Letters
In Reply My colleagues and I thank Gross and colleagues for giving us the opportunity to clarify our study.1 To determine whether a nodule was benign or malignant, we included the results of all biopsies conducted at the University of California, San Francisco, and linked the entire cohort of more than 8000 patients with the California Cancer Registry (CCR) that collects cancer incidence data on all patients who received a diagnosis in California and 22 additional states with whom the CCR shares data. By linking with the CCR, we learned about cancers that occurred as long as 6 years after ultrasonography and confirmed that nodules were benign as long as 11 years after ultrasonography. Thus, we know with a high degree of certainty which nodules were malignant or benign. In contrast, all previous of thyroid ultrasonography studies limited their analysis to patients who underwent immediate biopsy, where the decision to perform a biopsy was influenced by the ultrasonography result. This will miss cancers that would not have been considered suspicious on the ultrasonogram, and this ascertainment bias will overestimate the accuracy of ultrasonography. This is why we found a lower risk of cancer and lower predictive values associated with specific findings compared with prior reports: this reflects our complete follow-up of patients many years after ultrasonography to determine the true cancer status in the entire cohort. The completeness of cancer information makes our cohort the most representative and accurate way to estimate the risk of cancer among patients in whom incidental thyroid nodules are identified. We found that thyroid tumors occur at every size; in our sample, approximately a third were smaller than 10 mm, a third were between 10 and 20 mm, and a third were larger than 20 mm. However, it is only in nodules larger than 20 mm that there is a statistically significant increased risk of cancer. For the other size categories, most of the nodules identified are benign, and size cannot be used to identify nodules with a greater-thanaverage likelihood of cancer. We found that thyroid nodules 5 mm or larger were present in 56% of patients. In contrast, clinically apparent thyroid cancer is rare, affecting 1 in 10 000 people annually. Because of the high prevalence of nodules and the rarity of symptomatic cancer, only a minority of thyroid nodules is malignant. There are no imaging criteria that can be used (other than the 3 we report in our results: entirely solid, size >2 cm, or microcalcifications) that can distinguish nodules that are likely benign from those with an increased risk of malignancy. If it is deemed important to identify every microcarcinoma, then the only way to do this would be to biopsy every nodule seen on thyroid ultrasonography. This would require performing a biopsy in over half of the population who undergoes thyroid ultrasonography and performing multiple biopsies in the 34% of patients who have multiple thyroid nodules. The likelihood ratios presented in Table 6 of our article1 can be used to estimate a patient’s posttest risk of cancer, if you know from another source their pretest risk of harboring cancer. Rebecca Smith-Bindman, MD 1006
Author Affiliations: Department of Radiology and Biomedical Imaging, University of California, San Francisco; Department of Epidemiology and Biostatistics, University of California, San Francisco ; Department of Health Policy and Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco; Radiology Outcomes Research Lab, University of California, San Francisco. Corresponding Author: Rebecca Smith-Bindman, MD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 350 Parnassus Ave, Ste 307, San Francisco, CA 94143-0336 (rebecca.smith-bindman @ucsf.edu). Conflict of Interest Disclosures: None reported. 1. Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 2013;173(19):1788-1796.
Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention in Multivessel Disease To the Editor We read with great interest the meta-analysis by Sipahi et al1 in which 6 randomized clinical trials (RCTs) of percutaneous coronary intervention (PCI) vs coronary artery bypass grafting (CABG) in multivessel disease (MVD) were included. There was a significant reduction in 1-year-orgreater all-cause mortality with CABG compared with PCI (risk ratio [RR], 0.73; 95% CI, 0.62-0.86; P < .001). The design of included RCTs, however, is heterogeneous: ie, using exclusively bare-metal stents (BMS) in 3 trials, drug-eluting stents (DES) in 2 trials (SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] multivessel and FREEDOM [Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease] [references 12 and 16, respectively, in the original article1]), and both BMS and DES in 1 trial (CARDia [Coronary Artery Revascularization in Diabetes] [reference 7 in the original article 1 ]). The authors stated that their aim was to “overcome the power limitation” of the existing data sets.1(p224) Pooling heterogeneous-design RCTs just merely to overcome the power limitation (thereby, probably expecting statistically significant results), however, would be inappropriate. Regarding PCI with exclusive BMS vs CABG in MVD, previous meta-analyses2,3 of 4 RCTs demonstrated no statistically significant differences in all-cause mortality. Thus, cardiac interventionalists and surgeons are now interested in the evidence of PCI with exclusive DES vs CABG in MVD.4,5 To our knowledge, however, the results of only 2 RCTs (SYNTAX multivessel and FREEDOM) of PCI with DES vs CABG in MVD have been reported to date. Yan et al4 demonstrated, in their meta-analysis of unadjusted data, that all-cause mortality at 12 months (1 RCT and 11 observational studies enrolling a total of 7754 patients [RR, 0.98; 95% CI, 0.61-1.56; P = .92]) and 24 months (5 observational studies enrolling a total of 1374 patients [RR, 0.81; 95% CI, 0.55-1.18; P = .27]) were similar between PCI with DES and CABG in MVD. On the other hand, in our meta-analysis5 we pooled 2 crude hazard ratios from 2 RCTs and 19 adjusted HRs from 11 observational studies and suggested that PCI with DES may increase 1-year-or-greater all-cause mortality by 24% over CABG in MVD (hazard ratio, 1.24; 95% CI, 1.02-1.50; P = .03). To determine whether PCI with DES increases all-cause mortality
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over CABG in MVD, however, a greater number of RCTs would be required. Hisato Takagi, MD, PhD Takuya Umemoto, MD, PhD; for the ALICE Group Author Affiliations: Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan. Corresponding Author: Hisato Takagi, MD, PhD, Department of Cardiovascular Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan ([email protected]). Conflict of Interest Disclosures: None reported. Group Information: Members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group include Hisato Takagi, MD, PhD; Taku Watanabe, MD; Yusuke Mizuno, MD; Norikazu Kawai, MD; and Takuya Umemoto, MD, PhD. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230. 2. Takagi H, Kawai N, Umemoto T. Meta-analysis of four randomized controlled trials on long-term outcomes of coronary artery bypass grafting versus percutaneous coronary intervention with stenting for multivessel coronary artery disease. Am J Cardiol. 2008;101(9):1259-1262. 3. Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118(11):1146-1154. 4. Yan TD, Padang R, Poh C, et al. Drug-eluting stents versus coronary artery bypass grafting for the treatment of coronary artery disease: a meta-analysis of randomized and nonrandomized studies. J Thorac Cardiovasc Surg. 2011;141(5): 1134-1144. 5. Takagi H, Manabe H, Umemoto T. The Gordian knot of revascularization for multivessel coronary artery disease. J Thorac Cardiovasc Surg. 2011;142(1):241243.
To The Editor In a meta-analysis from 6 randomized clinical trials (RCTs), Sipahi et al1 reported 4.1 years’ outcome of 6055 patients randomized to percutaneous coronary interventions (PCIs) either with bare-metal stents (BMS) or drug-eluting stents (DES) vs coronary artery bypass graft (CABG) in multiple vessel disease. The authors concluded that CABG leads to a significant reduction in long-term mortality, myocardial infarction, and repeat revascularization procedures independently of diabetic status without differences in nonfatal stroke. Trial selection was made according to the number of stents and arterial conduits used in PCI/CABG arms. However, in the Estudio Randomizado Argentino Angioplastia vs Cirugia (ERACI) II trial, which was excluded,2 BMS were used in all patients and arterial conduits in 88.5% of patients, which is not significantly different from other BMS and CABG trials.1 In ERACI II, a lower incidence of death and myocardial infarction with PCI was observed in the first year and an advantage remained at 5 years. A meta-analysis of the 4 RCT comparing BMS vs CABG3 found almost identical survival (8.5% and 8.2%, respectively; P = .74); furthermore, in patients with diabetes, the survival for a composite of death, MI, and stroke were similar (21.4% [BMS] and 20.9% [CABG]; P = .79). There have been 8 RCTs that compared PCI either with BMS or DES vs CABG—2 of them were not included2,4 and in 1 trial the authors reported incomplete and underpowered data.1 If we pool the results from the 8 RCTs jamainternalmedicine.com
(7468 patients), mortality between PCI and CABG in a nondiabetic population remains similar (risk ratio [RR], 1.03; 95% CI, 0.77-1.37) and the only survival advantage with CABG is in a diabetic population (RR, 0.67; 95% CI, 0.52-0.86), despite an increased risk of nonfatal stroke (RR, 1.72; 95% CI, 1.18-2.53). As Sipahi et al1 pointed out, it is not certain that latestgeneration DES will reduce the incidence of death compared with the first generation; however, we also understand that when comparing late outcomes from studies of BMS, DES, and CABG, the only advantage of first-generation DES over BMS is a reduction in target vessel revascularization, with the penalty of an increase incidence of death, myocardial infarction, and stent thrombosis.5 Finally, taking into account that only a few RCTs comparing PCI with stents vs CABG were conducted, it is important that pooled data should include all of them. In summary, after the analysis of the results from the 8 trials, we must state that survival advantage with CABG was seen only in patients with diabetes. Alfredo E. Rodriguez, MD, PhD Carlos Fernandez-Pereira, MD, PhD Juan Mieres, MD Author Affiliations: Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine, Buenos Aires, Argentina. Corresponding Author: Alfredo E. Rodriguez MD, PhD, Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine, Callao 1441, 4B Buenos Aires, Argentina ([email protected]). Conflict of Interest Disclosures: None reported. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230. 2. Rodriguez AE, Baldi J, Fernández Pereira C, 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(4):582-588. 3. Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118(11):1146-1154. 4. Kamalesh M, Sharp TG, Tang XC, et al; VA CARDS Investigators. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol. 2013;61(8):808-816. 5. Rodriguez AE, Maree AO, Mieres J, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry. Eur Heart J. 2007;28 (17):2118-2125.
In Reply Regarding our meta-analysis examining the effects of bypass grafting vs stenting in patients with multivessel coronary disease,1 Takagi et al challenge our results by stating that the included trials were heterogeneous because some of them used bare-metal stents (BMS) and others used drug-eluting stents (DES). I disagree. Bare-metal stents and DES are homogenous in the sense that they do not have different survival rates, which was the main outcome of interest in our metaanalysis. Moreover, our subgroup analyses presented in our article show that stents lead to higher mortality regardless of whether they are BMS or DES, with an interaction P value of JAMA Internal Medicine June 2014 Volume 174, Number 6
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.56 for the type of stent used. Takagi et al also suggest that DES and bypass have similar mortality rates, referring to an obsolete meta-analysis that did not include the FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial2 or the long-term follow-up of SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial,3 the only 2 major randomized trials comparing DES with coronary artery bypass graft (CABG) in this setting. Instead, this meta-analysis by Yan et al4 included 11 observational studies, the results of which contradict substantially with gold-standard evidence from randomized trials and therefore are misleading. Rodriguez et al assert that we neglected to include 2 additional clinical trials in our meta-analysis, namely the Estudio Randomizado Argentino Angioplastia vs Cirugia (ERACI) II5 and the Coronary Artery Revascularization in Diabetes (VA CARDS)6 trials, and our results may therefore not be reliable. The ERACI-II trial from South America was a study with substandard clinical practice, with the lowest reported rate of arterial graft and stent use and the highest early surgical mortality among comparable trials.5 The trial did not meet the “>90% arterial graft use” and “>1 stent use in at least 70% of the cases” criteria for inclusion into meta-analysis and was therefore excluded from our meta-analysis.1 Nevertheless, we had stated the following in our article: “One well-known clinical trial from South America did not meet the study inclusion criteria because the frequency of the use of arterial grafts in the CABG arm and the frequency of stent use in the PCI [percutaneous coronary intervention] arm of this trial were too low.”1(p227) On the other hand, the results of the VA CARDS study became available in February 2013, after we performed our final literature search in December 2012, as stated in our article. VA CARDS is a prematurely stopped clinical trial enrolling only 25% of the intended sample size (N = 198). 6 Nevertheless, in this small trial, all-cause mortality was 5.0% for CABG and 21% for PCI (hazard ratio, 0.30; 95% CI, 0.110.80), supporting our main finding of increased mortality with stenting in multivessel coronary disease. In addition, Rodriguez et al claim that the superior survival with CABG is limited to patients with diabetes. I disagree. Our subgroup analysis of trials mostly including patients without diabetes shows a statistically significant reduced mortality with CABG compared with stenting (meta-analytic risk ratio, 0.72; 95% CI, 0.58-0.89 [P = .003]), with an interaction P value of .80 for comparison of effect in patients with diabetes vs patients without diabetes.1 Ilke Sipahi, MD
2. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. 3. Kappetein AP, Feldman TE, Mack MJ, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J. 2011;32 (17):2125-2134. 4. Yan TD, Padang R, Poh C, et al. Drug-eluting stents versus coronary artery bypass grafting for the treatment of coronary artery disease: a meta-analysis of randomized and nonrandomized studies. J Thorac Cardiovasc Surg. 2011;141(5): 1134-1144. 5. Rodriguez AE, Baldi J, Fernández Pereira C, 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(4):582-588. 6. Kamalesh M, Sharp TG, Tang XC, et al; VA CARDS Investigators. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol. 2013;61(8):808-816.
Did Extra Resources or the Medical Home Model Improve Care? To the Editor In their study of the pilot program of the Rhode Island Chronic Care Sustainability Initiative, Rosenthal et al1 attributed the minimal (and with 1 exception, nonsignificant) improvements they observed to a specific model, the patientcentered medical home. In an accompanying Invited Commentary, Grumbach2 urges an even more positive interpretation of these results; he argues for the widespread adoption of the patient-centered medical home model.2 Both the study and the commentary ignore the extra $2 million (approximately $45 000 per physician) that insurers provided to the patient-centered medical home practices (but not to controls). Perhaps extra resources for primary care, not the adoption of the patient-centered medical home model per se, are what is important. David U. Himmelstein, MD Steffie Woolhandler, MD, MPH Author Affiliations: City University of New York, School of Public Health, New York. Corresponding Author: David U. Himmelstein, MD, City University of New York, School of Public Health, 255 W 90th St, Apt 12A, New York, NY 10024-1152 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Rosenthal MB, Friedberg MW, Singer SJ, Eastman D, Li Z, Schneider EC. Effect of a multipayer patient-centered medical home on health care utilization and quality: the Rhode Island chronic care sustainability initiative pilot program. JAMA Intern Med. 2013;173(20):1907-1913. 2. Grumbach K. The patient-centered medical home is not a pill: implications for evaluating primary care reforms. JAMA Intern Med. 2013;173(20):1913-1914.
Author Affiliations: Department of Cardiology, Acibadem University Medical School, Istanbul, Turkey; Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Corresponding Author: Ilke Sipahi, MD, Department of Cardiology, Acibadem University Medical School, Acibadem Maslak Hospital, Buyukdere Cad 40, 34457 Istanbul, Turkey ([email protected]). Conflict of Interest Disclosures: None reported. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and
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morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230.
In Reply It is possible that the additional funds provided to practices in the patient-centered medical home pilot had a direct effect on the study outcomes that was not mediated by other changes. The establishment of a patient-centered medical home involves multiple changes to a practice. Thus, studying many variations of the changes would be needed to isolate the contribution of a single component, such as increased payments. We are unaware of evidence that increasing payments
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In Reply My colleagues and I thank Gross and colleagues for giving us the opportunity to clarify our study.1 To determine whether a nodule was benign or malignant, we included the results of all biopsies conducted at the University of California, San Francisco, and linked the entire cohort of more than 8000 patients with the California Cancer Registry (CCR) that collects cancer incidence data on all patients who received a diagnosis in California and 22 additional states with whom the CCR shares data. By linking with the CCR, we learned about cancers that occurred as long as 6 years after ultrasonography and confirmed that nodules were benign as long as 11 years after ultrasonography. Thus, we know with a high degree of certainty which nodules were malignant or benign. In contrast, all previous of thyroid ultrasonography studies limited their analysis to patients who underwent immediate biopsy, where the decision to perform a biopsy was influenced by the ultrasonography result. This will miss cancers that would not have been considered suspicious on the ultrasonogram, and this ascertainment bias will overestimate the accuracy of ultrasonography. This is why we found a lower risk of cancer and lower predictive values associated with specific findings compared with prior reports: this reflects our complete follow-up of patients many years after ultrasonography to determine the true cancer status in the entire cohort. The completeness of cancer information makes our cohort the most representative and accurate way to estimate the risk of cancer among patients in whom incidental thyroid nodules are identified. We found that thyroid tumors occur at every size; in our sample, approximately a third were smaller than 10 mm, a third were between 10 and 20 mm, and a third were larger than 20 mm. However, it is only in nodules larger than 20 mm that there is a statistically significant increased risk of cancer. For the other size categories, most of the nodules identified are benign, and size cannot be used to identify nodules with a greater-thanaverage likelihood of cancer. We found that thyroid nodules 5 mm or larger were present in 56% of patients. In contrast, clinically apparent thyroid cancer is rare, affecting 1 in 10 000 people annually. Because of the high prevalence of nodules and the rarity of symptomatic cancer, only a minority of thyroid nodules is malignant. There are no imaging criteria that can be used (other than the 3 we report in our results: entirely solid, size >2 cm, or microcalcifications) that can distinguish nodules that are likely benign from those with an increased risk of malignancy. If it is deemed important to identify every microcarcinoma, then the only way to do this would be to biopsy every nodule seen on thyroid ultrasonography. This would require performing a biopsy in over half of the population who undergoes thyroid ultrasonography and performing multiple biopsies in the 34% of patients who have multiple thyroid nodules. The likelihood ratios presented in Table 6 of our article1 can be used to estimate a patient’s posttest risk of cancer, if you know from another source their pretest risk of harboring cancer. Rebecca Smith-Bindman, MD 1006
Author Affiliations: Department of Radiology and Biomedical Imaging, University of California, San Francisco; Department of Epidemiology and Biostatistics, University of California, San Francisco ; Department of Health Policy and Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco; Radiology Outcomes Research Lab, University of California, San Francisco. Corresponding Author: Rebecca Smith-Bindman, MD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 350 Parnassus Ave, Ste 307, San Francisco, CA 94143-0336 (rebecca.smith-bindman @ucsf.edu). Conflict of Interest Disclosures: None reported. 1. Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 2013;173(19):1788-1796.
Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention in Multivessel Disease To the Editor We read with great interest the meta-analysis by Sipahi et al1 in which 6 randomized clinical trials (RCTs) of percutaneous coronary intervention (PCI) vs coronary artery bypass grafting (CABG) in multivessel disease (MVD) were included. There was a significant reduction in 1-year-orgreater all-cause mortality with CABG compared with PCI (risk ratio [RR], 0.73; 95% CI, 0.62-0.86; P < .001). The design of included RCTs, however, is heterogeneous: ie, using exclusively bare-metal stents (BMS) in 3 trials, drug-eluting stents (DES) in 2 trials (SYNTAX [Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery] multivessel and FREEDOM [Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease] [references 12 and 16, respectively, in the original article1]), and both BMS and DES in 1 trial (CARDia [Coronary Artery Revascularization in Diabetes] [reference 7 in the original article 1 ]). The authors stated that their aim was to “overcome the power limitation” of the existing data sets.1(p224) Pooling heterogeneous-design RCTs just merely to overcome the power limitation (thereby, probably expecting statistically significant results), however, would be inappropriate. Regarding PCI with exclusive BMS vs CABG in MVD, previous meta-analyses2,3 of 4 RCTs demonstrated no statistically significant differences in all-cause mortality. Thus, cardiac interventionalists and surgeons are now interested in the evidence of PCI with exclusive DES vs CABG in MVD.4,5 To our knowledge, however, the results of only 2 RCTs (SYNTAX multivessel and FREEDOM) of PCI with DES vs CABG in MVD have been reported to date. Yan et al4 demonstrated, in their meta-analysis of unadjusted data, that all-cause mortality at 12 months (1 RCT and 11 observational studies enrolling a total of 7754 patients [RR, 0.98; 95% CI, 0.61-1.56; P = .92]) and 24 months (5 observational studies enrolling a total of 1374 patients [RR, 0.81; 95% CI, 0.55-1.18; P = .27]) were similar between PCI with DES and CABG in MVD. On the other hand, in our meta-analysis5 we pooled 2 crude hazard ratios from 2 RCTs and 19 adjusted HRs from 11 observational studies and suggested that PCI with DES may increase 1-year-or-greater all-cause mortality by 24% over CABG in MVD (hazard ratio, 1.24; 95% CI, 1.02-1.50; P = .03). To determine whether PCI with DES increases all-cause mortality
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over CABG in MVD, however, a greater number of RCTs would be required. Hisato Takagi, MD, PhD Takuya Umemoto, MD, PhD; for the ALICE Group Author Affiliations: Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan. Corresponding Author: Hisato Takagi, MD, PhD, Department of Cardiovascular Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan ([email protected]). Conflict of Interest Disclosures: None reported. Group Information: Members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group include Hisato Takagi, MD, PhD; Taku Watanabe, MD; Yusuke Mizuno, MD; Norikazu Kawai, MD; and Takuya Umemoto, MD, PhD. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230. 2. Takagi H, Kawai N, Umemoto T. Meta-analysis of four randomized controlled trials on long-term outcomes of coronary artery bypass grafting versus percutaneous coronary intervention with stenting for multivessel coronary artery disease. Am J Cardiol. 2008;101(9):1259-1262. 3. Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118(11):1146-1154. 4. Yan TD, Padang R, Poh C, et al. Drug-eluting stents versus coronary artery bypass grafting for the treatment of coronary artery disease: a meta-analysis of randomized and nonrandomized studies. J Thorac Cardiovasc Surg. 2011;141(5): 1134-1144. 5. Takagi H, Manabe H, Umemoto T. The Gordian knot of revascularization for multivessel coronary artery disease. J Thorac Cardiovasc Surg. 2011;142(1):241243.
To The Editor In a meta-analysis from 6 randomized clinical trials (RCTs), Sipahi et al1 reported 4.1 years’ outcome of 6055 patients randomized to percutaneous coronary interventions (PCIs) either with bare-metal stents (BMS) or drug-eluting stents (DES) vs coronary artery bypass graft (CABG) in multiple vessel disease. The authors concluded that CABG leads to a significant reduction in long-term mortality, myocardial infarction, and repeat revascularization procedures independently of diabetic status without differences in nonfatal stroke. Trial selection was made according to the number of stents and arterial conduits used in PCI/CABG arms. However, in the Estudio Randomizado Argentino Angioplastia vs Cirugia (ERACI) II trial, which was excluded,2 BMS were used in all patients and arterial conduits in 88.5% of patients, which is not significantly different from other BMS and CABG trials.1 In ERACI II, a lower incidence of death and myocardial infarction with PCI was observed in the first year and an advantage remained at 5 years. A meta-analysis of the 4 RCT comparing BMS vs CABG3 found almost identical survival (8.5% and 8.2%, respectively; P = .74); furthermore, in patients with diabetes, the survival for a composite of death, MI, and stroke were similar (21.4% [BMS] and 20.9% [CABG]; P = .79). There have been 8 RCTs that compared PCI either with BMS or DES vs CABG—2 of them were not included2,4 and in 1 trial the authors reported incomplete and underpowered data.1 If we pool the results from the 8 RCTs jamainternalmedicine.com
(7468 patients), mortality between PCI and CABG in a nondiabetic population remains similar (risk ratio [RR], 1.03; 95% CI, 0.77-1.37) and the only survival advantage with CABG is in a diabetic population (RR, 0.67; 95% CI, 0.52-0.86), despite an increased risk of nonfatal stroke (RR, 1.72; 95% CI, 1.18-2.53). As Sipahi et al1 pointed out, it is not certain that latestgeneration DES will reduce the incidence of death compared with the first generation; however, we also understand that when comparing late outcomes from studies of BMS, DES, and CABG, the only advantage of first-generation DES over BMS is a reduction in target vessel revascularization, with the penalty of an increase incidence of death, myocardial infarction, and stent thrombosis.5 Finally, taking into account that only a few RCTs comparing PCI with stents vs CABG were conducted, it is important that pooled data should include all of them. In summary, after the analysis of the results from the 8 trials, we must state that survival advantage with CABG was seen only in patients with diabetes. Alfredo E. Rodriguez, MD, PhD Carlos Fernandez-Pereira, MD, PhD Juan Mieres, MD Author Affiliations: Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine, Buenos Aires, Argentina. Corresponding Author: Alfredo E. Rodriguez MD, PhD, Cardiac Unit, Otamendi Hospital, Buenos Aires School of Medicine, Callao 1441, 4B Buenos Aires, Argentina ([email protected]). Conflict of Interest Disclosures: None reported. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230. 2. Rodriguez AE, Baldi J, Fernández Pereira C, 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(4):582-588. 3. Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118(11):1146-1154. 4. Kamalesh M, Sharp TG, Tang XC, et al; VA CARDS Investigators. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol. 2013;61(8):808-816. 5. Rodriguez AE, Maree AO, Mieres J, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry. Eur Heart J. 2007;28 (17):2118-2125.
In Reply Regarding our meta-analysis examining the effects of bypass grafting vs stenting in patients with multivessel coronary disease,1 Takagi et al challenge our results by stating that the included trials were heterogeneous because some of them used bare-metal stents (BMS) and others used drug-eluting stents (DES). I disagree. Bare-metal stents and DES are homogenous in the sense that they do not have different survival rates, which was the main outcome of interest in our metaanalysis. Moreover, our subgroup analyses presented in our article show that stents lead to higher mortality regardless of whether they are BMS or DES, with an interaction P value of JAMA Internal Medicine June 2014 Volume 174, Number 6
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.56 for the type of stent used. Takagi et al also suggest that DES and bypass have similar mortality rates, referring to an obsolete meta-analysis that did not include the FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial2 or the long-term follow-up of SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial,3 the only 2 major randomized trials comparing DES with coronary artery bypass graft (CABG) in this setting. Instead, this meta-analysis by Yan et al4 included 11 observational studies, the results of which contradict substantially with gold-standard evidence from randomized trials and therefore are misleading. Rodriguez et al assert that we neglected to include 2 additional clinical trials in our meta-analysis, namely the Estudio Randomizado Argentino Angioplastia vs Cirugia (ERACI) II5 and the Coronary Artery Revascularization in Diabetes (VA CARDS)6 trials, and our results may therefore not be reliable. The ERACI-II trial from South America was a study with substandard clinical practice, with the lowest reported rate of arterial graft and stent use and the highest early surgical mortality among comparable trials.5 The trial did not meet the “>90% arterial graft use” and “>1 stent use in at least 70% of the cases” criteria for inclusion into meta-analysis and was therefore excluded from our meta-analysis.1 Nevertheless, we had stated the following in our article: “One well-known clinical trial from South America did not meet the study inclusion criteria because the frequency of the use of arterial grafts in the CABG arm and the frequency of stent use in the PCI [percutaneous coronary intervention] arm of this trial were too low.”1(p227) On the other hand, the results of the VA CARDS study became available in February 2013, after we performed our final literature search in December 2012, as stated in our article. VA CARDS is a prematurely stopped clinical trial enrolling only 25% of the intended sample size (N = 198). 6 Nevertheless, in this small trial, all-cause mortality was 5.0% for CABG and 21% for PCI (hazard ratio, 0.30; 95% CI, 0.110.80), supporting our main finding of increased mortality with stenting in multivessel coronary disease. In addition, Rodriguez et al claim that the superior survival with CABG is limited to patients with diabetes. I disagree. Our subgroup analysis of trials mostly including patients without diabetes shows a statistically significant reduced mortality with CABG compared with stenting (meta-analytic risk ratio, 0.72; 95% CI, 0.58-0.89 [P = .003]), with an interaction P value of .80 for comparison of effect in patients with diabetes vs patients without diabetes.1 Ilke Sipahi, MD
2. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. 3. Kappetein AP, Feldman TE, Mack MJ, et al. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J. 2011;32 (17):2125-2134. 4. Yan TD, Padang R, Poh C, et al. Drug-eluting stents versus coronary artery bypass grafting for the treatment of coronary artery disease: a meta-analysis of randomized and nonrandomized studies. J Thorac Cardiovasc Surg. 2011;141(5): 1134-1144. 5. Rodriguez AE, Baldi J, Fernández Pereira C, 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(4):582-588. 6. Kamalesh M, Sharp TG, Tang XC, et al; VA CARDS Investigators. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol. 2013;61(8):808-816.
Did Extra Resources or the Medical Home Model Improve Care? To the Editor In their study of the pilot program of the Rhode Island Chronic Care Sustainability Initiative, Rosenthal et al1 attributed the minimal (and with 1 exception, nonsignificant) improvements they observed to a specific model, the patientcentered medical home. In an accompanying Invited Commentary, Grumbach2 urges an even more positive interpretation of these results; he argues for the widespread adoption of the patient-centered medical home model.2 Both the study and the commentary ignore the extra $2 million (approximately $45 000 per physician) that insurers provided to the patient-centered medical home practices (but not to controls). Perhaps extra resources for primary care, not the adoption of the patient-centered medical home model per se, are what is important. David U. Himmelstein, MD Steffie Woolhandler, MD, MPH Author Affiliations: City University of New York, School of Public Health, New York. Corresponding Author: David U. Himmelstein, MD, City University of New York, School of Public Health, 255 W 90th St, Apt 12A, New York, NY 10024-1152 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Rosenthal MB, Friedberg MW, Singer SJ, Eastman D, Li Z, Schneider EC. Effect of a multipayer patient-centered medical home on health care utilization and quality: the Rhode Island chronic care sustainability initiative pilot program. JAMA Intern Med. 2013;173(20):1907-1913. 2. Grumbach K. The patient-centered medical home is not a pill: implications for evaluating primary care reforms. JAMA Intern Med. 2013;173(20):1913-1914.
Author Affiliations: Department of Cardiology, Acibadem University Medical School, Istanbul, Turkey; Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Corresponding Author: Ilke Sipahi, MD, Department of Cardiology, Acibadem University Medical School, Acibadem Maslak Hospital, Buyukdere Cad 40, 34457 Istanbul, Turkey ([email protected]). Conflict of Interest Disclosures: None reported. 1. Sipahi I, Akay MH, Dagdelen S, Blitz A, Alhan C. Coronary artery bypass grafting vs percutaneous coronary intervention and long-term mortality and
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morbidity in multivessel disease: meta-analysis of randomized clinical trials of the arterial grafting and stenting era. JAMA Intern Med. 2014;174(2):223-230.
In Reply It is possible that the additional funds provided to practices in the patient-centered medical home pilot had a direct effect on the study outcomes that was not mediated by other changes. The establishment of a patient-centered medical home involves multiple changes to a practice. Thus, studying many variations of the changes would be needed to isolate the contribution of a single component, such as increased payments. We are unaware of evidence that increasing payments
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