Costs of Periprocedural Complications in Patients Treated with Transcatheter Aortic Valve Replacement: Results from The PARTNER Trial Suzanne V. Arnold, MD on behalf of The PARTNER Trial Investigators and The PARTNER Publications Office ACC 2014 | Washington D.C. | March 30, 2014

Disclosures: None

Background Transcatheter aortic valve replacement (TAVR) improves survival and quality of life compared with nonsurgical therapy in patients with severe aortic stenosis TAVR is associated with high in-hospital and long- term costs A formal economic evaluation demonstrated that the benefits of TAVR were achieved at an acceptable incremental cost to society Reynolds et al. Circulation. 2012;125:1102-9.

Background With any emerging technology, complications should decrease with greater operator and site experience as well as improved devices Since complications were not rare in PARTNER, the costs of treating complications could have substantially impacted the overall cost of TAVR

Study Goal To estimate the incremental cost of specific peri-procedural complications of TAVR To estimate the contribution of peri- procedural complications to the overall cost of TAVR in The PARTNER Trial This will allow us better understand the potential economic benefits of avoiding such complications in the future and their impact on the cost-effectiveness of this rapidly evolving procedure.

Methods Patient Population As-treated TAVR patients in PARTNER I Cohorts A & B with billing data available Costs U.S. health care perspective 2010 U.S. dollars Combination of hospital billing data and resource- based accounting methods

Peri-Procedural Complications Death CVA major and minor Myocardial infarction Vascular complication Renal insufficiency serum creatinine >3 mg/dL Renal failure need for dialysis Major bleeding Arrhythmia high-degree AV block, atrial fibrillation or flutter, or ventricular tachycardia New permanent pacemaker Repeat TAVR Surgical AVR Adjudicated by a centralized, clinical events committee

Methods: Statistical Analysis Incremental costs and LOS of each complication, independent of demographic and clinical factors and other complications Series of models to identify patient predictors of complications, patient predictors of costs in patients without complications, potential interactions Saturated model included all complications Reduced model identified only complications significantly associated with costs (or LOS) Considered both log-transformed and untransformed costs

Results Patient Population Enrolled in PARTNER N=1057 Mean age: 84 years 47% female Mean AVA: 0.66 cm2 95% NYHA III-IV TAVR Patients N=519 –113 patients without billing data Billing Data Available N=406 No Complications N=225 ≥1 Complication N=181 (45%) 1 Complication N=79 (20%) 2 Complications N=36 (9%) ≥ 3 Complications N=66 (16%)

Results: Table 1 Characteristic Complication n=181 No Complication n=225 p-value Age (years) 84.4 ± 6.5 82.8 ± 7.4 0.022 Female 54% 41% 0.008 Prior bypass surgery 32% 47% 0.002 Peripheral vascular disease 38% 0.057 6MWT attempted 53% 63% 0.050 6MWT distance (m) 140 ± 89 158 ± 116 0.216 Aortic valve area (cm2) 0.64 ± 0.18 0.67 ± 0.21 0.074 STS predicted mortality (%) 11.9 ± 4.5 11.4 ± 3.8 0.262 Cohort B 39% 22% <0.001 Transfemoral approach 79% 80% 0.786

Complication Rates With Major Bleeding 7.1% 0.5%

Unadjusted Costs of Complications Mean cost for the initial hospitalization was $78,282 ± 40,790 ($47,322 excluding the valve) and the mean LOS was 10.3 days Patients with a complication had higher costs and longer LOS compared with those who did not Unadjusted incremental cost of $33,196 Unadjusted incremental LOS of 6.6 days

Adjusted Incremental Costs *Adjusted for age, sex, prior bypass surgery, peripheral vascular disease, diabetes, and STS mortality risk score; R2=0.41

Adjusted Incremental Costs *Adjusted for age, sex, prior bypass surgery, peripheral vascular disease, diabetes, and STS mortality risk score; R2=0.41

Adjusted Incremental LOS *Adjusted for age, sex, prior bypass surgery, peripheral vascular disease, diabetes, and STS mortality risk score; R2=0.29

Attributable Costs and LOS Attributable costs and LOS were calculated by multiplying the independent cost of the event from the regression model coefficients by its frequency in the study population This allows us to better understand the contribution of specific complications to the overall cost and LOS for the patients in PARTNER

Incremental Cost of Complication Frequency of Complication in PARTNER Attributable Costs Complication Incremental Cost of Complication Frequency of Complication in PARTNER Attributable Cost Death $42,008 4.9% $2,069 Major stroke $16,272 3.2% $521 Major bleeding $32,869 9.9% $3,238 Renal failure $68,051 2.2% $1,509 Arrhythmia $16,067 $514 Repeat TAVR $119,905 0.5% $591 Surgical AVR $26,070 1.7% $449 Total cost of complications  $8,892

Incremental LOS of Complication Frequency of Complication in PARTNER Attributable LOS Complication Incremental LOS of Complication Frequency of Complication in PARTNER Attributable LOS Death 4.3 4.9% 0.2 Major vascular + major bleed 4.0 7.1% 0.3 Major vascular - major bleed -1.4 4.4% -0.1 Minor vascular + major bleed 2.6 0.5% 0.0 Minor vascular - major bleed 1.7 7.4% 0.1 Major bleeding - vascular 17.4 2.2% 0.4 Renal failure 18.3 Arrhythmia 16.3% 0.7 Total LOS impact of complications  2.0 days

Costs and LOS of TAVR

Limitations Cost data were available for only 406 patients, which limits our ability to obtain precise estimates of the costs associated with rare complications These will need to be examined in larger datasets All patients were enrolled in a clinical trial, representing the earliest experience with TAVR at most sites Should have primarily affected rates of complications and the costs of uncomplicated hospitalizations Complications were defined by PARTNER Trial protocol, prior to VARC publication

Conclusions Peri-procedural complications were common and associated with substantial costs and increased LOS both on a per event basis (i.e., incremental cost or LOS) as well as on a per hospitalization basis (i.e., attributable cost or LOS) Bleeding, death, and post-procedure renal failure led to the greatest increases in overall costs Interventions targeted to reduce these complications would be expected to yield the greatest benefit in terms of improving the cost-effectiveness of TAVR

Conclusions Complications accounted for nearly 20% of non- implant related hospital costs Since ~80% of hospitalization costs were not related to complications, reductions in the cost of uncomplicated TAVR will also be necessary to optimize the value of the technology Either by reducing post-procedure LOS or through a “minimalist approach” to the implant procedure

Thank you

ADDITIONAL SLIDES

Complications Definitions Stroke (major) Focal neurologic deficit ≥24 hours or focal neurologic deficit lasting <24 hours with imaging findings of acute infarction or hemorrhage Modified Rankin Scale of ≥2 at ≥30 days after Stroke (minor) Acute stroke with Modified Rankin Scale of 0-1 at ≥30 days Renal insufficiency serum creatinine >3 mg/dL Renal failure need for renal replacement therapy Arrhythmia High-degree AV block, atrial fibrillation or flutter, or ventricular tachycardia Permanent pacemaker Arrhythmia requiring permanent pacemaker placement Repeat TAVR Implantation of new percutaneous aortic valve Surgical AVR Conversion to surgical aortic valve replacement

Complications Definitions Major bleeding Clear site of bleeding that met any one of the following: (1) caused death, (2) prolonged hospitalization ≥24 hours due to treatment of bleeding, (3) required pericardiocentesis or procedure for repair or hemostasis, (4) caused permanent disability (e.g. blindness, paralysis, hearing loss), (5) required transfusion of >3 units of blood within 24 hr period Myocardial infarction (1) acute MI demonstrated by autopsy, (2) emergent PCI or thrombolytics for acute STEMI, (3) peri-procedural MI (≤7 days post index procedure): new pathologic Q waves in ≥2 leads with elevation of CK-MB; or documented signs or symptoms of ischemia or new ischemic changes on ECG and CK-MB elevation >10xULN. (4) non-procedural MI (>7 days): new pathologic Q waves in ≥2 contiguous leads with elevation of CK, CK-MB or troponin and signs or symptoms of myocardial ischemia; or elevation of CK >2xULN with elevation of CK-MB or troponin and signs or symptoms of myocardial ischemia.

Complications Definitions Vascular complication (major) (1) any thoracic aortic dissection, (2) access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, or compartment syndrome) leading to either death, need for significant blood transfusions (> 3 units), unplanned percutaneous or surgical intervention, or irreversible end-organ damage (e.g., hypogastric artery occlusion causing visceral ischemia or spinal artery injury causing neurologic impairment), (3) distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage, or (4) left ventricular perforation. Vascular (minor) Vascular complication not meeting major criteria

Methods: Statistical Analysis Unadjusted hospital cost and LOS for all patients and for the complication categories are presented as mean ± standard deviation Unadjusted incremental costs and LOS of each complication: Mean cost or LOS of patients with complication – mean cost or LOS of patients without complication

Adjusted Incremental Costs Step 1: Identify patient factors associated with complications Logistic regression model with backwards selection p<0.1 with “any complication” as the dependent variable Step 2: Identify patient factors associated with costs in patients without complications GLM model with log-link with backward selection p<0.1 with costs as the dependent variable

Adjusted Incremental Costs Step 3: Independent predictors of costs reduced Linear regression model including age, sex, all covariates identified in Steps 1 & 2 all forced in Peri-procedural complications were included with backwards selection p<0.1 Interactions between vascular complications and bleeding and between arrhythmias and pacemaker were considered and retained if p<0.1 Step 4: Independent predictors of costs saturated Repeat Step 3 with all peri-procedural complications

Unadjusted Incremental Costs

Adjusted Incremental LOS *Adjusted for age, sex, prior bypass surgery, peripheral vascular disease, diabetes, and STS mortality risk score