Comparative Effectiveness of Hybrid Coronary Revascularization vs Coronary Artery Bypass Grafting

Comparative Effectiveness of Hybrid Coronary Revascularization vs Coronary Artery Bypass Grafting Ralf E Harskamp, MD, Thomas A Vassiliades, MD, FACS, Rajendra H Mehta, MD, MS, Robbert J de Winter, MD, PhD, Renato D Lopes, MD, PhD, Ying Xian, MD, PhD, Eric D Peterson, MD, MPH, John D Puskas, MD, MS, FACS, Michael E Halkos, MD, MS, FACS Hybrid coronary revascularization (HCR) combines minimally invasive left internal mammary artery to left anterior descending bypass with percutaneous coronary intervention of non-left anterior descending vessels. Its safety and effectiveness compared with conventional CABG have been under studied. STUDY DESIGN: Patients with multivessel disease and/or left main disease who underwent HCR at a US academic center between October 2003 and September 2013 were included. These patients were matched 1:3 to patients treated with CABG using a propensity-score matching algorithm. Conditional logistic regression and Cox regression analyses stratified on matched pairs were performed to evaluate the adjusted association between HCR and short- and long-term outcomes. RESULTS: The 30-day composite of death, MI, or stroke after HCR and CABG was 3.3% and 3.1% (odds ratio ¼ 1.07; 95% CI, 0.52e2.21; p ¼ 0.85) in the matched cohort of 1,224 patients (HCR, n ¼306; CABG, n ¼ 918). Hybrid coronary revascularization was associated with lower rates of in-hospital major morbidity (8.5% vs 15.5%; p ¼ 0.005), lower blood transfusion use (21.6% vs 46.6%; p < 0.001), lower chest tube drainage (690 mL; 25th to 75th percentile: 485 to 1,050 mL vs 920 mL, 25th to 75th percentile: 710 to 1,230 mL; p < 0.001), and shorter postoperative length of stay (<5-day stay: 52.6% vs 38.1%; p ¼ 0.001). During a 3-year follow-up period, mortality was similar after HCR and CABG (8.8% vs 10.2%; hazard ratio ¼ 0.91; 95% CI, 0.55e1.52; p ¼ 0.72). Subgroup analyses in patients stratified by 2-vessel, 3-vessel, left main disease, and by Society of Thoracic Surgeons risk scores rendered similar results. CONCLUSIONS: The use of HCR appeared to be safe, with faster recovery and similar outcomes when compared with conventional CABG. These findings were consistent irrespective of anatomic or predicted procedural risk. (J Am Coll Surg 2015;-:1e9.
2015 by the American College of Surgeons)

BACKGROUND:

artery (LAD) graft is thought to be responsible for the long-term advantage of CABG over percutaneous coronary intervention (PCI).3 However, PCI offers a much lower level of invasiveness, with faster recovery and less short-term complications, including fewer strokes.4 Therefore, patients at high surgical risk, as well as those with less complex CAD (and without diabetes) are believed to be better off with PCI. Although the debate about surgical vs percutaneous revascularization remains unsettled, a relatively new concept of hybrid coronary revascularization (HCR) has been introduced in an attempt to combine the strengths of CABG and PCI by combining the durability of the LIMA-LAD bypass graft with PCI for nonLAD lesions. A single LIMA-LAD grafting does not require a large operating field, and allows the use of sternal-sparing incisions without aortic manipulation and

Coronary artery bypass grafting is considered the gold standard for management of patients with complex multivessel coronary artery disease (CAD).1,2 The unparalleled patency and freedom from atherosclerosis of the left internal mammary artery (LIMA) to left anterior descending Disclosure Information: Nothing to disclose. Received December 30, 2014; Revised March 1, 2015; Accepted March 2, 2015. From the Duke Clinical Research Institute, Durham, NC (Harskamp, Mehta, Lopes, Xian, Peterson), Academic Medical Center, University of Amsterdam, The Netherlands (Harskamp, de Winter), Divisions of Cardiothoracic Surgery and Cardiology, Clinical Research Unit, Emory University School of Medicine, Atlanta, GA (Vassiliades, Halkos), and Department of Cardiothoracic Surgery, Mount Sinai Beth Israel, New York, NY (Puskas). Correspondence address: Ralf E Harskamp, MD, Duke Clinical Research Institute, 2400 Pratt St, Rm 7047B, Durham, NC 27705. email: r.e. [email protected]

ª 2015 by the American College of Surgeons Published by Elsevier Inc.

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Abbreviations and Acronyms

CAD HCR IMA LAD LIMA OR PCI STS

¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼

coronary artery disease hybrid coronary revascularization internal mammary artery left anterior descending left internal mammary artery odds ratio percutaneous coronary intervention Society of Thoracic Surgeons

mitigates the need for cardiopulmonary bypass. This has the theoretical potential for reducing the incidence of adverse neurologic events, bleeding, infection, and pulmonary complications associated with conventional on-pump CABG, and permits the long-term survival advantage conferred by LIMA-LAD bypass.5 For revascularization of non-LAD lesions, the use of PCI has been shown to offer similar patency compared with saphenous vein grafts used in conventional CABG, particularly when drugeluting stents are used.6 However, the safety and effectiveness of hybrid coronary revascularization is understudied, particularly in patients at higher procedural risk and those with left main or 3-vessel disease, a population usually referred for conventional revascularization. To address this, we compared 30-day and long-term clinical outcomes

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in a contemporary cohort of patients undergoing either HCR or conventional CABG at a US academic institution.

METHODS Study population and definitions The starting population included all eligible cases from the Emory University Institutional Society of Thoracic Surgeons (STS) Adult Cardiac Database between October 2003 and September 2013. At Emory, a custom data field was created within the STS database, which defined hybrid patients on an intent-to-treat basis to capture patients who either were converted to sternotomy for multivessel CABG, or to identify those who underwent only PCI or LIMA-LAD grafting without the second part of the hybrid procedure. To be considered a hybrid procedure, the case should involve a planned nonsternal LIMA-LAD bypass with PCI of one or more non-LAD lesions that were performed either in one setting or as 2-staged procedures. Those who underwent emergent PCI or angioplasty for acute coronary syndrome, then traditional multivessel CABG through median sternotomy, were not defined as a hybrid procedure for this study. In total 9,901 underwent CABG surgery or HCR on an intent-to-treat basis during the study period. From this starting population, we selected patients with

Figure 1. Flow diagram of the study population. Steps that led from the starting population to the propensity scoreematched study population. These patients were included in a sensitivity analysis of intention-to-treat for hybrid coronary revascularization (HCR). LMD, left main coronary artery disease; MVD, multivessel coronary artery disease.

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angiographically determined multivessel disease or left main disease, and applied a number of exclusion criteria, which are listed in Figure 1. From the remaining 8,560 patients after exclusions, we then matched those who underwent as-treated HCR with controls, that is, individuals who underwent elective or urgent conventional CABG surgery either with or without the use of cardiopulmonary bypass. A sensitivity analysis was performed in which the study population included patients who underwent HCR on an intent-to-treat, instead of an as-treated basis, which also included patients who were scheduled for HCR but ended up with an incomplete or different revascularization strategy. Diagnostic criteria for all baseline characteristics other than HCR were based on the STS registry definitions (http://www.sts.org). This study was conducted in accordance with the IRB of Emory University. The authors are solely responsible for the design, conduct, and analysis of this study, as well as the drafting and editing of the article, and its final contents. No extramural funding was used to support this work. Relative indications and contraindications of hybrid coronary revascularization At Emory, the consideration as well as timing and sequence of HCR are discussed by a multidisciplinary heart team for each case. The relative indications for a hybrid approach include the presence of proximal LAD disease amenable to minimally invasive LIMA-LAD bypass and the presence of non-LAD lesions considered to be amenable to PCI. Relative contraindications for HCR included a poor LAD target vessel, hemodynamic instability, earlier sternotomy or left thoracotomy, inability to tolerate single-lung ventilation, morbid obesity, and high-complex non-LAD lesions not considered suitable for PCI. Procedures and anticoagulation protocol for hybrid coronary revascularization The default strategy for HCR is to perform LIMA-LAD bypass first, because this approach allows surgery to be performed without a combination of dual antiplatelet therapy and heparin. For this strategy, 150 mg clopidogrel is administered after completion of the surgical part. An additional loading dose of 300 mg is given at the time of PCI. In cases where PCI is performed first, as is preferred in patients with critical non-LAD disease, surgery is performed under clopidogrel (75 mg once daily) and aspirin. In a minority of patients, HCR is performed as a concurrent, single-stage procedure in which LIMALAD bypass is performed first and directly followed by PCI of non-LAD lesions, in which a 600-mg loading dose of clopidogrel is administered through a nasogastric

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tube after confirmation of LIMA-LAD patency. At Emory, the surgical component of HCR was performed with an endoscopic atraumatic coronary artery bypass approach until 2009; thereafter, LIMA harvest was performed using robotic assistance (da Vinci Surgical System; Intuitive Surgical) through thoracoscopic incisions followed by a nonerib-spreading 3 to 4 cm minithoracotomy through which the LIMA-LAD anastomosis is manually performed. The PCI component of HCR is performed using standardized methods and techniques in which drug-eluting stents were used in most cases, which could involve both first-generation (sirolimus, paclitaxel) or newer generation (everolimus, zotarolimus) stent platforms. Outcomes Outcomes of interest included the composite of all-cause mortality, MI, and stroke at 30 days, as well as all-cause mortality at longitudinal follow-up. Secondary outcomes were in-hospital major morbidity (a composite of reoperation, renal failure, prolonged ventilation, and access site infections), bleeding complications, including CABGrelated bleeding, need for blood transfusions and chest tube drainage; and recovery parameters, short and long in-hospital length of stay. For clinical outcomes, data on death, MI, and stroke were limited to 30-day followup available through the STS database. In addition, follow-up information on all-cause mortality was obtained by querying the Social Security Death Index to determine dates of death for all patients in the study. Definitions for all short-term outcomes are based on STS Adult Cardiac Surgery Database definitions. In addition, CABG-related bleeding was defined according to the Bleeding Academic Research Consortium type 4 bleeding criteria,7 which include perioperative intracranial bleeding, reoperation after closure of sternotomy for the purpose of controlling bleeding, transfusion of 5 U whole blood or packed RBCs, chest tube output of 2 L within a 24-hour period. Statistical analysis From the starting population, a number of exclusion criteria were applied, resulting in a population of 306 patients who underwent HCR and 8,254 patients who underwent CABG (as shown in Fig. 1). We subsequently calculated propensity scores (or the probability of assignment to HCR or CABG) using multivariable logistic regression for each patient, using preoperative variables listed in Table 1. Each patient who underwent HCR was subsequently matched in a 3:1 ratio to patients who underwent conventional CABG, using nearest neighbormatching algorithm without replacement on the logit of

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Table 1.

Baseline Characteristics Before and after Propensity Score Matching

Characteristics

Age, y, mean  SD Sex, % Male White BMI, kg/m2, mean  SD Current smoker, % Diabetes, % Chronic lung disease, % Hypertension, % Cerebrovascular disease, % Peripheral artery disease, % eGFR, mean  SD Earlier MI, % Heart failure <14 d, % LVEF, mean  SD Ht <0.35, % Anemia, % Isolated LMD, % 2-VD, % 3-VD, % LM and VD, % Elective, % STS score, mean  SD

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HCR (n ¼ 306)

Unadjusted CABG (n ¼ 8,254)

SD

After PS matching HCR (n ¼ 306) CABG (n ¼ 918)

SD

64.6  11.6

63.3  10.7

11.6

64.6  11.6

64.8  10.4

1.5

70.3 78.8 28.4  5.3 20.6 36.9 3.6 91.5 17.3 11.1 75.0  27.0 47.4 12.4 54.7  9.4 27.1 39.9 11.1 45.8 34.0 9.2 65.0 1.6  2.2

72.7 76.6 29.3  6.0 28.4 42.1 5.8 87.8 18.1 15.8 71.8  25.3 52.8 22.8 51.7  12.5 27.1 39.9 8.2 18.0 50.5 23.2 53.2 2.0  2.7

5.4 5.3 17.1 19.3 10.7 11.8 13.1 1.9 14.9 12.1 10.7 31.5 31.8 0.0 0.0 27.5 38.5 50.0 42.2 49.9 2.7

70.3 78.8 28.4  5.3 20.6 36.9 3.6 91.5 17.3 11.1 75.0  27.0 47.4 12.4 54.7  9.4 27.1 39.9 11.1 45.8 34.0 9.2 65.0 1.6  2.2

67.4 78.5 28.3  5.5 19.2 39.0 4.4 92.4 18.7 12.3 74.3  25.6 48.4 13.4 54.5  11.2 26.9 38.6 10.1 46.0 33.4 10.5 65.5 1.7  2.0

6.4 0.5 1.4 3.5 4.3 4.1 3.1 3.6 3.8 2.7 2.0 3.0 1.9 0.5 2.6 3.1 0.4 1,1 4.5 0.9 3.3

eGFR, estimated glomerular filtration rate; Ht, hematocrit; LM and VD, left main coronary artery disease and also significant disease in another coronary artery; LMD, left main coronary artery disease; LVEF, left ventricular ejection fraction; PS, propensity score; STS, Society of Thoracic Surgeons; 2-VD, twovessel coronary artery disease; 3-VD, three-vessel coronary artery disease.

the propensity score using a caliper of width equal to 0.20 standard definitions of the logit of the propensity score. After propensity score matching, we tested whether the balance on the covariates was achieved through the matching procedures using standardized differences, in which an absolute standardized difference of <10% was considered negligible imbalance, and assessment of global imbalance (p > 0.99 after matching). Comparisons of the 30-day composite end point, as well as in-hospital outcomes, were performed using conditional logistic regression analyses accounting for the matched nature of the study population. Longitudinal outcomes were graphically displayed using the Kaplan-Meier method, and Cox proportional hazard regression analysis stratified on matched pairs was used to examine differences in longitudinal mortality. The proportional hazards assumption was evaluated by visual assessment by log minus log survival plots and were found valid. Statistical analyses were performed with IBM SPSS Statistics software, version 20.0 (IBM SPSS). Propensity score matching was performed using an SPSSR plugin for R packages (MatchIt, Ritools, and cem).8

RESULTS A total of 341 patients underwent HCR on an intent-totreat-basis between October 2003 and September 2013. Three patients were excluded based on exclusion criteria (no internal mammary artery [IMA] graft use: n ¼ 1, history of valve replacement: n ¼ 1; concomitant carotid surgery: n ¼ 1). Of the remaining 338 cases scheduled for HCR, 32 patients (9.5%) did not undergo one or both stages of HCR. Twenty-five patients underwent minimally invasive LIMA-LAD grafting, but the remaining lesions were medically managed instead of treated with PCI (n ¼ 23), or PCI was attempted but failed (n ¼ 2). In 7 patients, HCR was converted to conventional CABG. Of the remaining 306 patients who underwent HCR, the majority were performed as a staged procedure in which LIMA-LAD grafting was done first in 222 patients (72.5%), and PCI was performed first in 61 patients (19.9%). Twenty-three patients (7.5%) underwent HCR as a 1-stage procedure. Median time interval between the 2 stages was 3 days (25th to 75th percentile: 2 to 7 days).

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Procedural Characteristics of Patients in the Propensity-Score Matched Cohort

Characteristics

Total operating time, min, mean  SD Cardiopulmonary bypass use, % Bilateral IMA use, % IMA anastomosis, mean  SD Vein grafts, mean  SD Total grafts, mean  SD Drug-eluting stent use, n (%) PCI-treated vessels, % RCA or side branch CX or side branch CX and RCA Diagonal Diagonal and CX Diagonal and RCA LM LM and other Ramus intermedius

HCR (n ¼ 306)

CABG (n ¼ 918)

p Value

295  80 0.0 0.7 1.04  0.21

324  78 16.8 11.0 1.17  0.44 1.79  1.01 3.10  0.93

<0.001 <0.001 <0.001 <0.001

256 (83.7) 32.0 27.1 9.8 7.5 1.9 2.3 8.3 9.0 2.6

CX, circumflex coronary artery; HCR, hybrid coronary revascularization; IMA, internal mammary artery; LM, left main coronary artery; NA, not applicable; PCI, percutaneous coronary intervention; RCA, right coronary artery.

Clinical and procedural characteristics Patients who underwent HCR (n ¼ 306) with minimally invasive LIMA-LAD bypass surgery and PCI of non-LAD vessels were matched 1:3 to patients who underwent CABG using conventional median sternotomy with or without the use of cardiopulmonary bypass, using 22 preoperative variables. Demographics and clinical characteristics were well balanced after propensity score matching, as absolute standardized mean differences were all <10% (Table 1). In the matched cohort, the mean age was 65 years and patients were predominantly male. About half of patients had 2-vessel disease, one-third had 3-vessel disease, and one-fifth had left main coronary artery disease (either as isolated left main disease or with additional vessel disease). Mean STS risk score for mortality was 1.6%  2.2% in the HCR group and 1.7%  2.0% in the CABG group. As shown in Table 2, total surgical operating time was shorter in those who underwent HCR (295 vs 324 minutes). In the CABG group, most cases were performed without the use of cardiopulmonary bypass (83.2%), and 11% of patients were revascularized with bilateral IMA bypass use. In the HCR group, robotic-assisted LIMA-LAD harvest was used in 149 patients, and endoscopic atraumatic coronary artery bypass was performed in 117 patients. Drug-eluting stents were used in 256 (83.7%) patients. Angiographic assessment of the LIMA-LAD graft was available in all patients who had LIMA-LAD grafting first, as well as those who had 1-stage procedures. Angiographic LIMA

evaluation revealed a FitzGibbon A patency rate of 96.0% and FitzGibbon AþB patency rate of 97.6%. Short-term outcomes As shown in Table 3, the incidence of the composite of death, MI, and stroke at 30 days was comparable between patients who underwent HCR or CABG (3.3% vs 3.1%; p ¼ 0.85). Five deaths occurred in the HCR group vs 10 in the CABG group (1.6% vs 1.1%; p ¼ 0.46), 2 vs 8 had an MI (0.7% vs 0.9%; p ¼ 0.72), and there were 3 vs 16 strokes (1.0% vs 1.7%; p ¼ 0.36). In-hospital major morbidity (a composite of reoperation, renal failure, prolonged ventilation, and access site infections) was markedly lower in the HCR group (8.5% vs 15.5%; p ¼ 0.005). Although CABG-related bleeding was not significantly different (7.2% vs 9.3%; p ¼ 0.29), need for blood transfusions, as well as total chest tube drainage were significantly lower after HCR. Additionally, recovery parameters, as measured by length of hospital stay, favored the HCR group compared with conventional CABG. Longitudinal clinical outcomes Median follow-up time was 3.7 years in the matched cohort (25th to 75th percentiles: 1.6 to 6.2), we therefore truncated outcomes after 3 years. As illustrated in Figure 2, all-cause mortality was similar between HCR and CABG during 3 years of follow-up (hazard ratio ¼ 0.91; 95% CI, 0.55e1.52; p ¼ 0.72). In Supplementary Figure 1 (available at: http://www.journalacs.org), we

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Table 3.

Thirty-Day Major Adverse Cerebrovascular and Cardiovascular Events and In-Hospital Outcomes

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Characteristics

HCR (n ¼ 306)

CABG (n ¼ 918)

Composite of 30-d death, MI, stroke, n (%) Death MI Stroke In-hospital major morbidity, n (%) Reoperation Renal failure Prolonged ventilation, >24 h Access site infection Bleeding outcomes CABG-related bleeding, n (%) Need for blood transfusion, n (%) Chest tube drainage, mL/24 h Recovery parameters, n (%) Short PLOS, <5 d Long PLOS, >14 d

10 5 2 3 26 13 5 16 0

28 10 8 16 142 53 21 102 11

(3.3) (1.6) (0.7) (1.0) (8.5) (4.2) (1.7) (5.3) (0.0)

(3.1) (1.1) (0.9) (1.7) (15.5) (5.8) (2.3) (11.1) (1.2)

22 (7.2) 66 (21.6) 690 (485e1,050)

85 (9.3) 428 (46.6) 920 (710e1,230)

161 (52.6) 7 (2.3)

350 (38.1) 46 (5.0)

OR (95% CI)

1.07 1.50 0.75 0.56 0.55 0.74 0.71 0.48

(0.52e2.21) (0.51e4.39) (0.16e3.53) (0.16e1.93) (0.36e0.83) (0.40e1.35) (0.27e1.89) (0.28e0.81) d

0.78 (0.49e1.24) 0.46 (0.36e0.60) b ¼ 1.58, t ¼ 5.57* 1.38 (1.15e1.66) 0.46 (0.21e1.01)

p Value

0.85 0.46 0.72 0.36 0.005 0.32 0.50 0.006 d 0.29 <0.001 <0.001 0.001 0.053

*Linear regression models were used. HCR, hybrid coronary revascularization; OR, odds ratio; PLOS, postoperative length of stay.

have included the Kaplan-Meier curves of longitudinal outcomes after HCR vs off-pump or on-pump CABG (left panel), as well as HCR vs CABG with the use of single or bilateral IMA grafts (right panel). Using the HCR group

as a reference, the propensity score adjusted hazard ratios were 1.09 (95% CI, 0.62e1.91; p ¼ 0.77) and 0.85 (95% CI, 0.52e1.40; p ¼ 0.53) for off-pump CABG and on-pump CABG, respectively. Similarly, the propensity score adjusted hazard ratios were 0.89 (95% CI, 0.39e2.02; p ¼ 0.78) and 1.06 (95% CI, 0.51e2.20; p ¼ 0.88) for CABG with single and bilateral IMA graft use. Clinical outcomes stratified by extent of coronary artery disease and Society of Thoracic Surgeons risk score The 30-day composite of death, MI, stroke, and 3-year all-cause mortality after HCR and CABG stratified by extent of coronary artery disease and STS risk score are shown in Figure 3. Overall, no significant interaction was found for the 30-day composite outcomes for either extent of CAD (p value for interaction ¼ 0.95) or STS risk score (p value for interaction ¼ 0.18). Similarly, there were no significant interactions for extent of CAD or STS risk score for 3-year mortality (p value for interaction of 0.34 and p ¼ 0.14, respectively).

Figure 2. Kaplan-Meier estimates of all-cause mortality after hybrid coronary revascularization (HCR) vs CABG. Rates of death from any cause are truncated at 3 years after surgery. The hazard ratio was calculated using Cox modeling stratified on matched pairs. HR, hazard ratio.

Sensitivity analysis A sensitivity analysis was performed in which patients with HCR on an intent-to-treat basis (n ¼ 338) were 1:3 matched to patients who underwent conventional CABG (n ¼ 1,014). The composite of 30-day death, MI, and stroke was 3.0% in the HCR on an intent-to-treat basis group and 3.5% in the matched CABG group (odds ratio [OR] ¼ 0.86; 95% CI, 0.42e1.73; p ¼ 0.67). In-hospital

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Figure 3. Thirty-day major adverse cardiovascular and cerebrovascular events (MACCE) and 3year all-cause mortality after hybrid coronary revascularization (HCR) and CABG stratified by extent of coronary artery disease and Society of Thoracic Surgeons (STS) risk score. CAD, coronary artery disease; HR, hazard ratio; 2VD, two-vessel disease; 3VD, three-vessel disease; LMD, left main disease; OR, odds ratio; STS, Society of Thoracic Surgeons risk score (<1%, 1% to 2%, 2%).

major morbidity was 8.9% vs 14.6% (OR ¼ 0.61; 95% CI, 0.41e0.90; p ¼ 0.013). Coronary artery bypass grafterelated bleeding was 6.5% vs 8.8% (OR ¼ 0.74; 95% CI, 0.47e1.18; p ¼ 0.21). Three-year mortality was also comparable between these 2 groups (9.0% vs 9.5%; hazard ratio ¼ 0.90; 95% CI, 0.55e1.47; p ¼ 0.69).

DISCUSSION Hybrid coronary revascularization was first described in a case series in the late 1990s and, since then, has evolved as an alternative revascularization strategy in patients at high risk for conventional CABG, or those with low complex non-LAD lesions. Currently, approximately one-third of hospitals in the United States report the use of HCR as a revascularization strategy for the treatment of multivessel CAD.9 In these centers, use of HCR was rare, as only about 1,000 cases were performed in a 20-month time period; reflecting <1% of the total CABG volume of these centers. In the current study, we present the largest single-center cohort of patients who underwent a lessinvasive HCR strategy for treatment of multivessel CAD and/or left main disease. Although HCR is performed frequently, even in our center it represents <5% of the total CABG caseload. Compared with conventional

CABG, we found that HCR performed equally well, as illustrated by similar 30-day and 3-year clinical outcomes. These findings were consistent in a separate analysis in which we compared outcomes in patients with HCR on an intent-to-treat basis (including cases that were converted from HCR to CABG) with matched CABG cases. Additionally, we found no significant interaction between the extent of CAD, or preoperative risk and the relative of outcomes of HCR compared with CABG, suggesting that HCR might be equally safe in both lower- and higher-risk subgroups. Although similar clinical outcomes were found, HCR was associated with fewer in-hospital complications, and faster in-hospital recovery, which might reflect its less-invasive nature. To date, 7 observational studies have compared HCR (n ¼ 366) with CABG (n ¼ 824), and the findings of 6 of them have been summarized in a meta-analysis.10 The compiled data of these studies showed no difference for the composite of death, MI, stroke, or repeat revascularization during hospitalization (OR ¼ 0.63; 95% CI, 0.25e1.58; p ¼ 0.33), or after 1 year of follow-up (OR ¼ 0.49; 95% CI, 0.20e1.24; p ¼ 0.13). All-cause mortality at 3-year follow-up was similar between HCR and CABG (OR ¼ 0.73; 95% CI, 0.29e1.85; p ¼ 0.51). The most recent observational study, which was

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not included in the meta-analysis, involved an analysis from the STS Adult Cardiac Surgery Database,9 and showed no difference for the composite of in-hospital mortality and major morbidity between conventional CABG (n ¼ 198,622) and HCR, either as a staged (n ¼ 809) or concurrent procedure (n ¼ 141) after adjusting for confounders (OR ¼ 0.93; 95% CI, 0.75e1.16; p ¼ 0.53 and OR ¼ 0.94; 95% CI, 0.42e1.30; p ¼ 0.29, respectively). Similarly, no significant association was observed between operative mortality between HCR (either as staged or concurrent procedure) and CABG. A difference with the STS analysis and the data from the other observational studies is that the study from the STS involved data from virtually all US hospitals with CABG capabilities and, as such, the results from centers with limited experience with HCR and those using full sternotomy with the use of cardiopulmonary bypass were also included. Overall, the short-term outcomes as well as mortality at 3 years from previous research correspond with the findings from the current study. Hybrid coronary revascularization in high- and lowrisk populations Although HCR currently occupies a select niche of patients with favorable anatomic variants as well as high-risk patient subgroups, some centers have been pioneering in broader patient populations. Leacche and colleagues11 previously compared 30-day clinical outcomes in 381 patients (80 hybrid cases) stratified by SYNTAX score (32 vs 33) and euroSCORE (<5 vs 5). The authors found that HCR was a safe alternative to CABG in many patients, although not with high-risk patients with complex CAD (33 SYNTAX and >5 euroSCORE). Contrary to these findings, our study does not suggest a significant interaction between patients stratified by extent of vessel disease or by STS risk score. Certainly, the case selection process might have affected the difference in findings, as patients with certain high-risk anatomic and clinical characteristics were not included in our analysis. However, unlike our study, no attempt was made to adjust for confounding. Also, the conclusions from the high risk with complex CAD were based on a total of 36 patients (27 CABG and 9 HCR) with 0 and 3 events, respectively, which renders these results as hypothesis-generating, but far from conclusive. Additionally, in the study by Leacche and colleagues,11 patients with “unplanned” HCR were included, and conventional LIMA-LAD harvesting with the use of cardiopulmonary bypass was used in HCR cases. However, to adequately assess whether HCR yields similar or better clinical outcomes compared with conventional CABG or multivessel PCI, a number of well-designed clinical trials are warranted. Other important considerations include

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whether HCR is also cost-effective compared with conventional coronary revascularization strategies. Timing and sequence of hybrid coronary revascularization It is our understanding that the optimal timing and sequence of LIMA-LAD grafting and PCI is difficult to standardize, and each center should tailor its approach based on available resources, logistical challenges, and referring physician input. Currently, only one study assessed the impact of sequence of HCR on clinical outcomes; although nonrandomized and underpowered, there appears to be no difference in clinical outcomes, but, as expected, shorter hospital length of stay in the 1-stage HCR group.12 In our center, HCR was predominantly performed as a 2-stage LIMA-LAD first approach, as this is the most efficient strategy at Emory, in which operating room efficiency is not compromised by trying to accommodate both the interventional and surgical teams, and both teams can perform the procedure in their most familiar practice environment, and management of antiplatelet and antithrombotic therapy can be tailored to each physician’s preference.13 The advantages of performing HCR as a 1-stage procedure include minimal inconvenience for patient, complete revascularization in one setting and preventing the possibility of developing interval ischemia, and the ability to directly assess LIMA-LAD patency and to revise if technical errors are discovered. Future directions The findings from our study suggest that HCR can be safely performed in a selected patient population of patients with multivessel CAD, including those with left main involvement. Although these findings are in line with those from previous observational studies, as well as an analysis from the STS registry, they should be explored in randomized clinical studies. Gasior and colleagues14 recently published the results from POLMIDES (Prospective Randomised Pilot Study Evaluating the Safety and Efficacy of Hybrid Revascularisation in Multi-Vessel Coronary Artery Disease), a randomized feasibility trial that compared HCR with CABG. Overall, 198 patients were randomized to either HCR (n ¼ 98), which involved a staged procedure of LIMA-LAD using a minimally invasive direct coronary artery bypass approach, followed by PCI with drugeluting stents (Co-Cr everolimus eluting stents) performed within 36 hours of each other, or to CABG with or without cardiopulmonary bypass (n ¼ 102). Mean SYNTAX score was 23, mean number of lesion was 4, and a little more than 50% had 3-vessel disease. A conversion rate of 6.1% to CABG was found in the HCR group, in which 1 patient

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required an emergency conversion to full sternotomy. At 1year follow-up, freedom from the composite of death, MI, stroke, target vessel revascularization, or major bleeding was 89.8% in the HCR group and 92.2% in the CABG group (p ¼ 0.54). Additional randomized study is warranted to assess the consistency of results across various centers, using various HCR approaches and techniques. Study limitations Several limitations deserve to be mentioned. First, this study involves a nonrandomized comparison of 2 treatment strategies and, as such, involves selection bias. Although we used propensity score matching to statistically adjust for a number of identified confounders, we could not adjust for unmeasured confounders. Second, although we performed a sensitivity analysis based on an intention-to-treat vs as-treated analysis, we could not account for confounding due to competing risk (ie, death that occurs before either revascularization strategy as well as in between 2 stages, in the case of HCR). Third, detailed angiographic information (such as SYNTAX score) was not collected due to limitations of the database. Finally, although information on mid-term survival was collected, death from cardiovascular causes as well as information on additional outcomes, such as repeat surgical or PCIs, MI, and stroke were not collected.

CONCLUSIONS Hybrid coronary revascularization performed either as a staged or concurrent procedure was primarily performed in an older patient population with less comorbidity and less extensive CAD compared with conventional CABG. In a propensity score-matched population, HCR was associated with similar short and longitudinal outcomes, with fewer periprocedural complications and faster recovery. Author Contributions Study conception and design: Harskamp, Halkos Acquisition of data: Vassiliades, Puskas, Halkos Analysis and interpretation of data: Harskamp, Xian Drafting of manuscript: Harskamp, Mehta Critical revision: Harskamp, Peterson, Mehta, Vassiliades, de Winter, Lopes, Xian, Puskas, Halkos

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REFERENCES 1. Authors/Task Force Members, Windecker S, Kolh P, et al. 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;35:2541e2619. 2. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: Executive Summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2610e2642. 3. Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thoracic Surg 2004;77: 93e101. 4. Deb S, Wijeysundera HC, Ko DT, et al. Coronary artery bypass graft surgery vs percutaneous interventions in coronary revascularization: a systematic review. JAMA 2013;310: 2086e2095. 5. Narasimhan S, Srinivas VS, DeRose JJ Jr. Hybrid coronary revascularization: a review. Cardiol Rev 2011;19:101e107. 6. Harskamp RE, Zheng Z, Alexander JH, et al. Status quo of hybrid coronary revascularization for multi-vessel coronary artery disease. Ann Thoracic Surg 2013;96:2268e2277. 7. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736e2747. 8. Thoemmes F. Propensity score matching in SPSS. Available at: http://www.arxiv.org/pdf/1201.6385. Accessed November 4, 2014. 9. Harskamp RE, Brennan JM, Xian Y, et al. Practice patterns and clinical outcomes after hybrid coronary revascularization in the United States: an analysis from the society of thoracic surgeons adult cardiac database. Circulation 2014;130:872e879. 10. Harskamp RE, Bagai A, Halkos ME, et al. Clinical outcomes after hybrid coronary revascularization versus coronary artery bypass surgery: a meta-analysis of 1,190 patients. Am Heart J 2014;167:585e592. 11. Leacche M, Byrne JG, Solenkova NS, et al. Comparison of 30-day outcomes of coronary artery bypass grafting surgery verus hybrid coronary revascularization stratified by SYNTAX and euroSCORE. J Thoracic Cardiovas Surg 2013;145: 1004e1012. 12. Srivastava MC, Vesely MR, Lee JD, et al. Robotically assisted hybrid coronary revascularization: does sequence of intervention matter? Innovations 2013;8:177e183. 13. Halkos ME, Walker PF, Vassiliades TA, et al. Clinical and angiographic results after hybrid coronary revascularization. Ann Thoracic Surg 2014;97:484e490. 14. Gasior M, Zembala MO, Tajstra M, et al. Hybrid revascularization for multivessel coronary artery disease. JACC Cardiovascular Interv 2014;7:1277e1283.

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Supplementary Figure 1. Kaplan-Meier estimates of all-cause mortality up to 3 years after (A) hybrid coronary revascularization (HCR) vs on-pump or off-pump CABG (OPCAB/ONCAB) and (B) HCR vs CABG with single or bilateral mammary artery use (SIMA/BIMA). The hazard ratios were calculated using Cox modeling adjusting for the propensity score using the HCR group as a reference. HR, hazard ratio.

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