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Comparison of Long-Term Outcomes of Patients Having Surgical Aortic Valve Replacement With Versus Without Simultaneous Coronary Artery Bypass Grafting
ARTICLE IN PRESS Comparison of Long-Term Outcomes of Patients Having Surgical Aortic Valve Replacement With Versus Without Simultaneous Coronary Artery Bypass Grafting Markus Malmberg, MD, PhDa, Jarmo Gunn, MD, PhDa, Jussi Sipil€a, MD, PhDb,c, o, MD, PhD, MSocSca,g,h,i,* Essi Pikkarainen, MD, PhDd, P€aivi Rautava, MD, PhDe,f, and Ville Kyt€ Coronary artery disease is a common co-morbidity of aortic stenosis. When needed, adding coronary artery bypass grafting (CABG) to surgical aortic valve replacement (SAVR) is the standard treatment method, but the impact of concomitant CABG on long-term outcomes is uncertain. We compared long-term outcomes of SAVR patients with and without CABG. Hospital survivors aged ≥50 years discharged after SAVR § CABG in Finland between 2004 and 2014 (n = 6,870) were retrospectively studied using nationwide registries. Propensity score matching (1:1) was used to identify patients with comparable baseline features (n = 2,188 patient pairs, mean age 73 years). The end points were postoperative 10-year major adverse cardiovascular outcome (MACE), all-cause mortality, stroke, major bleeding, and myocardial infarction. Median follow-up was 6 years. Cumulative MACE rate (39.5% vs 35.6%; hazard ratio [HR] 1.04; p = 0.677) and mortality (32.7% vs 31.0%; HR 1.03; p = 0.729) after SAVR were comparable with or without CABG. Myocardial infarction was more common in patients with CABG (13.4% vs 6.9%; HR 1.47; p = 0.0495). Occurrence of stroke (15.1% vs 13.5%; p = 0.998) and major bleeding (20.0% vs 21.9%; p = 0.569) were comparable. There was no difference in gastrointestinal (8.1% vs 10.3%; p = 0.978) or intracranial bleeds (6.0% vs 5.5%; p = 0.794). The use of internal mammary artery in CABG did not have an impact on the results. In conclusion, matched patients with and without concomitant CABG had comparable long-term MACE, mortality, stroke, and major bleeding rates after SAVR. In conclusion, our results indicate that need for concomitant CABG has limited impact on long-term outcomes after initially successful SAVR. © 2019 Elsevier Inc. All rights reserved. (Am J Cardiol 2019;00:1−6)
Surgical aortic valve replacement (SAVR) and coronary artery bypass grafting (CABG) are the 2 most common surgical procedures in open heart surgery. The use of percutaneous technology in current era has offered more options and possibilities to treat more patients, even with advanced age and several co-morbidities.1,2 However, there is still clear necessity and indications for conventional open-heart surgery.1−3 In patients with significant coronary artery disease a Heart Center, Turku University Hospital and University of Turku, Turku, Finland; bDepartment of Neurology, Siun sote, North Karelia Central Hospital, Joensuu, Finland; cDepartment of Neurology, University of Turku, Turku, Finland; dDepartment of Cardiology, P€aij€at-H€ame Central Hospital, Lahti, Finland; eDepartment of Public Health, University of Turku, Turku, Finland; fTurku Clinical Research Centre, Turku University Hospital, Turku, Finland; gResearch Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; hCenter for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland; and iAdministative Center, Hospital District of Southwest Finland, Turku, Finland. Manuscript received October 20, 2019; revised manuscript received and accepted December 16, 2019. Funding: This work was supported by the Finnish Governmental Clinical Research Fund, Finnish Cultural Foundation, Finnish Cardiac Society. See page 5 for disclosure information. *Corresponding author: Tel: +358 40 5383511; fax: +358 2 3137206. E-mail address: [email protected] (V. Kyt€o).
0002-9149/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2019.12.015
undergoing SAVR, concomitant CABG is routinely performed.1 Adding CABG to SAVR increases the complexity of operation and increases in-hospital mortality.4−7 Impact to longer term outcomes is, however, unclear with findings of both comparable8 and poorer survival9 with concomitant CABG. Furthermore, influence of concomitant CABG to nonfatal long-term outcomes is not known. We investigated the effects of performing concomitant CABG to long-term outcomes after SAVR in a population-based, propensity matched study. Methods We studied the impact of concomitant CABG to longterm outcomes after initially successful SAVR. Propensity matching was used to identify balanced groups of patients who did or did not have concomitant CABG. The primary outcomes of interest were major adverse cardiovascular event defined as cardiovascular mortality, stroke, or myocardial infarction (MI), and all-cause mortality. Secondary outcomes were stroke, MI, and major bleeding (all, gastrointestinal, and intracranial). Outcomes were defined by following ICD-10 codes: MI as I21*-I22*, stroke as I60*I64*, cardiovascular death as I* as underlying cause of death, and bleeding as previously described.10 Outcomes www.ajconline.org
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were studied for 10-year occurrence after discharge form index surgical admission. The Care Register for Healthcare in Finland registry was used for retrospective identification of all patients aged ≥50 years who underwent first-time SAVR as primary operation, or CABG as primary and SAVR as secondary operation between January 1, 2004 and December 31, 2014, and who were discharged alive after surgery (n = 7,552). This nationwide, mandatory registry includes data on all hospital admissions in Finland.11 SAVRs were performed in 6 public hospitals (5 university hospitals and 1 central hospital) and 2 private hospitals during the study period. In Finland, coronary angiography is routinely performed to all patients aged ≥50 years before SAVR. Patients with concomitant surgery of other heart valves, surgery of aorta, surgery of other cardiac or pulmonary vasculature defects, previous cardiac surgery, CABG using other grafts than internal mammary artery (IMA) or saphenous veins, SAVR with homograft, or infective endocarditis were excluded, resulting to 6,870 patients with isolated SAVR § CABG (Supplementary Figure 1). Mortality data of patients was obtained from nationwide, mandatory cause of death registry held by Statistics Finland. Follow-up ended 10-years after SAVR operation or on December 31, 2016 (mortality) or December 31, 2014 (other outcomes), whichever came first. The study was approved by the National Institute for Health and Welfare of Finland (permissions no: THL/143/ 5.05.00/2015 and THL/1569/5.05.00/2016) and the Statistics Finland (TK53-1410-15). Baseline characteristics between groups were evaluated by standardized difference scores. Co-morbidities were evaluated with the Charlson comorbidity index including baseline MI, congestive heart failure, peripheral vascular disease, cerebrovascular disease, diabetes mellitus, renal disease, chronic pulmonary disease, dementia, rheumatic disease, peptic ulcer disease, liver disease, hemi- or
paraplegia, malignancies, and AIDS/HIV.12 Propensity score based on baseline characteristics (Table 1) was created using logistic regression and score was used for appropriate local optimal 1:1 caliber matching without replacing using 0.10 caliper width of the logit of the standard deviation.13 Distribution of propensity is presented in Supplementary Figure 2. Differences between groups were studied by Wilcoxon signed rank sum test as appropriate. Followup was calculated for survivors. Outcomes were studied using the Kaplan-Maier method and matched Cox regression adjusted for propensity score index with absence of concomitant CABG as reference. Proportional hazard assumptions were evaluated using Schoenfeld residuals. Cause-specific hazard models for competing risk due to death were applied in analysis of outcomes other than allcause mortality. Subgroup analyses were performed for matched patients with (n = 1,365 patient pairs) and without (n = 825 patient pairs) use of IMA for CABG. Results are given as the mean, median, percentage, or hazard ratio (HR) with 95% confidence interval (CI) or §SD. A p value <0.05 was considered statistically significant. Analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
Results Patients with SAVR and concomitant CABG were older, more often male, and received more often biological valve prosthesis than patient with SAVR only (Table 1). Baseline characteristics were balanced by propensity score matching resulting to a matched study population of 4,376 SAVR patients (2,188 with and 2,188 without concomitant CABG). After matching, there were no significant differences between the 2 groups (Table 1). Mean follow-up for mortality was 6.3 § 2.7 years (median 2,155 days) for matched
Table 1 Pre- and intraoperative features of surgical aortic valve replacement patients aged ≥50 years with or without concomitant coronary artery bypass grafting. All operated patients and propensity score matched cohort. Standardized difference >0.1 was considered significant. Variable
Age, years (SD) Women Aortic stenosis Mechanical valve prosthesis Urgent or emergency surgery Charlson comorbidity index score 0 1 2 3 ≥4 Atrial fibrillation Use of IMA Operation year Surgical Center IMA = Internal mammary artery.
Original cohort Coronary Bypass
Matched cohort Coronary Bypass
NO (n = 4,517)
YES (n = 2,353)
Standardized mean difference
NO (n = 2,188)
YES (n = 2,188)
Standardized mean difference
70.6 (8.9) 2056 (45.5%) 4052 (89.7%) 1458 (32.3%) 189 (4.2%)
72.9 (7.5) 841 (35.7%) 2099 (89.2%) 554 (23.5%) 121 (5.1%)
0.28 0.20 0.02 0.20 0.05 0.14
72.8 (8.2) 828 (37.8%) 1990 (91.0%) 518 (23.7%) 111 (5.1%)
72.7 (7.6) 818 (37.4%) 1960 (89.6%) 536 (24.5%) 106 (4.8%)
0.01 0.01 0.05 0.02 0.01 0.04
2808 (62.2%) 1069 (23.7%) 420 (9.3%) 143 (3.2%) 77 (1.7%) 741 (16.4%) -
1311 (55.7%) 632 (26.9%) 261 (11.1%) 96 (4.1%) 53 (2.3%) 328 (13.9%) 1470 (62.5%)
1252 (57.2%) 554 (25.3%) 249 (11.4%) 85 (3.9%) 48 (2.2%) 313 (14.3%)
1251 (57.2%) 572 (26.1%) 232 (10.6%) 84 (3.8%) 49 (2.2%) 311 (14.2%) 1363 (62.3%)
0.07 0.22 0.51
0.00 0.10 0.06
ARTICLE IN PRESS Valvular Heart Disease/Concomitant CABG With SAVR
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Figure 1. Freedom of major adverse cardiovascular event (MACE) after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
Figure 2. Survival after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in hospital survivors aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
cohort and 6.5 § 2.7 years (median 2,313 days) for original cohort with no difference between study groups (p = 0.383). Major adverse cardiovascular event occurred to 37.6% of all matched patients after discharge from SAVR (Figure 1). Cumulative MACE rate in SAVR patients without concomitant CABG was 5.4% at 1 year, 17.7% at 5 years, and 35.6% at 10 years after discharge. If CABG was performed in addition to SAVR, the MACE rate was at 1 year was 5.7%, 20.0% at 5 years, and 39.5% at 10 years after discharge. There was no difference within 10 year follow-up between study groups (HR 1.04, CI 0.86 to 1.25; p = 0.677). Cumulative MACE rate was comparable in subgroups of CABG patients with IMA (HR 1.00, CI 0.79 to 1.27; p = 0.983 vs no-CABG) and without IMA (HR 1.10, CI 0.81 to 1.50; p = 0.524 vs no-CABG). All-cause mortality was similar between matched patients at 1 year (4.2% with CABG vs 4.7% without CABG), 5 years (15.9% vs 15.0%, respectively), and 10 years (32.7% vs 31.0%, respectively) after discharge from SAVR (HR 1.03, CI 0.88 to 1.21; p = 0.729; Figure 2). When IMA was used for CABG 10-year mortality was 31.0% (HR 0.99, CI 0.81 to 1.21; p = 0.703 vs no-CABG). If CABG was performed solely with venous grafts, all-cause mortality within 10 years from discharge was 35.9% (HR 1.09; CI 0.84 to 1.40; p = 0.516 vs no-CABG). Occurrence of stroke did not differ between matched patients with and without CABG (Figure 3). Stroke rate was 2.2% in both groups within 1-year follow-up. At 5 years, stroke had occurred to 8.1% to those with and to 8.5% to those without CABG. Within 10 years, stroke rate was 13.5% with and 15.1% without CABG (HR 1.00, CI 0.75 to 1.33; p = 0.998). The use of IMA in CABG had no significant impact to occurrence of stroke with 10-year rate of 13.0% with IMA (HR 1.04, CI 0.72 to 1.49; p = 0.840 vs no-CABG) and 14.5% without use
of IMA (HR 0.93, CI 0.57 to 1.53; p = 0.785 vs noCABG). MI occurred more commonly to matched patients with concomitant CABG (Figure 3). In CABG treated group, the cumulative rate of MI was 1.8% at 1 year, 6.2% at 5 years, and 13.4% at 10 years after SAVR. In non-CABG group, 0.6% had MI at 1-year, 3.1% at 5-year, and 6.9% at 10-year follow-up. HR of MI following concomitant CABG was 1.47 (CI 1.00 to 2.15; p = 0.0495). Ten-year rate of MI was 12.8% in IMA subgroup (HR 1.50, CI 0.93 to 2.42; p = 0.097 vs no-CABG) and 13.4% in non-IMA CABG subgroup (HR 1.40, CI 0.74 to 2.66; p = 0.302 vs no-CABG). The cumulative rate of any major bleeding was comparable between matched study groups at 1 year (2.7% with CABG vs 2.3% without CABG), 5 years (9.7% vs 9.3%, respectively), and 10 years (20.0% vs 21.9%, respectively) after discharge from SAVR (HR 1.08, CI 0.83 to 1.40; p = 0.569; Figure 4). Occurrence of gastrointestinal bleeding (8.1% with vs 10.3% without CABG; HR 1.09, CI 0.72 to 1.65; p = 0.978) and intracranial bleeding (6.0% vs 5.5%; HR 1.07, CI 0.65 to 1.76; p = 0.794) within 10-year followup were also similar between those with and without CABG. Long-term bleeding rates were similar with or without CABG regardless of IMA use (19.3% with IMA; HR 0.99, CI 0.72 to 1.35; p = 0.938 and 21.9% without IMA; HR 1.32, CI 0.82 to 2.11; p = 0.255). Discussion The current population-based propensity score-matched investigation studied impact of concomitant CABG to longterm outcomes after initially successful SAVR. The main finding was that patients with or without CABG in addition to SAVR differed little in long-term outcomes. Patients with SAVR and concomitant CABG had more often MI,
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Figure 4. Occurrence of major bleeding after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
Figure 3. Occurrence of stroke (A) and myocardial infarction (B) after first-time surgical aortic valve replacement with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
but there were no differences in MACE, stroke, bleeding, and most of all, in long-term mortality. The indications and benefits of CABG in patients with coronary artery disease have been clearly established, even in patients with valvular diseases.1,3 It is well established that patients with significant coronary disease should undergo concomitant CABG when treated with SAVR.14,15 Addition of CABG increases the complexity and duration of operation.4,5 It is also shown to increase in-hospital mortality in large scale registry studies.6,7,9 Studies on influence of concomitant CABG to longer term survival are however scarce. Beach et al studied 10-year all-cause mortality of 2,164 propensity matched aortic stenosis patients undergoing SAVR using biological valve prosthesis with and without concomitant CABG found comparable survival between
groups (55% vs 50%, respectively).8 Two smaller studies using multivariate adjustment have found comparable midterm survival between SAVR and SAVR + CABG patients.16,17 Jamieson et al however found higher long-term mortality with concomitant CABG in a multivariate adjusted study of 3,229 SAVR patients.9 In the present study, we showed comparable all-cause mortality in 4,376 propensity matched SAVR patients with or without concomitant CABG at 1-year, 5-year, and 10-year (33% vs 31%, respectively). Both aortic valve stenosis and insufficiency patients as well as mechanical and biological prosthesis patients were included. Little is known for influence of concomitant CABG to other long-term outcomes than survival. We found composite MACE rates to be similar within 10-year follow-up after initially successful SAVR regardless of CABG. Five-year MACE occurrence has been studied in one smaller study of 285 SAVR patients aged ≥80 years which found comparable MACE rates with and without concomitant CABG.18 It should however be noted that definition of MACE differed from our study and included renal insufficiency and early death.18 Not surprisingly, we found higher rates of MI during long-term follow-up in those undergoing CABG. Interestingly however, 7% of SAVR patients whom were not treated with CABG had MI during follow-up. This suggests that intensive treatment of CAD risk-factors19 should be considered in all SAVR patients ≥50 years. Curiously, in contrast to MI rate, the long-term stroke rate was equal after SAVR with and without CABG, but stroke rate was notable in both groups. Further attention should thus be paid to prevention of stroke after SAVR with special reference to embolic events.10,20 Quality of life improves significantly after SAVR,21 and patients undergoing concomitant CABG may experience even more benefit from operation than patients with isolated SAVR.22
ARTICLE IN PRESS Valvular Heart Disease/Concomitant CABG With SAVR
Internal mammary graft is used routinely for bypass.23 Although IMA graft was used only in 62% of patients in our study, there were no significant differences in the end points between IMA versus non-IMA groups. This reflects the nature of the coronary artery disease of the patient with aortic valvular disease, since not all patients required bypass to left anterior descending artery. The follow-up time of our study does not however allow studying of very long-term differences induced by graft selection. The cumulative occurrence of major bleeding after SAVR increased steadily during long-term follow-up rate. At 10 years of follow-up, the rate of major bleeding in whole study population was up to 21%. The significance of this is underscored by the fact that these events only entailed bleeding leading to hospital admission or death. Additionally, the rate of intracranial bleeding was 6% in both groups over the study duration. Curiously, bleeding rates or locations were not influenced by concomitant CABG in our study. Since rates of MI were notably higher after CABG, and addition of antiplatelet is indicated after MI and especially after related percutaneous coronary intervention24 one would have expected higher bleeding rates, especially in gastrointestinal-tract, in the CABG group. This result may implicate underutilization of antiplatelets25 and PCI26 in SAVR + CABG patients after MI. The present study has some limitations. The major one is the retrospective use of registry data without access to more detailed clinical and operative information. We used nationwide, mandatory registry data, where diagnoses and operative codes were made by treating physicians and coding errors are possible, but it is unlikely that this would affect study groups differently.27 Co-morbidities and end points were defined according to previous investigations.10,28 Propensity score matching was used to identify patient groups with comparable baseline features. It is nevertheless possible that additional confounders may influence eligibility and extent of surgery and outcome. For example, it is possible that patients undergoing CABG in addition to SAVR may have less severe aortic stenosis and associated left ventricular hypertrophy.29 Since outcomes were recognized from registries, it is possible that some secondary outcomes might be underestimated. In addition, a single country design may limit the generalizability of the results. In conclusion, this nationwide propensity score matched analysis found patients with and without concomitant CABG to have comparable long-term MACE, mortality, stroke, and major bleeding rates after discharge from SAVR. Results indicate that need for concomitant CABG has limited impact on long-term outcomes after initially successful SAVR. Author Contributions Markus Malmberg: Investigation, Writing - Original Draft; Jarmo Gunn: Conceptualization, Investigation, Methodology, Validation, Resources, Writing - Review & Editing; Jussi Sipil€ a: Investigation, Data Curation, Writing - Review & Editing; Essi Pikkarainen: Writing - Review & Editing; P€ aivi Rautava: Resources, Data Curation,
5
Writing - Review & Editing, Funding acquisition; Ville Kyt€o: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing Review & Editing, Visualization, Supervision, Project administration, Funding acquisition. Disclosures Jarmo Gunn: Unrestricted academic research grant from Vifor Pharma. All other authors have no conflicts of interest to report. Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. amjcard.2019.12.015.
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improvement in cardiac valve surgery. J Am Coll Cardiol 2003;42: 1208–1214. Markou AL, de Jager MJ, Noyez L. The impact of coronary artery disease on the quality of life of patients undergoing aortic valve replacement. Interact Cardiovasc Thorac Surg 2011;13:128–132. Aldea GS, Bakaeen FG, Pal J, Fremes S, Head SJ, Sabik J, Rosengart T, Kappetein AP, Thourani VH, Firestone S, Mitchell JD, Society of thoracic S. The society of thoracic surgeons clinical practice guidelines on arterial conduits for coronary artery bypass grafting. Ann Thorac Surg 2016;101:801–809. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O’Gara PT, Sabatine MS, Smith PK, Smith SC Jr. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American college of cardiology/American heart association task force on clinical practice guidelines: an update of the 2011 ACCF/ AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-Elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-Elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 2016;134:e123–e155. Prami T, Khanfir H, Deleskog A, Hasvold P, Kyt€o V, Reissell E, Airaksinen J. Clinical factors associated with initiation of and persistence with ADP receptor-inhibiting oral antiplatelet treatment after acute coronary syndrome: a nationwide cohort study from Finland. BMJ Open 2016;6:e012604. Kyt€o V, Prami T, Khanfir H, Hasvold P, Reissell E, Airaksinen J. Usage of PCI and long-term cardiovascular risk in post-myocardial infarction patients: a nationwide registry cohort study from Finland. BMC Cardiovasc Disord 2019;19:123. Kyt€o V, Ahtela E, Sipil€a J, Rautava P, Gunn J. Mechanical versus biological valve prosthesis for surgical aortic valve replacement in patients with infective endocarditis. Interact Cardiovasc Thorac Surg 2019;29:386–392. Bjorck F, Sanden P, Renlund H, Svensson PJ, Sjalander A. Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden. Thromb Res 2015;136:216–220. Pereira JJ, Balaban K, Lauer MS, Lytle B, Thomas JD, Garcia MJ. Aortic valve replacement in patients with mild or moderate aortic stenosis and coronary bypass surgery. Am J Med 2005;118:735–742.
Surgical aortic valve replacement (SAVR) and coronary artery bypass grafting (CABG) are the 2 most common surgical procedures in open heart surgery. The use of percutaneous technology in current era has offered more options and possibilities to treat more patients, even with advanced age and several co-morbidities.1,2 However, there is still clear necessity and indications for conventional open-heart surgery.1−3 In patients with significant coronary artery disease a Heart Center, Turku University Hospital and University of Turku, Turku, Finland; bDepartment of Neurology, Siun sote, North Karelia Central Hospital, Joensuu, Finland; cDepartment of Neurology, University of Turku, Turku, Finland; dDepartment of Cardiology, P€aij€at-H€ame Central Hospital, Lahti, Finland; eDepartment of Public Health, University of Turku, Turku, Finland; fTurku Clinical Research Centre, Turku University Hospital, Turku, Finland; gResearch Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; hCenter for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland; and iAdministative Center, Hospital District of Southwest Finland, Turku, Finland. Manuscript received October 20, 2019; revised manuscript received and accepted December 16, 2019. Funding: This work was supported by the Finnish Governmental Clinical Research Fund, Finnish Cultural Foundation, Finnish Cardiac Society. See page 5 for disclosure information. *Corresponding author: Tel: +358 40 5383511; fax: +358 2 3137206. E-mail address: [email protected] (V. Kyt€o).
0002-9149/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2019.12.015
undergoing SAVR, concomitant CABG is routinely performed.1 Adding CABG to SAVR increases the complexity of operation and increases in-hospital mortality.4−7 Impact to longer term outcomes is, however, unclear with findings of both comparable8 and poorer survival9 with concomitant CABG. Furthermore, influence of concomitant CABG to nonfatal long-term outcomes is not known. We investigated the effects of performing concomitant CABG to long-term outcomes after SAVR in a population-based, propensity matched study. Methods We studied the impact of concomitant CABG to longterm outcomes after initially successful SAVR. Propensity matching was used to identify balanced groups of patients who did or did not have concomitant CABG. The primary outcomes of interest were major adverse cardiovascular event defined as cardiovascular mortality, stroke, or myocardial infarction (MI), and all-cause mortality. Secondary outcomes were stroke, MI, and major bleeding (all, gastrointestinal, and intracranial). Outcomes were defined by following ICD-10 codes: MI as I21*-I22*, stroke as I60*I64*, cardiovascular death as I* as underlying cause of death, and bleeding as previously described.10 Outcomes www.ajconline.org
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were studied for 10-year occurrence after discharge form index surgical admission. The Care Register for Healthcare in Finland registry was used for retrospective identification of all patients aged ≥50 years who underwent first-time SAVR as primary operation, or CABG as primary and SAVR as secondary operation between January 1, 2004 and December 31, 2014, and who were discharged alive after surgery (n = 7,552). This nationwide, mandatory registry includes data on all hospital admissions in Finland.11 SAVRs were performed in 6 public hospitals (5 university hospitals and 1 central hospital) and 2 private hospitals during the study period. In Finland, coronary angiography is routinely performed to all patients aged ≥50 years before SAVR. Patients with concomitant surgery of other heart valves, surgery of aorta, surgery of other cardiac or pulmonary vasculature defects, previous cardiac surgery, CABG using other grafts than internal mammary artery (IMA) or saphenous veins, SAVR with homograft, or infective endocarditis were excluded, resulting to 6,870 patients with isolated SAVR § CABG (Supplementary Figure 1). Mortality data of patients was obtained from nationwide, mandatory cause of death registry held by Statistics Finland. Follow-up ended 10-years after SAVR operation or on December 31, 2016 (mortality) or December 31, 2014 (other outcomes), whichever came first. The study was approved by the National Institute for Health and Welfare of Finland (permissions no: THL/143/ 5.05.00/2015 and THL/1569/5.05.00/2016) and the Statistics Finland (TK53-1410-15). Baseline characteristics between groups were evaluated by standardized difference scores. Co-morbidities were evaluated with the Charlson comorbidity index including baseline MI, congestive heart failure, peripheral vascular disease, cerebrovascular disease, diabetes mellitus, renal disease, chronic pulmonary disease, dementia, rheumatic disease, peptic ulcer disease, liver disease, hemi- or
paraplegia, malignancies, and AIDS/HIV.12 Propensity score based on baseline characteristics (Table 1) was created using logistic regression and score was used for appropriate local optimal 1:1 caliber matching without replacing using 0.10 caliper width of the logit of the standard deviation.13 Distribution of propensity is presented in Supplementary Figure 2. Differences between groups were studied by Wilcoxon signed rank sum test as appropriate. Followup was calculated for survivors. Outcomes were studied using the Kaplan-Maier method and matched Cox regression adjusted for propensity score index with absence of concomitant CABG as reference. Proportional hazard assumptions were evaluated using Schoenfeld residuals. Cause-specific hazard models for competing risk due to death were applied in analysis of outcomes other than allcause mortality. Subgroup analyses were performed for matched patients with (n = 1,365 patient pairs) and without (n = 825 patient pairs) use of IMA for CABG. Results are given as the mean, median, percentage, or hazard ratio (HR) with 95% confidence interval (CI) or §SD. A p value <0.05 was considered statistically significant. Analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina).
Results Patients with SAVR and concomitant CABG were older, more often male, and received more often biological valve prosthesis than patient with SAVR only (Table 1). Baseline characteristics were balanced by propensity score matching resulting to a matched study population of 4,376 SAVR patients (2,188 with and 2,188 without concomitant CABG). After matching, there were no significant differences between the 2 groups (Table 1). Mean follow-up for mortality was 6.3 § 2.7 years (median 2,155 days) for matched
Table 1 Pre- and intraoperative features of surgical aortic valve replacement patients aged ≥50 years with or without concomitant coronary artery bypass grafting. All operated patients and propensity score matched cohort. Standardized difference >0.1 was considered significant. Variable
Age, years (SD) Women Aortic stenosis Mechanical valve prosthesis Urgent or emergency surgery Charlson comorbidity index score 0 1 2 3 ≥4 Atrial fibrillation Use of IMA Operation year Surgical Center IMA = Internal mammary artery.
Original cohort Coronary Bypass
Matched cohort Coronary Bypass
NO (n = 4,517)
YES (n = 2,353)
Standardized mean difference
NO (n = 2,188)
YES (n = 2,188)
Standardized mean difference
70.6 (8.9) 2056 (45.5%) 4052 (89.7%) 1458 (32.3%) 189 (4.2%)
72.9 (7.5) 841 (35.7%) 2099 (89.2%) 554 (23.5%) 121 (5.1%)
0.28 0.20 0.02 0.20 0.05 0.14
72.8 (8.2) 828 (37.8%) 1990 (91.0%) 518 (23.7%) 111 (5.1%)
72.7 (7.6) 818 (37.4%) 1960 (89.6%) 536 (24.5%) 106 (4.8%)
0.01 0.01 0.05 0.02 0.01 0.04
2808 (62.2%) 1069 (23.7%) 420 (9.3%) 143 (3.2%) 77 (1.7%) 741 (16.4%) -
1311 (55.7%) 632 (26.9%) 261 (11.1%) 96 (4.1%) 53 (2.3%) 328 (13.9%) 1470 (62.5%)
1252 (57.2%) 554 (25.3%) 249 (11.4%) 85 (3.9%) 48 (2.2%) 313 (14.3%)
1251 (57.2%) 572 (26.1%) 232 (10.6%) 84 (3.8%) 49 (2.2%) 311 (14.2%) 1363 (62.3%)
0.07 0.22 0.51
0.00 0.10 0.06
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Figure 1. Freedom of major adverse cardiovascular event (MACE) after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
Figure 2. Survival after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in hospital survivors aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
cohort and 6.5 § 2.7 years (median 2,313 days) for original cohort with no difference between study groups (p = 0.383). Major adverse cardiovascular event occurred to 37.6% of all matched patients after discharge from SAVR (Figure 1). Cumulative MACE rate in SAVR patients without concomitant CABG was 5.4% at 1 year, 17.7% at 5 years, and 35.6% at 10 years after discharge. If CABG was performed in addition to SAVR, the MACE rate was at 1 year was 5.7%, 20.0% at 5 years, and 39.5% at 10 years after discharge. There was no difference within 10 year follow-up between study groups (HR 1.04, CI 0.86 to 1.25; p = 0.677). Cumulative MACE rate was comparable in subgroups of CABG patients with IMA (HR 1.00, CI 0.79 to 1.27; p = 0.983 vs no-CABG) and without IMA (HR 1.10, CI 0.81 to 1.50; p = 0.524 vs no-CABG). All-cause mortality was similar between matched patients at 1 year (4.2% with CABG vs 4.7% without CABG), 5 years (15.9% vs 15.0%, respectively), and 10 years (32.7% vs 31.0%, respectively) after discharge from SAVR (HR 1.03, CI 0.88 to 1.21; p = 0.729; Figure 2). When IMA was used for CABG 10-year mortality was 31.0% (HR 0.99, CI 0.81 to 1.21; p = 0.703 vs no-CABG). If CABG was performed solely with venous grafts, all-cause mortality within 10 years from discharge was 35.9% (HR 1.09; CI 0.84 to 1.40; p = 0.516 vs no-CABG). Occurrence of stroke did not differ between matched patients with and without CABG (Figure 3). Stroke rate was 2.2% in both groups within 1-year follow-up. At 5 years, stroke had occurred to 8.1% to those with and to 8.5% to those without CABG. Within 10 years, stroke rate was 13.5% with and 15.1% without CABG (HR 1.00, CI 0.75 to 1.33; p = 0.998). The use of IMA in CABG had no significant impact to occurrence of stroke with 10-year rate of 13.0% with IMA (HR 1.04, CI 0.72 to 1.49; p = 0.840 vs no-CABG) and 14.5% without use
of IMA (HR 0.93, CI 0.57 to 1.53; p = 0.785 vs noCABG). MI occurred more commonly to matched patients with concomitant CABG (Figure 3). In CABG treated group, the cumulative rate of MI was 1.8% at 1 year, 6.2% at 5 years, and 13.4% at 10 years after SAVR. In non-CABG group, 0.6% had MI at 1-year, 3.1% at 5-year, and 6.9% at 10-year follow-up. HR of MI following concomitant CABG was 1.47 (CI 1.00 to 2.15; p = 0.0495). Ten-year rate of MI was 12.8% in IMA subgroup (HR 1.50, CI 0.93 to 2.42; p = 0.097 vs no-CABG) and 13.4% in non-IMA CABG subgroup (HR 1.40, CI 0.74 to 2.66; p = 0.302 vs no-CABG). The cumulative rate of any major bleeding was comparable between matched study groups at 1 year (2.7% with CABG vs 2.3% without CABG), 5 years (9.7% vs 9.3%, respectively), and 10 years (20.0% vs 21.9%, respectively) after discharge from SAVR (HR 1.08, CI 0.83 to 1.40; p = 0.569; Figure 4). Occurrence of gastrointestinal bleeding (8.1% with vs 10.3% without CABG; HR 1.09, CI 0.72 to 1.65; p = 0.978) and intracranial bleeding (6.0% vs 5.5%; HR 1.07, CI 0.65 to 1.76; p = 0.794) within 10-year followup were also similar between those with and without CABG. Long-term bleeding rates were similar with or without CABG regardless of IMA use (19.3% with IMA; HR 0.99, CI 0.72 to 1.35; p = 0.938 and 21.9% without IMA; HR 1.32, CI 0.82 to 2.11; p = 0.255). Discussion The current population-based propensity score-matched investigation studied impact of concomitant CABG to longterm outcomes after initially successful SAVR. The main finding was that patients with or without CABG in addition to SAVR differed little in long-term outcomes. Patients with SAVR and concomitant CABG had more often MI,
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Figure 4. Occurrence of major bleeding after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
Figure 3. Occurrence of stroke (A) and myocardial infarction (B) after first-time surgical aortic valve replacement with or without concomitant coronary artery bypass grafting (CABG) in patients aged ≥50 years. HR = Hazard ratio. CI = 95% confidence intervals.
but there were no differences in MACE, stroke, bleeding, and most of all, in long-term mortality. The indications and benefits of CABG in patients with coronary artery disease have been clearly established, even in patients with valvular diseases.1,3 It is well established that patients with significant coronary disease should undergo concomitant CABG when treated with SAVR.14,15 Addition of CABG increases the complexity and duration of operation.4,5 It is also shown to increase in-hospital mortality in large scale registry studies.6,7,9 Studies on influence of concomitant CABG to longer term survival are however scarce. Beach et al studied 10-year all-cause mortality of 2,164 propensity matched aortic stenosis patients undergoing SAVR using biological valve prosthesis with and without concomitant CABG found comparable survival between
groups (55% vs 50%, respectively).8 Two smaller studies using multivariate adjustment have found comparable midterm survival between SAVR and SAVR + CABG patients.16,17 Jamieson et al however found higher long-term mortality with concomitant CABG in a multivariate adjusted study of 3,229 SAVR patients.9 In the present study, we showed comparable all-cause mortality in 4,376 propensity matched SAVR patients with or without concomitant CABG at 1-year, 5-year, and 10-year (33% vs 31%, respectively). Both aortic valve stenosis and insufficiency patients as well as mechanical and biological prosthesis patients were included. Little is known for influence of concomitant CABG to other long-term outcomes than survival. We found composite MACE rates to be similar within 10-year follow-up after initially successful SAVR regardless of CABG. Five-year MACE occurrence has been studied in one smaller study of 285 SAVR patients aged ≥80 years which found comparable MACE rates with and without concomitant CABG.18 It should however be noted that definition of MACE differed from our study and included renal insufficiency and early death.18 Not surprisingly, we found higher rates of MI during long-term follow-up in those undergoing CABG. Interestingly however, 7% of SAVR patients whom were not treated with CABG had MI during follow-up. This suggests that intensive treatment of CAD risk-factors19 should be considered in all SAVR patients ≥50 years. Curiously, in contrast to MI rate, the long-term stroke rate was equal after SAVR with and without CABG, but stroke rate was notable in both groups. Further attention should thus be paid to prevention of stroke after SAVR with special reference to embolic events.10,20 Quality of life improves significantly after SAVR,21 and patients undergoing concomitant CABG may experience even more benefit from operation than patients with isolated SAVR.22
ARTICLE IN PRESS Valvular Heart Disease/Concomitant CABG With SAVR
Internal mammary graft is used routinely for bypass.23 Although IMA graft was used only in 62% of patients in our study, there were no significant differences in the end points between IMA versus non-IMA groups. This reflects the nature of the coronary artery disease of the patient with aortic valvular disease, since not all patients required bypass to left anterior descending artery. The follow-up time of our study does not however allow studying of very long-term differences induced by graft selection. The cumulative occurrence of major bleeding after SAVR increased steadily during long-term follow-up rate. At 10 years of follow-up, the rate of major bleeding in whole study population was up to 21%. The significance of this is underscored by the fact that these events only entailed bleeding leading to hospital admission or death. Additionally, the rate of intracranial bleeding was 6% in both groups over the study duration. Curiously, bleeding rates or locations were not influenced by concomitant CABG in our study. Since rates of MI were notably higher after CABG, and addition of antiplatelet is indicated after MI and especially after related percutaneous coronary intervention24 one would have expected higher bleeding rates, especially in gastrointestinal-tract, in the CABG group. This result may implicate underutilization of antiplatelets25 and PCI26 in SAVR + CABG patients after MI. The present study has some limitations. The major one is the retrospective use of registry data without access to more detailed clinical and operative information. We used nationwide, mandatory registry data, where diagnoses and operative codes were made by treating physicians and coding errors are possible, but it is unlikely that this would affect study groups differently.27 Co-morbidities and end points were defined according to previous investigations.10,28 Propensity score matching was used to identify patient groups with comparable baseline features. It is nevertheless possible that additional confounders may influence eligibility and extent of surgery and outcome. For example, it is possible that patients undergoing CABG in addition to SAVR may have less severe aortic stenosis and associated left ventricular hypertrophy.29 Since outcomes were recognized from registries, it is possible that some secondary outcomes might be underestimated. In addition, a single country design may limit the generalizability of the results. In conclusion, this nationwide propensity score matched analysis found patients with and without concomitant CABG to have comparable long-term MACE, mortality, stroke, and major bleeding rates after discharge from SAVR. Results indicate that need for concomitant CABG has limited impact on long-term outcomes after initially successful SAVR. Author Contributions Markus Malmberg: Investigation, Writing - Original Draft; Jarmo Gunn: Conceptualization, Investigation, Methodology, Validation, Resources, Writing - Review & Editing; Jussi Sipil€ a: Investigation, Data Curation, Writing - Review & Editing; Essi Pikkarainen: Writing - Review & Editing; P€ aivi Rautava: Resources, Data Curation,
5
Writing - Review & Editing, Funding acquisition; Ville Kyt€o: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing Review & Editing, Visualization, Supervision, Project administration, Funding acquisition. Disclosures Jarmo Gunn: Unrestricted academic research grant from Vifor Pharma. All other authors have no conflicts of interest to report. Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. amjcard.2019.12.015.
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