Long Term Clinical Outcomes Following Drug-Eluting and Bare Metal Stenting in Massachusetts Laura Mauri, MD, MSc; Treacy Silverstein, B.Sc.; Ann Lovett, R.N., M.A.; Frederic S. Resnic, M.D., M.Sc.; and Sharon-Lise T. Normand, Ph.D. Brigham and Women’s Hospital, Harvard Medical School, Harvard School of Public Health Boston, Massachusetts Study funding from Massachusetts Department of Public Health November 4, 2007 American Heart Association Scientific Sessions

Drug-Eluting and Bare Metal Stenting in Massachusetts Background The data reported for available DES in the US indicate that these devices are important advancements by reducing the need for revascularization Long term clinical outcomes remain uncertain following DES use compared to BMS use in the general population

Drug-Eluting and Bare Metal Stenting in Massachusetts Background Randomized trials of DES have been limited in power to detect rare events and in generalizability to a broad range of practice patterns and patient populations Observational studies have been limited by possible residual selection bias and incomplete follow-up Studies comparing DES and BMS use have been performed in populations with restricted DES use

Drug-Eluting and Bare Metal Stenting in Massachusetts Objectives – To evaluate whether the use of DES is associated with increased rates of death or MI compared with BMS in general use representative of current US practice – To confirm whether the use of DES is associated with reduction in revascularization compared with BMS in general use representative of current US practice

Drug-Eluting and Bare Metal Stenting in Massachusetts Methods: Data source Mass-DAC All PCI in Massachusetts (>25000 stent procedures per year) Massachusetts Dept. of Public Health mandatory reporting Clinical and procedural factors collected prospectively using ACC NCDR instrument Mortality from hospital record, Mass. vital statistics and Social Security website Myocardial infarction and revascularization from Mass-DAC PCI and CABG data merged with hospital discharge data Index procedures performed April 2003 – September 2004 Non-Massachusetts residents excluded

Drug-Eluting and Bare Metal Stenting in Massachusetts Methods: Propensity Score Matched Analysis Patients assigned to DES or BMS groups based on treatment at index procedure Propensity score matching – Logistic regression to predict DES treatment by patient, procedural, hospital variables – Caliper matching of DES to BMS patients Primary outcomes: Matched risk differences for mortality, myocardial infarction and revascularization rates at 2 years Paired t-test, 2-sided alpha 0.05

Drug-Eluting and Bare Metal Stenting in Massachusetts 7 N=21,019 PCI Patients in Massachusetts April 1, September 30, 2004 Complete 2 year follow-up N=21,019 PCI Patients in Massachusetts April 1, September 30, 2004 Complete 2 year follow-up 1,538 non-residents excluded 564 adminstrative files not linkable N=18,917 PCI Patients N=18,917 N=11,516 DES Only Patients N=11,516 N=6,210 BMS Only Patients N=6,210 1,191 patients with both stent types excluded

35% BMS 65% DES 72% sirolimus, 28% paclitaxel eluting stents

Drug-Eluting and Bare Metal Stenting in Massachusetts Patient Characteristics before Match DES (n = 11516) BMS (n =6210) p value Age – yrs 64.4 ± ±13.0 <0.001 Female (%) Diabetes Mellitus (%) Insulin Dependent Diabetes Insulin Dependent Diabetes Hyperlipidemia (%) <0.001 Hypertension (%) <0.001 Current Smoker (%) <0.001 Prior PCI (%) Prior MI (%) Prior CABG (%) <0.001

Drug-Eluting and Bare Metal Stenting in Massachusetts Patient Characteristics before Match DES (n = 11516) BMS (n =6210) p value Congestive Heart Failure (%) <0.001 Chronic Lung Disease (%) History of Neoplasm (%) <0.001 History of GI Bleeding (%) <0.001 Chronic Renal Insufficiency (%) Dialysis (%) Clopidogrel Pretreatment (%) GpIIbIIIa Inhibitor Pretreatment (%) <0.001

Drug-Eluting and Bare Metal Stenting in Massachusetts Procedure Indications before Match DES (n = 11516) BMS (n =6210) p value Procedure status <0.001 Urgent (%) Urgent (%) Emergency/Salvage (%) Emergency/Salvage (%) Indication Non-ST elevation MI (%) Non-ST elevation MI (%) ST elevation MI (%) ST elevation MI (%) <0.001 Treatment for restenosis <0.001 Atheroablative therapy Thrombectomy3.17.7<0.001 Brachytherapy

Drug-Eluting and Bare Metal Stenting in Massachusetts Procedural Characteristics before Match DES (n = 11516) BMS (n =6210) p value Number of vessels treated 1.19 ± ± 0.36 <0.001 Number of lesions treated 1.44 ± ± 0.67 <0.001 Left anterior descending (%) Left anterior descending (%) <0.001 Circumflex (%) Circumflex (%) <0.001 Right coronary (%) Right coronary (%) <0.001 Left main (%) Left main (%) Saphenous vein graft (%) Saphenous vein graft (%)4.49.1<0.001 Arterial graft (%) Arterial graft (%)

Drug-Eluting and Bare Metal Stenting in Massachusetts, Unadjusted 2-Year Outcomes BMS(n=768/6210)DES(n=769/11516) 12.4% 6.7% Mortality P < RevascularizationDES(n=2297/11516)BMS(n=1488/6210) P < % 20.0% MIDES(n=1049/11516)BMS(n=754/6210) P < % 9.1 %

n=5441 DES n=5441 BMS Propensity matched pairs 63 variables

Drug-Eluting and Bare Metal Stenting in Massachusetts Patient Characteristics after Match DES (n = 5441) BMS (n =5441) % SD Age – yrs Female (%) Diabetes Mellitus (%) Hyperlipidemia (%) Hypertension (%) Current Smoker (%) Prior PCI (%) Prior MI (%) Prior CABG (%) *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

Drug-Eluting and Bare Metal Stenting in Massachusetts Patient Characteristics after Match DES (n = 5441) BMS (n =5441) %SD Congestive Heart Failure (NYHA 3-4) Chronic Lung Disease (%) History of Neoplasm (%) History of GI Bleeding (%) Chronic Renal Insufficiency (%) Dialysis (%) Clopidogrel Preadminstered (%) GpIIbIIIa Inhibitor Preadminstered (%) *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

Drug-Eluting and Bare Metal Stenting in Massachusetts Procedure Characteristics after Match DES (n = 5441) BMS (n =5441) %SD Procedure status Urgent (%) Urgent (%) Emergency/Salvage (%) Emergency/Salvage (%) Indication Non-ST elevation MI (%) Non-ST elevation MI (%) ST elevation MI (%) ST elevation MI (%) Treatment for restenosis Atheroablative therapy Thrombectomy Brachytherapy *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

Drug-Eluting and Bare Metal Stenting in Massachusetts Procedural Characteristics after Match DES (n = 5441) BMS (n =5441) %SD Multilesion treatment 2 lesions 2 lesions lesions 3 lesions lesions 4 lesions Target vessel Target vessel Left circumflex Left circumflex Right coronary Right coronary Left main Left main Saphenous vein graft Saphenous vein graft Arterial graft Arterial graft *%SD = Percent Standardized Difference Values <10% reflect well-matched characteristics

Drug-Eluting and Bare Metal Stenting in Massachusetts, Primary Results Propensity Matched 2-Year Outcomes BMS(n=647/5441)DES(n=514/5441) 11.9% 9.4% Mortality P < RevascularizationDES(n=1095/5441) BMS(n=1303/5441) P < % 20.1% MIDES(n=590/5441)BMS(n=643/5441) P = % 10.8%  = -3.8% [-5.4,-2.3]  = -1.0% [-2.2,+0.2]  = -2.4% [-3.6,-1.3]

Cumulative Incidence 10% 20% 30% 0 0% (At risk) Days DES5,4415,3385,2195,123 BMS5,4415,2795,1054,995 DES n=5,441 BMS n=5,441 Time after Initial Procedure (days) 11.9% 9.4% Drug-Eluting and Bare Metal Stenting in Massachusetts 2-Year Outcome in Matched Patients Mortality

(At risk) Days DES5,4415,1034,8964,729 BMS5,4415,0294,7474,569 DES n=5,441 BMS n=5,441 Time after Initial Procedure (days) 12.3% 11.2% Drug-Eluting and Bare Metal Stenting in Massachusetts 2-Year Outcome in Matched Patients MI Cumulative Incidence 10% 20% 30% 0 0%

(At risk) Days DES5,4414,9404,5814,309 BMS5,4414,9094,3033,992 DES n=5,441 BMS n=5,441 Time after Initial Procedure (days) 25.1% 20.9% Drug-Eluting and Bare Metal Stenting in Massachusetts 2-Year Outcome in Matched Patients Revascularization Cumulative Incidence 10% 20% 30% 0 0%

Drug-Eluting and Bare Metal Stenting in Massachusetts Matched Risk Differences at 2 years Myocardial Infarction DES10.8% BMS11.3% Mortality DES 9.4% BMS11.9% Revascularization DES20.1% BMS23.9% Favors DES Favors BMS Risk Difference (95% CI) -5%0 5%  = -2.4% [-3.6,-1.3] p<  = -1.0% [-2.2,+0.2] p=0.11  = -3.8% [-5.4,-2.3] p<0.0001

Drug-Eluting and Bare Metal Stenting in Massachusetts Sensitivity analyses Effect of differential rates of use of DES vs BMS over time 2 day mortality difference

n=3752 DES n=3752 BMS Propensity matched pairs adjusted for time on market

Drug-Eluting and Bare Metal Stenting in Massachusetts Sensitivity Analysis 2-Year Outcomes adjusted for time on market BMS(n=439/3752)DES(n=318/3752) 11.7% 8.5% Mortality P < RevascularizationDES(n=784/3752)BMS(n=858/3752) P = % 20.9% MIDES(n=370/3752)BMS(n=422/3752) P = % 10.8%  = -1.9% [-3.9,-0.1]  = -1.4% [-2.8,0.0]  = -3.2% [-4.6,-1.8]

Drug-Eluting and Bare Metal Stenting in Massachusetts Sensitivity analyses Adjustment for time on market is consistent with results of the primary analysis – larger observed difference favoring DES for mortality 2 day mortality difference after propensity match is small 2 day mortality 0.4% vs 0.8% (DES vs BMS)  = -0.4% at 2d vs  = -2.4% at 2 y

Drug-Eluting and Bare Metal Stenting in Massachusetts Comparison with PCI Practice Patterns and Other Studies Adult population DES patients BMS patients DES(%)Studyduration Sweden 1 9 million /03-12/04 Western Denmark 2 3 million /02-6/05 Ontario 3 9 million /03-3/05 Massachusetts 6 million /03-9/04 Distinguishing features: high rate of PCI/population, high rate of DES/procedure, study sample chosen to start with introduction of DES and to end when all patients had complete 2 year follow up. 1. Lagerqvist B et al. N Engl J Med 2007;356: Lagerqvist B et al. N Engl J Med 2007;356: Jensen, LO et al. JACC 2007;50(5): Tu J et al. NEJM 2007;357:

From the Massachusetts state dataset of 21,024 PCI unique patient procedures in Massachusetts from April September 2004 with complete 2y follow-up, propensity matched analysis of 10,882 patients demonstrated: No increase in rates of death, or myocardial infarction associated with DES as compared to BMS use at 2 years. – A significantly lower mortality rate was observed for DES at 2 years, and will be monitored as follow up proceeds to 3-5 years A lower rate of revascularization in patients treated with DES compared with BMS. Drug-Eluting and Bare Metal Stenting in Massachusetts Conclusions