 0.22), dual antiplatelet therapy (6.6% vs. 6.4%; p = 0.88), oral anticoagulant agents (15.8% vs. 15.8%; p = 0.85), or statins (86.4% vs. 85.0%; p = 0.42).
The 5-year incidence of the main clinical endpoint TVF was favorable and similar for the ZES and EES groups (13.2% vs. 14.2%; log-rank p = 0.62) (Table 3, Figure 2). The rates of the individual components of TVF were also similar for both stent arms: cardiac death (4.5% vs. 4.9%; log-rank p = 0.69); target vessel-related MI (3.1% vs. 2.6%; log-rank p = 0.47); and target vessel revascularization (7.6% vs. 8.6%; log-rank p = 0.46), respectively (Figure 2). In addition, the rates of the composite endpoints TLF (12.0% vs. 12.5%; log-rank p = 0.86), MACE (17.0% vs. 17.2%; log-rank p = 0.97), and the patient-oriented composite endpoint (22.8% vs. 23.3%; log-rank p = 0.86) were similar for both groups (Table 3).
Table 2. Target lesion characteristics and interventional procedures
Resolute Integrity ZES PROMUS Element EES p value N=1,205 lesions N=1,166 lesions De novo lesion* 1,147 (95.2) 1103 (94.6) 0.51
ACC/AHA lesion class B2/C 793 (65.8) 765 (65.6) 0.92
Reference vessel diameter (mm) 2.68 ± 0.59 2.70 ± 0.59 0.32
Implantation of assigned stents only 1,195 (99.2) 1,161 (99.6) 0.22
Number of stents per lesion 1.35 ± 0.68 1.36 ± 0.70 0.70
Total stent length per lesion (mm) 28.60 ± 18.51 29.71 ± 19.11 0.15
Direct stenting 352 (29.2) 326 (28.0) 0.50
Stent post dilation 887 (73.6) 920 (78.9) 0.002
Data are n (%) or mean ± SD. *Including chronic total occlusion, but not grafts or in-stent restenosis. ACC/AHA: American College of Cardiology/American Heart Association. ZES: zotarolimus-eluting stent. EES: everolimus-eluting stent. Details of lesion characteristics and interventional procedure have previously been reported.
42 | CHAPTER 3 T able 3 . Clinical out come at 5-y ear f ollo w-up Outc ome a t 5 y ears Outc ome diff er enc e betw een 1 and 5 y ears Resolute Integrity ZES PROMUS Elemen t EES Hazar d r a tio (95% CI) Plog-r ank Resolute Integrity ZES PROMUS Elemen t EES Diff e renc e (95%-CI) p v alue Ta rget v essel failur e 118 (13.2) 127 (14.2) 0.94 (0.73 – 1.21) 0.62 63 (7.5) 80 (9.3) -1.9 (-4.5 – 0.8) 0.17 Death (an y) 86 (9.5) 82 (9.1) 1.06 (0.78 – 1.43) 0.72 64 (7.2) 70 (7.8) -0.6 (-3.1 – 1.9) 0.64 C a rdiac death 40 (4.5) 44 (4.9) 0.92 (0.60 – 1.41) 0.69 25 (2.8) 34 (3.8) -1.0 (-2.6 – 0.7) 0.25 Ta rget v essel m y ocar dial infar c tion 28 (3.1) 23 (2.6) 1.23 (0.71 – 2.13) 0.47 8 (0.9) 11 (1.2) -0.3 (-1.3 – 0.7) 0.52 Ta rget v essel r e vascularization 66 (7.6) 75 (8.6) 0.88 (0.64 – 1.23) 0.46 42 (4.9) 49 (5.7) -0.8 (-2.9 – 1.3) 0.48 Ta
rget lesion failur
e 109 (12.0) 113 (12.5) 0.98 (0.75 – 1.27) 0.86 58 (6.8) 72 (8.4) -1.5 (-4.0 – 1.0) 0.24 M ajor adv erse car diac ev ents 154 (17.0) 156 (17.2) 1.00 (0.80-1.25) 0.97 96 (11.3) 112 (13.0) -1.7 (-4.8 – 1.4) 0.29 P a tient-orient ed c omposit e endpoint 207 (22.8) 211 (23.3) 0.98 (0.81-1.19) 0.86 125 (15.2) 137 (16.5) -1.3 (-4.8 – 2.2) 0.47 Definit e -or-pr obable st ent thr ombosis 13 (1.5) 12 (1.3) 1.09 (0.50 – 2.39) 0.83 8 (0.9) 4 (0.5) 0.4 (-0.3 – 1.2) 0.24 Definit e st ent thr ombosis 10 (1.1) 10 (1.1) 1.00 (0.42 – 2.41) 0.99 7 (0.8) 4 (0.5) 0.3 (-0.4 – 1.1) 0.36 V alues ar e n (%). CI: c onfidenc e int e rv al .
3
FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 43Figure 2. Primary endpoint and individual components
Kaplan-Meier curves for: (A) target vessel failure (TVF); (B) cardiac death; (C) target vessel-related myocardial infarction; and (D) target vessel revascularization for patients treated with Resolute Integrity zotarolimus-eluting (yellow) versus PROMUS Element everolimus-eluting stents (gray)
As shown in Table 3, the rates of definite or probable stent thrombosis were low for patients treated with ZES and EES (1.5% vs. 1.3%; log-rank p = 0.83). Due to an apparent dissimilarity between the Resolute Integrity ZES and PROMUS Element EES groups in the course of their time-to-event curves for definite or probable stent thrombosis, an additional post hoc landmark analysis at 12-month follow-up is displayed in Figure 3, Table 3. Definite or probable stent thrombosis occurred in 0.6% versus 0.9% (log-rank p = 0.41) of patients during the first year and in 0.9% vs. 0.5% (p = 0.24) during the second to fifth years.
Longitudinal stent deformation during the index procedure was observed in 9 of the patients treated with EES and in none of the patients treated with ZES. Between 1- and 5-year follow-up, 1 of these EES patients died from progressive heart failure (unrelated to the implanted study stent) whereas all other patients experienced no adverse event.
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Figure 3. Definite and probable stent thrombosis at 5-year follow-up
Kaplan-Meier curve of stent thrombosis for patients treated with Resolute Integrity zotarolimus-eluting (yellow) versus PROMUS Element everolimus-eluting stents (gray). Dual anti-platelet therapy (DAPT) means acetylsalicylic acid plus P2Y12-receptor antagonist.
DISCUSSION Main results
The present study reports the final 5-year clinical outcome of the randomized DUTCH PEERS trial, which assessed the safety and efficacy of the Resolute Integrity ZES versus PROMUS Element EES in treating all-comer patients (2). The rates of the main clinical endpoint TVF (13.2% vs. 14.2%) were relatively low and similar for both stent groups. There was also no significant between-group difference in the individual components of TVF (i.e., cardiac death, target vessel related MI, and clinically driven target vessel revascularization). Very late stent thrombosis was rare and the 5-year incidence of stent thrombosis was low and comparable in both groups (definite or probable, 1.5% vs. 1.3%). The present 5-year results are consistent with the main outcome of DUTCH PEERS trial at 1-year follow-up, which demonstrated noninferiority of ZES versus EES (2). Furthermore, landmark analyses at 1-year showed for all endpoints no statistically significant difference between the stent groups.
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FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 45Previous studies
A meta-analysis of randomized trials, comparing different types of ZES versus EES, showed comparable safety and efficacy at short-term to midterm follow-up (10). The same meta-analysis suggested that in real-world observational studies EES may be more safe and efficacious, a finding that was greatly driven by the outcome of studies that compared EES versus the no longer available Endeavor ZES, which was known to have a higher repeat revascularization risk (10,11). This underlines the importance of obtaining long-term outcome data from large-scale randomized all-comer trials to evaluate the clinical value of modified stents that may be considered to be derivatives. However, 5- year long-term outcomes of all-comers, treated either with Resolute Integrity ZES or with PROMUS Element EES, have not been reported yet (1).
The SORT OUT VI (Scandinavian Organization for Randomized Trials with Clinical Outcome VI) trial is the only other large-scale randomized trial that assessed the Resolute Integrity in all-comers (3). That study compared 1,502 patients treated with Resolute Integrity ZES versus 1,497 patients treated with biodegradable polymer-based biolimus-eluting Bio-Matrix Flex stents (Biosensors, Singapore) and showed at 3-year follow-up for both stents similar rates of the primary endpoint MACE (8.6% vs. 9.6%; p = 0.36) and all secondary endpoints, including definite or probable stent thrombosis (1.3% vs. 1.2%; p = 0.86) (12). In addition, some previous randomized studies compared the predecessor of the Resolute Integrity ZES (i.e., the Resolute ZES) with EES in broad patient populations and showed favorable 5-year outcomes for both devices (13–15).
So far, the PLATINUM (a Prospective, Randomized, Multicenter Trial to Assess an Everolimus- Eluting Coronary Stent System [PROMUS Element] for the Treatment of Up to Two de Novo Coronary Artery Lesions) trial is the only large-scale randomized study besides the DUTCH PEERS trial that has published 3-year follow-up data of PROMUS Element EES (13). In the PLATINUM trial, 758 patients treated with the platinum-chromium PROMUS Element EES were compared to 749 patients treated with the cobalt-chromium Xience V EES (Abbott Vascular, Santa Clara, California) (4). The study showed a favorable safety and efficacy for both stent groups: the TLF rate was 5.9% versus 7.1% (p = 0.40); the rate of a composite endpoint of all-cause death, MI, or target vessel revascularization was 11.4% versus 12.7% (p = 0.48); and the incidence of definite or probable stent thrombosis was low and comparable in both treatment arms (0.7% vs. 0.5%; p = 0.76) (4).
Nevertheless, the PLATINUM trial did not assess all- comers but rather a population of low- to medium- risk patients who experienced stable or unstable angina and required PCI for up to 2 de novo coronary lesions in vessels with a diameter of at least 2.5 mm. The present 5-year follow-up of the DUTCH PEERS trial supports the favorable 3-year findings of the PLATINUM trial in a much broader patient population. Besides this, our results are consistent with long-term outcomes in the COMPARE II (Abluminal biodegradable
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polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent) trial, which compared the predecessor of the PROMUS Element (i.e., the PROMUS EES) or Xience V EES to a biodegradable-polymer biolimus-eluting stent (14).
Stent thrombosis
Although the risk of very late stent thrombosis is attenuated with the introduction of second-generation DES (15–18), each individual case represents an important adverse event that can result in a large MI or death. A recent study in 64 patients with very late DES thrombosis, assessed by optical coherence tomography, revealed a median time from DES implantation until very late stent thrombosis of 4.7 years (interquartile range: 3.1 to 7.5 years) (19). This emphasizes the need for a prolonged follow-up of clinical DES trials. It is reassuring that the rate of very late stent thrombosis is low in the present 5-year analysis of the DUTCH PEERS trial, as well as in other studies with 5-year follow-up (14,20–22). Longitudinal stent deformation
Longitudinal stent deformation has been identified as a potential trade-off of newer generation DES due to a decreased longitudinal stability caused by thinner stent struts and a reduced number of connectors (23,24). However, in the DUTCH PEERS trial, longitudinal stent deformation was observed only in 0.6% of the implanted PROMUS Element EES and in none of the Resolute Integrity ZES (2). A recent meta-analysis of randomized trials showed a higher risk of observing longitudinal stent deformation in PROMUS Element EES than in other newer-generation DES that was not associated with worse clinical outcome at 1-year follow-up (25). The findings of the present analysis of the DUTCH PEERS trial extend our knowledge, as they show that longitudinal stent deformation, which was recognized and directly managed by the operator in the majority of cases, was not associated with very late adverse clinical events.
Study limitations
This analysis of the 5-year follow-up was pre-specified but the findings should be considered hypothesis generating. The high 5-year follow-up rate (>99%) and the independent monitoring and adjudication support the validity of the data, but our study is not powered to assess low- incidence adverse events. Nevertheless, in the absence of long-term data from other or even larger randomized all-comer studies to compare both DES, we believe that these data are of interest. From base- line to 5-year follow-up there was an increase in the proportion of patients on oral anticoagulation from 8.8% to 15.8%, which may be most likely related to an increase in the prevalence of atrial fibrillation during this study with long-term follow-up; the latter remains hypothetical,
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FIVE YEAR OUTCOME DUTCH PEERS TRIAL | 47as we did not assess reasons for starting oral anticoagulation. We cannot exclude some degree of selection during enrollment, as 56.2% of all eligible patients were enrolled (2). Nevertheless, it may be fair to state that this enrollment rate is relatively high for an all-comer DES trial, and the high proportion of patients who underwent the index PCI for an acute MI (45.1%) underlines that this trial provides information that is relevant to routine clinical practice.
CONCLUSIONS
At 5-year follow-up, the Resolute Integrity ZES and PROMUS Element EES showed similar and sustained results in the terms of safety and efficacy for treating a broad population of all-comers.
PERSPECTIVES What is known?
Newer-generation DES are superior to first generation DES. The DUTCH PEERS randomized trial has shown low rates of adverse clinical events, such as target vessel MI, repeat target vessel revascularization, and stent thrombosis for 2 newer-generation DES: the Resolute Integrity ZES and the PROMUS Element EES. However, data on the 5-year safety and efficacy of both stents are not available yet.
What is new?
The present long-term results of the DUTCH PEERS trial provide a strong signal of similar and sustained safety and efficacy of both metallic DES after 5 years of follow-up in a broad population of all-comer patients.
What is next?
These data are useful to interpret the long-term outcome of novel DES and to put the long-term clinical outcome after treatment with bioresorbable vascular scaffolds into perspective.
