Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Via Radial Access Anticoagulated With Bivalirudin Versus Heparin

JACC: CARDIOVASCULAR INTERVENTIONS

VOL.

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

-, NO. -, 2017

ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2017.03.021

Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Via Radial Access Anticoagulated With Bivalirudin Versus Heparin A Report From the National Cardiovascular Data Registry Ion S. Jovin, MD, SCD,a,b Rachit M. Shah, MBBS,a Dhavalkumar B. Patel, MBBS, MPH,a Sunil V. Rao, MD,c Dmitri V. Baklanov, MD,d Issam Moussa, MD,e Kevin F. Kennedy, MS,d Eric A. Secemsky, MD, MSC,f,g Robert W. Yeh, MD, MSC,f Michael C. Kontos, MD,a George W. Vetrovec, MDa

ABSTRACT OBJECTIVES The aim of this study was to compare bivalirudin with heparin as anticoagulant agents in patients with ST-segment elevation myocardial infarction treated with radial primary percutaneous coronary intervention (PCI). BACKGROUND Recent studies in which PCI was performed predominantly via radial access did not show bivalirudin to be superior to heparin. METHODS Outcomes were compared in patients with STEMI included in the National Cardiovascular Data Registry CathPCI database from 2009 to 2015 who underwent primary PCI via radial access and who were anticoagulated with bivalirudin or heparin. RESULTS The sample included 67,368 patients, of whom 29,660 received bivalirudin and 37,708 received heparin. The 2 groups of patients did not differ significantly in their mean age or percentage of men. The unadjusted comparison showed no significant difference in the rate of the composite endpoint of death, myocardial infarction, or stroke (4.6% vs. 4.7%; p ¼ 0.47) and a significantly higher rate of acute stent thrombosis (1.00% vs. 0.60%; p < 0.001) with bivalirudin compared with heparin. After adjusting for multiple variables, including a propensity score reflecting the probability of receiving bivalirudin, the odds ratio of the composite endpoint of death, myocardial infarction, or stroke for bivalirudin versus heparin was 0.95 (95% confidence interval: 0.87 to 1.05; p ¼ 0.152), and the odds ratio for acute stent thrombosis was 2.11 (95% confidence interval: 1.73 to 2.57) for bivalirudin versus heparin. Major bleeding rates were not significantly different. CONCLUSIONS In patients undergoing primary PCI via transradial access anticoagulated with bivalirudin or heparin, there was no difference in the composite endpoint of death, myocardial infarction, or stroke. (J Am Coll Cardiol Intv 2017;-:-–-) Published by Elsevier on behalf of the American College of Cardiology Foundation.

From the aVirginia Commonwealth University, Richmond, Virginia; bMcGuire VAMC, Richmond, Virginia; cDuke University, Durham, North Carolina; dMid America Heart Institute, Kansas City, Missouri; eRutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; fHarvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and the g

Massachusetts General Hospital, Boston, Massachusetts. This work was supported by a grant from the Virginia Commonwealth

University Pauley Heart Center to Dr. Jovin. Dr. Rao is a consultant to Medtronic, MedAxiom, Boston Scientific, and Svelte. Dr. Kontos is a consultant to AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 17, 2017; revised manuscript received February 27, 2017, accepted March 9, 2017.

2

Jovin et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

T

ABBREVIATIONS AND ACRONYMS

he use of the direct thrombin inhibi-

METHODS

tor bivalirudin during percutaneous has

PATIENT POPULATION. The National Cardiovascular

proved to be an effective alternative to stan-

Data Registry (NCDR) CathPCI registry, which is

dard unfractionated heparin therapy (alone

cosponsored by the American College of Cardiology

or in combination with glycoprotein [GP]

and the Society for Cardiovascular Angiography and

IIb/IIIa inhibitors) with similar ischemic

Interventions, has been previously described (17,18).

adverse events but with a reduction in major

The CathPCI registry collects data on patient and

bleeding (1). In the setting of primary PCI for

hospital characteristics, clinical presentation, treat-

ST-segment elevation myocardial infarction

ments, and outcomes for PCI procedures from more

(STEMI), the HORIZONS-AMI (Harmonizing

than 1,800 sites across the United States. Data are

Outcomes With Revascularization and Stents

entered into NCDR-certified software at participating

in Acute Myocardial Infarction) trial showed

institutions and exported in a standard format to

that the use of bivalirudin was associated with a

the American College of Cardiology. There is a

significant reduction in bleeding events and also

comprehensive data quality program, including both

CI = confidence interval GP = glycoprotein MI = myocardial infarction NCDR = National Cardiovascular Data Registry

OR = odds ratio PCI = percutaneous coronary intervention

STEMI = ST-segment elevation myocardial infarction

-, NO. -, 2017 - 2017:-–-

Bivalirudin Versus Heparin in STEMI

coronary

intervention

(PCI)

mortality at 30 days (2) and until 3-year follow-up

data quality report specifications for data capture

(3) compared with patients treated with GP IIb/IIIa

and transmission

inhibitors plus heparin. However, most of the inter-

comprehensive description of NCDR data elements

ventional procedures included in HORIZONS-AMI

and definitions is available at http://www.ncdr.com/

were performed through the transfemoral approach,

webncdr/cathpci/home/datacollection.

and an

auditing program.

A

and data on patients who underwent treatment

The study population consisted of patients with

through the transradial approach are sparse (4,5).

STEMI treated with immediate primary PCI from July

The transradial approach for PCI has been associated

1, 2009, to September 30, 2015. Patients were

with a significant reduction in bleeding complica-

excluded if they underwent PCI through access of a

tions and in some studies also with a significant

nonfemoral

reduction in mortality in patients with STEMI (6,7)

brachial), if they had unknown data on medications

compared with the transfemoral approach. The

used for anticoagulation, or if they were treated with

improved outcomes with bivalirudin have been ques-

thrombolytic therapy. After these exclusions, 622,709

tioned by more recent studies, such as EUROMAX

patients from 1,584 sites were included in the analysis

(European Ambulance Acute Coronary Syndrome

of outcomes according to access site. The primary

Angiography Trial) (8), which enrolled more patients

analysis consisted of 74,502 patients with STEMI

treated via the radial access, and also by 3 other

accessed via the radial artery for primary PCI from

recent studies (HEAT-PPCI [Unfractionated Heparin

1,328 sites.

and

nonradial

artery

(i.e.,

ulnar,

Versus Bivalirudin in Primary Percutaneous Coronary Intervention] [9], NAPLES [Novel Approaches for

STATISTICAL

Preventing or Limiting Events] III [10], and BRAVE

characteristics were compared by approach (radial

ANALYSIS. Patient

4 [Bavarian Reperfusion Alternatives Evaluation]

vs. femoral and overall). Patient characteristics,

[11]). In contrast, a network meta-analysis found an

including demographics, history and risk factors,

improved survival in patients treated with bivaliru-

coronary

din compared with those treated with heparin (12).

devices, laboratory values, intraprocedure and post-

Finally, 2 recently published studies in all-comers

procedure events, and hospital characteristics, were

showed no benefit with bivalirudin compared with

compared. The primary endpoint was a composite

heparin when PCI is performed via radial access

of in-hospital death, myocardial infarction (MI),

(13,14). Thus, whether bivalirudin is truly superior

and stroke. Secondary endpoints were bleeding and

to heparin with or without GP IIb/IIIa inhibitors

bleeding requiring transfusion, length of stay, and

and can reduce bleeding events and improve out-

acute stent thrombosis. Acute stent thrombosis was

comes in patients treated through the transradial

defined as repeat PCI on the previously implanted

approach during primary PCI is still not well under-

stent during the index admission. Categorical vari-

stood (15,16).

ables are presented as frequency (percentage), and

anatomy,

PCI

procedure,

and

hospital

lesions

and

The aim of this study was to compare the outcomes

differences between the 2 groups were assessed

of patients with acute STEMI who underwent primary

using the chi-square test or the Wilcoxon summed

PCI through the transradial approach and who were

rank test. Continuous variables are presented as

anticoagulated with either bivalirudin or with hepa-

mean  SD and were compared using the Student

rin with or without GP IIb/IIIa inhibitors.

t test.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017

Jovin et al.

- 2017:-–-

Bivalirudin Versus Heparin in STEMI

To assess the impact of bivalirudin (vs. heparin) on outcomes, we used a hierarchical multivariate

F I G U R E 1 Consolidated Standards of Reporting Trials Flow

Diagram of Patients’ Inclusion in the Study

model clustered by site with a random intercept. To account for patient differences between groups, we developed a propensity score to receive bivalirudin using a saturated logistic regression model. This model included a variety of demographic, history, and risk factors (age, sex, race, insurance, glomerular filtration rate, smoking, hypertension, dyslipidemia, family history of coronary artery disease, prior MI, prior heart failure, valve surgery, prior PCI, prior coronary artery bypass grafting, current dialysis, prior cardiovascular disease, prior peripheral artery disease, claudication, diabetes mellitus, antianginal medications, heart failure in the previous 2 weeks, prior shock, prior cardiac arrest, and GP IIb/IIIa inhibitors). The C statistic for the propensity score was 0.70 (p < 0.001), suggesting good discriminatory power for the score. In addition to adjusting for the propensity to receive bivalirudin as a covariate, we additionally adjusted for the published models reflecting probability of bleeding (19) and of mortality (20) as derived from the CathPCI registry. Additionally, to account for the temporal changes over the study cohort, we tested the interaction between bivalirudin (vs. heparin)

The study cohort (cohort 2) is the gray-shaded box.

and year of procedure. Also, because there was a suggestion of the effect of bivalirudin being related to less use of GP IIb/IIIa inhibitors, we analyzed the temporal trends of GP IIb/IIIa inhibitors. Finally, we

PCI. They were also less likely to present with shock

performed

or cardiac arrest.

a

sensitivity

analysis

in

which

we

compared patients receiving bivalirudin with and

The clinical characteristics of the 67,368 patients

without GP IIb/IIIa inhibitors with those receiving

who underwent primary PCI via the radial approach

heparin with and without GP IIb/IIIa inhibitors. The

are detailed in Table 2. Of these patients, 29,660

final comparison between bivalirudin and heparin is

(44%) were anticoagulated with bivalirudin, and the

shown as odds ratios (ORs) and 95% confidence

remaining 42,158 received unfractionated heparin.

intervals (CIs). A p value <0.05 was considered to

There were no significant differences in the age or

indicate statistical significance. SAS version 9.4 (SAS

proportion of men between the 2 groups. Patients

Institute, Cary, North Carolina) was used for all

who received bivalirudin were more likely to not have

analyses.

insurance, more likely to be on antianginal medications, and less likely to have histories of recent heart

RESULTS

failure or to have experienced cardiac arrest in the previous 24 hours.

The number of patients included in the study and the

The procedural characteristics of the 2 groups are

exclusion criteria are depicted in Figure 1. The char-

shown in Table 3. The patients who received bivalir-

acteristics of the 622,709 patients with STEMI in the

udin received a slightly but statistically significant

NCDR database undergoing primary PCI via femoral

higher dose of contrast, were markedly less likely to

and radial access between the third quarter of 2009

receive GP IIb/IIIa inhibitors or clopidogrel, and were

and the third quarter of 2015 are depicted in Table 1.

more likely to receive prasugrel as an antiplatelet

Only 67,368 patients (10.8%) underwent the proced-

agent than patients who received heparin. The use of

ure via the radial approach. These patients tended to

GP IIb/IIIa inhibitors decreased markedly over time

be younger and more often male and were less likely

in patients treated with heparin (from 79% in 2009

to have prior coronary artery bypass grafting, MI, or

to 47% in 2016), whereas it remained relatively

3

4

Jovin et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017 - 2017:-–-

Bivalirudin Versus Heparin in STEMI

T A B L E 1 Femoral Versus Radial Access

Arterial Access Site

Bivalirudin

Total (n ¼ 622,709)

Femoral (n ¼ 555,341)

Radial (n ¼ 67,368)

p Value

299,067 (48.0%)

269,407 (48.5%)

29,660 (44.0%)

<0.001

61.7  12.9

61.9  13.0

60.3  12.4

<0.001

444,123 (71.3%)

393,628 (70.9%)

50,495 (75.0%)

Demographics Age (yrs)

<0.001

Sex Male Female

178,586 (28.7%)

161,713 (29.1%)

16,873 (25.0%)

Race: white

543,010 (87.2%)

483,747 (87.1%)

59,263 (88.0%)

<0.001

87,946 (14.1%)

79,158 (14.3%)

8,788 (13.0%)

<0.001

72.1  17.2

71.8  17.3

74.7  15.7

<0.001

Insurance payers: none GFR GFRi History Current/recent smoker (#1 yr)

253,793 (40.8%)

225,611 (40.7%)

28,182 (41.9%)

<0.001

Hypertension

416,278 (66.8%)

372,115 (67.0%)

44,163 (65.6%)

<0.001

Dyslipidemia

369,090 (59.4%)

330,339 (59.6%)

38,751 (57.6%)

<0.001

Family history of premature CAD

119,995 (19.3%)

106,306 (19.2%)

13,689 (20.3%)

<0.001

Prior MI

121,352 (19.5%)

110,074 (19.8%)

11,278 (16.7%)

<0.001

Prior heart failure

32,864 (5.3%)

30,011 (5.4%)

2,853 (4.2%)

<0.001

4,126 (0.7%)

3,714 (0.7%)

412 (0.6%)

133,041 (21.4%)

120,793 (21.8%)

12,248 (18.2%)

<0.001

35,928 (5.8%)

34,780 (6.3%)

1,148 (1.7%)

<0.001

6,826 (1.1%)

6,472 (1.2%)

354 (0.5%)

<0.001

Cerebrovascular disease

47,948 (7.7%)

43,338 (7.8%)

4,610 (6.8%)

<0.001

Peripheral artery disease

37,992 (6.1%)

33,946 (6.1%)

4,046 (6.0%)

0.273

64,168 (10.3%)

58,070 (10.5%)

6,098 (9.1%)

<0.001

160,898 (25.8%)

143,913 (25.9%)

16,985 (25.2%)

<0.001

46,562 (7.5%)

43,249 (7.8%)

3,313 (4.9%)

Prior valve surgery/procedure Prior PCI Prior CABG Currently on dialysis

Chronic lung disease Diabetes mellitus

0.083

Catheterization laboratory visit <0.001

Angina classification within 2 weeks No symptoms CCS I

5,993 (1.0%)

5,505 (1.0%)

488 (0.7%)

CCS II

16,789 (2.7%)

15,584 (2.8%)

1,205 (1.8%)

CCS III

77,330 (12.4%)

70,440 (12.7%)

6,890 (10.2%)

CCS IV

474,905 (76.4%)

419,513 (75.7%)

55,392 (82.3%)

270,364 (43.4%)

242,722 (43.7%)

27,642 (41.1%)

<0.001

Heart failure within 2 weeks

49,496 (7.9%)

44,583 (8.0%)

4,913 (7.3%)

<0.001

Cardiomyopathy/left ventricular dysfunction

42,334 (6.8%)

38,491 (6.9%)

3,843 (5.7%)

<0.001

Cardiogenic shock within 24 h

54,429 (8.7%)

51,976 (9.4%)

2,453 (3.6%)

<0.001

Cardiac arrest within 24 h

56,571 (9.1%)

53,044 (9.6%)

3,527 (5.2%)

<0.001

45.9  12.8

45.8  12.8

46.8  12.2

<0.001

Antianginal medication within 2 weeks

Pre-PCI left ventricular ejection fraction (%) Values are n (%) or mean  SD.

CABG ¼ coronary artery bypass grafting; CAD ¼ coronary artery disease; CCS ¼ Canadian Cardiovascular Society; GFR ¼ glomerular filtration rate; GFRi ¼ indexed glomerular filtration rate; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention.

unchanged in patients treated with bivalirudin (from

was not significantly different in the bivalirudin

23% to 21%, respectively). Because heparin is often

group compared with the heparin group (4.6% vs.

used in the emergency department in patients with

4.7%, respectively, p ¼ 0.47) although there were

STEMI and in the cardiac catheterization laboratory in

fewer deaths in the bivalirudin group. There were

the spasmolytic cocktail administered during radial

fewer bleeding episodes (6.8% vs. 8.1%, respectively,

procedures, two-thirds of the patients anticoagulated

p < 0.001) but an increased incidence of acute stent

with bivalirudin during PCI received a bolus of hep-

thrombosis in the group of patients who received

arin beforehand.

bivalirudin (1.03% vs. 0.62; p < 0.001). This group

The unadjusted outcomes are shown in Table 4. The main composite outcome of death, MI, and stroke

also had a slightly but statistically significant shorter length of stay.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017

Jovin et al.

- 2017:-–-

Bivalirudin Versus Heparin in STEMI

T A B L E 2 Bivalirudin Versus Heparin in Patients Undergoing Transradial Primary Percutaneous Coronary Intervention

Anticoagulant Total (n ¼ 67,368)

Bivalirudin (n ¼ 29,660)

Heparin (n ¼ 37,708)

p Value

60.3  12.4

60.3  12.3

60.4  12.4

0.524

50,495 (75.0%)

22,201 (74.9%)

28,294 (75.0%)

Demographics Age (yrs) Sex

0.586

Male Female

16,873 (25.0%)

7,459 (25.1%)

9,414 (25.0%)

Race: white

59,263 (88.0%)

26,125 (88.1%)

33,138 (87.9%)

8,788 (13.0%)

4,027 (13.6%)

4,761 (12.6%)

74.7  15.7

74.9  15.7

74.7  15.8

Insurance payers: none

0.425 <0.001

GFR GFRi

0.088

History Current/recent smoker (#1 yr)

28,182 (41.9%)

12,443 (42.0%)

15,739 (41.8%)

0.567

Hypertension

44,163 (65.6%)

19,456 (65.6%)

24,707 (65.5%)

0.839

Dyslipidemia

38,751 (57.6%)

17,009 (57.4%)

21,742 (57.7%)

0.420

Family history of premature CAD

13,689 (20.3%)

5,999 (20.2%)

7,690 (20.4%)

0.580

Prior MI

11,278 (16.7%)

4,894 (16.5%)

6,384 (16.9%)

0.138 0.489

Prior heart failure Prior PCI Prior CABG Currently on dialysis

2,853 (4.2%)

1,274 (4.3%)

1,579 (4.2%)

12,248 (18.2%)

5,331 (18.0%)

6,917 (18.3%)

0.216

1,148 (1.7%)

512 (1.7%)

636 (1.7%)

0.693 0.760

354 (0.5%)

153 (0.5%)

201 (0.5%)

Cerebrovascular disease

4,610 (6.8%)

2,080 (7.0%)

2,530 (6.7%)

0.121

Peripheral artery disease

4,046 (6.0%)

1,835 (6.2%)

2,211 (5.9%)

0.079

Chronic lung disease

6,098 (9.1%)

2,740 (9.2%)

3,358 (8.9%)

0.135

16,985 (25.2%)

7,553 (25.5%)

9,432 (25.0%)

0.179

67,368 (100.0%)

29,660 (100.0%)

37,708 (100.0%)

3,313 (4.9%)

1,523 (5.1%)

1,790 (4.8%)

CCS I

488 (0.7%)

228 (0.8%)

260 (0.7%)

CCS II

1,205 (1.8%)

557 (1.9%)

648 (1.7%)

CCS III

6,890 (10.2%)

3,122 (10.5%)

3,768 (10.0%)

CCS IV

55,392 (82.3%)

24,203 (81.7%)

31,189 (82.8%)

27,642 (41.1%)

12,391 (41.8%)

15,251 (40.5%)

Heart failure within 2 week

4,913 (7.3%)

2,088 (7.0%)

2,825 (7.5%)

0.025

Cardiomyopathy or left ventricular systolic dysfunction

3,843 (5.7%)

1,660 (5.6%)

2,183 (5.8%)

0.285

Diabetes mellitus Catheterization laboratory visit CAD presentation STEMI or equivalent Angina classification within 2 week

0.003

No symptoms

Antianginal medication within 2 week

Pre-operative evaluation before noncardiac surgery

<0.001

90 (0.1%)

39 (0.1%)

51 (0.1%)

0.894

Cardiogenic shock within 24 h

2,453 (3.6%)

1,036 (3.5%)

1,417 (3.8%)

0.068

Cardiac arrest within 24 h

3,527 (5.2%)

1,473 (5.0%)

2,054 (5.4%)

0.005

46.8  12

46.9  12

46.8  12

0.379

Rural

11,199 (16.6%)

5,264 (17.8%)

5,935 (15.7%)

Suburban

18,853 (28.0%)

8,612 (29.0%)

10,241 (27.2%)

Urban

37,307 (55.4%)

15,780 (53.2%)

21,527 (57.1%)

Teaching hospital

38,206 (56.7%)

15,798 (53.3%)

22,408 (59.4%)

<0.001

Public hospital

27,507 (40.8%)

11,550 (38.9%)

15,957 (42.3%)

<0.001

Onsite surgical backup

54,643 (81.1%)

24,076 (81.2%)

30,567 (81.1%)

0.714

Average yearly PCIs

774.7  509.5

729.5  479.9

810.2  528.9

<0.001

Pre-PCI left ventricular ejection fraction (%)* Hospital

<0.001

Hospital location

Values are mean  SD or n (%). *n ¼ 24,878. STEMI ¼ ST-segment elevation myocardial infarction; other abbreviations as in Table 1.

were

administration of bivalirudin was not significantly

included in a multivariate model to evaluate the

The

patient

and

associated with the outcome, whereas female sex,

relationship

composite

age, prior cardiovascular disease and peripheral

endpoint of death, MI, or stroke (Figure 2). The

vascular disease, a history of diabetes and a history of

between

procedural them

and

variables the

5

Jovin et al.

6

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017 - 2017:-–-

Bivalirudin Versus Heparin in STEMI

T A B L E 3 Procedural Variables of Patients Undergoing Transradial Primary Percutaneous

Coronary Intervention

death, MI, and stroke was not statistically significant (OR: 0.95; 95% CI: 0.87 to 1.05; p ¼ 0.358) for the patients receiving bivalirudin compared with the

Anticoagulant

patients receiving heparin (Figure 3). The OR for

Total (n ¼ 67,368)

Bivalirudin (n ¼ 29,660)

Heparin (n ¼ 37,708)

p Value

Contrast volume (ml)

183.8  77.2

185.4  77.3

182.5  77.0

<0.001

stent thrombosis remained statistically significant

Fluoroscopy time (min)

14.8  10.3

14.8  10.1

14.8  10.5

0.869

(OR: 2.11; 95% CI: 1.73 to 2.57; p < 0.001), whereas the

1.5  0.8

1.5  0.8

1.5  0.8

0.156

adjusted length of stay was not statistically signifi-

Minimum stent diameter (mm)

3.0 (2.5–3.5)

3.0 (2.5–3.5)

3.0 (2.5–3.5)

0.001

cant. Because the number of procedures performed

Total stent length (mm)

30.5  18.1

30.7  18.3

30.3  18.0

0.008

via the radial approach is increasing constantly in the

Procedure information

Number of stents

Diseased vessels

0.088

1

38,633 (57.3%) 16,886 (56.9%)

2

19,449 (28.9%) 8,604 (29.0%) 10,845 (28.8%)

3

9,286 (13.8%)

4,170 (14.1%)

29,197 (43.3%)

6,781 (22.9%)

21,747 (57.7%)

bleeding was also not statistically significant (OR: 0.98; 95% CI: 0.91 to 1.05; p ¼ 0.57). The OR for acute

United States, as more operators are adopting the technique, we also tested for interaction between the endpoints and time. We found no statistically

5,116 (13.6%)

significant interaction with time for any of the

Procedure medications GP IIb/IIIa inhibitors

22,416 (59.4%) <0.001 <0.001

Unfractionated heparin No

9,792 (14.5%)

9,792 (33.0%)

0 (0.0%)

Yes

57,513 (85.4%) 19,805 (66.8%) 37,708 (100.0%)

Aspirin

62,086 (92.2%) 27,279 (92.0%) 34,807 (92.3%)

Clopidogrel

32,257 (47.9%) 13,437 (45.3%) 18,820 (49.9%) <0.001

Prasugrel

13,762 (20.5%)

7,061 (23.9%)

6,701 (17.9%)

<0.001

Ticagrelor

16,536 (27.2%)

7,460 (27.2%)

9,076 (27.3%)

0.772

adjusted endpoints. The sensitivity analysis revealed different results depending

0.109

on

the

constellation

chosen.

Thus,

comparing patients who received bivalirudin without GP IIb/IIIa inhibitors with patients receiving heparin without GP IIb/IIIa inhibitors (Online Table 1, Online Figure 1) showed a significantly lower rate of the composite of death, MI, or stroke for patients anti-

Values are mean  SD, median (interquartile range), or n (%).

coagulated with bivalirudin, which remained signifi-

GP ¼ glycoprotein.

cant after adjustments (OR: 0.84; 95% CI: 0.74 to 0.96; p ¼ 0.004). Comparing patients who received bivalirudin heart failure, cardiogenic shock, and cardiac arrest in the period preceding the index event were.

without

GP

IIb/IIIa

inhibitors

with

patients receiving heparin with GP IIb/IIIa inhibitors (Online Table 2, Online Figure 2) showed no signifi-

After adjusting for multiple variables and the propensity score, the OR for the main composite of

cant difference in the composite endpoint, which remained not significant after adjustments (OR: 0.89; 95% CI: 0.79 to 1.01; p ¼ 0.052). Both subgroup analyses showed a significantly lower risk for bleeding

T A B L E 4 Outcomes of Patients Undergoing Transradial Primary Percutaneous

with bivalirudin. Finally, comparing patients who

Coronary Intervention

received bivalirudin with and without GP IIb/IIIa inhibitors with patients receiving heparin without GP

Anticoagulant

CVA/stroke Tamponade

Total (n ¼ 67,368)

Bivalirudin (n ¼ 29,660)

Heparin (n ¼ 37,708)

347 (0.5%)

156 (0.5%)

IIb/IIIa inhibitors (Online Table 3, Online Figure 3) p Value

showed a significantly lower rate of the composite of

191 (0.5%)

0.728

death, MI, or stroke for patients anticoagulated with bivalirudin, which remained significant after adjust-

92 (0.1%)

34 (0.1%)

58 (0.2%)

0.171

Death

1,728 (2.6%)

720 (2.4%)

1,008 (2.7%)

0.045

MI (biomarker positive)

1,232 (1.8%)

557 (1.9%)

675 (1.8%)

0.399

Cardiogenic shock

1,956 (2.9%)

811 (2.7%)

1,145 (3.0%)

0.020

Heart failure

2,071 (3.1%)

879 (3.0%)

1,192 (3.2%)

0.138

Other vascular complications requiring treatment

144 (0.2%)

63 (0.2%)

81 (0.2%)

0.945

RBC/whole blood transfusion

1,637 (2.4%)

660 (2.2%)

977 (2.6%)

0.002

Observed bleeding rate

5,075 (7.5%)

2,011 (6.8%)

3,064 (8.1%)

<0.001

4.4  5.3

4.3  4.2

4.5  6.1

<0.001

Length of stay (discharge-procedureþ1)

ments (OR: 0.89; 95% CI: 0.79 to 1.00; p ¼ 0.049). The risk for bleeding was not significantly different between the 2 groups.

DISCUSSION In a large cohort of real-world patients in the United States, we found that there was no significant differ-

Acute stent thrombosis

540 (0.80%)

306 (1.03%)

234 (0.62%)

<0.001

ence in the rate of a composite of death, MI, and

Subacute stent thrombosis

395 (0.59%)

191 (0.64%)

204 (0.54%)

0.082

stroke in patients undergoing primary transradial

Death/MI/stroke

3,126 (4.6%)

1,357 (4.6%)

1,769 (4.7%)

0.476

PCI for STEMI whether they were anticoagulated

Values are n (%) or mean  SD. CVA ¼ cerebrovascular accident; MI ¼ myocardial infarction; RBC ¼ red blood cell.

with bivalirudin or unfractionated heparin. A significant strength of our study is the sample size, which is the largest reported in a study comparing the

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017

Jovin et al.

- 2017:-–-

Bivalirudin Versus Heparin in STEMI

2 anticoagulation strategies specifically in patients with STEMI undergoing primary PCI via the radial

F I G U R E 2 Forest Plot Showing the Various Subgroups and the Adjusted Odds Ratio of

Reaching the Main Endpoint of In-Hospital Death, Myocardial Infarction, or Stroke

approach. In addition, our data are representative of current clinical practice in the United States, as more than 80% of PCI centers participate in the CathPCI registry. Our results are in line with recently published trials such as the HEAT-PPCI trial (9), which randomized 1,829 patients to primary transradial PCI using bivalirudin or unfractionated heparin with provisional GP IIa/IIIa inhibitors. Adverse events occurred less often in the group of patients randomized to heparin compared with those randomized to bivalirudin. However, the use of GP IIb/IIIa inhibitors was significantly lower in both arms of the trial compared with our cohort. In the BRIGHT (Bivalirudin in Acute Myocardial Infarction vs. Glycoprotein IIb/IIIa and Heparin: A Randomised Controlled Trial) trial (21), net clinical

outcomes

were

better

with

bivalirudin

compared with heparin and heparin with tirofiban in patients with acute MI treated with PCI, but this was due primarily to a reduction in bleeding in the patients receiving bivalirudin, as the rates of major adverse cardiac events were similar between the groups. The MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic

CVD ¼ cardiovascular disease; GFR ¼ glomerular filtration rate; G2B3A ¼ glycoprotein IIb/IIIa inhibitors; HF ¼ heart failure; MI ¼ myocardial infarction; PAD ¼ peripheral artery disease.

Implementation of Angiox) investigators compared bivalirudin versus heparin and femoral access versus radial access (22,23) in patients presenting with acute

inhibitors. However, the total number of patients

coronary syndrome in a 2  2 design study. They

done via the transradial approach was only 200 (of

found that the rates of major adverse cardiovascular

3,340).

events and net adverse clinical events were not

Whether the lack of differences in the patient

significantly lower in patients treated with bivalir-

groups anticoagulated with bivalirudin and heparin

udin compared with those treated with heparin.

found in this study is related mostly to the fact that

Interestingly, they found that this held true for the

we selected only patients who underwent primary

patients who had the procedure done via the radial

PCI via the transradial approach, which is known to

approach and for those who had the procedure done

lead to fewer access site bleeding events (15), or

via the femoral approach.

whether it is related to a better understanding and

This is in contradistinction to the findings of the

more judicious use of anticoagulation in the setting of

HORIZONS AMI study (2), in which patients with

acute intervention is unclear, but our data are

STEMI had significantly better outcomes if they were

consistent with data from contemporary studies of

anticoagulated with bivalirudin compared with hep-

patients with acute coronary syndrome and STEMI.

arin. The majority of procedures in the HORIZONS

Our study shows that in transradial primary PCI,

AMI study were done via the transfemoral approach,

even with a high percentage of patients receiving GP

but a post hoc analysis (4) revealed that the trans-

IIb/IIIa inhibitors, the outcomes are not significantly

radial approach was associated with reduced major

different between patients anticoagulated with biva-

bleeding and improved event-free survival. The rate

lirudin and heparin. This aspect is important because

of major adverse cardiovascular events and the rate of

it was thought that the use of GP IIb/IIIa inhibitors

death or reinfarction at 30 days was the same,

was a significant contributor to the increased rate of

respectively, in the patients who were treated via the

bleeding and the poorer outcomes with heparin. Our

transradial approach and who received either biva-

data suggest that in transradial primary PCI, this may

lirudin or heparin with provisional GP IIb/IIIa

not be an issue.

7

8

Jovin et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017 - 2017:-–-

Bivalirudin Versus Heparin in STEMI

F I G U R E 3 Forest Plot Showing the Adjusted Odds Ratios for Various Outcomes

Including the Main Endpoint of In-Hospital Death, Myocardial Infarction, or Stroke

reduction in mortality or transfusion rates in patients treated with bivalirudin. We also found an increased incidence of acute stent

thrombosis

associated

with

bivalirudin

compared with heparin. This remained significant after adjustments in the multivariate model. This finding is consistent among most trials and is thought to be related to the short half-life of bivalirudin. However, a pre-specified analysis of the MATRIX antithrombin therapy study did not find superior outcomes with prolonged infusions of bivalirudin compared with no post-PCI infusions (22). In our study, the increase in acute stent thrombosis was not associated with an increase in death or an increase in the composite endpoint. The current American College of Cardiology/ American Heart Association guidelines (29) give both bivalirudin and heparin a class I indication for anticoagulation of patients with STEMI undergoing primary PCI. Our data support the equipoise of the 2 anticoagulant agents in patients undergoing primary PCI via the radial approach and are consistent with the opinion of a number of interventional cardiologists

MI ¼ myocardial infarction.

surveyed about the comparison between heparin and bivalirudin (30). As the number of transradial procedures increases in the United States (31), this issue will

Among the individual endpoints in our study, all-

become more important because of the cost difference

cause death seemed to favor bivalirudin in the un-

between the 2 agents. Bivalirudin is easier to use: it has

adjusted analysis, but there was no statistically

a rapid onset, it does not need activated clotting time

significant association with improved mortality after

monitoring during PCI, and, according to the findings

adjusting for multiple variables and for the pro-

of the MATRIX study, it does not need to be infused

pensity score. The same finding applied to bleeding,

post-PCI (22). This will have to be balanced against its

which seemed to be reduced by bivalirudin compared

cost in a cost-effectiveness analysis.

with heparin in the unadjusted analysis. However, in

Our sensitivity analysis provides some insights

the multivariate model, the OR did not reach statis-

into direct comparisons of bivalirudin and heparin

tical significance.

when GP IIb/IIIa inhibitors are forced out of the

These results are consistent with those of some of

equation and suggests that in the direct comparison,

the newer trials such as HEAT-PPCI, EUROMAX, and

bivalirudin may have superior outcomes. However,

BRAVE 4, although in EUROMAX, there was a signif-

our study showed that in the real world, more than a

icant

bivalirudin

third of patients with STEMI undergoing transradial

It was thought that bleeding is an important

who receive bivalirudin also receive GP IIb/IIIa

reduction

of

bleeding

with

compared with heparin. contributor to major cardiovascular events in patients

PCI who receive heparin and about a fifth of patients inhibitors.

undergoing PCI in the setting of acute coronary syndrome and STEMI (24–26). The benefit of bivalirudin

STUDY

therapy was thought to be related primarily to the

analysis of the data from the NCDR CathPCI registry,

LIMITATIONS. This

reduction in bleeding; however, an analysis of the

not a randomized clinical trial; as such, our analysis

HORIZONS AMI data showed that this did not

may be prone to biases that remained despite our

completely explain the benefit (3). Some earlier

use of a propensity score to try to minimize them. A

studies (2,27) suggested that treatment with bivalir-

substantial number of patients anticoagulated with

udin improved mortality in patients with STEMI, but

bivalirudin received some amount of heparin, but an

a more recent meta-analysis comparing bivalirudin

analysis from the HORIZONS AMI study showed that

and heparin did not find a mortality advantage with

these patients do not have worse outcomes than

bivalirudin (28). Our data also showed no significant

patients who are anticoagulated with heparin only

was

a

retrospective

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017

Jovin et al.

- 2017:-–-

Bivalirudin Versus Heparin in STEMI

(32). The data yield only in-hospital outcomes and do not allow us to make statements about longer term outcomes, but previous studies have shown that the first few days after a STEMI are the days when the patient is at the highest risk for events (33–35).

udin or with heparin during primary PCI via the transradial approach is associated with similar rates cardiovascular

in-hospital

outcomes,

notwithstanding an increase in acute stent thrombosis in patients receiving bivalirudin.

Virginia Commonwealth University/McGuire VAMC, Broad

Rock

newer trials have questioned this assertion.

Boulevard,

111J,

primary PCI via transradial access anticoagulated with bivalirudin or heparin, there was no difference in the composite endpoint of death, MI, or stroke. WHAT IS NEXT? A randomized trial in patients treated exclusively via transradial primary PCI and anticoagulated with bivalirudin versus heparin as well as a cost-effectiveness analysis

ADDRESS FOR CORRESPONDENCE: Dr. Ion S. Jovin,

1201

with superior outcomes compared with heparin, but results from

NCDR CathPCI registry suggest that in patients undergoing

Our data suggest that anticoagulation with bivalir-

adverse

WHAT IS KNOWN? Bivalirudin was thought to be associated

WHAT IS NEW? Our data from a large cohort of patients in the

CONCLUSIONS

of

PERSPECTIVES

Richmond,

comparing heparin versus bivalirudin would help practitioners and hospitals make better decisions regarding anticoagulation in these patients.

Virginia 23249. E-mail: [email protected].

REFERENCES 1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–63. 2. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–30. 3. Stone GW, Clayton T, Deliargyris EN, Prats J, Mehran R, Pocock SJ. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI trial (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction). J Am Coll Cardiol 2014;63:15–20. 4. Genereux P, Mehran R, Palmerini T, et al., for the HORIZONS AMI Trial Investigators. Radial access in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty in acute myocardial infarction: the HORIZONS-AMI trial. EuroIntervention 2011;7: 905–16. 5. Hamon M, Rasmussen LH, Manoukian SV, et al. Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial. EuroIntervention 2009;5:115–20. 6. Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. 7. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute

Coronary Syndrome) study. J Am Coll Cardiol 2012;60:2481–9.

Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Eur Heart J 2016;37:1902–9.

8. Steg PG, van ’t Hof A, Hamm CW, et al., for the EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J

15. Appleton DL, Cooke RH, Rao SV, Jovin IS. Anticoagulation in transradial percutaneous coronary intervention. Catheter Cardiovasc Interv

Med 2013;369:2207–17.

2014;83:237–42.

9. Shahzad A, Kemp I, Mars C, et al., for the HEATPPCI Investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384:1849–58.

16. Baklanov DV, Kim S, Marso SP, Subherwal S, Rao SV. Comparison of bivalirudin and radial access across a spectrum of preprocedural risk of bleeding in percutaneous coronary intervention: analysis from the National Cardiovascular Data Registry. Circ Cardiovasc Interv 2013;6:347–53.

10. Briguori C, Visconti G, Focaccio A, et al. Novel approaches for preventing or limiting events

17. Brindis RG, Fitzgerald S, Anderson HV, Shaw RE, Weintraub WS, Williams JF. The Amer-

(Naples) III trial: randomized comparison of bivalirudin versus unfractionated heparin in patients at increased risk of bleeding undergoing transfemoral elective coronary stenting. J Am Coll Cardiol Intv 2015;8:414–23.

ican College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR): building a national clinical data repository. J Am Coll Cardiol 2001;37: 2240–5.

11. Schulz S, Richardt G, Laugwitz KL, et al., for the Bavarian Reperfusion Alternatives Evaluation I. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014;35: 2285–94. 12. Kinaird T, Medic G, Casella G, et al. Relative efficacy of bivalirudin versus heparin monotherapy in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a network meta-analysis. J Blood Medicine 2013;4:129–40. 13. MacHaalany J, Abdelaal E, Bataille Y, et al. Benefit of bivalirudin versus heparin after transradial and transfemoral percutaneous coronary intervention. Am J Cardiol 2012;110:1742–8. 14. Perdoncin E, Seth M, Dixon S, et al. The comparative efficacy of bivalirudin is markedly attenuated by use of radial access: insights from

18. Rao SV, Dai D, Subherwal S, et al. Association between periprocedural bleeding and long-term outcomes following percutaneous coronary intervention in older patients. J Am Coll Cardiol Intv 2012;5:958–65. 19. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. Jama 2010;303:2156–64. 20. Shaw RE, Anderson HV, Brindis RG, et al. Development of a risk adjustment mortality model using the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR) experience: 1998–2000. J Am Coll Cardiol 2002;39: 1104–12. 21. Han Y, Guo J, Zheng Y, et al., for the BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial

9

10

Jovin et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL.

-, NO. -, 2017 - 2017:-–-

Bivalirudin Versus Heparin in STEMI

infarction: the BRIGHT randomized clinical trial. JAMA 2015;313:1336–46.

results from an observational database. Circ Cardiovasc Qual Outcomes 2012;5:52–61.

Registry (2007 to 2011). J Am Coll Cardiol 2013; 61:420–6.

22. Valgimigli M, Frigoli E, Leonardi S, et al., for the MATRIX Investigators. Bivalirudin or unfrac-

28. Capodanno D, Gargiulo G, Capranzano P, Mehran R, Tamburino C, Stone GW. Bivalirudin

tionated heparin in acute coronary syndromes. N Engl J Med 2015;373:997–1009.

versus heparin with or without glycoprotein IIb/ IIIa inhibitors in patients with STEMI undergoing primary PCI: an updated meta-analysis of 10, 350 patients from five randomized clinical trials. Eur Heart J Acute Cardiovasc Care 2015;65: 27–38.

32. Dangas GD, Mehran R, Nikolsky E, et al. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction: the HORIZONS-SWITCH analysis. J Am Coll Cardiol

23. Valgimigli M, Gagnor A, Calabro P, et al., for the MATRIX Investigators. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet 2015;385: 2465–76. 24. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774–82. 25. Hamon M, Mehta S, Steg PG, et al. Impact of transradial and transfemoral coronary interventions on bleeding and net adverse clinical events in acute coronary syndromes. EuroIntervention 2011;7:91–7. 26. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical out-

29. O’Gara PT, Kushner FG, Ascheim DD, et al., for the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127: e362–425. 30. Adamo M, Byrne RA, Baumbach A, Haude M, Windecker S, Valgimigli M. Assessing the cardiology community position on transradial intervention and the use of bivalirudin in patients with

comes in patients with acute coronary syndromes. JAMA 2004;292:1555–62.

acute coronary syndrome undergoing invasive management: results of an EAPCI survey. EuroIntervention 2016;12:1154–63.

27. Pinto DS, Ogbonnaya A, Sherman SA, Tung P, Normand SL. Bivalirudin therapy is associated with improved clinical and economic outcomes in ST-elevation myocardial infarction patients un-

31. Baklanov DV, Kaltenbach LA, Marso SP, et al. The prevalence and outcomes of transradial percutaneous coronary intervention for STsegment elevation myocardial infarction: anal-

dergoing percutaneous coronary intervention:

ysis from the National Cardiovascular Data

2011;57:2309–16. 33. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2: 349–60. 34. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673–82. 35. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357: 2001–15.

KEY WORDS anticoagulation, bivalirudin, heparin, percutaneous coronary intervention, ST-segment elevation myocardial infarction, transradial A PPE NDI X For supplemental tables and figures, please see the online version of this article.