Appropriate patient selection or health care rationing Appropriate patient selection or health care rationing? Lessons from surgical aortic valve replacement in the Placement of Aortic Transcatheter Valves I trial  Wilson Y. Szeto, MD, Lars G. Svensson, MD, PhD, Jeevanantham Rajeswaran, PhD, John Ehrlinger, PhD, Rakesh M. Suri, MD, Craig R. Smith, MD, Michael Mack, MD, D. Craig Miller, MD, Patrick M. McCarthy, MD, Joseph E. Bavaria, MD, Lawrence H. Cohn, MD, Paul J. Corso, MD, Robert A. Guyton, MD, Vinod H. Thourani, MD, Bruce W. Lytle, MD, Mathew R. Williams, MD, John G. Webb, MD, Samir Kapadia, MD, E. Murat Tuzcu, MD, David J. Cohen, MD, Hartzell V. Schaff, MD, Martin B. Leon, MD, Eugene H. Blackstone, MD  The Journal of Thoracic and Cardiovascular Surgery  Volume 150, Issue 3, Pages 557-568.e11 (September 2015) DOI: 10.1016/j.jtcvs.2015.05.073 Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Survival after AVR in PARTNER-IA, referenced to expected survival in an age-, sex, and race-matched US population. Each symbol represents a death. Vertical bars are confidence limits of nonparametric Kaplan-Meier estimates equivalent to ±1 standard error, and the solid line enclosed within a dashed 68% confidence band equivalent to ±1 standard error represents parametric estimates. Numbers below the horizontal axis are patients remaining at risk. Dash-dot-dash line represents age-, sex-, and race-matched expected survival in the US population. Inset shows instantaneous risk of death (hazard function) referenced to an age-, sex, and race-matched US population. AVR, Aortic valve replacement. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Random Forest for Survival partial dependency plots of 1-year predicted survival. Random Forest for Survival is a completely nonparametric method for survival analysis that, in this case, was based on all 102 variables used in the multivariable parametric analysis.15,16,E11 Each graph presents a risk-adjusted estimate of the independent effect of a continuous variable identified as a risk factor in the parametric analysis; however, these depictions make no model assumptions. Circles and solid lines represent risk-adjusted estimates, and dashed lines indicate the 68% confidence band equivalent to ±1 standard error. A, Albumin (g/dL). B, Aortic clamp time (min). C, Body mass index (kg/m2). D, Effective prosthetic aortic valve orifice area at hospital discharge by echocardiography (cm2/m2). The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Unadjusted Kaplan-Meier estimates of survival after surgical AVR. Each symbol represents a death. Vertical bars are 68% confidence limits equivalent to ±1 standard error. Numbers below the horizontal axis are patients remaining at risk. A, Survival stratified by prior CABG (squares) or not (circles). B, Survival stratified by history of cancer (squares) or not (circles). C, Survival stratified by degree of prosthesis–patient mismatch: none/mild (circles), moderate (squares), severe (triangles). AVR, Aortic valve replacement; CABG, coronary artery bypass grafting. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Profile of patients who are likely to have worse 1-, 2-, and 3-year survival after surgical AVR than after contemporary standard therapy (“natural history”). These curves are solutions from the multivariable equations in Table E2. Values for the 3 patients illustrated are in the above table. A, A 70-year-old obese patient with low albumin and considerable left ventricular hypertrophy. Note that after a prolonged early phase of surgical risk, long-term risk is better than standard therapy and survival curves cross. B, A 90-year-old patient with moderate symptoms, albumin 3.04 g/dL, and a left ventricular mass index of only 70 g/m2. Note that to 4 years, survival after surgical AVR is predicted to be worse than after standard therapy. C, An 86-year-old patient with cardiac cachexia, mixed severe aortic stenosis and aortic regurgitation, and ischemic heart disease previously treated with CABG. This patient is predicted to do well after surgery, but then to have elevated mid-term risk. Survival with standard therapy also is reasonable. Thus, subjecting the patient to surgical AVR is not expected to increase the patient's longevity. AVR, Aortic valve replacement; BMI, body mass index; NYHA, New York Heart Association; AR, aortic regurgitation; AS, aortic stenosis; CABG, coronary artery bypass grafting; BAV, balloon aortic valvotomy; HCT, hematocrit; WBC, white blood cell; LV, left ventricle. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 CONSORT-style diagram of PARTNER-I trial. SAVR, Surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E2 Observed versus expected operative mortality over the spectrum of expected risk. Top smoothed curve depicts the density of patients along the scale of expected probability of operative mortality. Symbols represent observed mortality within deciles of expected mortality. Dashed line is line of identity. Note that observed risk was worse than expected at both lower and upper ends of the spectrum of expected mortality, and better or equivalent in the center of the distribution of risk values (∼8%-11%). The refinement parameterE13,E14 estimate is 0.21, suggesting that observed responses varied more than the national average. However, the estimated standard error of this parameter is 0.37. This may be due to smaller sample size or few events. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E3 Observed versus expected occurrence of stroke over the spectrum of expected risk. Format is as in Figure E2. Note that there was little correlation between observed and expected occurrence. The refinement parameter estimate is 0.24 ± 0.89. Interpretation is similar to that of Figure E2. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E4 Cumulative distribution of predicted probability of operative mortality using contemporary STS models (blue curve to left) versus the STS score used in the PARTNER-I trial. Predicted mortality calculated from contemporary STS models3,4 was lower than the PARTNER-I risk score, which was based on an older STS model.7 STS, Society of Thoracic Surgeons; PARTNER, Placement of Aortic Transcatheter Valves. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E5 Observed versus expected renal failure over the spectrum of expected risk. Format is as in Figure E2. In general, renal failure occurred less often than expected, except for the lowest risk decile. The refinement parameter estimate is 0.87 ± 0.41, a somewhat larger standard error for a point estimate of this magnitude. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E6 Observed versus expected prolonged postoperative length of stay over the spectrum of expected risk. Format is as in Figure E2. Patients had a prolonged postoperative length of stay more often than expected. The refinement parameter estimate is 0.60 ± 0.29, a somewhat larger standard error for a point estimate of this magnitude. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E7 Partial dependency plot of 1-year survival and age at surgical AVR. Squares and solid line represent risk-adjusted estimates, and dashed lines indicate the 68% confidence band. Older age was not a reliable risk factor in the parametric model; nevertheless, this risk-adjusted graph indicates that patients aged more than approximately 88 years are at progressively higher risk of 1-year mortality than younger patients. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E8 Observed survival after surgical AVR compared with that predicted for comparable PARTNER-IB standard therapy patients (based on Table E2). A, Survival comparisons. For surgical AVR, each symbol represents a death by the Kaplan-Meier estimator, vertical bars represent 68% confidence limits of these nonparametric estimates, and smooth solid curve and 68% confidence band represent parametric estimates. Standard therapy curve and its confidence limits represent the ensemble average of individual survival curves generated for each AVR patient based on their characteristics and the multivariable equation for survival of patients receiving standard therapy. B, Time-related area between survival curves shown in A, expressed as time-related lifetime gained by AVR compared with standard therapy. By 3 years of follow-up, surgical AVR, on average, added 0.75 years to patients' lives. AVR, Aortic valve replacement. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E9 Nomograms of survival after surgical AVR based on 3 different risk profiles noted in the table and the multivariable model for death (Table 4). AVR, Aortic valve replacement; BMI, body mass index; CABG, coronary artery bypass grafting. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E10 Cumulative distribution of difference in survival between surgical AVR and standard therapy. Note that because of prolonged early risk, more surgical patients have worse survival than standard therapy patients at 1 year (red line going to the left of 0), but few have worse survival at 2 (brown line) and 3 (blue line) years. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure E11 Paradoxical apparent increasing survival benefit of AVR in older patients, referenced to the US population. A, Survival after AVR stratified by age groups in a 9-institution study of 13,258 patients.5 Of these, 1700 were aged 50 years or less (circles), 8562 were aged 50 to 75 years (squares), and 2996 were aged 75 years or more (triangles). Each symbol represents a death. Vertical bars are confidence limits equivalent to ±1 standard error, and the solid lines represent parametric estimates. Numbers below horizontal axis are patients remaining at risk. Dash-dot-dash lines represent age-, sex-, and race-matched expected survival in the US population. B, Instantaneous risk of death (hazard function) stratified by age groups in the 9-institution study.5 Solid lines are point estimates, and dash-dot-dash lines are risk of death in the US population. C, Survival after AVR at a single institution.E15 Survival of younger patients was worse than that of the general population, but in elderly patients it was commensurate. Format is as in Figure E11, A. D, Instantaneous risk of death after AVR at a single institution.E15 Format is as in Figure E11, B. AVR, Aortic valve replacement. The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Survival after AVR in PARTNER-IA referenced to expected survival in an age-, sex-, and race-matched US population (dash-dot-dash line). The Journal of Thoracic and Cardiovascular Surgery 2015 150, 557-568.e11DOI: (10.1016/j.jtcvs.2015.05.073) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions