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Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year—Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS)

Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in... Hindawi Journal of Interventional Cardiology Volume 2020, Article ID 5458064, 11 pages https://doi.org/10.1155/2020/5458064 Clinical Study Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year—Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS) 1 1 1 1 Vladimir Ganyukov , Nikita Kochergin, Aleksandr Shilov, Roman Tarasov, 2 2,3 1 4 1 Jan Skupien, Wojciech Szot, Aleksandr Kokov , Vadim Popov, Kirill Kozyrin, 1 1 2,5 Olga Barbarash, Leonid Barbarash, and Piotr Musialek Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russia Jagiellonian University School of Medicine, Krakow, Poland Dept. of Nuclear Medicine, John Paul II Hospital, Krakow, Poland Federal State Budgetary Institution A. V. Vishnevsky Institute of Surgery, Moscow, Russia Jagiellonian University Dept. of Cardiac & Vascular Diseases, John Paul II Hospital, Krakow, Poland Correspondence should be addressed to Vladimir Ganyukov; ganyukov@mail.ru and Piotr Musialek; pmusialek@szpitaljp2.krakow.pl Received 16 June 2019; Accepted 9 September 2019; Published 3 January 2020 Academic Editor: Faisal Latif Copyright © 2020 Vladimir Ganyukov et al. ‚is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. Optimal revascularization strategy in multivessel (MV) coronary artery disease (CAD) eligible for percutaneous man- agement (PCI) and surgery remains unresolved. We evaluated, in a randomized clinical trial, residual myocardial ischemia (RI) and clinical outcomes of MV-CAD revascularization using coronary artery bypass grafting (CABG), hybrid coronary revas- cularization (HCR), or MV-PCI. Methods. Consecutive MV-CAD patients (n  155) were randomized (1 :1 :1) to conventional CABG (LIMA-LAD plus venous grafts) or HCR (MIDCAB LIMA-LAD followed by PCI for remaining vessels) or MV-PCI (everolimus-eluting CoCr stents) under Heart Team agreement on equal technical and clinical feasibility of each strategy. SPECT at 12 months (primary endpoint of RI that the trial was powered for; a measure of revascularization midterm e–cacy and an independent predictor of long-term prognosis) preceded routine angiographic control. Results. Data are given, respectively, for the CABG, HCR, and MV-PCI arms. Incomplete revascularization rate was 8.0% vs. 7.7% vs. 5.7% (p  0.71). Hospital stay was 13.8 vs.13.5 vs. 4.5 days (p < 0.001), and sick-leave duration was 23 vs.16 vs. 8 weeks (p < 0.001). At 12 months, RI was 5 (2, 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with noninferiority p values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Rates of angiographic graft stenosis/occlusion or in-segment restenosis were 20.4% vs. 8.2% vs. 5.9% (p  0.05). Clinical target vessel/graft failure occurred in 12.0% vs. 11.5% vs. 11.3% (p  0.62). Major adverse cardiac and cerebral event (MACCE) rate was similar (12% vs. 13.4% vs. 13.2%; p  0.83). Conclusion. In this ¢rst randomized controlled study comparing CABG, HCR, and MV-PCI, residual myocardial ischemia and MACCE were similar at 12 months. ‚ere was no midterm indication of any added value of HCR. Hospital stay and sick-leave duration were shortest with MV-PCI. While longer-term follow-up is warranted, these ¢ndings may impact patient and physician choices and healthcare resources utilization. ‚is trial is registered with NCT01699048. 2 Journal of Interventional Cardiology evaluated all the inclusion/exclusion criteria with a partic- 1. Introduction ular attention given to equal angiographic and clinical /e optimal revascularization strategy in multivessel coro- feasibility to perform CABG or HCR or PCI. All consecutive nary artery disease (MV-CAD) remains unresolved. /e HT-cleared patients were offered participation in the study. longevity of the left internal mammary artery (LIMA) to /ose enrolled in the study (155 out of 204 HT-identified LAD graft contributes substantially to the survival benefit of eligible patients over 31 months; NB. 24%, subjects refused coronary artery bypass grafting (CABG), while the major random allocation of the treatment strategy) were ran- benefit of multivessel percutaneous intervention (PCI) is domized (external randomization on a 1:1:1 ratio) to nd lesser invasiveness [1]. With contemporary (2 generation) standard surgical revascularization (CABG with LIMA to drug-eluting stents (DES), combined restenosis and LAD and venous grafts to other vessels as a standard of thrombosis rate is lower than saphenous vein graft failure reference) or HCR (MIDCAB LIMA-LAD plus PCI for non- [2, 3]. Excellent outcomes of the LIMA-LAD graft and LAD vessel/s) or MV-PCI until all study arms reached 50 favourable outcomes of contemporary DES are the basis for subjects. In HCR, MIDCAB LIMA-LAD was always a first- active consideration of hybrid coronary revascularization stage procedure; PCI for the remaining vessels was per- (HCR; LIMA-LAD plus DES-PCI for remaining vessel/s) as formed within 3 days from surgery. All PCIs employed the “third” contemporary revascularization approach to everolimus-eluting CoCr stents (Xience, Abbott Vascular, treat patients with MV-CAD [1, 2, 4–9]. HCR is defined as a Abbott Park, Illinois, USA) as a standard of reference DES planned intervention combining cardiac surgery with a [3]. Treatment was within 7 days from randomization. catheter-based intervention performed within a predefined Prior to this trial, the study team had built experience in time [2, 4]. HCR employing a combination of a minimally performing the trial procedures (yearly volume of over 700 invasive LIMA-LAD graft procedure with PCI using DES to CABG with over 100 LIMA-LAD MIDCAB, and over 800 non-LAD vessels is receiving increasing attention [10–12] PCIs). /e study was sponsored by the Russian Academy of but it has not yet been evaluated in a clinical trial involving Sciences (RAS 056-2013-0012). /e sponsor had no influ- the two leading MV-CAD revascularization modalities, ence on the study protocol, management, or data analysis. CABG and PCI [1]. Primary follow-up point was at 12±1 months. Analysis Single-photon emission computed tomography was intention to treat (ITT). (SPECT) myocardial perfusion imaging, with percent is- chemic myocardium (residual ischemia, RI, calculated by subtracting the rest from stress total perfusion defect) is not 2.2. Primary Endpoint. Primary endpoint was residual is- only an objective method to compare the outcome of cor- chemia at 12±1 months by SPECT, with protocol-mandated onary revascularization but also there is a direct propor- SPECT preceding (by 3–7 days) the protocol-mandated tional relationship between RI extent and prognosis [13]. angiographic control. SPECT protocol and data analysis /is makes RI an attractive quantitative endpoint with an were according to those in the COURAGE Nuclear substudy evidenced relationship to long-term cardiovascular events. [13]. In brief, patients underwent a 1- or 2-day protocol with 99m 99m HREVS (Hybrid coronary REvascularization Versus rest Tc sestamibi combined with stress Tc sestamibi. Stenting or Surgery) was designed as the first randomized /e percent ischemic myocardium was calculated by sub- controlled study to assess safety and efficacy of the three tracting the rest from the stress total perfusion defect. contemporary MV-CAD revascularization modalities SPECT analysis was performed in a blinded fashion in an employing RI as the quantifiable primary endpoint. external nuclear medicine laboratory (Dept. of Nuclear Medicine, John Paul II Hospital, Krakow, Poland) using Quantitative Perfusion SPECT software (Cedars-Sinai 2. Materials and Methods Medical Center, Los Angeles, CA, USA). 2.1. Study Design. /e HREVS trial was a prospective, randomized, open label, multiarm parallel-group, safety and efficacy study. /e study protocol was approved by the local 2.3. Secondary Endpoints. Secondary endpoints included (i) ethics committee and it complies with the Declaration of incomplete revascularization (on a lesion- and patient-ba- Helsinki. Written informed consent was obtained from all sis), (ii) MACCE (a composite of all-cause death, myocardial study participants. All consecutive patients with angiogra- infarction (MI), stroke, and clinically driven target vessel phy-confirmed MV-CAD involving LAD and a significant revascularization) at 30 days and 12 months, (iii) length of (≥70% diameter stenosis, DS, on quantitative coronary hospitalization, use of postdischarge inpatient institutional rehabilitation program, and sick-leave duration, and (iv) angiography, QCA) lesion in at least one major non-LAD epicardial vessel of ≥2.5mm in diameter, amenable to PCI target vessel (TV) or graft failure (TFV; a composite of and CABG and HCR, were screened by a local Heart Team cardiac death, TV-MI, and clinically driven target vessel (HT). Lesions of 50–70% DS were subjected to functional revascularization, TVR) at 12 months after randomization. evaluation and were considered the study target lesions (i.e, For endpoint definitions, see Appendix B. were labelled for revascularization) if lesion-related myo- Angiographic analysis was verified, inclusive of blinded cardial ischemia was present on functional testing (fractional analysis of baseline angiograms and SYNTAX score calcu- flow reserve, FFR, or SPECT stress imaging). A list of in- lation, by an external laboratory using complete angio- clusion/exclusion criteria is provided in Appendix A. HT graphic data. Clinical events were adjudicated by an external Journal of Interventional Cardiology 3 clinical events committee that had access to patient source (n �53) following HT agreement on equal technical and data. clinical feasibility of each of the 3 coronary revascularization modes. Baseline clinical and procedural characteristics of the study patients are shown in Table 1. Of note, the mean age 2.4. Revascularization, Pharmacological Treatment, and An- was 62±7 years, and the majority of the patients were males giographic Follow-Up. For the CABG procedure, venous (71.6%). More than one half of the patients had a prior MI revascularization (except LIMA to LAD) was performed (55.5%). Left ventricular ejection fraction (LVEF) was according to routine practice in the study centre. In the HCR 54.5±8.0%. One half of the study patients had 2-vessel group, MIDCAB was always a first-stage procedure and it disease (50.3%), whereas ≥3 vessel CAD was present in the was followed, within 3 days, by PCI. other half (49.7%). Mean angiographic SYNTAX Score was Aspirin was prescribed before revascularization for all 19.4±2.9, whereas EuroScore II was 1.71±0.76. Baseline study patients and it was continued indefinitely. For PCI characteristics were similar between the study arms (including HCR PCI), UFH was used (i.v. bolus of 100 IU (Table 1). Numbers of diseased vessels and index lesions as per kilogram body weight followed by adjustment according well as CR stents and grafts are given in Table 1. to target-activated clotting time of 250 to 300 seconds). /e HCR patients, except 5 (9.8%) who required con- Antiplatelet regimen included clopidogrel routinely (loading version to CABG (Table 2), had per-protocol PCI within 3 dose of 300mg at the time of PCI unless used in advance; days (in most cases at 24–48h) after performing MIDCAB then 75mg daily, recommended duration of treatment LIMA-LAD anastomosis that was always the first stage of 12months) and aspirin (75mg once daily) indefinitely. HCR. /e reasons for HCR conversion to conventional on- Complete revascularization was defined as successful re- pump CABG with median sternotomy were either technical vascularization, by means of either surgery (bypassing) or PCI surgical (n �2) or there was hemodynamic instability fol- (stenting), of all HT-determined target lesions. Incomplete lowing LIMA-LAD grafting that required other lesions’ revascularization was evaluated on a lesion- and patient-basis. revascularization on an ad hoc basis (n �3). All other pa- Any potential angiography (±PCI) performed for clinical tients in the HCR group (47/52) continued to the PCI stage reason(s) prior to the study primary follow-up point had no of HCR and underwent, at that point, angiographic LIMA influence on adhering to protocol-mandated angiographic control. /is showed LIMA thrombotic occlusion in 1 case control at 12±1 months. (2.1%) resolved by PCI of the native artery, LAD, using the Postprocedure lifestyle modification and medication study DES. /us, the HCR LIMA immediate patency rate regimen were according to guideline recommendations. was 46/47 (97.9%). Patent LIMAs and native LADs showed TIMI-3 flow in absence of any anastomosis stenosis >50% DS that might warrant considering a need for intervention. 2.5. Statistical Analysis. Central database management and Target coronary revascularization was incomplete, on a statistical analysis were external. For the primary endpoint, per-lesion basis, in 3.7% (5/136) in the CABG group versus RI differences between the study arms (with CABG taken as 2.7% (4/149) and 2.1% (3/146) lesions in the HCR and PCI reference) were tested against a prespecified noninferiority groups, respectively (p � 0.71). On a per-patient basis, in- margin of 4.2 percentage points based on literature data of complete revascularization rate was 8.0% (4/50) vs. 7.7% (4/ the clinically relevant threshold of RI difference (see Ap- 52) vs. 5.7% (3/53) patients (p � 0.86) (Table 1). pendix D). p values <0.025 were considered significant to Bleeding was more prevalent, and it was greater (for BARC adjust for two comparisons of the primary endpoint. In evaluation see Table 2), in the study arms involving surgery. addition, comparison of each vs. each revascularization /ere were 4 transfusions in CABG (8.0%), 2 in HCR (3.9%), method was performed with the RI differences between the and none in the MV-PCI arm (p � 0.066). /ere was one study arms (expressed as positive values) tested against a death ≤30 days that occurred in the HCR group (the patient prespecified noninferiority margin of 4.2 percentage points experienced periprocedural MI and stroke that led to death). and the p value spending function to calculate overall type I /e length of hospitalization, use of inpatient rehabili- error rate. /us, the additional analysis was deliberately tation, and sick-leave duration were higher with surgery performed in absence of defining a reference method of (CABG or HCR), with hospitalization length and institu- MVD revascularization. To control type I error rate, we tional rehabilitation similar in the CABG and HCR arms calculated the overall type I error rate in three pairwise (Table 2). /irty-day MACCE rate was 8% vs. 5.8% vs. 3.8% comparisons of the treatment arms from the formula (respectively, CABG, HCR, and PCI, p � 0.37), and it was (1 − p ) � (1 − p ) × (1 − p ) × (1 − p ), and p was total 1 2 3 total driven mainly by periprocedural MI (Table 2). considered statistically significant when <0.05. At 12±1 months, all alive patients (n �149) underwent For comparisons of secondary endpoints and clinical protocol-mandated SPECT that was followed by protocol- characteristics, nominal p values <0.05 were considered mandated control angiography. None of the 5 patients with significant. Power calculations are described in Appendix C. repeat revascularization prior to the primary follow-up at 12±1 months (Table 1) was alive at the point of protocol- 3. Results mandated SPECT (5 out of 6 deaths before 12±1 months One hundred and fifty-five consecutive patients with MV- occurred in patients with repeat revascularization). Median RI at 12 months was mild in all study arms; 5 (2, CAD, who met the inclusion/exclusion criteria, were ran- domized to CABG (n �50), HCR (n �52), or MV-PCI 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with the 4 Journal of Interventional Cardiology Table 1: Baseline and procedural characteristics according to randomization arm . Characteristic CABG (n �50) HCR (n �52) PCI (n �53) p Age (years) 61.3±6.8 62.0± 7.4 61.7±7.7 0.80 Male sex 70.0% (35) 75.0% (39) 69.8% (37) 0.90 Current smoking 50.0% (25) 46.1% (24) 47.2% (25) 0.92 Arterial hypertension 66.0% (33) 65.4% (34) 67.9% (36) 0.96 Diabetes mellitus 22.0% (11) 17.3% (9) 20.7% (11) 0.83 Chronic kidney disease 0% (0) 1.9% (1) 5.7% (3) 0.32 COPD/BA 4.0% (2) 7.7% (4) 11.3% (6) 0.43 Previous MI 56.0% (28) 51.9% (27) 58.5% (31) 0.79 Prior stroke 6% (3) 7.7% (4) 5.7% (3) 0.92 Peripheral vascular disease 24.0% (12) 30.8% (16) 30.2% (16) 0.70 LVEF (%) 54.0±7.4 56.2± 6.3 53.3±9.9 0.159 LVEF≤45% 12% (6) 5.8% (3) 20.8% (11) 0.070 EuroSCORE II 1.70±0.76 1.71±0.72 1.70±0.79 1.0 Affected vessels: 2 42.0% (21) 51.9% (27) 56.6% (30) ≥3 58.0% (29) 48.1% (25) 43.4% (23) 0.32 Affected vessels (mean) 2.7±0.6 2.5± 0.6 2.5±0.6 — No. of index lesions 2 42.0% (21) 36.5% (19) 50.9% (27) 3 44.0% (22) 42.3% (22) 30.2% (16) >3 14.0% (7) 21.2% (11) 18.9% (10) 0.35 No. of index lesions (mean) 2.7±0.7 2.9± 0.8 2.7±0.9 — SYNTAX score 19.3±3.0 19.4± 3.0 19.5±2.7 0.91 No. of grafts 1 0% (0) 90.4% (47) — 2 46.0% (23) 5.8% (3) — ≥3 54.0% (27) 3.8% (2) — NA Arterial grafts 37.8% (50) 77.6% (52) — NA Venous grafts 62.2% (82) 22.4% (15) — NA No. of grafts (mean) — — No. of stents 0 2.6±0.7 1.1±0.4 1 — 9.6% (5) 0 2 — 48.1% (25) 0 3 or more — 32.7% (17) 51.9% (27) NA No. of stents (mean) — 9.6% (5) 49.1% (26) — — 1.5± 0.9 2.7±0.9 Incomplete TLR (per patient) 8.0% (4) 7.7% (4) 5.7% (3) 0.86 Incomplete TLR (per total number target lesions in 3.7% (5/136) 2.7% (4/149) 2.1% (3/146) 0.71 study group) Values are means±SD or percentages (counts). Data are shown as per randomization (intention-to-treat population). CABG: coronary-artery bypass grafting; HCR: hybrid coronary revascularization; PCI: percutaneous coronary intervention. COPD/BA: chronic obstructive pulmonary disease/bronchial ‡ § ǁ asthma. MI: myocardial infarction. LVEF: left ventricular ejection fraction. EuroSCORE II: /e European System for Cardiac Operative Risk Evaluation (EuroSCORE); a clinical model for calculating the risk of death after cardiac surgery. SYNTAX score: Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score; an angiographic model for evaluating coronary artery disease extensiveness. TLR, target lesion revascularization, given per total number of lesions to be revascularized according to Heart Team recommendation. similar in all three treatment modalities (CABG 20/49, noninferiority p values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Between-group differences were sig- 40.8%; HCR 21/49; 42.9%; MV-PCI 26/51; 51.0%, p � 0.56). nificantly smaller than the prespecified noninferiority As shown in Figure 2, the three treatment modalities were margin of 4.2% and the trial met its primary endpoint of associated with a similar freedom from MACCE at 12 noninferiority (Figure 1). /e ITT-based conclusion was the months. same when patients with conversion from HCR were ex- Angiographic control at 12 months demonstrated 9 cluded (per protocol analysis) and when the patients with SVGs and 1 LIMA stenosis/occlusion in the CABG group conversion from HCR were reclassified to the CABG group (10/49, 20.4%), 3 LIMA stenoses/occlusions and 1 in- (per treatment analysis). /ere were no differences in the segment restenosis in the HCR group (4/49, 8.2%), and 3 primary endpoint in patients with 2-vessel disease vs. >2- in-segment restenoses in the PCI group (3/51, 5.9%); vessel disease. /ere were also no differences according to p � 0.05. Twelve-month TV or graft failure (composite of SYNTAX score. Proportion of patients with RI>5% was cardiac death, TV-MI, and clinically driven TVR) was Journal of Interventional Cardiology 5 Table 2: HREVS study endpoints according to randomization group. Endpoint CABG HCR PCI p value Primary endpoint at 12 months N �49 N �49 N �51 ∗∗ RI (SPECT) 6.7 (4.6, 8.8) 6.4 (4.3, 8.5) 7.9 (5.9, 9.8) 0.45 Secondary endpoints at 12 months N �50 N �52 N �53 MACCE (death/stroke/MI/clinically driven repeat 12.0% (6) 13.4% (7) 13.2% (7) 0.83 revascularization) Death 2.0% (1) 5.8% (3) 3.8% (2) 0.78 Stroke 0% (0) 3.8% (2) 0% (0) 0.21 MI 8% (4) 5.8% (3) 7.5% (4) 0.66 Clinically driven TVR 2.0% (1) 1.9% (1) 5.7% (3) 0.54 Angiography-driven TVR 2.0% (1) 11.5% (6) 11.3% (6) 0.139 Total TVR 4.0% (2) 13.5% (7) 17.0% (9) 0.095 Secondary endpoints at 30 days MACCE (death/stroke/MI/clinically driven repeat 8% (4) 5.8% (3) 3.8% (2) 0.37 revascularization) Death 0% (0) 1.9% (1) 0% (0) 0.66 Stroke 0% (0) 1.9% (1) 0% (0) 0.66 MI 8% (4) 5.8% (3) 3.8% (2) 0.37 Repeat revascularization 0% (0) 1.9% (1) 0% (0) 0.66 Conversion to CABG NA 9.6% (5) 0 0.027 Bleeding BARC 0–1 80.0% (40) 80.8% (42) 98.1% (52) BARC 2 0% (0) 9.6% (5) 1.9% (1) BARC 3–4 20.0% (10) 9.6% (5) 0% (0) 0.001 Hospital stay (days) 13.8 (12.5, 15.1) 13.5 (12.2, 14.8) 4.5 (3.2, 5.8) <0.001 Institutional rehabilitation 100% (49) 97.9% (48) 56.8% (29) <0.001 Sick leave (weeks) 23 (21, 25) 16 (15, 18) 8 (6, 10) <0.001 ∗ ∗∗ Data are presented as means (95% confidence interval) or percentages (counts). Evaluable in patients alive at 12±1 months. p � 0.046 on combined noninferiority analysis that the study was powered for (cf. Figure 1). CABG vs. HCR MV-PCI vs. CABG (p = 0.029) p = 0.016 MV-PCI vs. HCR (p = 0.003) HCR vs. CABG p = 0.0006 MV-PCI vs. CABG (p = 0.015) –4 –3 –2 –1 0 1 2 3 4 5 6 –4 –3 –2 –1 0 1 2 3 4 5 6 Difference in residual ischemia at 12 months Difference in residual ischemia at 12 months (a) (b) Figure 1: Noninferiority analysis for the SPECT-based residual ischemia at 12 months in the three treatment arms with CABG as a reference method (a) and assuming no single reference method (b). Point estimates and 90% confidence intervals for the differences in RI between treatment modalities are shown with solid vertical gridline indicating the null difference and interrupted vertical gridline indicating the noninferiority margin of 4.2 percentage points. (a) Respective p values are for noninferiority of MV-PCI vs CABG and HCR vs. CABG. To adjust for two comparisons with CABG as the reference p values were considered statistically significant when <0.025. (b) p values are for pairwise noninferiority tests with 95% one-sided confidence intervals. Overall p for noninferiority is 0.046. 12.0% (CABG) versus 11.5% (HCR) versus 11.3% (PCI) angiography-driven) at 12 months numerically favoured (p � 0.99). Angiography-driven revascularization was CABG, with 4.0% (CABG) versus 13.5% (HCR) versus performed in 1 of 50 (2.0%) CABG patients versus 12/105 17.0% (PCI) (p � 0.095), and 4.0% in the CABG arm (2/ (11.4%) subjects with any PCI at baseline (combined HCR 50) but 15.2% (16/105) in the combined HCR plus MV- plus MV-PCI arm) (p � 0.062). As shown in Table 2, total PCI cohort (p � 0.058; for individual group data, see TVR rate (sum of clinically driven and control Table 2). 6 Journal of Interventional Cardiology 100 20 50 10 50 46 46 44 44 52 49 47 46 45 53 51 51 50 46 0 3 69 12 0 31 6 9 2 Follow-up (months) Follow-up (months) CABG CABG: 6 events in 50 patients HCR HCR: 7 events in 52 patients PCI PCI: 7 events in 53 patients (a) (b) Figure 2: MACCE-free survival (a) and cumulative risk of MACCE (b) during 12-month follow-up according to the treatment arm. Panel A shows MACCE-free survival, whereas the cumulative risk of MACCE is depicted in Panel B. Numbers of patients at risk are shown above the horizontal axis in panel A. Pairwise comparisons of treatment arms with Cox proportional hazards model are shown at the bottom of panel B. MACCE—Major Adverse Cardiac or Cerebral Event. invasiveness of CABG and the increased risk of repeat re- 4. Discussion vascularization with PCI [2, 16]. /e optimal revasculari- zation approach would thus need to combine a decreased /e primary endpoint of this first randomized controlled nd study, comparing conventional CABG, MV-PCI using 2 invasiveness plus low risk of perioperative complications generation standard-of-reference DES, and HCR in patients and an increased durability and survival. A combination of a minimally invasive LIMA-LAD graft procedure with PCI with MV-CAD amenable to treatment with any of the three guideline-accepted modalities, was SPECT-determined RI at using DES to non-LAD vessels eliminates aortic manipu- lation and extracorporeal circulation, resulting in a potential 12 months. Based on the noninferiority margin of the trial, the three strategies were similar after 12 months in terms of to decrease the risk of perioperative complications [1, 4, 11, 12, 17]. /us, the “third” revascularization strat- RI (Figure 1) that is an established measure of CR efficacy and a predictor of long-term prognosis. Other important egy—HCR—might have potential advantages beyond PCI and CABG alone [1, 4–12, 18, 19]. Although HCR was first findings, with potential relation to healthcare resources’ utilization, are shorter hospital stay, less need to use insti- introduced over 20 years ago [4], today the potential of this strategy in MV-CAD patients appears neither sufficiently tutional in-patient rehabilitation, and shorter sick-leave duration with the percutaneous route of coronary revas- determined [1, 2, 10] nor fully utilized [9, 19]. Some fun- cularization in MV-CAD. Although underpowered for damental HCR concerns include the complexity of patient logistics; the presence of surgical and endovascular stage clinical events, HREVS suggests similar 12-month MACCE rates with all three treatment strategies (Figure 2), a finding (with “naturally” incomplete revascularization at the HCR first-stage); the timing of antiplatelet therapy, optimal that requires confirmation in a larger multicentre study. /e primary focus of HREVS is RI at 12 months by timing of the HCR stages; and technical aspects of the surgical intervention (access site, and the role of thoraco- SPECT. Myocardial perfusion SPECTimaging is not only an objective method to compare the outcome of coronary re- scopic or robotic approaches) [5–11]. /us far, HCR outcomes have been compared mostly vascularization but also there is a direct proportional rela- tionship between the extent of RI and prognosis [14, 15]. with standard CABG [1, 6, 8], and included only one ran- Taking into account that the groups were randomized, domized study that, however, did not have a percutaneous treatment arm [6]. Another observational study compared comparable in their basic characteristics, and the fact that the groups received high level of complete revascularization conventional CABG to MV-PCI [18]. Retrospective series and meta-analyses have reported low mortality rates (0% to (92% vs. 92.3% vs. 94.3%), it can be concluded that within the assumed noninferiority margin, the three strategies 2%) and event-free survival rates of 83% to 92% for HCR at 6 to 12 months of follow-up and similar outcomes of HCR in occurred similar with respect to RI at 12 months. /is main result is broadly consistent with the analysis of the secondary comparison with standard revascularization options [5, 8]. In the single randomized trial of HCR vs. conventional endpoints (Table 2, Figure 2). /e two typically applied techniques for MV-CAD CABG, the HCR arm demonstrated, at 12 months, similar to CABG cumulative occurrence of major adverse cardiac interventional management, CABG and MV-PCI, have clinically relevant disadvantages that include the events [6]. In that study, 6.1% HCR patients required MACCE-free survival (%) Cumulative risk of MACCE (%) Journal of Interventional Cardiology 7 A recently funded US National Institutes of Health conversion to standard CABG [6], a result broadly consis- tent with our present findings (Table 2). (NIH) Hybrid Coronary Revascularization Trial (HCR, NCT03089398), a 2354 patient study with 5-year follow-up, HREVS is the first randomized controlled study com- paring outcomes of the three guideline-accepted treatment might be able to overcome only some of the HREVS lim- strategies in MV-CAD patients. In HREVS, the HCR pa- itations because the NIH HCR Trial compares HCR vs. MV- tients underwent two-stage revascularization with MIDCAB PCI in absence of the CABG arm. first, followed by PCI using the second-generation ever- olimus-eluting stents. /e use of a standard-of-reference nd 4.1. Limitations. /is study has several limitations as listed [3, 20, 21] 2 generation DES in HREVS, the device that below. showed some of the best results in the interventional treatment of CAD patients, suggests that HREVS patients (i) HREVS was not powered for clinical events, al- were offered a maximized benefit from the choice of stent though the center enrolment rate and volume in the endovascular arm and in the HCR arm. exceeded by over 10-fold typical yearly contribu- Prior work indicated that MIDCAB, when compared to tions in the pivotal BEST Trial comparing MV-PCI conventional sternotomy CABG, results in less surgical with CABG that was itself underpowered due to an trauma, decreased risk of bleeding and infectious compli- insufficient and slow enrolment that included only cations, and may shorten the length of hospitalization 20% of the eligible patients [20]. [4, 11, 12]. /e latter, however, is not supported by our (ii) Recruitment challenges were related not only to the findings, a result that may be partly driven (note ITT fundamental requirement of equal technical and analysis) by the conversion rate (9.8%) from HCR to CABG clinical feasibility of either of the tested strategies in HREVS (Table 2). but also to the patient’s (and family’s) natural In the HREVS HCR arm, PCI was performed within 3 gravitation towards less invasive treatment (evi- days after surgery (in majority of patients, within 24–48h denced by nearly 1 in 4 refusal rate to random after surgery). /is allowed consistency of hemostasis in treatment allocation due to PCI preference); thus, absence of DAPT at the time of surgery (the patients were overall recruitment rate in HREVS was >75%. operated on aspirin and loaded with clopidogrel at the time (iii) HREVS did not evaluate quality of life, an area of PCI) as well as angiographic control of the LIMA-to-LAD where clinically relevant differences might exist, graft during the endovascular stage. Lack of ad hoc total consistent with our findings on the sick-leave du- revascularization in the HCR group with LIMA-to-LAD ration and time-to-return to work, favouring less MIDCAB, however, was associated with hemodynamic in- invasive treatment strategies. stability and myocardial ischemia in 3 patients who required conversion to sternotomy to perform ad hoc revasculari- (iv) Any generalizability of the findings needs to take zation of the remaining lesions by CABG. into account the moderate MVD angiographic Although HREVS will continue to monitor its study par- complexity in this study (reflecting the requirement ticipants up to 5 years, a larger multicentre study involving of technical feasibility of CABG, HCR, and MV- HCR along CABG and MV-PCI would be required to deter- PCI; thus, the need to exclude the left main coronary mine, by clinical outcomes, the optimal interventional treat- artery stenosis not amenable to HCR, severely ment strategy in MV-CAD. /is is relevant also because calcific lesions, complex bifurcations, or chronic evidence is accumulating that using multiple arterial grafts in total occlusion that may favour surgery) and the CABG may be associated with improved clinical outcomes particular sequence and timing of HCR procedures when compared to either conventional CABG with LIMA to as per the HREVS protocol. LAD and SVGs to other vessels [22], CABG using bilateral mammary arteries plus SVGs [23], or to MV-PCI [24]. Al- though HREVS indicates no significant differences in 12- 4.2.Strengths. Fundamental strengths of HREVS include the month TVF between the three treatment modalities, the an- following: giographic control at 1 year suggested sizable differences in (i) Use of quantifiable primary endpoint of RI at graft stenosis/occlusion or in-segment restenosis rates (20.4% 12 months that is independently predictive, in a vs. 8.2% vs. 5.9% for CABG vs. HCR vs. MV-PCI; p � 0.05) gradient manner, of cardiac death or MI that may affect long-term outcomes [25]. Whether these dif- [13–15, 26], and the trial appropriate power for ferential 12-month anatomical revascularization results affect noninferiority comparison of the 3 treatment longer-term clinical outcomes [25] remains to be established. modalities [13, 27]. Importantly, the lower rates of institutional rehabilita- tion use in the MV-PCI arm are not necessarily beneficial (ii) /ere were no identifiable clinical or angiographic differences between the patients who agreed to because the patients who opt not to use the institutional rehabilitation services might benefit from those. random treatment allocation in HREVS and entered the study versus those who were Heart Team–labelled /e prevalence and extent of bleeding with (any) surgery (Table 2) should serve as an important consideration point as eligible for enrolment but did not accept random in support of PCI rather than CABG or HCR in some (if not treatment allocation, in favour of generalizability of most of) moderate SYNTAX patients. the findings to similar patients outside the trial. 8 Journal of Interventional Cardiology Table 3: Inclusion and exclusion criteria of the HREVS trial. Inclusion criteria Exclusion criteria 1. Acute coronary syndrome (ACS) 2. Any previous coronary revascularization (CABG, 1. Male or female ≥18 years of age HCR, or PCI) 2. II–IV Canadian Cardiovascular Society functional 3. Presence of any condition or abnormality that in class of angina the opinion of the investigator would compromise 3. Angiographically confirmed multivessel coronary the safety of the patient or the quality of the data artery diseases involving LAD, with lesions severity 4. Pregnancy ≥70% diameter stenosis (DS) by quantitative 5. Stenosis of the left main coronary artery requiring coronary angiography (QCA), or 50–70% DS with revascularization functional evidence of ischemia by either FFR ≤0.80 6. Significant calcification or occlusion of a major or stress SPECT coronary vessel 4. At least 1 month after acute MI (in patients with 7. Left ventricle aneurysm or valvular heart disease history of MI) requiring surgical management 5. Heart team-determined indication to coronary 8. Comorbidity associated with an increased revascularization with equal feasibility to perform procedural risk for any of the treatment strategies or complete revascularization using either of the three other study procedures methods (HCR, MVD-PCI, CABG) 9. Peripheral arterial disease with pain-free walking 6. Written informed consent for participation in the distance ≤50m study, including random treatment allocation and 10. Life expectancy ≤5 years compliance with study requirements inclusive of 11. Inability to comply with dual antiplatelet therapy follow-up visits and 12±1 month SPECTfollowed by (DAPT) control angiography 12. Inability to undergo follow-up procedures including long-term follow-up 13. Participation in another clinical study (iii) Mandatory angiographic control at 12 months is a Appendix particular strength of the present study as it verified the midterm anatomic quality of A. HREVS Trial Inclusion/Exclusion Criteria revascularization. Table 3 shows the inclusion and exclusion criteria of the (iv) HREVS results add importantly to the present HREVS trial. knowledge in the context of (a) increasing pene- tration of percutaneous revascularization [28], (b) suggestions that optimized PCI might lead to B. Endpoint and Other Definitions CABG-like outcomes in MV-CAD [29], and (c) increasing Heart Team recommendations of first- MI and stroke were defined according to international line percutaneous approach [2, 28]. guidelines (1, 2); other definitions were according to the Academic Research Consortium (3). In brief, clinically driven (v) Rather than generating hypotheses on the basis of TVR was defined as percutaneous revascularization or bypass historical comparative data [29], HREVS was a real-life of the target lesion or any segment of the epicardial coronary randomized trial with multiarm parallel-group design. artery containing the target lesion or more proximal vessels that may have been traversed by the angioplasty guidewire during the index procedure, driven by ischemic symptoms 5. Conclusion presence or presence of other clinical abnormalities leading to In patients with MV-CAD amenable to CABG, HCR, and an angiogram prior to the protocol-mandated point at 12±1 MV-PCI, the quantitative endpoint of residual myocardial months from randomization. Angiography-driven TVR was ischemia at 12 months, which is predictive in a gradient TVR resulting from performing protocol-required control manner of cardiac death and adverse cardiac events angiography at 12±1 months. Target vessel (TV) or graft [13–15, 26], was similar with all three guideline- failure was defined as a composite of cardiac death, target accepted revascularization strategies. MV-CAD PCI, using vessel-MI, and clinically driven TVR of the artery containing contemporary best-in-class drug-eluting stents, was the target lesion (i.e., one of the index lesions in a given associated with a shorter hospital stay, less inpatient reha- patient) within 12 months after randomization (3). bilitation, and shorter sick-leave duration than CABG or HCR. While extended follow-up will determine longer-term C. Power Calculations outcomes from the present study, a larger-scale multicentre trial powered for clinical endpoints would be warranted. Power calculations and statistical analysis are consistent with Nevertheless, any effective execution of such a large-scale reference 4 and reference 5. With recruitment of 50 subjects study seems unlikely [20]. per group, the study had 80% power to exclude with a Journal of Interventional Cardiology 9 noninferiority t-test with the 2.5% type I error rate (adjusted (5) Walker E, Nowacki AS. “Understanding Equiva- for two comparisons with the reference arm), the margin set lence and Noninferiority Testing”. Journal of at 4.2 percentage points, which we considered a reasonable General Internal Medicine, vol. 26, no 2, pp.192–96, minimum clinically significant difference. An absolute 4.2 2011. percentage points difference is associated with an increased (6) Berman DS, Hachamovitch R, Shaw LJ, et al. “Roles of risk of MI, whereas 4.9 percentage points is cut-off for an nuclear cardiology, cardiac computed tomography, increased risk of death (6, 7), and the generally accepted and cardiac magnetic resonance: Noninvasive risk clinically significant ischemia interval is set at 5%, with 5% stratification and a conceptual framework for the se- considered a clinically significant difference (8, 9). Based on lection of noninvasive imaging tests in patients with literature data (8), the assumed standard deviation of per- known or suspected coronary artery disease”. J Nucl cent ischemic myocardium was 7. Med, vol. 47, no 7, pp. 1107–18, 2006. (7) Shaw LJ, Wilson PW, Hachamovitch R, et al. D. Additional Information on Statistical “Improved near term coronary artery disease risk Analysis and Study Conduct and Reporting classification with gated stress myocardial perfusion SPECT”. JACC Cardiovasc Imaging, vol. 3, no 11, /e continuous variables are presented as the mean ±SD, pp. 1139–48, 2010. unless with skewed distribution, for which medians with (8) Shaw LJ, Berman DS, Maron DJ, et al. “Optimal quartiles are presented. /e categorical variables are sum- medical therapy with or without percutaneous marized as percent and count. Study endpoints were reported coronary intervention to reduce ischemic burden: as means±SD with 95% confidence intervals or as percent- Results from the Clinical Outcomes Utilizing Re- ages, where applicable. Analysis was intention to treat. Con- vascularization and Aggressive Drug Evaluation tinuous variables were compared using unbalanced ANOVA (COURAGE) trial nuclear substudy”. Circulation, when distributions were approximately normal. Kruskal– vol. 117, no 10, pp. 1283–91, 2008. Wallis test was used to compare medians of significantly (9) Farzaneh-Far A, Phillips HR, Shaw LK, et al. “Is- skewed variables. Proportions were compared with the chi chemia change in stable coronary artery disease is test or the Fisher exact test, as appropriate. A noninferiority an independent predictor of death and myocardial analysis for the primary endpoint was performed using the infarction”. JACC Cardiovasc Imaging, vol. 5, no7, t-distribution-based confidence intervals assuming a non- pp. 715–24, 2012. inferiority margin of 4.2 RI percentage points. To adjust for two comparisons with CABG as the reference p values were (10) Juszczak E, Altman DG, Hopewell S, Schulz K. considered statistically significant when <0.025. A 2-sided “Reporting of Multi-Arm Parallel-Group Randomized nominal p value <0.05 was considered statistically significant trials: Extension of the CONSORT 2020 Statement”. in secondary endpoint analysis. Product-limit survivor func- JAMA, vol. 321, no 16, pp. 1610–1620, 2019. tion estimate was used in MACCE analysis, and Cox pro- portional hazards model was applied to estimate hazard ratios Abbreviations of MACCE between study arms. Statistical analysis was per- formed with SAS 9.4 software (SAS Institute, Cary, NC, USA). CABG: Coronary artery bypass grafting HREVS study conduct and reporting were consistent DAPT: Dual antiplatelet therapy with the updated CONSORT 2010 guidelines [10]. FFR: Fractional flow reserve HCR: Hybrid coronary revascularization E. Appendix Literature HT: Heart team MACCE: Major adverse cardiac and cerebrovascular (1) /ygesen K, Alpert JS, Jaffe AS, et al. “Fourth events (death/stroke/myocardial infarction universal definition of myocardial infarction”. (MI)/clinically-driven TVR) Circulation, vol. 138, no 20, pp. e618–e651, 2018. MIDCAB: Minimally invasive direct coronary artery bypass (2) Sacco RL, Kasner SE, Broderick JP, et al. “An MV- Multivessel coronary artery disease updated definition of stroke for the 21st century: A CAD: statement for healthcare professionals from the PCI: Percutaneous coronary intervention American Heart Association/American Stroke As- RI: Residual myocardial ischemia sociation”. Stroke, vol. 44, no 7, pp. 2064–89, 2013. SPECT: Single-photon emission computed tomography TVR: Target vessel revascularization (3) Cutlip DE, Chauhan MS, Baim DS et al. “Clinical TVF: Target vessel failure. restenosis after coronary stenting: Perspectives from multicentre clinical trials”. JACC, vol. 40, no 12, pp. 2082–2089, 2002. Data Availability (4) (International Committee of Medical Journal Edi- tors/no authors listed). Uniform requirements for Clinical, imaging, and statistical data used to support the manuscripts submitted to biomedical journals. Ann findings of this study are included within the article and Intern Med, vol. 126, no 1, pp. 36–47, 1997. within the supplementary information file (Appendix). 10 Journal of Interventional Cardiology [10] V. F. Panoulas, A. Colombo, A. Margonato, and F. Maisano, Disclosure “Hybrid coronary revascularization,” Journal of the American HREVS was a Late-Breaking Clinical Trial at the Trans- College of Cardiology, vol. 65, no. 1, pp. 85–97, 2015. [11] A. Diegeler, H. /iele, V. Falk et al., “Comparison of stenting catheter Cardiovascular /erapeutics (TCT 2017), and it was with minimally invasive bypass surgery for stenosis of the left subsequently rated within the TCT 2017 Top 10 Highlights anterior descending coronary artery,” New England Journal of [30]. Medicine, vol. 347, no. 8, pp. 561–566, 2002. [12] S. Wu, Y. Ling, Y. Fu et al., “Mid-term follow-up outcomes of Conflicts of Interest 2-staged hybrid coronary revascularization compared with off-pump coronary artery bypass for patients with multivessel None of the authors has any disclosure relevant to this coronary artery disease,” Videosurgery and Other Mini- manuscript to report. invasive Techniques, vol. 12, no. 2, pp. 178–185, 2017. [13] L. J. Shaw, D. S. Berman, D. J. Maron et al., “Optimal medical therapy with or without percutaneous coronary intervention Authors’ Contributions to reduce ischemic burden: results from the Clinical Out- comes Utilizing Revascularization and Aggressive Drug VG, LB, and PM were involved in conception and design of Evaluation (COURAGE) trial nuclear substudy,” Circulation, research; VG, NK, AS, RT, VP, KK, OB, and LB were re- vol. 117, no. 10, pp. 1283–1291, 2008. sponsible for data acquisition; VG, JS, RT, and PM were [14] D. S. Berman, R. Hachamovitch, L. J. 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Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year—Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS)

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Copyright © 2020 Vladimir Ganyukov et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Interventional Cardiology Volume 2020, Article ID 5458064, 11 pages https://doi.org/10.1155/2020/5458064 Clinical Study Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year—Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS) 1 1 1 1 Vladimir Ganyukov , Nikita Kochergin, Aleksandr Shilov, Roman Tarasov, 2 2,3 1 4 1 Jan Skupien, Wojciech Szot, Aleksandr Kokov , Vadim Popov, Kirill Kozyrin, 1 1 2,5 Olga Barbarash, Leonid Barbarash, and Piotr Musialek Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russia Jagiellonian University School of Medicine, Krakow, Poland Dept. of Nuclear Medicine, John Paul II Hospital, Krakow, Poland Federal State Budgetary Institution A. V. Vishnevsky Institute of Surgery, Moscow, Russia Jagiellonian University Dept. of Cardiac & Vascular Diseases, John Paul II Hospital, Krakow, Poland Correspondence should be addressed to Vladimir Ganyukov; ganyukov@mail.ru and Piotr Musialek; pmusialek@szpitaljp2.krakow.pl Received 16 June 2019; Accepted 9 September 2019; Published 3 January 2020 Academic Editor: Faisal Latif Copyright © 2020 Vladimir Ganyukov et al. ‚is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. Optimal revascularization strategy in multivessel (MV) coronary artery disease (CAD) eligible for percutaneous man- agement (PCI) and surgery remains unresolved. We evaluated, in a randomized clinical trial, residual myocardial ischemia (RI) and clinical outcomes of MV-CAD revascularization using coronary artery bypass grafting (CABG), hybrid coronary revas- cularization (HCR), or MV-PCI. Methods. Consecutive MV-CAD patients (n  155) were randomized (1 :1 :1) to conventional CABG (LIMA-LAD plus venous grafts) or HCR (MIDCAB LIMA-LAD followed by PCI for remaining vessels) or MV-PCI (everolimus-eluting CoCr stents) under Heart Team agreement on equal technical and clinical feasibility of each strategy. SPECT at 12 months (primary endpoint of RI that the trial was powered for; a measure of revascularization midterm e–cacy and an independent predictor of long-term prognosis) preceded routine angiographic control. Results. Data are given, respectively, for the CABG, HCR, and MV-PCI arms. Incomplete revascularization rate was 8.0% vs. 7.7% vs. 5.7% (p  0.71). Hospital stay was 13.8 vs.13.5 vs. 4.5 days (p < 0.001), and sick-leave duration was 23 vs.16 vs. 8 weeks (p < 0.001). At 12 months, RI was 5 (2, 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with noninferiority p values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Rates of angiographic graft stenosis/occlusion or in-segment restenosis were 20.4% vs. 8.2% vs. 5.9% (p  0.05). Clinical target vessel/graft failure occurred in 12.0% vs. 11.5% vs. 11.3% (p  0.62). Major adverse cardiac and cerebral event (MACCE) rate was similar (12% vs. 13.4% vs. 13.2%; p  0.83). Conclusion. In this ¢rst randomized controlled study comparing CABG, HCR, and MV-PCI, residual myocardial ischemia and MACCE were similar at 12 months. ‚ere was no midterm indication of any added value of HCR. Hospital stay and sick-leave duration were shortest with MV-PCI. While longer-term follow-up is warranted, these ¢ndings may impact patient and physician choices and healthcare resources utilization. ‚is trial is registered with NCT01699048. 2 Journal of Interventional Cardiology evaluated all the inclusion/exclusion criteria with a partic- 1. Introduction ular attention given to equal angiographic and clinical /e optimal revascularization strategy in multivessel coro- feasibility to perform CABG or HCR or PCI. All consecutive nary artery disease (MV-CAD) remains unresolved. /e HT-cleared patients were offered participation in the study. longevity of the left internal mammary artery (LIMA) to /ose enrolled in the study (155 out of 204 HT-identified LAD graft contributes substantially to the survival benefit of eligible patients over 31 months; NB. 24%, subjects refused coronary artery bypass grafting (CABG), while the major random allocation of the treatment strategy) were ran- benefit of multivessel percutaneous intervention (PCI) is domized (external randomization on a 1:1:1 ratio) to nd lesser invasiveness [1]. With contemporary (2 generation) standard surgical revascularization (CABG with LIMA to drug-eluting stents (DES), combined restenosis and LAD and venous grafts to other vessels as a standard of thrombosis rate is lower than saphenous vein graft failure reference) or HCR (MIDCAB LIMA-LAD plus PCI for non- [2, 3]. Excellent outcomes of the LIMA-LAD graft and LAD vessel/s) or MV-PCI until all study arms reached 50 favourable outcomes of contemporary DES are the basis for subjects. In HCR, MIDCAB LIMA-LAD was always a first- active consideration of hybrid coronary revascularization stage procedure; PCI for the remaining vessels was per- (HCR; LIMA-LAD plus DES-PCI for remaining vessel/s) as formed within 3 days from surgery. All PCIs employed the “third” contemporary revascularization approach to everolimus-eluting CoCr stents (Xience, Abbott Vascular, treat patients with MV-CAD [1, 2, 4–9]. HCR is defined as a Abbott Park, Illinois, USA) as a standard of reference DES planned intervention combining cardiac surgery with a [3]. Treatment was within 7 days from randomization. catheter-based intervention performed within a predefined Prior to this trial, the study team had built experience in time [2, 4]. HCR employing a combination of a minimally performing the trial procedures (yearly volume of over 700 invasive LIMA-LAD graft procedure with PCI using DES to CABG with over 100 LIMA-LAD MIDCAB, and over 800 non-LAD vessels is receiving increasing attention [10–12] PCIs). /e study was sponsored by the Russian Academy of but it has not yet been evaluated in a clinical trial involving Sciences (RAS 056-2013-0012). /e sponsor had no influ- the two leading MV-CAD revascularization modalities, ence on the study protocol, management, or data analysis. CABG and PCI [1]. Primary follow-up point was at 12±1 months. Analysis Single-photon emission computed tomography was intention to treat (ITT). (SPECT) myocardial perfusion imaging, with percent is- chemic myocardium (residual ischemia, RI, calculated by subtracting the rest from stress total perfusion defect) is not 2.2. Primary Endpoint. Primary endpoint was residual is- only an objective method to compare the outcome of cor- chemia at 12±1 months by SPECT, with protocol-mandated onary revascularization but also there is a direct propor- SPECT preceding (by 3–7 days) the protocol-mandated tional relationship between RI extent and prognosis [13]. angiographic control. SPECT protocol and data analysis /is makes RI an attractive quantitative endpoint with an were according to those in the COURAGE Nuclear substudy evidenced relationship to long-term cardiovascular events. [13]. In brief, patients underwent a 1- or 2-day protocol with 99m 99m HREVS (Hybrid coronary REvascularization Versus rest Tc sestamibi combined with stress Tc sestamibi. Stenting or Surgery) was designed as the first randomized /e percent ischemic myocardium was calculated by sub- controlled study to assess safety and efficacy of the three tracting the rest from the stress total perfusion defect. contemporary MV-CAD revascularization modalities SPECT analysis was performed in a blinded fashion in an employing RI as the quantifiable primary endpoint. external nuclear medicine laboratory (Dept. of Nuclear Medicine, John Paul II Hospital, Krakow, Poland) using Quantitative Perfusion SPECT software (Cedars-Sinai 2. Materials and Methods Medical Center, Los Angeles, CA, USA). 2.1. Study Design. /e HREVS trial was a prospective, randomized, open label, multiarm parallel-group, safety and efficacy study. /e study protocol was approved by the local 2.3. Secondary Endpoints. Secondary endpoints included (i) ethics committee and it complies with the Declaration of incomplete revascularization (on a lesion- and patient-ba- Helsinki. Written informed consent was obtained from all sis), (ii) MACCE (a composite of all-cause death, myocardial study participants. All consecutive patients with angiogra- infarction (MI), stroke, and clinically driven target vessel phy-confirmed MV-CAD involving LAD and a significant revascularization) at 30 days and 12 months, (iii) length of (≥70% diameter stenosis, DS, on quantitative coronary hospitalization, use of postdischarge inpatient institutional rehabilitation program, and sick-leave duration, and (iv) angiography, QCA) lesion in at least one major non-LAD epicardial vessel of ≥2.5mm in diameter, amenable to PCI target vessel (TV) or graft failure (TFV; a composite of and CABG and HCR, were screened by a local Heart Team cardiac death, TV-MI, and clinically driven target vessel (HT). Lesions of 50–70% DS were subjected to functional revascularization, TVR) at 12 months after randomization. evaluation and were considered the study target lesions (i.e, For endpoint definitions, see Appendix B. were labelled for revascularization) if lesion-related myo- Angiographic analysis was verified, inclusive of blinded cardial ischemia was present on functional testing (fractional analysis of baseline angiograms and SYNTAX score calcu- flow reserve, FFR, or SPECT stress imaging). A list of in- lation, by an external laboratory using complete angio- clusion/exclusion criteria is provided in Appendix A. HT graphic data. Clinical events were adjudicated by an external Journal of Interventional Cardiology 3 clinical events committee that had access to patient source (n �53) following HT agreement on equal technical and data. clinical feasibility of each of the 3 coronary revascularization modes. Baseline clinical and procedural characteristics of the study patients are shown in Table 1. Of note, the mean age 2.4. Revascularization, Pharmacological Treatment, and An- was 62±7 years, and the majority of the patients were males giographic Follow-Up. For the CABG procedure, venous (71.6%). More than one half of the patients had a prior MI revascularization (except LIMA to LAD) was performed (55.5%). Left ventricular ejection fraction (LVEF) was according to routine practice in the study centre. In the HCR 54.5±8.0%. One half of the study patients had 2-vessel group, MIDCAB was always a first-stage procedure and it disease (50.3%), whereas ≥3 vessel CAD was present in the was followed, within 3 days, by PCI. other half (49.7%). Mean angiographic SYNTAX Score was Aspirin was prescribed before revascularization for all 19.4±2.9, whereas EuroScore II was 1.71±0.76. Baseline study patients and it was continued indefinitely. For PCI characteristics were similar between the study arms (including HCR PCI), UFH was used (i.v. bolus of 100 IU (Table 1). Numbers of diseased vessels and index lesions as per kilogram body weight followed by adjustment according well as CR stents and grafts are given in Table 1. to target-activated clotting time of 250 to 300 seconds). /e HCR patients, except 5 (9.8%) who required con- Antiplatelet regimen included clopidogrel routinely (loading version to CABG (Table 2), had per-protocol PCI within 3 dose of 300mg at the time of PCI unless used in advance; days (in most cases at 24–48h) after performing MIDCAB then 75mg daily, recommended duration of treatment LIMA-LAD anastomosis that was always the first stage of 12months) and aspirin (75mg once daily) indefinitely. HCR. /e reasons for HCR conversion to conventional on- Complete revascularization was defined as successful re- pump CABG with median sternotomy were either technical vascularization, by means of either surgery (bypassing) or PCI surgical (n �2) or there was hemodynamic instability fol- (stenting), of all HT-determined target lesions. Incomplete lowing LIMA-LAD grafting that required other lesions’ revascularization was evaluated on a lesion- and patient-basis. revascularization on an ad hoc basis (n �3). All other pa- Any potential angiography (±PCI) performed for clinical tients in the HCR group (47/52) continued to the PCI stage reason(s) prior to the study primary follow-up point had no of HCR and underwent, at that point, angiographic LIMA influence on adhering to protocol-mandated angiographic control. /is showed LIMA thrombotic occlusion in 1 case control at 12±1 months. (2.1%) resolved by PCI of the native artery, LAD, using the Postprocedure lifestyle modification and medication study DES. /us, the HCR LIMA immediate patency rate regimen were according to guideline recommendations. was 46/47 (97.9%). Patent LIMAs and native LADs showed TIMI-3 flow in absence of any anastomosis stenosis >50% DS that might warrant considering a need for intervention. 2.5. Statistical Analysis. Central database management and Target coronary revascularization was incomplete, on a statistical analysis were external. For the primary endpoint, per-lesion basis, in 3.7% (5/136) in the CABG group versus RI differences between the study arms (with CABG taken as 2.7% (4/149) and 2.1% (3/146) lesions in the HCR and PCI reference) were tested against a prespecified noninferiority groups, respectively (p � 0.71). On a per-patient basis, in- margin of 4.2 percentage points based on literature data of complete revascularization rate was 8.0% (4/50) vs. 7.7% (4/ the clinically relevant threshold of RI difference (see Ap- 52) vs. 5.7% (3/53) patients (p � 0.86) (Table 1). pendix D). p values <0.025 were considered significant to Bleeding was more prevalent, and it was greater (for BARC adjust for two comparisons of the primary endpoint. In evaluation see Table 2), in the study arms involving surgery. addition, comparison of each vs. each revascularization /ere were 4 transfusions in CABG (8.0%), 2 in HCR (3.9%), method was performed with the RI differences between the and none in the MV-PCI arm (p � 0.066). /ere was one study arms (expressed as positive values) tested against a death ≤30 days that occurred in the HCR group (the patient prespecified noninferiority margin of 4.2 percentage points experienced periprocedural MI and stroke that led to death). and the p value spending function to calculate overall type I /e length of hospitalization, use of inpatient rehabili- error rate. /us, the additional analysis was deliberately tation, and sick-leave duration were higher with surgery performed in absence of defining a reference method of (CABG or HCR), with hospitalization length and institu- MVD revascularization. To control type I error rate, we tional rehabilitation similar in the CABG and HCR arms calculated the overall type I error rate in three pairwise (Table 2). /irty-day MACCE rate was 8% vs. 5.8% vs. 3.8% comparisons of the treatment arms from the formula (respectively, CABG, HCR, and PCI, p � 0.37), and it was (1 − p ) � (1 − p ) × (1 − p ) × (1 − p ), and p was total 1 2 3 total driven mainly by periprocedural MI (Table 2). considered statistically significant when <0.05. At 12±1 months, all alive patients (n �149) underwent For comparisons of secondary endpoints and clinical protocol-mandated SPECT that was followed by protocol- characteristics, nominal p values <0.05 were considered mandated control angiography. None of the 5 patients with significant. Power calculations are described in Appendix C. repeat revascularization prior to the primary follow-up at 12±1 months (Table 1) was alive at the point of protocol- 3. Results mandated SPECT (5 out of 6 deaths before 12±1 months One hundred and fifty-five consecutive patients with MV- occurred in patients with repeat revascularization). Median RI at 12 months was mild in all study arms; 5 (2, CAD, who met the inclusion/exclusion criteria, were ran- domized to CABG (n �50), HCR (n �52), or MV-PCI 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with the 4 Journal of Interventional Cardiology Table 1: Baseline and procedural characteristics according to randomization arm . Characteristic CABG (n �50) HCR (n �52) PCI (n �53) p Age (years) 61.3±6.8 62.0± 7.4 61.7±7.7 0.80 Male sex 70.0% (35) 75.0% (39) 69.8% (37) 0.90 Current smoking 50.0% (25) 46.1% (24) 47.2% (25) 0.92 Arterial hypertension 66.0% (33) 65.4% (34) 67.9% (36) 0.96 Diabetes mellitus 22.0% (11) 17.3% (9) 20.7% (11) 0.83 Chronic kidney disease 0% (0) 1.9% (1) 5.7% (3) 0.32 COPD/BA 4.0% (2) 7.7% (4) 11.3% (6) 0.43 Previous MI 56.0% (28) 51.9% (27) 58.5% (31) 0.79 Prior stroke 6% (3) 7.7% (4) 5.7% (3) 0.92 Peripheral vascular disease 24.0% (12) 30.8% (16) 30.2% (16) 0.70 LVEF (%) 54.0±7.4 56.2± 6.3 53.3±9.9 0.159 LVEF≤45% 12% (6) 5.8% (3) 20.8% (11) 0.070 EuroSCORE II 1.70±0.76 1.71±0.72 1.70±0.79 1.0 Affected vessels: 2 42.0% (21) 51.9% (27) 56.6% (30) ≥3 58.0% (29) 48.1% (25) 43.4% (23) 0.32 Affected vessels (mean) 2.7±0.6 2.5± 0.6 2.5±0.6 — No. of index lesions 2 42.0% (21) 36.5% (19) 50.9% (27) 3 44.0% (22) 42.3% (22) 30.2% (16) >3 14.0% (7) 21.2% (11) 18.9% (10) 0.35 No. of index lesions (mean) 2.7±0.7 2.9± 0.8 2.7±0.9 — SYNTAX score 19.3±3.0 19.4± 3.0 19.5±2.7 0.91 No. of grafts 1 0% (0) 90.4% (47) — 2 46.0% (23) 5.8% (3) — ≥3 54.0% (27) 3.8% (2) — NA Arterial grafts 37.8% (50) 77.6% (52) — NA Venous grafts 62.2% (82) 22.4% (15) — NA No. of grafts (mean) — — No. of stents 0 2.6±0.7 1.1±0.4 1 — 9.6% (5) 0 2 — 48.1% (25) 0 3 or more — 32.7% (17) 51.9% (27) NA No. of stents (mean) — 9.6% (5) 49.1% (26) — — 1.5± 0.9 2.7±0.9 Incomplete TLR (per patient) 8.0% (4) 7.7% (4) 5.7% (3) 0.86 Incomplete TLR (per total number target lesions in 3.7% (5/136) 2.7% (4/149) 2.1% (3/146) 0.71 study group) Values are means±SD or percentages (counts). Data are shown as per randomization (intention-to-treat population). CABG: coronary-artery bypass grafting; HCR: hybrid coronary revascularization; PCI: percutaneous coronary intervention. COPD/BA: chronic obstructive pulmonary disease/bronchial ‡ § ǁ asthma. MI: myocardial infarction. LVEF: left ventricular ejection fraction. EuroSCORE II: /e European System for Cardiac Operative Risk Evaluation (EuroSCORE); a clinical model for calculating the risk of death after cardiac surgery. SYNTAX score: Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score; an angiographic model for evaluating coronary artery disease extensiveness. TLR, target lesion revascularization, given per total number of lesions to be revascularized according to Heart Team recommendation. similar in all three treatment modalities (CABG 20/49, noninferiority p values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Between-group differences were sig- 40.8%; HCR 21/49; 42.9%; MV-PCI 26/51; 51.0%, p � 0.56). nificantly smaller than the prespecified noninferiority As shown in Figure 2, the three treatment modalities were margin of 4.2% and the trial met its primary endpoint of associated with a similar freedom from MACCE at 12 noninferiority (Figure 1). /e ITT-based conclusion was the months. same when patients with conversion from HCR were ex- Angiographic control at 12 months demonstrated 9 cluded (per protocol analysis) and when the patients with SVGs and 1 LIMA stenosis/occlusion in the CABG group conversion from HCR were reclassified to the CABG group (10/49, 20.4%), 3 LIMA stenoses/occlusions and 1 in- (per treatment analysis). /ere were no differences in the segment restenosis in the HCR group (4/49, 8.2%), and 3 primary endpoint in patients with 2-vessel disease vs. >2- in-segment restenoses in the PCI group (3/51, 5.9%); vessel disease. /ere were also no differences according to p � 0.05. Twelve-month TV or graft failure (composite of SYNTAX score. Proportion of patients with RI>5% was cardiac death, TV-MI, and clinically driven TVR) was Journal of Interventional Cardiology 5 Table 2: HREVS study endpoints according to randomization group. Endpoint CABG HCR PCI p value Primary endpoint at 12 months N �49 N �49 N �51 ∗∗ RI (SPECT) 6.7 (4.6, 8.8) 6.4 (4.3, 8.5) 7.9 (5.9, 9.8) 0.45 Secondary endpoints at 12 months N �50 N �52 N �53 MACCE (death/stroke/MI/clinically driven repeat 12.0% (6) 13.4% (7) 13.2% (7) 0.83 revascularization) Death 2.0% (1) 5.8% (3) 3.8% (2) 0.78 Stroke 0% (0) 3.8% (2) 0% (0) 0.21 MI 8% (4) 5.8% (3) 7.5% (4) 0.66 Clinically driven TVR 2.0% (1) 1.9% (1) 5.7% (3) 0.54 Angiography-driven TVR 2.0% (1) 11.5% (6) 11.3% (6) 0.139 Total TVR 4.0% (2) 13.5% (7) 17.0% (9) 0.095 Secondary endpoints at 30 days MACCE (death/stroke/MI/clinically driven repeat 8% (4) 5.8% (3) 3.8% (2) 0.37 revascularization) Death 0% (0) 1.9% (1) 0% (0) 0.66 Stroke 0% (0) 1.9% (1) 0% (0) 0.66 MI 8% (4) 5.8% (3) 3.8% (2) 0.37 Repeat revascularization 0% (0) 1.9% (1) 0% (0) 0.66 Conversion to CABG NA 9.6% (5) 0 0.027 Bleeding BARC 0–1 80.0% (40) 80.8% (42) 98.1% (52) BARC 2 0% (0) 9.6% (5) 1.9% (1) BARC 3–4 20.0% (10) 9.6% (5) 0% (0) 0.001 Hospital stay (days) 13.8 (12.5, 15.1) 13.5 (12.2, 14.8) 4.5 (3.2, 5.8) <0.001 Institutional rehabilitation 100% (49) 97.9% (48) 56.8% (29) <0.001 Sick leave (weeks) 23 (21, 25) 16 (15, 18) 8 (6, 10) <0.001 ∗ ∗∗ Data are presented as means (95% confidence interval) or percentages (counts). Evaluable in patients alive at 12±1 months. p � 0.046 on combined noninferiority analysis that the study was powered for (cf. Figure 1). CABG vs. HCR MV-PCI vs. CABG (p = 0.029) p = 0.016 MV-PCI vs. HCR (p = 0.003) HCR vs. CABG p = 0.0006 MV-PCI vs. CABG (p = 0.015) –4 –3 –2 –1 0 1 2 3 4 5 6 –4 –3 –2 –1 0 1 2 3 4 5 6 Difference in residual ischemia at 12 months Difference in residual ischemia at 12 months (a) (b) Figure 1: Noninferiority analysis for the SPECT-based residual ischemia at 12 months in the three treatment arms with CABG as a reference method (a) and assuming no single reference method (b). Point estimates and 90% confidence intervals for the differences in RI between treatment modalities are shown with solid vertical gridline indicating the null difference and interrupted vertical gridline indicating the noninferiority margin of 4.2 percentage points. (a) Respective p values are for noninferiority of MV-PCI vs CABG and HCR vs. CABG. To adjust for two comparisons with CABG as the reference p values were considered statistically significant when <0.025. (b) p values are for pairwise noninferiority tests with 95% one-sided confidence intervals. Overall p for noninferiority is 0.046. 12.0% (CABG) versus 11.5% (HCR) versus 11.3% (PCI) angiography-driven) at 12 months numerically favoured (p � 0.99). Angiography-driven revascularization was CABG, with 4.0% (CABG) versus 13.5% (HCR) versus performed in 1 of 50 (2.0%) CABG patients versus 12/105 17.0% (PCI) (p � 0.095), and 4.0% in the CABG arm (2/ (11.4%) subjects with any PCI at baseline (combined HCR 50) but 15.2% (16/105) in the combined HCR plus MV- plus MV-PCI arm) (p � 0.062). As shown in Table 2, total PCI cohort (p � 0.058; for individual group data, see TVR rate (sum of clinically driven and control Table 2). 6 Journal of Interventional Cardiology 100 20 50 10 50 46 46 44 44 52 49 47 46 45 53 51 51 50 46 0 3 69 12 0 31 6 9 2 Follow-up (months) Follow-up (months) CABG CABG: 6 events in 50 patients HCR HCR: 7 events in 52 patients PCI PCI: 7 events in 53 patients (a) (b) Figure 2: MACCE-free survival (a) and cumulative risk of MACCE (b) during 12-month follow-up according to the treatment arm. Panel A shows MACCE-free survival, whereas the cumulative risk of MACCE is depicted in Panel B. Numbers of patients at risk are shown above the horizontal axis in panel A. Pairwise comparisons of treatment arms with Cox proportional hazards model are shown at the bottom of panel B. MACCE—Major Adverse Cardiac or Cerebral Event. invasiveness of CABG and the increased risk of repeat re- 4. Discussion vascularization with PCI [2, 16]. /e optimal revasculari- zation approach would thus need to combine a decreased /e primary endpoint of this first randomized controlled nd study, comparing conventional CABG, MV-PCI using 2 invasiveness plus low risk of perioperative complications generation standard-of-reference DES, and HCR in patients and an increased durability and survival. A combination of a minimally invasive LIMA-LAD graft procedure with PCI with MV-CAD amenable to treatment with any of the three guideline-accepted modalities, was SPECT-determined RI at using DES to non-LAD vessels eliminates aortic manipu- lation and extracorporeal circulation, resulting in a potential 12 months. Based on the noninferiority margin of the trial, the three strategies were similar after 12 months in terms of to decrease the risk of perioperative complications [1, 4, 11, 12, 17]. /us, the “third” revascularization strat- RI (Figure 1) that is an established measure of CR efficacy and a predictor of long-term prognosis. Other important egy—HCR—might have potential advantages beyond PCI and CABG alone [1, 4–12, 18, 19]. Although HCR was first findings, with potential relation to healthcare resources’ utilization, are shorter hospital stay, less need to use insti- introduced over 20 years ago [4], today the potential of this strategy in MV-CAD patients appears neither sufficiently tutional in-patient rehabilitation, and shorter sick-leave duration with the percutaneous route of coronary revas- determined [1, 2, 10] nor fully utilized [9, 19]. Some fun- cularization in MV-CAD. Although underpowered for damental HCR concerns include the complexity of patient logistics; the presence of surgical and endovascular stage clinical events, HREVS suggests similar 12-month MACCE rates with all three treatment strategies (Figure 2), a finding (with “naturally” incomplete revascularization at the HCR first-stage); the timing of antiplatelet therapy, optimal that requires confirmation in a larger multicentre study. /e primary focus of HREVS is RI at 12 months by timing of the HCR stages; and technical aspects of the surgical intervention (access site, and the role of thoraco- SPECT. Myocardial perfusion SPECTimaging is not only an objective method to compare the outcome of coronary re- scopic or robotic approaches) [5–11]. /us far, HCR outcomes have been compared mostly vascularization but also there is a direct proportional rela- tionship between the extent of RI and prognosis [14, 15]. with standard CABG [1, 6, 8], and included only one ran- Taking into account that the groups were randomized, domized study that, however, did not have a percutaneous treatment arm [6]. Another observational study compared comparable in their basic characteristics, and the fact that the groups received high level of complete revascularization conventional CABG to MV-PCI [18]. Retrospective series and meta-analyses have reported low mortality rates (0% to (92% vs. 92.3% vs. 94.3%), it can be concluded that within the assumed noninferiority margin, the three strategies 2%) and event-free survival rates of 83% to 92% for HCR at 6 to 12 months of follow-up and similar outcomes of HCR in occurred similar with respect to RI at 12 months. /is main result is broadly consistent with the analysis of the secondary comparison with standard revascularization options [5, 8]. In the single randomized trial of HCR vs. conventional endpoints (Table 2, Figure 2). /e two typically applied techniques for MV-CAD CABG, the HCR arm demonstrated, at 12 months, similar to CABG cumulative occurrence of major adverse cardiac interventional management, CABG and MV-PCI, have clinically relevant disadvantages that include the events [6]. In that study, 6.1% HCR patients required MACCE-free survival (%) Cumulative risk of MACCE (%) Journal of Interventional Cardiology 7 A recently funded US National Institutes of Health conversion to standard CABG [6], a result broadly consis- tent with our present findings (Table 2). (NIH) Hybrid Coronary Revascularization Trial (HCR, NCT03089398), a 2354 patient study with 5-year follow-up, HREVS is the first randomized controlled study com- paring outcomes of the three guideline-accepted treatment might be able to overcome only some of the HREVS lim- strategies in MV-CAD patients. In HREVS, the HCR pa- itations because the NIH HCR Trial compares HCR vs. MV- tients underwent two-stage revascularization with MIDCAB PCI in absence of the CABG arm. first, followed by PCI using the second-generation ever- olimus-eluting stents. /e use of a standard-of-reference nd 4.1. Limitations. /is study has several limitations as listed [3, 20, 21] 2 generation DES in HREVS, the device that below. showed some of the best results in the interventional treatment of CAD patients, suggests that HREVS patients (i) HREVS was not powered for clinical events, al- were offered a maximized benefit from the choice of stent though the center enrolment rate and volume in the endovascular arm and in the HCR arm. exceeded by over 10-fold typical yearly contribu- Prior work indicated that MIDCAB, when compared to tions in the pivotal BEST Trial comparing MV-PCI conventional sternotomy CABG, results in less surgical with CABG that was itself underpowered due to an trauma, decreased risk of bleeding and infectious compli- insufficient and slow enrolment that included only cations, and may shorten the length of hospitalization 20% of the eligible patients [20]. [4, 11, 12]. /e latter, however, is not supported by our (ii) Recruitment challenges were related not only to the findings, a result that may be partly driven (note ITT fundamental requirement of equal technical and analysis) by the conversion rate (9.8%) from HCR to CABG clinical feasibility of either of the tested strategies in HREVS (Table 2). but also to the patient’s (and family’s) natural In the HREVS HCR arm, PCI was performed within 3 gravitation towards less invasive treatment (evi- days after surgery (in majority of patients, within 24–48h denced by nearly 1 in 4 refusal rate to random after surgery). /is allowed consistency of hemostasis in treatment allocation due to PCI preference); thus, absence of DAPT at the time of surgery (the patients were overall recruitment rate in HREVS was >75%. operated on aspirin and loaded with clopidogrel at the time (iii) HREVS did not evaluate quality of life, an area of PCI) as well as angiographic control of the LIMA-to-LAD where clinically relevant differences might exist, graft during the endovascular stage. Lack of ad hoc total consistent with our findings on the sick-leave du- revascularization in the HCR group with LIMA-to-LAD ration and time-to-return to work, favouring less MIDCAB, however, was associated with hemodynamic in- invasive treatment strategies. stability and myocardial ischemia in 3 patients who required conversion to sternotomy to perform ad hoc revasculari- (iv) Any generalizability of the findings needs to take zation of the remaining lesions by CABG. into account the moderate MVD angiographic Although HREVS will continue to monitor its study par- complexity in this study (reflecting the requirement ticipants up to 5 years, a larger multicentre study involving of technical feasibility of CABG, HCR, and MV- HCR along CABG and MV-PCI would be required to deter- PCI; thus, the need to exclude the left main coronary mine, by clinical outcomes, the optimal interventional treat- artery stenosis not amenable to HCR, severely ment strategy in MV-CAD. /is is relevant also because calcific lesions, complex bifurcations, or chronic evidence is accumulating that using multiple arterial grafts in total occlusion that may favour surgery) and the CABG may be associated with improved clinical outcomes particular sequence and timing of HCR procedures when compared to either conventional CABG with LIMA to as per the HREVS protocol. LAD and SVGs to other vessels [22], CABG using bilateral mammary arteries plus SVGs [23], or to MV-PCI [24]. Al- though HREVS indicates no significant differences in 12- 4.2.Strengths. Fundamental strengths of HREVS include the month TVF between the three treatment modalities, the an- following: giographic control at 1 year suggested sizable differences in (i) Use of quantifiable primary endpoint of RI at graft stenosis/occlusion or in-segment restenosis rates (20.4% 12 months that is independently predictive, in a vs. 8.2% vs. 5.9% for CABG vs. HCR vs. MV-PCI; p � 0.05) gradient manner, of cardiac death or MI that may affect long-term outcomes [25]. Whether these dif- [13–15, 26], and the trial appropriate power for ferential 12-month anatomical revascularization results affect noninferiority comparison of the 3 treatment longer-term clinical outcomes [25] remains to be established. modalities [13, 27]. Importantly, the lower rates of institutional rehabilita- tion use in the MV-PCI arm are not necessarily beneficial (ii) /ere were no identifiable clinical or angiographic differences between the patients who agreed to because the patients who opt not to use the institutional rehabilitation services might benefit from those. random treatment allocation in HREVS and entered the study versus those who were Heart Team–labelled /e prevalence and extent of bleeding with (any) surgery (Table 2) should serve as an important consideration point as eligible for enrolment but did not accept random in support of PCI rather than CABG or HCR in some (if not treatment allocation, in favour of generalizability of most of) moderate SYNTAX patients. the findings to similar patients outside the trial. 8 Journal of Interventional Cardiology Table 3: Inclusion and exclusion criteria of the HREVS trial. Inclusion criteria Exclusion criteria 1. Acute coronary syndrome (ACS) 2. Any previous coronary revascularization (CABG, 1. Male or female ≥18 years of age HCR, or PCI) 2. II–IV Canadian Cardiovascular Society functional 3. Presence of any condition or abnormality that in class of angina the opinion of the investigator would compromise 3. Angiographically confirmed multivessel coronary the safety of the patient or the quality of the data artery diseases involving LAD, with lesions severity 4. Pregnancy ≥70% diameter stenosis (DS) by quantitative 5. Stenosis of the left main coronary artery requiring coronary angiography (QCA), or 50–70% DS with revascularization functional evidence of ischemia by either FFR ≤0.80 6. Significant calcification or occlusion of a major or stress SPECT coronary vessel 4. At least 1 month after acute MI (in patients with 7. Left ventricle aneurysm or valvular heart disease history of MI) requiring surgical management 5. Heart team-determined indication to coronary 8. Comorbidity associated with an increased revascularization with equal feasibility to perform procedural risk for any of the treatment strategies or complete revascularization using either of the three other study procedures methods (HCR, MVD-PCI, CABG) 9. Peripheral arterial disease with pain-free walking 6. Written informed consent for participation in the distance ≤50m study, including random treatment allocation and 10. Life expectancy ≤5 years compliance with study requirements inclusive of 11. Inability to comply with dual antiplatelet therapy follow-up visits and 12±1 month SPECTfollowed by (DAPT) control angiography 12. Inability to undergo follow-up procedures including long-term follow-up 13. Participation in another clinical study (iii) Mandatory angiographic control at 12 months is a Appendix particular strength of the present study as it verified the midterm anatomic quality of A. HREVS Trial Inclusion/Exclusion Criteria revascularization. Table 3 shows the inclusion and exclusion criteria of the (iv) HREVS results add importantly to the present HREVS trial. knowledge in the context of (a) increasing pene- tration of percutaneous revascularization [28], (b) suggestions that optimized PCI might lead to B. Endpoint and Other Definitions CABG-like outcomes in MV-CAD [29], and (c) increasing Heart Team recommendations of first- MI and stroke were defined according to international line percutaneous approach [2, 28]. guidelines (1, 2); other definitions were according to the Academic Research Consortium (3). In brief, clinically driven (v) Rather than generating hypotheses on the basis of TVR was defined as percutaneous revascularization or bypass historical comparative data [29], HREVS was a real-life of the target lesion or any segment of the epicardial coronary randomized trial with multiarm parallel-group design. artery containing the target lesion or more proximal vessels that may have been traversed by the angioplasty guidewire during the index procedure, driven by ischemic symptoms 5. Conclusion presence or presence of other clinical abnormalities leading to In patients with MV-CAD amenable to CABG, HCR, and an angiogram prior to the protocol-mandated point at 12±1 MV-PCI, the quantitative endpoint of residual myocardial months from randomization. Angiography-driven TVR was ischemia at 12 months, which is predictive in a gradient TVR resulting from performing protocol-required control manner of cardiac death and adverse cardiac events angiography at 12±1 months. Target vessel (TV) or graft [13–15, 26], was similar with all three guideline- failure was defined as a composite of cardiac death, target accepted revascularization strategies. MV-CAD PCI, using vessel-MI, and clinically driven TVR of the artery containing contemporary best-in-class drug-eluting stents, was the target lesion (i.e., one of the index lesions in a given associated with a shorter hospital stay, less inpatient reha- patient) within 12 months after randomization (3). bilitation, and shorter sick-leave duration than CABG or HCR. While extended follow-up will determine longer-term C. Power Calculations outcomes from the present study, a larger-scale multicentre trial powered for clinical endpoints would be warranted. Power calculations and statistical analysis are consistent with Nevertheless, any effective execution of such a large-scale reference 4 and reference 5. With recruitment of 50 subjects study seems unlikely [20]. per group, the study had 80% power to exclude with a Journal of Interventional Cardiology 9 noninferiority t-test with the 2.5% type I error rate (adjusted (5) Walker E, Nowacki AS. “Understanding Equiva- for two comparisons with the reference arm), the margin set lence and Noninferiority Testing”. Journal of at 4.2 percentage points, which we considered a reasonable General Internal Medicine, vol. 26, no 2, pp.192–96, minimum clinically significant difference. An absolute 4.2 2011. percentage points difference is associated with an increased (6) Berman DS, Hachamovitch R, Shaw LJ, et al. “Roles of risk of MI, whereas 4.9 percentage points is cut-off for an nuclear cardiology, cardiac computed tomography, increased risk of death (6, 7), and the generally accepted and cardiac magnetic resonance: Noninvasive risk clinically significant ischemia interval is set at 5%, with 5% stratification and a conceptual framework for the se- considered a clinically significant difference (8, 9). Based on lection of noninvasive imaging tests in patients with literature data (8), the assumed standard deviation of per- known or suspected coronary artery disease”. J Nucl cent ischemic myocardium was 7. Med, vol. 47, no 7, pp. 1107–18, 2006. (7) Shaw LJ, Wilson PW, Hachamovitch R, et al. D. Additional Information on Statistical “Improved near term coronary artery disease risk Analysis and Study Conduct and Reporting classification with gated stress myocardial perfusion SPECT”. JACC Cardiovasc Imaging, vol. 3, no 11, /e continuous variables are presented as the mean ±SD, pp. 1139–48, 2010. unless with skewed distribution, for which medians with (8) Shaw LJ, Berman DS, Maron DJ, et al. “Optimal quartiles are presented. /e categorical variables are sum- medical therapy with or without percutaneous marized as percent and count. Study endpoints were reported coronary intervention to reduce ischemic burden: as means±SD with 95% confidence intervals or as percent- Results from the Clinical Outcomes Utilizing Re- ages, where applicable. Analysis was intention to treat. Con- vascularization and Aggressive Drug Evaluation tinuous variables were compared using unbalanced ANOVA (COURAGE) trial nuclear substudy”. Circulation, when distributions were approximately normal. Kruskal– vol. 117, no 10, pp. 1283–91, 2008. Wallis test was used to compare medians of significantly (9) Farzaneh-Far A, Phillips HR, Shaw LK, et al. “Is- skewed variables. Proportions were compared with the chi chemia change in stable coronary artery disease is test or the Fisher exact test, as appropriate. A noninferiority an independent predictor of death and myocardial analysis for the primary endpoint was performed using the infarction”. JACC Cardiovasc Imaging, vol. 5, no7, t-distribution-based confidence intervals assuming a non- pp. 715–24, 2012. inferiority margin of 4.2 RI percentage points. To adjust for two comparisons with CABG as the reference p values were (10) Juszczak E, Altman DG, Hopewell S, Schulz K. considered statistically significant when <0.025. A 2-sided “Reporting of Multi-Arm Parallel-Group Randomized nominal p value <0.05 was considered statistically significant trials: Extension of the CONSORT 2020 Statement”. in secondary endpoint analysis. Product-limit survivor func- JAMA, vol. 321, no 16, pp. 1610–1620, 2019. tion estimate was used in MACCE analysis, and Cox pro- portional hazards model was applied to estimate hazard ratios Abbreviations of MACCE between study arms. Statistical analysis was per- formed with SAS 9.4 software (SAS Institute, Cary, NC, USA). CABG: Coronary artery bypass grafting HREVS study conduct and reporting were consistent DAPT: Dual antiplatelet therapy with the updated CONSORT 2010 guidelines [10]. FFR: Fractional flow reserve HCR: Hybrid coronary revascularization E. Appendix Literature HT: Heart team MACCE: Major adverse cardiac and cerebrovascular (1) /ygesen K, Alpert JS, Jaffe AS, et al. “Fourth events (death/stroke/myocardial infarction universal definition of myocardial infarction”. (MI)/clinically-driven TVR) Circulation, vol. 138, no 20, pp. e618–e651, 2018. MIDCAB: Minimally invasive direct coronary artery bypass (2) Sacco RL, Kasner SE, Broderick JP, et al. “An MV- Multivessel coronary artery disease updated definition of stroke for the 21st century: A CAD: statement for healthcare professionals from the PCI: Percutaneous coronary intervention American Heart Association/American Stroke As- RI: Residual myocardial ischemia sociation”. Stroke, vol. 44, no 7, pp. 2064–89, 2013. SPECT: Single-photon emission computed tomography TVR: Target vessel revascularization (3) Cutlip DE, Chauhan MS, Baim DS et al. “Clinical TVF: Target vessel failure. restenosis after coronary stenting: Perspectives from multicentre clinical trials”. JACC, vol. 40, no 12, pp. 2082–2089, 2002. Data Availability (4) (International Committee of Medical Journal Edi- tors/no authors listed). Uniform requirements for Clinical, imaging, and statistical data used to support the manuscripts submitted to biomedical journals. 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Fu et al., “Mid-term follow-up outcomes of Conflicts of Interest 2-staged hybrid coronary revascularization compared with off-pump coronary artery bypass for patients with multivessel None of the authors has any disclosure relevant to this coronary artery disease,” Videosurgery and Other Mini- manuscript to report. invasive Techniques, vol. 12, no. 2, pp. 178–185, 2017. [13] L. J. Shaw, D. S. Berman, D. J. Maron et al., “Optimal medical therapy with or without percutaneous coronary intervention Authors’ Contributions to reduce ischemic burden: results from the Clinical Out- comes Utilizing Revascularization and Aggressive Drug VG, LB, and PM were involved in conception and design of Evaluation (COURAGE) trial nuclear substudy,” Circulation, research; VG, NK, AS, RT, VP, KK, OB, and LB were re- vol. 117, no. 10, pp. 1283–1291, 2008. sponsible for data acquisition; VG, JS, RT, and PM were [14] D. S. Berman, R. Hachamovitch, L. J. 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