Annals of internal medicine ORIGINAL RESEARCH Comparative Effectiveness of Multivessel Coronary bypass Surgery and Multivessel Percutaneous Coronary Intervention A Cohort Study Mark A Hlatky, MD; Derek B. Boothroyd, PhD; Laurence Baker, PhD; Dhruv S Kazi, MD, MS: Matthew D. Solomon, MD, PhD Tara L. Chang, MD, MS: David Shilane, PhD; and Alan S Go, MD Background: Randomized trials of coronary artery bypass graft lower mortality was significantly greater(interaction P <0.002 for (CABG)surgery and percutaneous coronary intervention(PCI) sug- each)among patients with diabetes(HR, 0. 88), a history of tobacco gest that patient characteristics modify the effect of treatment use(HR, 0.82), heart failure(HR, 0.84), and peripheral arterial disease(HR, 0.85). The overall predicted difference in survival be- tween CABG and PCI treatment over 5 years was 0.053 life-year Objective: To assess whether clinical characteristics modify the comparative effectiveness of CABG versus PCI in an unselected, (range, -0.017 to 0.579 life-years). Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI Limitation: Treatments were chosen by patients and physicians Setting: United States, 1992 to 2008 rather than being randomly assigned Patients: Medicare beneficiaries aged 66 years or older Conclusion: Multivessel CABG is associated with lower long-term mortality than multivessel PCI in the community setting. This asso- Intervention: Multivessel CABG or multivessel PCI ciation is substantially modified by patient characteristics, with im- provement in survival concentrated among patients with diabetes, Measurements: The CABG-PCl hazard ratio(HR) for all-cause tobacco use, heart failure, or peripheral arterial disease mortality, with prespecified treatment-by-covariate interaction tests and the absolute difference in life-years of survival in dinical sub- Primary Funding Source: National Heart, Lung, and Blood groups after CABG or PCI, both over 5 years of follow-up Institute Results: Among 105 156 propensity score-matched patients Ann Intem Med.2013;158:727-734. www.annals.org CABG was associated with lower mortality than PCI(HR, 0.92 For author affiliations, see end of text. 5%cl,0.90to0.951:P<0.001).AssociationofCabgwithThisartidewaspublishedatwww.annals.orgon23April2013. oronary artery bypass graft( CABG)surgery and per- treatments overall and in targeted subgroups by using read cutaneous coronary intervention(PCI) are among the ily available data from nationally representative patients most common major procedures performed worldwide. treated in real-world practices Either can be used to treat multivessel coronary artery dis- The purpose of this study was to compare the mortal- ease, and their comparative effectiveness has been assessed ity rates of Medicare beneficiaries who had multivessel in several randomized trials(1-7). A recent collaborative CABG or multivessel PCi and to assess whether the com- analysis of 10 trials comparing CABG with PCI showed parative effectiveness of these procedures was modified by that overall mortality risk was slightly, but not signifi- patient characteristics cantly, reduced by CABG and that the effect of CABG treatment on mortality was significantly modifed by dia METHODS betes mellitus and age(8) Randomized trials are accepted as the reference stan- The study population comprised fee-for-service Medi dard for comparing treatments but are diffcult to perform care beneficiaries who had multivessel CABg or multives and usually enroll patients selectively. For example, only sel PCI between 1992 and 2008. To permit a 1-year look about 10 000 patients have been randomly assigned to conditions, we restricted the study population to individ- CABG or PCI, a tiny fraction of the millions of patients uals aged 66 years or older who had Part A and Part B worldwide who have had one of these procedures. Al- though the high-quality data from randomized trials can be dicare coverage and were not enrolled in a medicare leveraged into treatment recommendations, it has been in- HMO. The index coronary revascularization procedures creasingly recognized that patients enrolled in clinical trials are generally younger and healthier than those seen in everyday practice. Furthermore, these trials are generally ee a/so underpowered to examine variation in the treatment effect Print according to clinical characteristics of the patient. analysis Summary for Patients 1-24 of Medicare claims provides the opportunity to compare O 2013 American College of Physicians727
Comparative Effectiveness of Multivessel Coronary Bypass Surgery and Multivessel Percutaneous Coronary Intervention A Cohort Study Mark A. Hlatky, MD; Derek B. Boothroyd, PhD; Laurence Baker, PhD; Dhruv S. Kazi, MD, MS; Matthew D. Solomon, MD, PhD; Tara I. Chang, MD, MS; David Shilane, PhD; and Alan S. Go, MD Background: Randomized trials of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) suggest that patient characteristics modify the effect of treatment on mortality. Objective: To assess whether clinical characteristics modify the comparative effectiveness of CABG versus PCI in an unselected, general patient population. Design: Observational treatment comparison using propensity score matching and Cox proportional hazards models. Setting: United States, 1992 to 2008. Patients: Medicare beneficiaries aged 66 years or older. Intervention: Multivessel CABG or multivessel PCI. Measurements: The CABG–PCI hazard ratio (HR) for all-cause mortality, with prespecified treatment-by-covariate interaction tests, and the absolute difference in life-years of survival in clinical subgroups after CABG or PCI, both over 5 years of follow-up. Results: Among 105 156 propensity score–matched patients, CABG was associated with lower mortality than PCI (HR, 0.92 [95% CI, 0.90 to 0.95]; P 0.001). Association of CABG with lower mortality was significantly greater (interaction P 0.002 for each) among patients with diabetes (HR, 0.88), a history of tobacco use (HR, 0.82), heart failure (HR, 0.84), and peripheral arterial disease (HR, 0.85). The overall predicted difference in survival between CABG and PCI treatment over 5 years was 0.053 life-years (range, 0.017 to 0.579 life-years). Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI. Limitation: Treatments were chosen by patients and physicians rather than being randomly assigned. Conclusion: Multivessel CABG is associated with lower long-term mortality than multivessel PCI in the community setting. This association is substantially modified by patient characteristics, with improvement in survival concentrated among patients with diabetes, tobacco use, heart failure, or peripheral arterial disease. Primary Funding Source: National Heart, Lung, and Blood Institute. Ann Intern Med. 2013;158:727-734. www.annals.org For author affiliations, see end of text. This article was published at www.annals.org on 23 April 2013. Coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) are among the most common major procedures performed worldwide. Either can be used to treat multivessel coronary artery disease, and their comparative effectiveness has been assessed in several randomized trials (1–7). A recent collaborative analysis of 10 trials comparing CABG with PCI showed that overall mortality risk was slightly, but not signifi- cantly, reduced by CABG and that the effect of CABG treatment on mortality was significantly modified by diabetes mellitus and age (8). Randomized trials are accepted as the reference standard for comparing treatments but are difficult to perform and usually enroll patients selectively. For example, only about 10 000 patients have been randomly assigned to CABG or PCI, a tiny fraction of the millions of patients worldwide who have had one of these procedures. Although the high-quality data from randomized trials can be leveraged into treatment recommendations, it has been increasingly recognized that patients enrolled in clinical trials are generally younger and healthier than those seen in everyday practice. Furthermore, these trials are generally underpowered to examine variation in the treatment effect according to clinical characteristics of the patient. Analysis of Medicare claims provides the opportunity to compare treatments overall and in targeted subgroups by using readily available data from nationally representative patients treated in real-world practices. The purpose of this study was to compare the mortality rates of Medicare beneficiaries who had multivessel CABG or multivessel PCI and to assess whether the comparative effectiveness of these procedures was modified by patient characteristics. METHODS The study population comprised fee-for-service Medicare beneficiaries who had multivessel CABG or multivessel PCI between 1992 and 2008. To permit a 1-year lookback period and document the presence of comorbid conditions, we restricted the study population to individuals aged 66 years or older who had Part A and Part B Medicare coverage and were not enrolled in a Medicare HMO. The index coronary revascularization procedures See also: Print Summary for Patients....................... I-24 Annals of Internal Medicine Original Research © 2013 American College of Physicians 727
ORIGINAL RESEARCH I Comparative Effectiveness of CABG and PCI Contex We used propensity score matching to create the final Although randomized, controlled trials have shown small analysis cohort. We used all of the baseline characteristics reductions in mortality with coronary artery bypass graft listed in the Table as predictors of receiving CABG or PCI (CABG) surgery versus percutaneous coronary intervention as well as a history of ventricular tachycardia, ventricular (PCI) for coronary revascularization, the restrictive enroll fibrillation, other arrhythmias, implantable cardioverter- ment may limit generalizability to patients in real-world defibrillator. valvular heart disease. stroke, transient isch- emic attack, intracranial hemorrhage, other cerebrovascular Contribution disease, fluid and electrolyte abnormalities, gastrointestinal bleed anemla,F ascular disease, hypoth This comparative effectiveness study using data from roidism, chronic liver disease, AIDS, systemic cancer, obe- Medicare recipients found that CABG was associated with sity, dementia, depression, psychosis, alcohol use, or drug a small mortality benefit versus PCI and certain patient characteristics modified the association. The expected use. We matched each patient who received a multivessel survival advantage varies widely among individual PCI with one who received a multivessel CABG by using a Patients with diabetes, a history of smoking, peripheral greedy algorithm(9)that first matched propensity scores at arterial disease, and heart failure had a particular benefit; 7 digits, then at 6 digits, and so forth, down to a 2-digi those without these factors had slightly better survival match (that is, agreement at the 0.01 level of propensity ith PCI score). We also required that patients be matched by year of index procedure, diabetes status, and age within 1 year. Clinical details of individual patients could not be assessed In the primary analysis, we compared the propensity score-matched cohort of CABG and PCI patients over the first 5-year follow-up by using Cox proportional hazards Individual clinical variables are associated with differences models. We tested the treatment-by-covariate interaction in the benefits of cabg versus pcl with key baseline factors and reported the interaction P value. We repeated the interaction test after additional ad The editors justment for the baseline covariates in the Table. The modifiers of potential treatment effect analyzed included factors tested previously(8)in the pooled analysis of ran were identified from the 20% random sample of Part a domized trials(age, sex, diabetes, hypertension, hyperlipid Comorbid conditions were defined by using diagnosis emia, smoking, unstable angina, prior myocardial infarc- and procedure codes(available on request) found in Part tion [MI], heart failure, and peripheral arterial disease),as A and Part b data(a 5% random sample from 1992 to well as prespecified additional factors of interest that were 1997 and a 20% random sample from 1998 to 2008). We ot available in the previous analysis (race, chronic kidney excluded patients with procedures done before 1992 be disease, cerebrovascular disease, and atrial fibrillation cause of the unavailability of some necessary data during After testing the hypothesis that the comparative effec that period, but we looked back to 1986 to exclude pa- tiveness of CABG and PCI varied according to prespecified tients with prior CABG or PCI during that period. This baseline patient characteristics, we estimated the difference study was approved by the Stanford University Institu- in length of survival between these treatments as a function tional Review board We identified patients by using procedure codes for of patient characteristics. We calculated the life-years multivessel CABG (International Classification of Diseases added by CABG compared with PCI during 5 years of by using rtional hazards model. te 9th Revision, Clinical Modification [ICD-9-CM], codes develop a practical but individualized prediction of survival multivessel PCI(before October 2005: ICD-9-CM code benefit, we used 13 patient characteristics as predictors and 36.05: after October 2005: ICD-9.- CM code 00. 66 plus included selected interaction terms. For each 00.41,00.42, or 00.43 or Current Procedural Terminok- study population, we entered their baseline characteristics gy code 92981 or 92984). We excluded patients if they into the model to generate a predicted survival curve after ad single-vessel PCI or CABG, had concomitant cardiac treatment with CABG. We then numerically integrated procedures(such as valve replacement) at the time of this curve to estimate the life-years of survival over 5 years CABG or PCI, were of unknown race, or had end-stage We repeated this process with the treatment variable set to renal disease and were receiving long-term dialysis PCI. We then subtracted the life-years of survival predicted We defined comorbid conditions by using outpatient after PCI from those predicted after CABG to produce an and inpatient encounters in the year before the index pro- individualized estimate of the effect of CABG compared cedure. We considered a comorbid condition to be present with PCI for each patient in the study population. We if it was recorded as a primary or secondary diagnosis code used SAS, version 9.3(SAS Institute, Cary, North Caro- 21 May 2013 Annals of Internal Medicine Volume 158. Number 10 www.annals.org
were identified from the 20% random sample of Part A data. Comorbid conditions were defined by using diagnosis and procedure codes (available on request) found in Part A and Part B data (a 5% random sample from 1992 to 1997 and a 20% random sample from 1998 to 2008). We excluded patients with procedures done before 1992 because of the unavailability of some necessary data during that period, but we looked back to 1986 to exclude patients with prior CABG or PCI during that period. This study was approved by the Stanford University Institutional Review Board. We identified patients by using procedure codes for multivessel CABG (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM], codes 36.12, 36.13, 36.14, 36.16, or 36.11 plus 36.15) and multivessel PCI (before October 2005: ICD-9-CM code 36.05; after October 2005: ICD-9-CM code 00.66 plus 00.41, 00.42, or 00.43 or Current Procedural Terminology code 92981 or 92984). We excluded patients if they had single-vessel PCI or CABG, had concomitant cardiac procedures (such as valve replacement) at the time of CABG or PCI, were of unknown race, or had end-stage renal disease and were receiving long-term dialysis. We defined comorbid conditions by using outpatient and inpatient encounters in the year before the index procedure. We considered a comorbid condition to be present if it was recorded as a primary or secondary diagnosis code at either encounter. We used propensity score matching to create the final analysis cohort. We used all of the baseline characteristics listed in the Table as predictors of receiving CABG or PCI, as well as a history of ventricular tachycardia, ventricular fibrillation, other arrhythmias, implantable cardioverterdefibrillator, valvular heart disease, stroke, transient ischemic attack, intracranial hemorrhage, other cerebrovascular disease, fluid and electrolyte abnormalities, gastrointestinal bleeding, anemia, pulmonary vascular disease, hypothyroidism, chronic liver disease, AIDS, systemic cancer, obesity, dementia, depression, psychosis, alcohol use, or drug use. We matched each patient who received a multivessel PCI with one who received a multivessel CABG by using a greedy algorithm (9) that first matched propensity scores at 7 digits, then at 6 digits, and so forth, down to a 2-digit match (that is, agreement at the 0.01 level of propensity score). We also required that patients be matched by year of index procedure, diabetes status, and age within 1 year. In the primary analysis, we compared the propensity score–matched cohort of CABG and PCI patients over the first 5-year follow-up by using Cox proportional hazards models. We tested the treatment-by-covariate interaction with key baseline factors and reported the interaction P value. We repeated the interaction test after additional adjustment for the baseline covariates in the Table. The modifiers of potential treatment effect analyzed included factors tested previously (8) in the pooled analysis of randomized trials (age, sex, diabetes, hypertension, hyperlipidemia, smoking, unstable angina, prior myocardial infarction [MI], heart failure, and peripheral arterial disease), as well as prespecified additional factors of interest that were not available in the previous analysis (race, chronic kidney disease, cerebrovascular disease, and atrial fibrillation). After testing the hypothesis that the comparative effectiveness of CABG and PCI varied according to prespecified baseline patient characteristics, we estimated the difference in length of survival between these treatments as a function of patient characteristics. We calculated the life-years added by CABG compared with PCI during 5 years of follow-up by using a Cox proportional hazards model. To develop a practical but individualized prediction of survival benefit, we used 13 patient characteristics as predictors and included selected interaction terms. For each patient in the study population, we entered their baseline characteristics into the model to generate a predicted survival curve after treatment with CABG. We then numerically integrated this curve to estimate the life-years of survival over 5 years. We repeated this process with the treatment variable set to PCI. We then subtracted the life-years of survival predicted after PCI from those predicted after CABG to produce an individualized estimate of the effect of CABG compared with PCI for each patient in the study population. We used SAS, version 9.3 (SAS Institute, Cary, North Carolina), to perform all statistical analyses. Context Although randomized, controlled trials have shown small reductions in mortality with coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) for coronary revascularization, the restrictive enrollment may limit generalizability to patients in real-world practice. Contribution This comparative effectiveness study using data from Medicare recipients found that CABG was associated with a small mortality benefit versus PCI and certain patient characteristics modified the association. The expected survival advantage varies widely among individuals. Patients with diabetes, a history of smoking, peripheral arterial disease, and heart failure had a particular benefit; those without these factors had slightly better survival with PCI. Caution Clinical details of individual patients could not be assessed. Implication Individual clinical variables are associated with differences in the benefits of CABG versus PCI. —The Editors Original Research Comparative Effectiveness of CABG and PCI 728 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 www.annals.org
Comparative Effectiveness of CABG and PCI ORIGINAL RESEARCH Table Baseline Clinical Characteristics All Patients, Propensity Score-Matched Patients, cABG(n=194223) Pc|n=57330) cABG(n=5257Pa(m=52578) 6670y 31.3 29.0 270 7344 23.1 23.3 6.8 433 9 925 33.4 Chronic kidney disease Peripheral arterial disease 21.6 Cerebrovascular disease Prior MI 13.4 11.4 Heart failure 13.9 13.2 Atrial fibrillation Primary diagnosis of MI 4.4 Middle Atlantic South atlanti East South Central West South Central 11.8 11.8 11.8 East North Central 19.9 20.1 West North Central Pacific 8.6 Year of procedure 2.6 1995-2003 479 33.6 CABG coronary artery bypass graft; MI myocardial infarction: PCI percutancous coronary intervention Role of the Funding Source whom had multivessel CABG and 57 330 of whom had The National Heart, Lung, and Blood Institute spon- multivessel PCI ored the study but had no role in its design or conduct; In the propensity score analysis, the strongest predi the collection, management, analysis, or interpretation of tors of receiving CABG rather than PCI were calendar the data; or the preparation, review, or apl year,age, sex, diabetes, cerebrovascular disease, peripheral manuscript arterial disease, atrial fibrillation, and region. The propen- sity score model had an overall c-statistic of 0.673. We matched 92% of the patients who had multivessel PCI RESULTS with patients who had multivessel CABG; 10 080 patient e identified 611 729 initial CABG and PCI proce pairs were matched on 5 to 7 digits of propensity score, dures between 1992 and 2008 in the 20% sample of Medi- 16 677 on 4 digits, 20 767 on 3 digits, and 5054 on 2 care beneficiaries aged 66 years or older with available Part digits B data. We excluded 48 707 patients because of concomi- cant cardiac procedures performed at the time of CABG or population were similar between patients who received PCI, 300 378 who had single-vessel revascularization, CABG and those who received PCI Table). The typical 2982 because the number of treated vessels could not be patient was a 75-year-old white man with hypertension measured,and 8109 with end-stage renal disease. The eli- and the median follow-up was 4.3 years. Overall, survival ble population comprised 251 553 patients; 194 223 of at 5 years was 74. 1% after CABG and 71.9%after PCI
Role of the Funding Source The National Heart, Lung, and Blood Institute sponsored the study but had no role in its design or conduct; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. RESULTS We identified 611 729 initial CABG and PCI procedures between 1992 and 2008 in the 20% sample of Medicare beneficiaries aged 66 years or older with available Part B data. We excluded 48 707 patients because of concomitant cardiac procedures performed at the time of CABG or PCI, 300 378 who had single-vessel revascularization, 2982 because the number of treated vessels could not be measured, and 8109 with end-stage renal disease. The eligible population comprised 251 553 patients; 194 223 of whom had multivessel CABG and 57 330 of whom had multivessel PCI. In the propensity score analysis, the strongest predictors of receiving CABG rather than PCI were calendar year, age, sex, diabetes, cerebrovascular disease, peripheral arterial disease, atrial fibrillation, and region. The propensity score model had an overall c-statistic of 0.673. We matched 92% of the patients who had multivessel PCI with patients who had multivessel CABG; 10 080 patient pairs were matched on 5 to 7 digits of propensity score, 16 677 on 4 digits, 20 767 on 3 digits, and 5054 on 2 digits. The baseline clinical characteristics of the matched population were similar between patients who received CABG and those who received PCI (Table). The typical patient was a 75-year-old white man with hypertension, and the median follow-up was 4.3 years. Overall, survival at 5 years was 74.1% after CABG and 71.9% after PCI Table. Baseline Clinical Characteristics Characteristic All Patients, % Propensity Score–Matched Patients, % CABG (n 194 223) PCI (n 57 330) CABG (n 52 578) PCI (n 52 578) Age 66–70 y 31.3 29.0 30.0 29.8 71–75 y 31.8 27.0 27.6 27.9 76–80 y 24.1 22.7 23.1 23.3 81–85 y 10.7 14.6 14.7 14.6 86 y 2.1 6.8 4.6 4.4 Female 33.8 43.3 41.2 42.0 Race White 92.4 91.9 92.5 92.1 Black 4.3 4.6 4.4 4.6 Other 3.3 3.5 3.2 3.3 Diabetes 36.0 33.4 33.3 33.3 Hypertension 77.6 78.7 78.5 78.6 Hyperlipidemia 29.1 28.0 28.0 28.5 Tobacco use 18.1 18.6 18.1 19.0 Chronic kidney disease 5.1 5.7 5.4 5.5 Peripheral arterial disease 21.6 18.2 17.4 18.3 Cerebrovascular disease 22.0 16.9 16.6 16.9 Prior MI 13.4 11.6 10.9 11.4 Heart failure 13.1 13.9 12.5 13.2 Unstable angina 38.4 29.5 30.4 29.9 Atrial fibrillation 9.5 12.2 11.2 11.6 Primary diagnosis of MI 21.4 29.6 28.2 28.4 Metropolitan area 72.4 73.0 73.0 73.0 U.S. Census region New England 4.4 4.3 4.2 4.4 Middle Atlantic 13.5 11.9 12.0 12.3 South Atlantic 21.7 21.6 21.5 21.4 East South Central 8.9 7.1 7.1 7.3 West South Central 12.1 11.8 11.8 11.8 East North Central 19.9 19.6 20.2 20.1 West North Central 8.4 10.1 10.3 9.9 Mountain 3.7 4.9 4.6 4.6 Pacific 7.3 8.6 8.4 8.3 Year of procedure 1992–1994 7.6 3.2 2.6 2.6 1995–2003 58.9 46.8 47.9 47.9 2004–2008 33.6 50.0 49.5 49.5 CABG coronary artery bypass graft; MI myocardial infarction; PCI percutaneous coronary intervention. Comparative Effectiveness of CABG and PCI Original Research www.annals.org 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 729
ORIGINAL RESEARCH I Comparative Effectiveness of CABG and PCI Figure 1. Kaplan-Meier survival curves for multivessel CABG and multivessel PCI among Medicare beneficiaries matched on propensity score. Patients available for follow-up, n 44252389233209825609195021460210377 44541386033153824934188731414110031 9971874 CABG coronary artery bypass graft; PCI= percutaneous coronary intervention. Treatment Effect Modification on, the mean increase in life expectancy Compared with PCI, the association of CABG with from CABG compared with PCI in the 5 years after cor- all-cause mortality over the 5-year follow-up was signifi- onary revascularization was 0.053 life-years(P< 0.001) cantly modified by race, diabetes, tobacco use, peripheral Estimated life -years added by CABG varied widely across arterial disease, and heart failure(Figure 2). Each of these the 105 156 patients in the, however(Figure 3). Median interactions remained significant after additional adjust- predicted change in life expectancy from CABG was 0.029 ment for the baseline characteristics listed in Figure 2(in- teraction P= 0.047 for diabetes, 0.004 for tobacco use, is, favored PCI) and the 95th percentile was 0.235 life- <0.001 for heart failure, <0.014 for peripheral arterial years. Patients with diabetes, heart failure, tobacco use,or disease, and <0.014 for race). Interaction of race and treat- peripheral arterial disease had higher predicted differences ment was primarily due to patients of "other race"because in their life expectancy when treated with CABG(Figure the difference between white and black patients was not 4). A substantial proportion of patients(41%)were pre gnificant either without (interaction P (interaction P=0.057) additional adjustment for baseline These patients were characterized by the absence of diabe- characteristics, whereas the difference between white pa- tes, heart failure, tobacco use, peripheral vascular disease tients and those of other races was significant both without and a primary diagnosis of MI on hospitalization. Exar (interaction P= 0.003)and with(interaction P=0.025) ples of individualized estimates of the CABG-PCI survival additional adjustment difference as a function of baseline clinical characteristics 73021 May 2013 Annals of Internal Medicine Volume 158. Number 10 www.annals.org
(Figure 1), with a CABG–PCI hazard ratio (HR) for allcause mortality of 0.92 (95% CI, 0.90 to 0.95). Treatment Effect Modification Compared with PCI, the association of CABG with all-cause mortality over the 5-year follow-up was signifi- cantly modified by race, diabetes, tobacco use, peripheral arterial disease, and heart failure (Figure 2). Each of these interactions remained significant after additional adjustment for the baseline characteristics listed in Figure 2 (interaction P 0.047 for diabetes, 0.004 for tobacco use, 0.001 for heart failure, 0.014 for peripheral arterial disease, and 0.014 for race). Interaction of race and treatment was primarily due to patients of “other race” because the difference between white and black patients was not significant either without (interaction P 0.20) or with (interaction P 0.057) additional adjustment for baseline characteristics, whereas the difference between white patients and those of other races was significant both without (interaction P 0.003) and with (interaction P 0.025) additional adjustment. Differences in Life Expectancy Based on individualized predictions of survival in the study population, the mean increase in life expectancy from CABG compared with PCI in the 5 years after coronary revascularization was 0.053 life-years (P 0.001). Estimated life-years added by CABG varied widely across the 105 156 patients in the, however (Figure 3). Median predicted change in life expectancy from CABG was 0.029 life-years, but the 5th percentile was 0.006 life-year (that is, favored PCI) and the 95th percentile was 0.235 lifeyears. Patients with diabetes, heart failure, tobacco use, or peripheral arterial disease had higher predicted differences in their life expectancy when treated with CABG (Figure 4). A substantial proportion of patients (41%) were predicted to have better survival after PCI than after CABG. These patients were characterized by the absence of diabetes, heart failure, tobacco use, peripheral vascular disease, and a primary diagnosis of MI on hospitalization. Examples of individualized estimates of the CABG–PCI survival difference as a function of baseline clinical characteristics Figure 1. Kaplan–Meier survival curves for multivessel CABG and multivessel PCI among Medicare beneficiaries matched on propensity score. CABG 44 252 38 923 32 098 25 609 19 502 14 602 10 377 6867 4009 1904 PCI 44 541 38 603 31 538 24 934 18 873 14 141 10 031 6729 3997 1874 Survival Year CABG PCI 0 1 2 3 4 5 6 7 8 9 10 0.0 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Patients available for follow-up, n CABG coronary artery bypass graft; PCI percutaneous coronary intervention. Original Research Comparative Effectiveness of CABG and PCI 730 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 www.annals.org
Comparative Effectiveness of CABG and PCI ORIGINAL RESEARCH Figure 2. Five-year Kaplan-Meier survival estimates and CABG-PCI hazard ratios and associated 95% Cls in subgroups of the propensity score-matched cohort. 5-y Survival Hazard Ratio (95% CI) Hazard Ratio (95% CI All patients 74.1 092090095) Aged 66-70y 832 092(0.86097) ged71-75 092(0.87-0.97) Aged 76-80 Aged 81-85 y 61.0 0910.86096) 49.5 0970089-1.06) 74.8 091(0.88095) Female 73.2 094(0.90097 White 74.5 722 091(0.89-094) 098(088-1.10) Other race 114(098-1.31) No diabetes 76.2 74 095(092-098) 0.002 696 088(084091 No tobacco us 73 72.1 0.94(0.92097 <0.001 76.0 71.0 082(0.77-0.88) No chronic kidney disease 73 092090095) Chronic kidney disease 50.4 459 092(0.85-1.00) 75.8 74.5 095(092098) <0.001 Peripheral arterial disease 65.7 59.8 0850.80089 75.6 73.7 093(0.90096) Cerebrovascular diseas 66.5 089(085095) 75.1 1 93 0.162 Prior Ml 0.89083-0.95) No heart failure 775 762 <0.001 51 724 093(090096) 9 0910.87-096) No atrial fibrillation 75 74.0 0930091-096) Atrial fibrillation 60.5 .6 0.88(0.83094) 0.129 Primary diagnosis not 76 742 093 rimary diagnosis MI 66.1 090(0.86-094 0.155 Favors CABg Favors PCI CABG -coronary artery bypass graft: MI=myocardial infarction: PCI percutar additional baseline covariates 21 May 2013 Annals of Internal Medicine Volume 158.Number 10 731
Figure 2. Five-year Kaplan–Meier survival estimates and CABG–PCI hazard ratios and associated 95% CIs in subgroups of the propensity score–matched cohort. All patients Aged 66–70 y Aged 71–75 y Aged 76–80 y Aged 81–85 y Aged ≥86 y Male Female White Black Other race No diabetes Diabetes No tobacco use Tobacco use No chronic kidney disease Chronic kidney disease No peripheral arterial disease Peripheral arterial disease No cerebrovascular disease Cerebrovascular disease No prior MI Prior MI No heart failure Heart failure No unstable angina Unstable angina No atrial fibrillation Atrial fibrillation Primary diagnosis not MI Primary diagnosis MI CABG Characteristic 5-y Survival Hazard Ratio (95% CI) Favors CABG Favors PCI Hazard Ratio (95% CI) Interaction P Value* 74.1 83.2 78.0 70.4 61.0 49.5 74.8 73.2 74.5 67.1 71.3 76.2 69.6 73.7 76.0 75.3 50.4 75.8 65.7 75.6 66.5 75.1 66.8 77.5 51.7 72.4 77.9 75.8 60.5 76.2 68.7 PCI 71.9 81.7 76.3 67.6 56.9 46.9 72.6 70.9 72.2 65.9 73.5 74.7 66.1 72.1 71.0 73.2 45.9 74.5 59.8 73.7 62.5 73.1 63.1 76.2 44.6 70.3 75.4 74.0 55.6 74.2 66.1 0.92 (0.90–0.95) 0.92 (0.86–0.97) 0.92 (0.87–0.97) 0.92 (0.87–0.96) 0.91 (0.86–0.96) 0.97 (0.89–1.06) 0.91 (0.88–0.95) 0.94 (0.90–0.97) 0.91 (0.89–0.94) 0.98 (0.88–1.10) 1.14 (0.98–1.31) 0.95 (0.92–0.98) 0.88 (0.84–0.91) 0.94 (0.92–0.97) 0.82 (0.77–0.88) 0.92 (0.90–0.95) 0.92 (0.85–1.00) 0.95 (0.92–0.98) 0.85 (0.80–0.89) 0.93 (0.90–0.96) 0.89 (0.85–0.95) 0.93 (0.91–0.96) 0.89 (0.83–0.95) 0.96 (0.93–0.98) 0.84 (0.79–0.88) 0.93 (0.90–0.96) 0.91 (0.87–0.96) 0.93 (0.91–0.96) 0.88 (0.83–0.94) 0.93 (0.90–0.96) 0.90 (0.86–0.94) – 0.81 0.35 0.007 0.002 <0.001 0.97 <0.001 0.22 0.162 <0.001 0.52 0.129 0.155 1.0 1.1 1.2 1.3 0.7 0.8 0.9 CABG coronary artery bypass graft; MI myocardial infarction; PCI percutaneous coronary intervention. * P values for the interaction with treatment are from models that adjusted only for CABG treatment, the covariate, and their interaction but not for additional baseline covariates. Comparative Effectiveness of CABG and PCI Original Research www.annals.org 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 731
ORIGINAL RESEARCH I Comparative Effectiveness of CABG and PCI Figure 3. Distribution of the estimated life-years of survival added by CABG compared with PCI over 5-y follow-up 10 Favors Pc1 Favors CABG Predicted Difference(CABG-PCD) in 5-y Survival, y population is indicated on the vertical axis, te-years of survival added over 5-y follow-up are shown on th d-whisker plot indicates the 50th percentile as the the box: the 25th and 75th percentiles as the left and right edges and the 5th and 95th percentiles as the left and right respectively. The mean is indicated by the point within the box. tery bypass graft; PCI= percutaneous coronary in areprovidedintheAppendix(availableatwww.annalsmeDicare(10).Thisbodyofevidencesuggeststhattheuse of CABG rather than PCI is likely to reduce mortality for the average patient with multivessel coronary disease DISCUSSION Although the expected fo an average pa Comparative effectiveness research aims to provide in- are clearly important, outcomes for individual patients may formation needed by decision makers, particularly phy differ. In this study, we found that several patient charac- cians and their patients, to choose among alternative teristics significantly modified the comparative effective approaches to clinical management. Therefore, it is impor- less of CABG and PCI such that the expected survival tant to understand not only how treatments affect an v- difference between the procedures varied widely among in- erage patient"but also how their effectiveness may vary dividuals(Figure 3). Patients with a history of peripheral among specific patients with different characteristics. Ran arterial disease, tobacco use, diabetes, or heart failure had a domized clinical trials are well-suited to compare treatment particular survival advantage from CABG(Figures 2 and 4). Conversely, patients with none of these characteristics ity criteria and limited sample sizes, they are less had slightly better survival with PCI. This variation in the suitable for examining variations in clinical effectiveness comparative effectiveness of CABG and PCI underscores across patient populations treated in typical practice the importance of individualizing treatment The comparative effectiveness of treatments is usually In our study, we evaluated the treatment effectiveness measured in relative terms by using HRs, risk ratios, or of coronary revascularization among a large population of odds ratios. These relative measures are well-suited to assess real-world patients and providers. Coronary artery bypass whether the treatment"works" in a consistent manner grafting was associated with significantly lower mortality across studies and patient subgroups. However, even with than PCI in the overall patient population, with an HR of the same relative risk reduction, the absolute risk difference 0.92(CL, 0.90 to 0.95; P< 0.001). This finding is similar from treatment is larger among high-risk patients. In this to the overall HR of 0.91 found in a prior analysis of study, we calculated the expected absolute difference in pooled data from 10 randomized trials( 8)and is consistent survival over 5 years to illustrate the substantial variation with the results of a recent study comparing CABG and among patients in the comparative effectiveness of CABG PCI on the basis of data from clinical registries linked with and PCI(Figure 3). The number of life-years added by 73221 May 2013 Annals of Internal Medicine Volume 158. Number 10 www.annals.org
are provided in the Appendix (available at www.annals .org). DISCUSSION Comparative effectiveness research aims to provide information needed by decision makers, particularly physicians and their patients, to choose among alternative approaches to clinical management. Therefore, it is important to understand not only how treatments affect an “average patient” but also how their effectiveness may vary among specific patients with different characteristics. Randomized clinical trials are well-suited to compare treatment efficacy for the average patient, but because of their narrow eligibility criteria and limited sample sizes, they are less suitable for examining variations in clinical effectiveness across patient populations treated in typical practice settings. In our study, we evaluated the treatment effectiveness of coronary revascularization among a large population of real-world patients and providers. Coronary artery bypass grafting was associated with significantly lower mortality than PCI in the overall patient population, with an HR of 0.92 (CI, 0.90 to 0.95; P 0.001). This finding is similar to the overall HR of 0.91 found in a prior analysis of pooled data from 10 randomized trials (8) and is consistent with the results of a recent study comparing CABG and PCI on the basis of data from clinical registries linked with Medicare (10). This body of evidence suggests that the use of CABG rather than PCI is likely to reduce mortality for the average patient with multivessel coronary disease. Although the expected outcomes for an average patient are clearly important, outcomes for individual patients may differ. In this study, we found that several patient characteristics significantly modified the comparative effectiveness of CABG and PCI such that the expected survival difference between the procedures varied widely among individuals (Figure 3). Patients with a history of peripheral arterial disease, tobacco use, diabetes, or heart failure had a particular survival advantage from CABG (Figures 2 and 4). Conversely, patients with none of these characteristics had slightly better survival with PCI. This variation in the comparative effectiveness of CABG and PCI underscores the importance of individualizing treatment. The comparative effectiveness of treatments is usually measured in relative terms by using HRs, risk ratios, or odds ratios. These relative measures are well-suited to assess whether the treatment “works” in a consistent manner across studies and patient subgroups. However, even with the same relative risk reduction, the absolute risk difference from treatment is larger among high-risk patients. In this study, we calculated the expected absolute difference in survival over 5 years to illustrate the substantial variation among patients in the comparative effectiveness of CABG and PCI (Figure 3). The number of life-years added by Figure 3. Distribution of the estimated life-years of survival added by CABG compared with PCI over 5-y follow-up. Matched Cohort, % Predicted Difference (CABG – PCI) in 5-y Survival, y Favors PCI Favors CABG –0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0 5 10 15 20 25 The percentage of the study population is indicated on the vertical axis, and the life-years of survival added over 5-y follow-up are shown on the horizontal axis. The box-and-whisker plot indicates the 50th percentile as the line within the box; the 25th and 75th percentiles as the left and right edges of the box, respectively; and the 5th and 95th percentiles as the left and right whiskers, respectively. The mean is indicated by the point within the box. CABG coronary artery bypass graft; PCI percutaneous coronary intervention. Original Research Comparative Effectiveness of CABG and PCI 732 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 www.annals.org
Comparative Effectiveness of CABG and PCI ORIGINAL RESEARCH CABG over 5 years is an underestimate of the lifetime Peripheral arterial disease may serve as a marker for pa effect of treatment because the CABG and PCI survival tients with more extensive coronary atherosclerosis, for curves are separated for up to 10 years(Figure 1)and whom CABG may provide a greater survival advantage, ubsequent follow-up is limited. Although a lifetime esti- but data on coronary anatomy were not available in this mate of the life-years added by CABG would be preferable, study to evaluate this possibility it would require many additional extrapolations Neverthe Compared with PCI, CABG was associated with lower effectiveness of CABG and PCI further amplify the d e mortality among patents with a history of tobacco use, but less, our finding that the variations in the comparativ the reasons for this association are uncertain previous ferences in expected survival among patient subgroups studies have shown that patients who quit smoking after (Figure 4)is an important insight for clinical decisio coronary revascularization have better outcomes than those who continue to smoke(12, 13)and that DaTes(14) Because patients with diabetes have a higher risk and a likely to quit smoking after CABG than after PCI (14) disproportionate treatment effect from CABG relative to More patients in this study may have quit smoking after PCI(Figure 2), they have a particularly large difference in CABG than after PCI, adding to any survival advantage survival if treated with CABG rather than PCI (Figure 4) from the procedure itself. Data available in this study did The strong effect of CABG on survival compared with PCI not distinguish between current and former smokers, and among patients with diabetes and multivessel coronary dis- we could not identify patients who continued to smoke ease was recently confirmed by a large randomized trial of after revascularization. Further study of the complex rela 1900 patients(11) tionships among smoking, coronary revascularization, and Coronary artery bypass grafting was also associated outcomes is warranted with a particularly lower mortality than PCI among pa- Coronary artery bypass grafting was also associated tients with a history of peripheral arterial disease(Figures 2 with lower mortality than PCI among patients with a his- and 4). A similar trend was present in the pooled data from tory of heart failure(interaction P<0.001). Such patients 10 randomized trials, but only 665 patients in that study have not been well-represented in clinical trials. Only 3% had peripheral arterial disease and the interaction test was of patients in the 10 randomized trials had a history of not significant(interaction P= 0.33). Our study includes heart failure, compared with 13% in our analysis of Medi- more than 18 000 patients with a diagnosis of peripheral care beneficiaries. Consequently, the comparative effective- arterial disease, so it had sufficient statistical power to de- ness of CABG and PCI in patients with heart failure tect a difference in the treatment effect in this subgroup. has not been well-studied. The claims data we used for Figure 4. Distribution of the estimated life-years of survival added by CABG compared with PCI over 5 y in clinical subgroups No Yes Diabetes Heart Failure Peripheral Arterial Disease nd-whisker plots indicate the 50ch percentile as the line within the box; the 25th and 75th percentiles as the bottom and of the box ely: and the Sth and 95th- ses a Prcutaneous coronary intervention the bottom and top whiskers, respectively. The mean is indicated by the poi the box CABG coronary artery by 21 May 2013 Annals of Internal Volume158· Number107
CABG over 5 years is an underestimate of the lifetime effect of treatment because the CABG and PCI survival curves are separated for up to 10 years (Figure 1) and subsequent follow-up is limited. Although a lifetime estimate of the life-years added by CABG would be preferable, it would require many additional extrapolations. Nevertheless, our finding that the variations in the comparative effectiveness of CABG and PCI further amplify the differences in expected survival among patient subgroups (Figure 4) is an important insight for clinical decision making. Because patients with diabetes have a higher risk and a disproportionate treatment effect from CABG relative to PCI (Figure 2), they have a particularly large difference in survival if treated with CABG rather than PCI (Figure 4). The strong effect of CABG on survival compared with PCI among patients with diabetes and multivessel coronary disease was recently confirmed by a large randomized trial of 1900 patients (11). Coronary artery bypass grafting was also associated with a particularly lower mortality than PCI among patients with a history of peripheral arterial disease (Figures 2 and 4). A similar trend was present in the pooled data from 10 randomized trials, but only 665 patients in that study had peripheral arterial disease and the interaction test was not significant (interaction P 0.33). Our study includes more than 18 000 patients with a diagnosis of peripheral arterial disease, so it had sufficient statistical power to detect a difference in the treatment effect in this subgroup. Peripheral arterial disease may serve as a marker for patients with more extensive coronary atherosclerosis, for whom CABG may provide a greater survival advantage, but data on coronary anatomy were not available in this study to evaluate this possibility. Compared with PCI, CABG was associated with lower mortality among patients with a history of tobacco use, but the reasons for this association are uncertain. Previous studies have shown that patients who quit smoking after coronary revascularization have better outcomes than those who continue to smoke (12, 13) and that patients are more likely to quit smoking after CABG than after PCI (14). More patients in this study may have quit smoking after CABG than after PCI, adding to any survival advantage from the procedure itself. Data available in this study did not distinguish between current and former smokers, and we could not identify patients who continued to smoke after revascularization. Further study of the complex relationships among smoking, coronary revascularization, and outcomes is warranted. Coronary artery bypass grafting was also associated with lower mortality than PCI among patients with a history of heart failure (interaction P 0.001). Such patients have not been well-represented in clinical trials. Only 3% of patients in the 10 randomized trials had a history of heart failure, compared with 13% in our analysis of Medicare beneficiaries. Consequently, the comparative effectiveness of CABG and PCI in patients with heart failure has not been well-studied. The claims data we used for Figure 4. Distribution of the estimated life-years of survival added by CABG compared with PCI over 5 y in clinical subgroups. Predicted Difference (CABG – PCI) in 5-y Survival, y Favors PCI Favors CABG No Yes Tobacco Use No Yes Diabetes No Yes Heart Failure No Yes Peripheral Arterial Disease –0.1 0.0 0.1 0.2 0.3 0.4 0.5 The box-and-whisker plots indicate the 50th percentile as the line within the box; the 25th and 75th percentiles as the bottom and top edges of the box, respectively; and the 5th and 95th percentiles as the bottom and top whiskers, respectively. The mean is indicated by the point within the box. CABG coronary artery bypass graft; PCI percutaneous coronary intervention. Comparative Effectiveness of CABG and PCI Original Research www.annals.org 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 733
ORIGINAL RESEARCH I Comparative Effectiveness of CABG and PCI this study lack important clinical details about Potential Conflicts of Interest: Disclosures can be viewed at www patients, such as measures of left ventricular fund myocardial ischemia, and the extent of coronary Reproducible Research Statement: Study Protocol: The protocol is fully This study used nonrandomized data to compare the described in the manuscript. Statistical code. Available on request. Data effectiveness of CABG and PCl. Comparing treatments by set: Medicare data sets are available to qualified researchers but cannot be using observational data has been controversial because of released by the investigators. potential biases related to treatment selection and the lack Requests for Single Mark A. Hltaky, MD, Stanford Univer- of data on important clinical factors that might affect out sity School of Medici Redwood Building, 259 Campus Drive, We used 2 mitigate these obstacles. Fi Stanford, CA 9430 we restricted the population to patients with multivessel PCI or multivessel isolated CABG, which produced a pop- annals. org Current author addresses and author contributions are available at www ulation that more closely resembled patients eligible for randomized trials of these procedures. Second, we used propensity score matching to further control for potential References treatment selection bias, which closely balanced observed 1. BARI Investigators. The final 10-year follow-up results from the BARI ran- patient characteristics Table) that differed greatly in the 2. King SB 3rd, Kosinski AS, Guyton RA, Lembo N), Weintraub ws. Eight initial study population. This yielded an estimate of the year mortality in the Emory Angioplasty versus Surgery Trial(EAST). JAm Coll CABG-PCI HR(0.92)that was similar to the one Cardiol. 2000: 35: 1116-21[PMID: 10758949 derived from pooling randomized trial data(0.91). Our 3. Serruys Pw, Ong AT, van Herwerden LA, Sousa JE, Jatene A, Bonnier J) finding that several baseline clinical characteristics modi treatment of multivessel disease: the final analysis of the Arterial revascularization fied the comparative treatment effectiveness of CABG and Therapies Study (ARTS)randomized trial. JAm Coll Cardiol. 2005: 46-575-81 PCI is also consistent with the results of the earlier pool analysis(8). The broad agreement between the present 4. Booth J, Clayton T, Pepper J, Nugara F, Flather M, Sigwart U, et al; Sos study and the results of the pooled randomized trials sug- sus percutancous coronary intervention in patients with multivessel coronary ar. gests that carefully conducted analyses of obser rational tery disease: six-year follow-up from the Stent or Surgery Trial(SoS).Circulation. data can provide reliable estimates of real-world treatment 2008; 118 381-8.[PMID: 186069191 effectiveness 5. Hueb W, Lopes N, Gersh BJ, Soares PR, Ribeiro EE, Pereira AC, et al. Ten-year follow-up survival of the Medicine, AngiopLasty, or Surgery Study The major limitation of this study is that it is based on (MASS I): a randomized controlled dinical trial of 3 therapeutic strategies for claims data and lacks detail on many key baseline clinical multivessel coronary artery disease. Circulation. 2010: 122: 949-57. [PMID: characteristics and information on medications and behav- 207331021 6. Rodriguez AE, Baldi J, Fernandez Pereira C, Navia J, Rodriguez Alemparte G s during subsequent follow-up. These limitations may M, Delacasa A, et al: ERACI II Investigators. Five- year follow-up of the Argen- be particularly relevant to our analyses of tobacco use and heart failure, which seem to modify the CABG-PCi treat- surgery in patients with multiple vessel disease(ERACI ID). J Am Coll Cardiol. ment effect but may be correlated with other unobserved 2005;46:582-8PMID:16098419 clinical characteristics. In addition, the claims data used 7. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack 1, et al; SYNTAX Investigators. Percutaneous coronary intervention versus in this study do not contain information on symptom severity or on the functional status or quality of life of 2009, 360: 961-72.(PMID: 19228612 coronary artery disease. N Engl JMed. Patients. 8. Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks This study provides strong evidence that clinical char- interventions for multivessel disease: a collaborative analysis of individual patient acteristics modify the comparative effectiveness of CABG data from ten randomised trials. Lancet. 2009: 373: 1190-7. [PMID: 19303634 and PCI on mortality, especially for diabetes, which had 9. Parsons LS. Reducing bias in a propensity score matched-pair sample using been previously shown (8). Our study suggests that addi- greedy matching techniques. Presented at 26th Annual SAS Users Group Inter- ational Conference, 22-25 April 2001, Long Beach, California. ease,and heart failure, also modify the CABG-PCI treat- ED, Kolm P, et al. Comparative effectiveness of revascularization strategie ment effect. These variations in comparative effectiveness N Engl Med.2012;366:1467-76. [PMID:22452338 underscore the need to per 11. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, dations for coronary revascularization among patients with et al; FREEDOM Trial l treatment recommen for multivessel revascularization in patients with diabetes. N Engl JMed. 2012: 367: 2375-84. [PMID: 231213231 coronary disease. 12. van Domburg RT, Meeter K, van Berkel DE, Veldkamp RF, van Herw- erden LA, Bogers AJ. Smoking cessation reduces mortality after coronary artery From Stanford University School of Medicine, Stanford; Kaiser Per bypass surgery: a 20-year follow-up study. J Am Coll Cardiol. 2000: 36: 878-83 nente Northern California, Oakland; and University of California, San [PMID:10987614] Francisco, San Francisco, California 13. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR Jr. Effect of smoki on the lon vascularization. N Engl J Med. 1997: 336: 755-61. [PMID: 90526531 pport: By grant HL099872 from the National Heart, Crouse JR 3rd, Hagaman AP. Smoking cessation in relation to cardiac procedures. Am) Epidemiol. 1991: 134: 699-703. [PMID: 1951275] 21 May 2013 Annals of Internal Medicine Volume 158. Number 10 www.annals.org
this study lack important clinical details about these patients, such as measures of left ventricular function, myocardial ischemia, and the extent of coronary artery disease. This study used nonrandomized data to compare the effectiveness of CABG and PCI. Comparing treatments by using observational data has been controversial because of potential biases related to treatment selection and the lack of data on important clinical factors that might affect outcomes. We used 2 steps to mitigate these obstacles. First, we restricted the population to patients with multivessel PCI or multivessel isolated CABG, which produced a population that more closely resembled patients eligible for randomized trials of these procedures. Second, we used propensity score matching to further control for potential treatment selection bias, which closely balanced observed patient characteristics (Table) that differed greatly in the initial study population. This yielded an estimate of the overall CABG–PCI HR (0.92) that was similar to the one derived from pooling randomized trial data (0.91). Our finding that several baseline clinical characteristics modi- fied the comparative treatment effectiveness of CABG and PCI is also consistent with the results of the earlier pooled analysis (8). The broad agreement between the present study and the results of the pooled randomized trials suggests that carefully conducted analyses of observational data can provide reliable estimates of real-world treatment effectiveness. The major limitation of this study is that it is based on claims data and lacks detail on many key baseline clinical characteristics and information on medications and behaviors during subsequent follow-up. These limitations may be particularly relevant to our analyses of tobacco use and heart failure, which seem to modify the CABG–PCI treatment effect but may be correlated with other unobserved clinical characteristics. In addition, the claims data used in this study do not contain information on symptom severity or on the functional status or quality of life of patients. This study provides strong evidence that clinical characteristics modify the comparative effectiveness of CABG and PCI on mortality, especially for diabetes, which had been previously shown (8). Our study suggests that additional factors, particularly smoking, peripheral arterial disease, and heart failure, also modify the CABG–PCI treatment effect. These variations in comparative effectiveness underscore the need to personalize treatment recommendations for coronary revascularization among patients with multivessel coronary disease. From Stanford University School of Medicine, Stanford; Kaiser Permanente Northern California, Oakland; and University of California, San Francisco, San Francisco, California. Grant Support: By grant HL099872 from the National Heart, Lung, and Blood Institute. Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNumM12 -1564. Reproducible Research Statement: Study protocol: The protocol is fully described in the manuscript. Statistical code: Available on request. Data set: Medicare data sets are available to qualified researchers but cannot be released by the investigators. Requests for Single Reprints: Mark A. Hltaky, MD, Stanford University School of Medicine, HRP Redwood Building, 259 Campus Drive, Stanford, CA 94305-5405; e-mail, hlatky@stanford.edu. Current author addresses and author contributions are available at www .annals.org. References 1. BARI Investigators. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol. 2007;49:1600-6. [PMID: 17433949] 2. King SB 3rd, Kosinski AS, Guyton RA, Lembo NJ, Weintraub WS. Eightyear mortality in the Emory Angioplasty versus Surgery Trial (EAST). J Am Coll Cardiol. 2000;35:1116-21. [PMID: 10758949] 3. Serruys PW, Ong AT, van Herwerden LA, Sousa JE, Jatene A, Bonnier JJ, et al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol. 2005;46:575-81. [PMID: 16098418] 4. Booth J, Clayton T, Pepper J, Nugara F, Flather M, Sigwart U, et al; SoS Investigators. Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial (SoS). Circulation. 2008;118:381-8. [PMID: 18606919] 5. Hueb W, Lopes N, Gersh BJ, Soares PR, Ribeiro EE, Pereira AC, et al. Ten-year follow-up survival of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation. 2010;122:949-57. [PMID: 20733102] 6. Rodriguez AE, Baldi J, Ferna´ndez Pereira C, Navia J, Rodriguez Alemparte M, Delacasa A, et al; ERACI II Investigators. Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II). J Am Coll Cardiol. 2005;46:582-8. [PMID: 16098419] 7. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360:961-72. [PMID: 19228612] 8. Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373:1190-7. [PMID: 19303634] 9. Parsons LS. Reducing bias in a propensity score matched-pair sample using greedy matching techniques. Presented at 26th Annual SAS Users Group International Conference, 22–25 April 2001, Long Beach, California. 10. Weintraub WS, Grau-Sepulveda MV, Weiss JM, O’Brien SM, Peterson ED, Kolm P, et al. Comparative effectiveness of revascularization strategies. N Engl J Med. 2012;366:1467-76. [PMID: 22452338] 11. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375-84. [PMID: 23121323] 12. van Domburg RT, Meeter K, van Berkel DF, Veldkamp RF, van Herwerden LA, Bogers AJ. Smoking cessation reduces mortality after coronary artery bypass surgery: a 20-year follow-up study. J Am Coll Cardiol. 2000;36:878-83. [PMID: 10987614] 13. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR Jr. Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization. N Engl J Med. 1997;336:755-61. [PMID: 9052653] 14. Crouse JR 3rd, Hagaman AP. Smoking cessation in relation to cardiac procedures. Am J Epidemiol. 1991;134:699-703. [PMID: 1951275] Original Research Comparative Effectiveness of CABG and PCI 734 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 www.annals.org
Annals of internal medicine Current Author Addresses: Drs. Hlatky, Boothroyd, Baker, and APPENDIX: EXAMPLES OF INDIVIDUALIZED ESTIMATES OF silane: Stanford University School of Medicine, HRP Redwood Build- TREATMENT EFFECTIVENESS g, 259 Campus Drive, Stanford, CA 94305-5405 7e estimated individualized changes in life expectancy after Dr. Kazi: UCSF Division of Cardiology, San Francisco General Hospi- CABG rather than PCI by using a Cox proportional hazards al, 1001 Potrero Avenue, SGl, San Francisco, CA 94110. Drs. Solomon and Go: Division of Research. Kaiser Permanente north- model with 13 covariates: age, sex, race, diabetes, tobacco use, ern California, 2000 Broadway, Oakland, CA 94612 chronic kidney disease, peripheral vascular disease, cerebrovascu Dr. Chang: Stanford University School of Medicine, Nephrology Divi- lar disease, prior MI, heart failure, unstable angina, atrial fibril- sion, 777 Welch Road, Room D100, Palo Alto, CA 94304 ation,and a primary diagnosis of MI at the same hospitalization as the revascularization procedure. Individualized treatment esti- mates as a function of these variables will be made available on Author Contributions: Conception and design: M.A. Hlatky, L. Baker A.S. Go aWebsitethepossibleformatofwhichcanbeseenathttp Analysis and interpretation of the data: M.A. Hlatky, D B. Boothroyd //med. stanford. edu/hsr/cabg-pci. Example patients are described D.S. Kazi, M.D. Solomon, T.I. Chang, D. Shilane, A.S. Go. Drafting of the article: M.A. Hlatky Example 1: A 70-year-old black man with diabetes and pe ritical revision of the article for important intellectual content: D.B. ripheral vascular disease but no tobacco use or heart failure. The Boothroyd, D.S. Kazi, M D. Solomon, T.L. Chang, D. Shilane, A.S. Go. median number of life-years added over 5 years by CABG among Final approval of the article: M.A. Hlatky, D B. Boothroyd, L. Baker, 43 similar patients in the data set was 0.079(range, 0.067 to D.S. Kazi, M.D. Solomon, T.I. Chang, D. Shilane, A.S. Go. Provision of study materials or patients: L. Baker. 0. 139 life-years) Statistical expertise: M.A. Hlatky, D B. Boothroyd, D. Shilane. Example 2: A 75-year-old white woman with diabetes but Obtaining of funding: M.A. Hlatky, A.S. Go ithout heart failure, peripheral vascular disease, or tobacco use. Administrative, technical, or logistic support: M.A. HLatky, L. Baker. The median number of life-years added over 5 years by CABG Collection and assembly of data: D B. Boothroyd, L. Baker. among 2267 similar patients in the data set was 0.007(range, 0.005 to 0.133 life-years) agnosis of acute MI. The median number of life-years added over 5 years by CABG among 2596 similar patients in the data set was -0.014(range, -0.012 to -0.028 life-years)(that is, the pre- dicted survival was better with PCI Example 4: A 77-year-old white woman with diabetes, pe ripheral vascular disease, and heart failure but no tobacco use. The median number of life-years added over 5 years by CABG among 176 similar patients in the data set was 0. 286(range, 0. 211 to 0.502 life-years w-302 21 May 2013 Annals of Internal Medicine 158.Number www.annals.org
Current Author Addresses: Drs. Hlatky, Boothroyd, Baker, and Shilane: Stanford University School of Medicine, HRP Redwood Building, 259 Campus Drive, Stanford, CA 94305-5405. Dr. Kazi: UCSF Division of Cardiology, San Francisco General Hospital, 1001 Potrero Avenue, SG1, San Francisco, CA 94110. Drs. Solomon and Go: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612. Dr. Chang: Stanford University School of Medicine, Nephrology Division, 777 Welch Road, Room D100, Palo Alto, CA 94304. Author Contributions: Conception and design: M.A. Hlatky, L. Baker, A.S. Go. Analysis and interpretation of the data: M.A. Hlatky, D.B. Boothroyd, D.S. Kazi, M.D. Solomon, T.I. Chang, D. Shilane, A.S. Go. Drafting of the article: M.A. Hlatky. Critical revision of the article for important intellectual content: D.B. Boothroyd, D.S. Kazi, M.D. Solomon, T.I. Chang, D. Shilane, A.S. Go. Final approval of the article: M.A. Hlatky, D.B. Boothroyd, L. Baker, D.S. Kazi, M.D. Solomon, T.I. Chang, D. Shilane, A.S. Go. Provision of study materials or patients: L. Baker. Statistical expertise: M.A. Hlatky, D.B. Boothroyd, D. Shilane. Obtaining of funding: M.A. Hlatky, A.S. Go. Administrative, technical, or logistic support: M.A. Hlatky, L. Baker. Collection and assembly of data: D.B. Boothroyd, L. Baker. APPENDIX: EXAMPLES OF INDIVIDUALIZED ESTIMATES OF TREATMENT EFFECTIVENESS We estimated individualized changes in life expectancy after CABG rather than PCI by using a Cox proportional hazards model with 13 covariates: age, sex, race, diabetes, tobacco use, chronic kidney disease, peripheral vascular disease, cerebrovascular disease, prior MI, heart failure, unstable angina, atrial fibrillation, and a primary diagnosis of MI at the same hospitalization as the revascularization procedure. Individualized treatment estimates as a function of these variables will be made available on a Web site, the possible format of which can be seen at http: //med.stanford.edu/hsr/cabg-pci. Example patients are described below. Example 1: A 70-year-old black man with diabetes and peripheral vascular disease but no tobacco use or heart failure. The median number of life-years added over 5 years by CABG among 43 similar patients in the data set was 0.079 (range, 0.067 to 0.139 life-years). Example 2: A 75-year-old white woman with diabetes but without heart failure, peripheral vascular disease, or tobacco use. The median number of life-years added over 5 years by CABG among 2267 similar patients in the data set was 0.007 (range, 0.005 to 0.133 life-years). Example 3: A 66-year-old white man without diabetes, heart failure, peripheral vascular disease, tobacco use, or a primary diagnosis of acute MI. The median number of life-years added over 5 years by CABG among 2596 similar patients in the data set was 0.014 (range, 0.012 to 0.028 life-years) (that is, the predicted survival was better with PCI). Example 4: A 77-year-old white woman with diabetes, peripheral vascular disease, and heart failure but no tobacco use. The median number of life-years added over 5 years by CABG among 176 similar patients in the data set was 0.286 (range, 0.211 to 0.502 life-years). Annals of Internal Medicine W-302 21 May 2013 Annals of Internal Medicine Volume 158 • Number 10 www.annals.org
