Original Contribution

Initial Experience of Bioabsorbable Polymer Everolimus-Eluting Synergy Stents in High-Risk Patients Undergoing Complex Percutaneous Coronary Intervention With Early Discontinuation of Dual-Antiplatelet Therapy

Rebecca L. Noad, MB, PhD;  Colm G. Hanratty, MD;  Simon J. Walsh, MD

Rebecca L. Noad, MB, PhD;  Colm G. Hanratty, MD;  Simon J. Walsh, MD

Abstract: Aims. As more elderly and co-morbid patients require percutaneous revascularization, 1 year of dual-antiplatelet therapy (DAPT) becomes concerning. Synergy stents (Boston Scientific) allow for early cessation of DAPT. This study assessed those in our unit who underwent percutaneous coronary intervention (PCI) with a Synergy stent to examine a minimum of 6 months of clinical outcomes after early discontinuation of DAPT. Methods and Results. All non-trial patients in our unit who had PCI with a Synergy stent from August 2013 to February 2016 were retrospectively analyzed. Follow-up was by medical record review or direct contact for postprocedural complications or adverse events. In total, 185 patients underwent PCI with a Synergy stent during the study period. The mean patient age was 72.0 ± 11.0 years (range, 41-97 years). Stenting involved left main stem (14.1%), multivessel disease (33.0%), and chronic total occlusion (33.0%). DAPT discontinuation occurred in 78.4% by 3 months with no stent thrombosis. Three patients required target-vessel revascularization (TVR) by 1 year. There were no cardiac deaths or myocardial infarctions. Twenty-five patients were able to have non-cardiac procedures within the study period. Conclusion. The use of the Synergy everolimus-eluting stent allows for early discontinuation of DAPT, reducing risk of bleeding complications and facilitating non-cardiac procedures, without an increase in stent thrombosis and with excellent results for TVR.

J INVASIVE CARDIOL 2017;29(2):36-41. Epub 2016 December 15.

Key words: dual-antiplatelet therapy, complex PCI, Synergy stent


There are conflicting data in the literature regarding optimal dual-antiplatelet therapy (DAPT) duration after percutaneous coronary intervention (PCI). One year of DAPT became standard practice after PCI in many countries after the publication of the large-scale randomized controlled trials that demonstrated benefits with this approach using first-generation drug-eluting stent (DES) implantation given the increased risk of stent thrombosis (ST) – even late and very late ST – on meta-analysis, compared with bare-metal stent (BMS) implantation.1 Treatment guidelines subsequently recommended 12 months of DAPT after PCI as the standard of care, especially after DES implantation; this remains the current guideline in the United States.2 As stent technology evolved, several clinical studies suggested that there was little or no benefit to patients when shorter courses of DAPT were compared with more prolonged treatment after second-generation DES implantation. 3-6 Therefore, the most recent European guidelines for myocardial revascularization have recommended 6 months of DAPT after implantation of a DES for stable angina, but 12 months of DAPT for PCI with DES implantation for an acute coronary syndrome. 7 Most recently, a large multicenter trial has shown that selected patients may benefit from very long courses (2.5 years) of DAPT.8 In the DAPT study, continued DAPT led to reduced major adverse cardiovascular event (MACE) and ST rates, although at the expense of increased bleeding. However, none of the trials or guideline documents examined the extent or complexity of PCI performed.

Nevertheless, DAPT duration should be carefully considered at an individual patient level, where the need for concomitant anticoagulation or the presence of established risks for bleeding will often lead to shortened courses of DAPT. Historically, due to concerns about the risk of ST with first-generation DESs, this would have frequently led to clinicians treating patients with BMS implantation. For the treatment of more complex coronary disease, it has been clear for some time that each iteration of DES technology has reduced morbidity after PCI and this approach is currently difficult to justify clinically when complex lesions require treatment. The definition of complex PCI is arbitrary. Our institution defines complex PCIs as procedures known to be at a higher risk for technical failure or increased morbidity and/or mortality compared with a baseline for outcomes from national data. This includes PCI that involves rotational atherectomy, treatment of chronic total occlusion (CTO), left-main stem (LMS) disease, or PCI that occurs when there is a high risk of adverse outcomes for the patient and two Consultant Cardiologists are involved in the procedure. Using these criteria, of the 5346 PCI procedures performed at the Belfast Trust from September 2012 to August 2014, 23% of cases could be considered to involve complex PCI.

As progressively older and co-morbid patients are considered for complex procedures, the need for 1 year (or longer) of DAPT becomes an increasing concern. The use of DAPT may preclude concurrent non-cardiac procedures, and is associated with an increased risk of bleeding in an already frail population. Any new technology that allows the safe cessation of DAPT at an earlier stage is extremely relevant in today’s practice. The Synergy everolimus-eluting platinum-chromium coronary stents (Boston Scientific) demonstrate complete drug elution by 3 months with early polymer absorption9,10 and are associated with early healing/stent coverage.11 The most recent Synergy instructions for use (IFU) state that “in selected higher-risk patients where the physician determines that the risks outweigh the benefits of continued DAPT, it may be reasonable to interrupt or discontinue therapy after 1 month based on low ST rates and no observed increased risk for ST as shown in the current literature.” However, the IFU also recommends that “patients who require premature discontinuation of antiplatelet therapy should be monitored closely and have their antiplatelet therapy restarted as soon as possible per the discretion of their treating physicians.”

To date, studies assessing the Synergy stent have continued DAPT for at least 6 months,9,10 and there are limited “real world” data to compare the safety of this technology after early cessation of DAPT, particularly for patients with complex coronary disease undergoing contemporary PCI. It is worth noting that while the EVOLVE II study recruited patients with more complex disease than the EVOLVE trial, the more recent study excluded those with long lesions, small and large diameter vessels, 3-vessel disease, LMS disease, and CTOs.10 

The Synergy DES has been available for clinical use in the Belfast Trust since August 2013. These stents are currently procured at increased cost to the organization compared with workhorse DESs. For this reason, their use has been limited to clinical indications where DAPT treatment was planned to be of short duration (or had the potential to require early discontinuation), particularly when complex PCI was indicated. 

 This was a retrospective audit to assess the first 185 patients in our unit who had PCI with a Synergy DES. We aimed to assess safety outcomes after early discontinuation of DAPT in addition to clinical performance with efficacy of treatment over a minimum 6-month follow-up period. 

The primary endpoint for outcomes was target-lesion failure (TLF), defined as the composite occurrence of any target-lesion revascularization, myocardial infarction (MI) related to the target vessel, or any cardiac death. This outcome is in use in contemporary trials.10,11 ST was examined as a secondary endpoint.

Methods

Patient population. All patients in our unit who underwent PCI (except those enrolled in multicenter clinical trials) with a Synergy stent under the care of Dr Hanratty or Dr Walsh from August 2013 to February 2016 were entered in this study. Patients were included in the following studies over the same time period: 70 Syntax II (NCT02015832), 72 Consistent CTO (NCT02227771), 16 Celtic Bifurcation (NCT02232815), and 24 Ideal LM (NCT02303717). As a result of study-related confidentiality agreements, outcomes for these patients will be reported with the main trial results. However, there have been no cases of definite or probable ST in the study patients. 

According to usual care, all patients provided written informed consent for treatment by PCI. Baseline and procedural characteristics were routinely recorded and entered into a procedural database that is used for ongoing data returns for the annual British Cardiovascular Interventional Society audit. This is a mandatory requirement for all PCI procedures performed in our unit. Follow-up was by review of medical records and direct telephone contact with the patient for postprocedural complications or adverse events.

Procedures and follow-up. All PCIs were performed according to standard care. Prior to the index procedure, all patients were pre-loaded with 300 mg aspirin and a second antiplatelet (600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor). Glycoprotein IIb/IIIa use was permitted if deemed necessary by the operators. Decisions regarding lesion preparation, stent use, and stent optimization occurred at operator discretion. A maintenance dose of DAPT was continued for at least 3 months, following which the patient could continue with single-antiplatelet therapy (SAPT) or convert to oral anticoagulation (OAC) therapy (without antiplatelet treatment) at the physician’s discretion. Clinical follow-up was obtained by hospital records including electronic records (which encompass all health-care facilities in Northern Ireland), clinic visits, and direct telephone contact. The occurrence of MACE (including death from any cause, cardiac death, MI, and repeat revascularization) were recorded, as were any non-cardiac procedures that occurred once DAPT had been discontinued.

Device description. The Synergy stent consists of a thin-strut (74 µm), balloon-expandable, platinum-chromium alloy stent platform delivering everolimus from an ultrathin (4 µm) absorbable poly(lactic-co-glycolic acid) polymer, which is only applied to the abluminal side of the stent. Everolimus is completely eluted after 3 months, after which the polymer dissipates by approximately 4 months, thus minimizing polymer exposure to the vessel.9,10 

Outcomes and definitions. The primary endpoint of this study was TLF. This device-oriented endpoint is reported in other trials of contemporary PCI as suggested by the Academic Research Consortium (ARC).10,12,13 Cardiac death was defined as any death other than those specifically attributed to a non-cardiac cause. MI was defined according to the universal definition.14 ST was classified according to ARC criteria.13

Statistical analysis. Continuous parametric variables were presented as mean ± standard deviation, and continuous non-parametric variables as median (interquartile range [IQR]). Categorical variables were presented as counts and percentages. The analysis was performed using IBM SPSS Statistics for Mac, version 20.0 (IBM Corporation).

Results

Patient population. A total of 185 patients underwent PCI with a Synergy stent during the study period. One-year follow-up data are available for 86% of the cohort. The mean age was 72.0 ± 11.0 years (IQR, 41-97 years), 35.7% of the cohort was defined as elderly (age >75 years) and 11.4% defined as very elderly (age >85 years). Mean EuroSCORE was 13.9 ± 13.9 (IQR, 0.88-76.5). Median HASBLED score was 3 (IQR, 1-5), with 62.1% of patients scoring ≥3 indicating high bleeding risk. The indication for Synergy stent use was as follows: frail and/or very elderly (15.1%); concurrent anticoagulation (30.3%); need for a non-cardiac procedure (10.8%); increased bleeding risk (30.3%); or other (13.5%). Non-ST or ST-elevation MI was the presenting complaint in 32.4% of patients (Table 1).

Procedural details and medications. The coronary disease was complex, with 97.3% of patients having an American Heart Association/American College of Cardiology class C lesion, and 23.8% of patients had been turned down for surgical revascularization at a Heart Team meeting. The LMS was treated in 14.1%, multivessel disease was treated in 33.0%, calcification requiring rotablation was present in 8.64%, non-LMS bifurcation disease requiring side-branch stenting was present in 10.3%, and CTO intervention was needed in 33.0%. Mean Syntax score was 21.0 ± 10.5 (IQR, 6-53). Mean stent length/patient was 71.8 ± 40.2 mm, with 1.40 ± 0.62 lesions treated and 2.57 ± 1.33 stents implanted per patient (Table 2). 

When compared with the inclusion/exclusion criteria for the EVOLVE II trial,9 81% would have been ineligible for participation due to lesion length, number of vessels involved, LMS disease, CTO, or ST-elevation MI diagnosis.

In 145 patients, DAPT was planned to discontinue by 3 months and was to be followed by either SAPT or OAC. This occurred for all 145 patients. A further 40 patients who were identified as being at risk for early interruption of DAPT were recommended to continue DAPT for 12 months (if possible) due to an acute coronary syndrome presentation. All patients have now completed this course. Therefore, 95.6% of the patients studied are now on either SAPT or OAC (Table 3). 

Clinical outcomes and thrombosis. For the primary endpoint by 1 year, there were 2 TVRs by PCI and 1 patient underwent coronary artery bypass graft surgery for in-stent restenosis. The overall TVR rate was 1.16% (3/259) at 1 year. During maximum follow-up available, there was 1 additional TVR by PCI occurring at 17 months. 

By 1-year follow-up (median follow-up per patient, 611 days [IQR, 350-783 days]) a total of 9 patients had died from non-cardiac causes (2 patients from cancer, 2 patients from non-cardiac organ failure, 3 patients from sepsis, 1 patient from ruptured abdominal aortic aneurysm, and 1 patient from vascular complication post transcatheter aortic valve implantation), and 1 patient died from heart failure. 

Despite the patient and lesion complexity, there were no cases of ST either while taking DAPT or after discontinuation of antiplatelet therapy (acute, subacute, or late ST). There have also been no ST events beyond 1 year. Twenty-five patients were able to undergo a non-cardiac procedure after 3 months of DAPT, at a median time of 179 days (IQR, 114-260 days) post PCI. Fourteen of these procedures were for carcinoma or dysplasia, and 2 procedures were major vascular surgeries (Table 3). 

Discussion

This study is one of the first to report the use of Synergy stents in a complex lesion (defined locally) and complex patient population, with early discontinuation of DAPT. These results provide an examination of the real-world safety and efficacy of the Synergy stent. Overall, Synergy stents were associated with very low rates of TLF and ST up to 1 year, despite the cessation of DAPT at 3 months in the majority of patients.

The complexity of disease treated in our small cohort is much higher than reported in the “more comers” EVOLVE 2 study (Synergy and Promus Element Plus stents) and GHOST-EU registry (bioresorbable vascular scaffold).10,12 The lesion complexity also exceeds the “all comers” Xience V USA (Xience V)15 and Resolute studies (Xience and Integrity Resolute)16 and is more comparable to the Syntax trial (Taxus Express).17 In our cohort, the percentage of treated LMS disease was 14.1% and higher than all but 1 of the studies where these lesions were treated: EVOLVE 2 excluded LMS;9 GHOST-EU, 1%;11 Xience V USA, 2%;14 Resolute, 2%;16 and Syntax, 34%.18 Our per-patient proportion of CTO cases (33.0%) exceeds all of the studies where these lesions were treated: EVOLVE 2 excluded CTOs;9 GHOST-EU, 8%;12 Xience V USA, 3%;15 Resolute, 17%;16 all-comers Syntax group, 18%.19 The mean stent length of 71.8 mm in our cohort is also longer than most of the other studies: EVOLVE 2, 21 mm;10 GHOST-EU, 33 mm;12 Xience V USA, 21 mm;15 and Resolute, 36 mm;16 and Syntax, which was longer at 86 mm.18

With each iteration of DES technology, thrombosis rates have continued to fall. An analysis from over 94,000 PCIs in the SCAAR registry demonstrated 2-year definite ST rates of 1.3% with first-generation DES vs 0.6% with second-generation DES (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.41-0.79).20 We previously reported a 30-day subacute ST rate of 0.4% in patients discharged 6 hours after a PCI with no per-lesion exclusions for treatment by PCI or same-day discharge (patients with acute ST-elevation MI were excluded).21 In the present study, although total numbers were small, there were no incidences of ST before or after interruption of DAPT up to 1 year despite the complexity of the disease treated. This compares favorably with other studies. EVOLVE 2 reported a definite or probable ST rate of 0.4% at 12 months with Synergy stents and 0.6% with Promus Element Plus stents (DAPT recommended for at least 6 months and 12 months for those at low risk of bleeding).10 In the GHOST-EU registry, definite or probable scaffold thrombosis rates were 1.5% at 30 days and 2.1% at 6 months (93.6% of patients were prescribed DAPT for 1 year).12 In the Xience V USA study, DAPT was discontinued at 6 months with no late ST, and a low rate of definite or probable ST at 0.84% for the overall study population.15 The Resolute study reported 12-month definite or probable ST at 1.6% for zotarolimus-eluting stents and 0.7% for everolimus-eluting stents (DAPT recommended for at least 6 months).16 The ST rate at 12 months with first-generation paclitaxel-eluting stents was substantial at 3.3% in the Syntax study, where the disease complexity was more similar to our current cohort (minimum 6 months DAPT, 71% of PCI patients on DAPT at 1 year).17 

The results for TVR are also continuing to improve. In this study, 1.62% of patients required revascularization by 12 months, a result that is directly comparable to EVOLVE 2 (2.6% by 12 months in less complex disease).10 With regard to the device-specific endpoint of TLF, there were no cardiac deaths or MIs in our patients. Thus, the TLF rate is 3/259 (1.16%). This also compares favorably to other trials: EVOLVE 2, 6.7% Synergy and 6.5% Promus Element Plus;10 GHOST-EU, 4.4% at 6 months and 10.1% at 12 months;12 Xience V USA, 6.7% at 12 months;15 Resolute, 8.2% for zotarolimus-eluting stents and 8.3% for everolimus-eluting stents;16 whereas Syntax reported a 13.5% TVR rate at 1 year for paclitaxel-eluting stents.17

There has been recognition that 1 year of DAPT may not be beneficial to a significant proportion of patients. Examining HASBLED scores in our population showed 62.1% were classified as high risk (ie, estimated bleeding risk per year between 3.4% and 12.5%). Despite these risks, there were no incidences of major bleeding during follow-up, indicating that this group benefited from early discontinuation of antiplatelet therapy. In our study, 78.4% of patients were prescribed DAPT for 3 months only, followed by SAPT or OAC. A further 21.6% were advised to continue for 1 year, the majority of whom (66.6%) had a non-ST or ST-elevation MI indication for PCI. Therefore, this approach seems potentially safe and feasible after PCI with Synergy DES for selected patients, despite treating complex coronary disease.

The early cessation of DAPT allowed 16 patients in the study to undergo a non-cardiac procedure, which would have otherwise been deferred. There was a significant rate of cancer in the group, some of which led to mortality.

It is also clear that the complexity of patients referred for PCI is ever-increasing. In this study, 35.7% of patients were >75 years old, with a mean age of 72 years, compared with 64 years in EVOLVE 2,10 62 years in the GHOST-EU registry,12 64 years in XIENCE V USA,15 64 years in Resolute,16 and 65 years in Syntax.17 The EuroSCORE was significantly higher in the study group (13.9 vs 4.0 in the Syntax trial.17 Therefore, this represents a relatively elderly cohort with significant co-morbidity, a population more likely to experience bleeding complications with prolonged DAPT and potentially best served by an early cessation strategy. 

Impact on daily practice. This study demonstrates that it is possible to discontinue DAPT at 3 months, even in complex PCI, without compromising safety outcomes. This can facilitate non-cardiac surgery or reduce risk of bleeding in a frail, co-morbid population.

Study limitations. This is a 2-operator, single-center study and a limited number of patients were included. As such, any findings require confirmation in a larger population and should be viewed as hypothesis generating. All efforts were made to ensure the accuracy of the data. However, data regarding outcomes and complications were monitored locally and are not independently adjudicated.

Conclusion

In this small cohort, the use of Synergy stents allows for early discontinuation of DAPT, reducing the risk of bleeding complications and facilitating non-cardiac procedures, without an increase in the incidence of ST. The results for TLF and clinical outcomes are excellent for a group of patients with significant co-morbidities and complex coronary lesions.

References 

1.    Bavry AB, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med. 2006;119:1056-1061. 

2.    Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574-e651.

3.    Gwon H-C, Hahn J-Y, Park K-W, et al. Six-month versus 12-month dual-antiplatelet therapy after implantation of drug-eluting stents: the efficacy of Xience/Promus versus Cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125:505-513.

4.    Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual-antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-1348.

5.    Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMISE randomized trial. JAMA. 2013;310:2510-2522.

6.    Gilard M, Barragan P, Noryani AAL, et al. 6- versus 24-month dual-antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin. The randomized, multicenter ITALIC trial. J Am Coll Cardiol. 2015;65:777-786.

7.    Authors/Task Force members, Windecker S, Kolh P, Alfonso F. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619.

8.    Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual-antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-2166. 

9.    Meredith IT, Verheye S, Dubois CL, et al. Primary endpoint results of the EVOLVE trial. J Am Coll Cardiol. 2012;58:1362-1370.

10.    Kereiakes DJ, Meredith IT, Windecker S, et al. Primary outcomes of the EVOLVE II trial: a prospective randomized investigation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent. Circ Cardiovasc Interv. 2015;8. 

11.    Koppara T, Cheng Q, Yahagi K, et al. Thrombogenicity and early vascular healing response in metallic biodegradable polymer-based and fully bioabsorbable drug-eluting stents. Circ Cardiovasc Interv. 2015;8:e002427. 

12.    Capodanno A, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. EuroIntervention. 2015;10:1144-1153.

13.    Cutlip DE, Windecker S, Mehran R, et al. Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344-2351.

14.    Taylor J. Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2506-2507.

15.    Krucoff MW, Rutledge DR, Gruberg L, et al. A new era of prospective real-world safety evaluation. Primary report of XIENCE V USA (XIENCE V Everolimus eluting coronary stent systemt condition-of-approval post-market study). JACC Cardiovasc Interv. 2011;4:1298-1309.

16.    Serruys PW, Silber S, Garg S, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med. 2010;363:136-146. 

17.    Serruys PW, Morrice M-C, Keppetein P, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360:961-972.

18.    Banning AP, Westaby S, Morrice M-C, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol. 2010;55:1067-1075. 

19.    Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact or incomplete angiographic revascularization on clinical outcomes and its association with total occlusions. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol. 2013;61:282-294.

20.    Sarno G, Lagerqvist B, Frobert O, et al. Lower risk of ST and restenosis with unrestricted use of ‘new-generation’ drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J. 2012;33:606-613.

21.    Hodkinson EC, Ramsewak A, Murphy JC, et al. An audit of outcomes after same-day discharge post-PCI in acute coronary syndrome and elective patients. J Interv Cardiol. 2013;26:570-577.


From the Cardiology Department, Belfast Health and Social Care Trust, Northern Ireland. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hanratty and Dr Walsh report speaker/proctoring honoraria from Boston Scientific. Dr Noad reports no conflicts of interest regarding the content herein.

Manuscript submitted August 22, 2016, final acceptance given September 1, 2016.

Address for correspondence: Rebecca Noad, MB, PhD, Cardiology Department, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, Northern Ireland. Email: rnoad01@qub.ac.uk

/sites/invasivecardiology.com/files/36-41%20Noad%20JIC%202017%20Feb%20wm.pdf