1. Association Between Use of Bleeding Avoidance Strategies and Risk of Periprocedural Bleeding Among Patients Undergoing Percutaneous Coronary Intervention Marso et al. JAMA 2010;303:2156-2164

2. Background Percutaneous coronary intervention (PCI) is performed approximately 1 million times annually in the United States. The safety of PCI continues to be excellent with very low rates of death, myocardial infarction (MI), and need for urgent revascularization. PCI-related bleeding occurs in approximately 2-6% of patients in national PCI databases; marked institutional variability in rates exists. Bleeding complications are associated with increased length of stay, hospital costs, and important clinical complications such as death and MI.

3. Objective To describe the use of 2 bleeding avoidance strategies1) vascular closure devices and 2) bivalirudinand associated post-PCl bleeding rates in a nationally representative PCI population. Examine clinical usage patterns of these strategies as a function of bleeding risk. Marso et al. JAMA 2010;303:2156-2164

4. Study Patients & Exclusions NCDR ® CathPCI Registry ® Patients undergoing PCI via the femoral artery Exclusion criteria: –>1 PCI procedure during same stay –Incomplete data on bleeding –PCI via radial, brachial artery –Cardiogenic shock –Missing device data –Death in cath lab –Unknown bleeding event data Marso et al. JAMA 2010;303:2156-2164

5. Candidate Bleeding Avoidance Strategies Bivalirudin Vascular closure devices Both therapies (bivalirudin + vascular closure) Marso et al. JAMA 2010;303:2156-2164

6. Bleeding Risk Strata Bleeding risk score calculated for each patient using NCDR bleeding risk model 1 Clinical elements used to calculate bleeding risk score: –STEMI/non-STEMI –Female sex –Previous CHF –No previous PCI –NYHA/CCS Class IV CHF –PVD –Age –Estimated glomerular filtration rate Marso et al. JAMA 2010;303:2156-2164 1 Mehta et al. Circ Cardiovasc Intervent 2009;2:222-229

7. Study Outcomes In-hospital bleeding according to NCDR data definition: –Requiring transfusion and/or –Prolonged hospital stay and/or –Decrease in hemoglobin >3 g/dL Marso et al. JAMA 2010;303:2156-2164

8. Statistical Analysis Patients categorized into 3 groups of bleeding risk based on NCDR bleeding risk score: –Low (<1%) –Intermediate (1-3%) –High (>3%) Propensity score matching with site adjustment using 26 clinical variables for each bleeding avoidance strategy performed to minimize confounding Population was well matched (standard difference plot on next slide) Marso et al. JAMA 2010;303:2156-2164

9. Standardized Difference Before and After Propensity Matching Marso et al. JAMA 2010;303:2156-2164

10. Study Population Marso et al. JAMA 2010;303:2156-2164

11. Patient Characteristics Total (N=1,522,935) Manual Compression (N = 529,247) Vascular Closure Devices (N=363,583) Bivalirudin N = 353,769) Both (N = 276,336) Age, mean (SD), y64.3 (12.1)63.87 (12.33)63.34 (12.26)65.43 (11.86)64.77 (11.80) Male, N (%)1,011,992 (66.5)350,424 (66.21)250,753 (68.97)225,235 (63.67)185,580 (67.16) White, N (%)1,289,673 (84.8)449,617 (85.05)301,908 (83.18)303,317 (85.82)234,831 (85.11) Height, mean (SD), cm171.30 (10.84)171.22 (10.89)171.73 (10.77)170.81 (10.90)171.50 (10.73) Weight, mean (SD), kg87.71 (20.45)87.25 (20.42)88.22 (20.28)87.29 (20.71)88.47 (20.40) Body mass index, mean (SD), kg/m 2 29.8 (6.3)29.7 (6.3)29.8 (6.2)29.8 (6.4)30.0 (6.3) Obesity, N (%)643,500 (42.25)219,470 (41.47)153,233 (42.15)150,813 (42.63)119,984 (43.42) Current CHF, N (%)136,489 (8.96)48,658 (9.19)30,799 (8.47)33,173 (9.38)23,859 (8.63) NYHA class, N (%) I480,785 (31.57)160,016 (30.24)125,209 (34.44)107,678 (30.44)87,882 (31.81) II355,937 (23.37)107,093 (20.24)79,475 (21.86)90,682 (25.64)78,687 (28.48) III415,651 (27.30)146,439 (27.67)87,352 (24.03)107,952 (30.52)73,908 (26.75) IV270,376 (17.76)115,629 (21.85)71,508 (19.67)47,412 (13.40)35,827 (12.97) All P<0.001 Marso et al. JAMA 2010;303:2156-2164

12. Patient Characteristics Total (N=1,522,935) Manual Compression (N = 529,247) Vascular Closure Devices (N=363,583) Bivalirudin (N = 353,769) Both (N = 276,336) Coronary artery disease risk factors, N (%) Diabetes509,455 (33.45)173,024 (32.69)113,130 (31.12)129,335 (36.56)93,966 (34.00) Hypertension1,190,098 (78.15)405,122 (76.55)272,906 (75.06)290,085 (82.00)221,985 (80.33) Dyslipidemia1,167,108 (76.64)392,248 (74.12)269,478 (74.12)283,174 (80.05)222,208 (80.42) Smoking, N (%) Never600,315 (38.87)196,423 (37.12)143,554 (39.49)138,026 (39.02)114,318 (41.37) Past543,091 (35.17)178,466 (33.72)121,980 (33.55)132,027 (37.32)102,545 (37.11) Current400,845 (25.96)154,297 (29.16)97,995 (26.96)83,681 (23.66)59,439 (21.51) Estimated glomerular filtration rate, mean (SD) 73.77 (29.62)73.60 (29.88)75.02 (30.48)72.46 (29.06)74.09 (28.61) Family history of coronary artery disease, N (%) 392,815 (25.80)135,320 (25.57)100,704 (27.70)86,660 (24.50)70,131 (25.38) Coronary artery disease history, N (%) PCI576,207 (37.84)182,518 (34.49)125,649 (34.56)151,835 (42.92)116,205 (42.05) CABG291,773 (19.16)98,038 (18.52)59,980 (16.50)79,189 (22.39)54,566 (19.75) Myocardial infarction427,655 (28.08)144,381 (27.28)96,191 (26.46)106,403 (30.08)80,690 (29.20) Other cardiovascular disease history, N (%) CHF136,483 (8.96)54,661 (10.33)32,255 (8.87)43,082 (12.18)28,751 (10.40) All P<0.001 Marso et al. JAMA 2010;303:2156-2164

13. Patient Characteristics Total (N=1,522,935) Manual Compression (N = 529,247) Vascular Closure Devices (N=363,583) Bivalirudin (N = 353,769) Both (N = 276,336) Cerebrovascular disease 174,811 (11.48) 60,260 (11.39) 34,638 (9.53) 48,214 (13.63) 31,699 (11.47) Peripheral vascular disease 181,787 (11.74) 65,568 (12.39) 33,064 (9.09) 50,678 (14.33) 29,477 (10.67) Previous valve surgery17,267 (1.13)5,929 (1.12)3,672 (1.01)4,505 (1.27)3,161 (1.14) Previous transplant3,463 (0.23)1,257 (0.24)732 (0.20)899 (0.25)575 (0.21) Chronic lung disease248,918 (16.35) 86,586 (16.36) 52,995 (14.58) 6,5139 (18.41) 44,198 (15.99) Renal failure83,029 (5.45)30,004 (5.67)18,028 (4.96)21,369 (6.04)13,628 (4.93) All P<0.001 Marso et al. JAMA 2010;303:2156-2164 All data are N (%)

14. Admission Characteristics Total (N=1,522,935) Manual Compression (N = 529,247) Vascular Closure Devices (N=363,583) Bivalirudin (N = 353,769) Both (N = 276,336) No symptoms196,190 (12.88)55,961 (10.57)42,224 (11.61)54,346 (15.36)43,659 (15.80) Atypical chest pain113,339 (7.44)32,570 (6.15)27,031 (7.44)27,758 (7.85)25,980 (9.40) Stable angina260,582 (17.11)73,109 (13.81)57,179 (15.73)69,093 (19.53)61,201 (22.15) Unstable angina527,624 (34.65)168,813 (31.90)113,413 (31.19)142,473 (40.27)102,925 (37.25) Non-STEMI238,305 (15.65)98,866 (18.68)64,921 (17.86)43,239 (12.22)31,279 (11.32) STEMI186,810 (12.27)99,900 (18.88)58,796 (16.17)16,843 (4.76)11,271 (4.08) PCI type Elective758,110 (49.79)220,576 (41.68)157,348 (43.28)212,562 (60.09)167,624 (60.67) Urgent553,524 (36.35)196,634 (37.16)140,023 (38.52)121,995 (34.49)94,872 (34.34) Emergency209,465 (13.76)110,990 (20.97)65,758 (18.09)19,011 (5.37)13,706 (4.96) Salvage1,662 (0.11)968 (0.18)422 (0.12)172 (0.05)100 (0.04) All P<0.001 Marso et al. JAMA 2010;303:2156-2164 All data are N (%)

15. Hospital Characteristics Total (N=1,522,935) Manual Compression (N = 529,247) Vascular Closure Devices (N=363,583) Bivalirudin (N = 353,769) Both (N = 276,336) Region, N (%) West244,853 (16.11)71,085 (13.47)73,065 (20.15)41,801 (11.83)58,902 (21.36) Northeast177,930 (11.71)56,353 (10.68)60,120 (16.58)28,392 (8.04)33,065 (11.99) Midwest505,125 (33.24)198,609 (37.63)119,220 (32.88)104,043 (29.45)83,253 (30.19) South591,568 (38.93)201,679 (38.22)110,237 (30.40)179,071 (50.68)100,581 (36.47) Community type, N (%) Rural177,441 (15.92)59,727 (15.44)54,008 (21.02)31,542 (11.48)32,164 (16.38) Urban937,476 (84.08)327,222 (84.56)202,931 (78.98)243,165 (88.52)164,158 (83.62) Profit type, N (%) Government23,838 (1.57)7,895 (1.49)4,948 (1.36)5,988 (1.69)5,007 (1.81) Private/community1,356,756 (89.09)465,238 (87.91)319,915 (87.99)318,550 (90.04)253,053 (91.57) University142,341 (9.35)56,114 (10.60)38,720 (10.65)29,231 (8.26)18,276 (6.61) Annual PCI volume, mean (SD)1095.81 (795.18) 1058.04 (704.88) 981.16 (732.27) 1303.62 (782.65) 1052.94 (678.44) Marso et al. JAMA 2010;303:2156-2164 All P<0.001

16. Bleeding Rates* Intermediate N=746,727 *NCDR bleeding risk 3% Low* N=475,152 High N=301,056 MCBCB M = Manual comp. C = Closure only B = Bival only BC = Bival+closure MCBCBMC BMC B Overall Low (<1%) Intermediate (1-3%) High (>3%) P<0.001 all intra-risk group comparisons *Overall bleeding = 30,429 (2%)

17. Treatment (N) Bleeding N (%) Odds Ratio (95% CI) NNT (95% CI) Reduction in Bleeding Events per 1,000 Patients Treated (95% CI) Manual compression508,45513,597 (2.7)1 [Reference] Vascular closure devices205,6065,050 (2.5)0.77 (0.73-0.80)148 (130-175)6.7 (5.7-7.7) Bivalirudin172,4713,224 (1.9)0.67 (0.63-0.70)118 (107-132)8.5 (7.6-9.3) Both130,3781,361 (1.0)0.38 (0.35-0.42)70 (68-74)14.2 (13.5-14.8) Total1,016,91023,232 (2.3) Estimated Bleeding ReductionsAll Patients (Propensity Adjusted) Marso et al. JAMA 2010;303:2156-2164

18. Estimated Bleeding Reductions (Propensity Adjusted) Treatment (N) Bleeding N (%) Odds Ratio (95% CI) NNT (95% CI) Reduction in Bleeding Events per 1,000 Patients Treated (95% CI) Low Risk, <1% Manual compression144,5941,320 (0.9)1 [Reference] Vascular closure devices54,217532 (1.0)1.07 (0.93-1.22)NS Bivalirudin48,378296 (0.6)0.65 (0.56-0.77)315 (247-470)3.2 (2.1-4.0) Both41,999166 (0.4)0.42 (0.34-0.51)188( 167-222)5.3 (4.5-6.0) Total289,1882,314 (0.8) Intermediate Risk, 1-3% Manual compression252,8985,722 (2.3)1 [Reference] Vascular closure devices103,0952,077 (2.0)0.76 (0.71-0.81)169 (141-217)5.9 (4.6-7.1) Bivalirudin85,8001,311 (1.5)0.69 (0.63-0.74)153 (131-187)6.5 (5.3-7.6) Both64,003573 (0.9)0.39 (0.35-0.44)80 (75-86)12.5 (11.6-13.3) Total505,7969,683 (1.9) High Risk, >3% Manual compression110,9636,555 (5.9)1 [Reference] Vascular closure devices48,2942,441 (5.1)0.79 (0.75-0.82)81 (66-109)12.3 (9.2-15.3) Bivalirudin38,2931,617 (4.2)0.67 (0.62-0.73)56 (49-66)17.9 (15.1-20.6) Both24,376622 (2.6)0.42 (0.38-0.47)33 (31-36)30.5 (27.9-32.8) Total221,92611,235 (5.1) Marso et al. JAMA 2010;303:2156-2164

19. Bleeding Avoidance Strategy Use by Pre-PCI Bleeding Risk MCBCB Low (<1%) M = Manual comp. C = Closure only B = Bival only BC = Bival+closure P<0.001 for all intra-risk group comparisons MCBCB Intermediate (1-3%) MCBCB High (>3%) Intermediate N=746,727 *NCDR bleeding risk 3% Low* N=475,152 High N=301,056 Risk-Treatment Paradox

20. Limitations Observational, non-randomized study Potential unmeasured confounding No data on activated clotting time Contraindications to use of bleeding avoidance therapies: –Bivalirudin: in the setting of other anticoagulants, PCI of chronic total occlusion –Vascular closure devices: high risk anatomy Data insufficient to warrant abandoning use of manual compression in favor of vascular closure devices: –Adequately powered randomized trial assessing bleeding endpoints is needed

21. Conclusions In 1.5 million PCI patients in the NCDR: –Post-PCI bleeding occurred in 2% –Use of bivalirudin plus vascular closure devices was associated with an absolute 3.8% lower rate in PCI related bleeding in high risk patients –To prevent 1 bleeding event in high risk patients would require treating 33 patients with both therapies –High risk patients were least likely to receive both strategies (risk-treatment paradox) Marso et al. JAMA 2010;303:2156-2164