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

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.

Objective

• To describe the use of 2 bleeding avoidance strategies—1) vascular closure devices and 2) bivalirudin—and 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

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

Candidate Bleeding Avoidance Strategies• Bivalirudin • Vascular closure devices• Both therapies (bivalirudin + vascular

closure)

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

Bleeding Risk Strata

• Bleeding risk score calculated for each patient using NCDR bleeding risk model1

• 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;303:2156-21641 Mehta et al. Circ Cardiovasc Intervent 2009;2:222-229

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

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

Standardized Difference Before and After Propensity Matching

Chronic Lung DiseasePrevious Valve Surgery

Previous Cardiac TransplantCerebrovascular Disease

Previous CHFGender

Family History of CADWhite Race

CHFRenal Failure

DiabetesPrevious CABG

Previous MIPVDBMIAge

History of SmokingHypertension

HyprcholesterolemiaPrevious PCI

NYHA Class III/IVSTEMI

Standardized Difference0 10 20 30 40 50

Before MatchAfter Match

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

Study Population

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

FinalStudyPopulation:N=1,522,935

ManualCompressionN=529,247(35%)

VascularClosureDeviceN=363,583(24%)

BothStrategiesN=276,336(18%)

Exclusions:236,473(13%)•>1in-hospital PCIprocedure:91,874(5%)•Dataincompleteforcalculationofexpected

bleedingrate:69,247(4%)•PCI of aradial ornon-femoral artery:35,951(2%)•Cardiogenicshock:34,842(2%)•Missingdevicedata:3,384(<1%)•Death incatheterization lab:1,111(<1%)•Bleedingeventunknown:64(<1%)

BivalirudinN=353,769(23%)

Lowrisk:115,510(32%)Intermediaterisk:178,200(49%)

Highrisk:69,873(19%)

Lowrisk:113,118(32%)Intermediaterisk:174,131(49%)

Highrisk:66,520(19%)

Lowrisk:99,967 (36%)Intermediaterisk:133,033 (48%)

Highrisk:43,336(16%)

Lowrisk:146,557(28%)Intermediaterisk:261,363(49%)

Highrisk:121,327(23%)

1,759,408 RecordsfromNCDRVersion3.042004-2008

Patient CharacteristicsTotal

(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), y 64.3 (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), cm 171.30 (10.84) 171.22 (10.89) 171.73 (10.77) 170.81 (10.90) 171.50 (10.73)

Weight, mean (SD), kg 87.71 (20.45) 87.25 (20.42) 88.22 (20.28) 87.29 (20.71) 88.47 (20.40)

Body mass index, mean (SD), kg/m2

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 (%)

I 480,785 (31.57) 160,016 (30.24) 125,209 (34.44) 107,678 (30.44) 87,882 (31.81)

II 355,937 (23.37) 107,093 (20.24) 79,475 (21.86) 90,682 (25.64) 78,687 (28.48)

III 415,651 (27.30) 146,439 (27.67) 87,352 (24.03) 107,952 (30.52) 73,908 (26.75)

IV 270,376 (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

Patient CharacteristicsTotal (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 (%)

Diabetes 509,455 (33.45) 173,024 (32.69) 113,130 (31.12) 129,335 (36.56) 93,966 (34.00)

Hypertension 1,190,098 (78.15) 405,122 (76.55) 272,906 (75.06) 290,085 (82.00) 221,985 (80.33)

Dyslipidemia 1,167,108 (76.64) 392,248 (74.12) 269,478 (74.12) 283,174 (80.05) 222,208 (80.42)

Smoking , N (%)

Never 600,315 (38.87) 196,423 (37.12) 143,554 (39.49) 138,026 (39.02) 114,318 (41.37)

Past 543,091 (35.17) 178,466 (33.72) 121,980 (33.55) 132,027 (37.32) 102,545 (37.11)

Current 400,845 (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 (%)

PCI 576,207 (37.84) 182,518 (34.49) 125,649 (34.56) 151,835 (42.92) 116,205 (42.05)

CABG 291,773 (19.16) 98,038 (18.52) 59,980 (16.50) 79,189 (22.39) 54,566 (19.75)

Myocardial infarction 427,655 (28.08) 144,381 (27.28) 96,191 (26.46) 106,403 (30.08) 80,690 (29.20)

Other cardiovascular disease history , N (%)

CHF 136,483 (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

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 surgery 17,267 (1.13) 5,929 (1.12) 3,672 (1.01) 4,505 (1.27) 3,161 (1.14)

Previous transplant 3,463 (0.23) 1,257 (0.24) 732 (0.20) 899 (0.25) 575 (0.21)

Chronic lung disease 248,918 (16.35)

86,586 (16.36)

52,995 (14.58)

6,5139 (18.41)

44,198 (15.99)

Renal failure 83,029 (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 (%)

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 symptoms 196,190 (12.88) 55,961 (10.57) 42,224 (11.61) 54,346 (15.36) 43,659 (15.80)

Atypical chest pain 113,339 (7.44) 32,570 (6.15) 27,031 (7.44) 27,758 (7.85) 25,980 (9.40)

Stable angina 260,582 (17.11) 73,109 (13.81) 57,179 (15.73) 69,093 (19.53) 61,201 (22.15)

Unstable angina 527,624 (34.65) 168,813 (31.90) 113,413 (31.19) 142,473 (40.27) 102,925 (37.25)

Non-STEMI 238,305 (15.65) 98,866 (18.68) 64,921 (17.86) 43,239 (12.22) 31,279 (11.32)

STEMI 186,810 (12.27) 99,900 (18.88) 58,796 (16.17) 16,843 (4.76) 11,271 (4.08)

PCI type

Elective 758,110 (49.79) 220,576 (41.68) 157,348 (43.28) 212,562 (60.09) 167,624 (60.67)

Urgent 553,524 (36.35) 196,634 (37.16) 140,023 (38.52) 121,995 (34.49) 94,872 (34.34)

Emergency 209,465 (13.76) 110,990 (20.97) 65,758 (18.09) 19,011 (5.37) 13,706 (4.96)

Salvage 1,662 (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 (%)

Hospital CharacteristicsTotal

(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 (%)

West 244,853 (16.11) 71,085 (13.47) 73,065 (20.15) 41,801 (11.83) 58,902 (21.36)

Northeast 177,930 (11.71) 56,353 (10.68) 60,120 (16.58) 28,392 (8.04) 33,065 (11.99)

Midwest 505,125 (33.24) 198,609 (37.63) 119,220 (32.88) 104,043 (29.45) 83,253 (30.19)

South 591,568 (38.93) 201,679 (38.22) 110,237 (30.40) 179,071 (50.68) 100,581 (36.47)

Community type, N (%)

Rural 177,441 (15.92) 59,727 (15.44) 54,008 (21.02) 31,542 (11.48) 32,164 (16.38)

Urban 937,476 (84.08) 327,222 (84.56) 202,931 (78.98) 243,165 (88.52) 164,158 (83.62)

Profit type, N (%)

Government 23,838 (1.57) 7,895 (1.49) 4,948 (1.36) 5,988 (1.69) 5,007 (1.81)

Private/community 1,356,756 (89.09) 465,238 (87.91) 319,915 (87.99) 318,550 (90.04) 253,053 (91.57)

University 142,341 (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;303:2156-2164All P<0.001

Bleeding Rates*

Intermediate† N=746,727

*NCDR bleeding risk <1%†NCDR bleeding risk 1-3%‡NCDR bleeding risk >3%

Low*N=475,152

High‡ N=301,056

M C BCB

2.8

0.9

2.3

6.1

2.1

0.9

1.9

4.6

1.6

0.6

1.4

3.8

0.90.4

0.8

2.3

0

1

2

3

4

5

6

7

Ble

ed

ing

(%

)

M = Manual comp. C = Closure only B = Bival onlyBC = Bival+closure

M C BCB M C BCB M C BCB

Overall Low(<1%)

Intermediate(1-3%)

High(>3%)

P<0.001 all

intra-risk groupcomparisons

*Overall bleeding = 30,429 (2%)

Treatment(N)

BleedingN (%)

Odds Ratio (95% CI)

NNT(95% CI)

Reduction in Bleeding Events per 1,000 Patients

Treated (95% CI)

Manual compression 508,455 13,597 (2.7) 1 [Reference]

Vascular closure devices 205,606 5,050 (2.5) 0.77 (0.73-0.80) 148 (130-175) 6.7 (5.7-7.7)

Bivalirudin 172,471 3,224 (1.9) 0.67 (0.63-0.70) 118 (107-132) 8.5 (7.6-9.3)

Both 130,378 1,361 (1.0) 0.38 (0.35-0.42) 70 (68-74) 14.2 (13.5-14.8)

Total 1,016,910 23,232 (2.3)

Estimated Bleeding Reductions—All Patients (Propensity Adjusted)

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

Estimated Bleeding Reductions (Propensity Adjusted)

Treatment(N)

BleedingN (%)

Odds Ratio (95% CI)

NNT(95% CI)

Reduction in Bleeding Events per 1,000 Patients Treated (95% CI)

Low Risk, <1%

Manual compression 144,594 1,320 (0.9) 1 [Reference]

Vascular closure devices 54,217 532 (1.0) 1.07 (0.93-1.22) NS NS

Bivalirudin 48,378 296 (0.6) 0.65 (0.56-0.77) 315 (247-470) 3.2 (2.1-4.0)

Both 41,999 166 (0.4) 0.42 (0.34-0.51) 188( 167-222) 5.3 (4.5-6.0)

Total 289,188 2,314 (0.8)

Intermediate Risk, 1-3%

Manual compression 252,898 5,722 (2.3) 1 [Reference]

Vascular closure devices 103,095 2,077 (2.0) 0.76 (0.71-0.81) 169 (141-217) 5.9 (4.6-7.1)

Bivalirudin 85,800 1,311 (1.5) 0.69 (0.63-0.74) 153 (131-187) 6.5 (5.3-7.6)

Both 64,003 573 (0.9) 0.39 (0.35-0.44) 80 (75-86) 12.5 (11.6-13.3)

Total 505,796 9,683 (1.9)

High Risk, >3%

Manual compression 110,963 6,555 (5.9) 1 [Reference]

Vascular closure devices 48,294 2,441 (5.1) 0.79 (0.75-0.82) 81 (66-109) 12.3 (9.2-15.3)

Bivalirudin 38,293 1,617 (4.2) 0.67 (0.62-0.73) 56 (49-66) 17.9 (15.1-20.6)

Both 24,376 622 (2.6) 0.42 (0.38-0.47) 33 (31-36) 30.5 (27.9-32.8)

Total 221,926 11,235 (5.1)

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

Bleeding Avoidance Strategy Use by Pre-PCI Bleeding Risk

30.8

35

40.3

24.3 23.9 23.223.8 23.3 22.12117.8

14.4

0

5

10

15

20

25

30

35

40

45

Ble

ed

ing

(%

)

M C BCB

Low(<1%)

M = Manual comp. C = Closure only B = Bival onlyBC = Bival+closure

P<0.001 for all

intra-risk groupcomparisons

M C BCB

Intermediate(1-3%)

M C BCB

High(>3%)

Intermediate† N=746,727

*NCDR bleeding risk <1%†NCDR bleeding risk 1-3%‡NCDR bleeding risk >3%

Low*N=475,152

High‡ N=301,056

Risk-Treatment ParadoxRisk-Treatment Paradox

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

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