Effect of Short Procedural Duration with Bivalirudin

Research

JAMA Cardiology | Brief Report Effect of Short Procedural Duration With Bivalirudin on Increased Risk of Acute Stent Thrombosis in Patients With STEMI A Secondary Analysis of the HORIZONS-AMI Randomized Clinical Trial

Hector Tamez, MD, MPH; Duane S. Pinto, MD, MPH; Ajay J. Kirtane, MD, SM; Claire Litherland, MS; Robert W. Yeh, MD, MSc; George D. Dangas, MD; Roxana Mehran, MD; Efthymios N. Deliargyris, MD; Guillermo Ortiz, MD; C. Michael Gibson, MS, MD; Gregg W. Stone, MD

Supplemental content IMPORTANCE Bivalirudin has been associated with reduced bleeding and mortality during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). However, increased rates of acute stent thrombosis (AST) have been noted when bivalirudin is discontinued at the end of the procedure, which is perhaps related to this medication’s short half-life.

OBJECTIVES To evaluate the clinical effect of procedure duration on AST when either bivalirudin or heparin plus glycoprotein IIb/IIIa receptor inhibitor (GPI) is used.

DESIGN, SETTING, AND PARTICIPANTS An ad hoc analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) clinical trial was performed between March 1, 2015, and April 30, 2016, on patients who underwent primary percutaneous coronary intervention with stents and were randomized 1:1 to bivalirudin or heparin plus GPI. Defined as the difference between the patient’s arrival at the catheterization laboratory and the patient’s final angiogram. Participants included 3602 patients with STEMI, aged 18 years or older, who were undergoing primary percutaneous coronary intervention and presenting less than 12 hours from symptom onset.

MAIN OUTCOMES AND MEASURES Clinical events committee–adjudicated definite AST (occurring Յ24 hours after percutaneous coronary intervention).

RESULTS Among patients included in this analysis, procedure time was identified in 1286 receiving bivalirudin and 1412 receiving heparin plus GPI. Shorter procedures were defined as the lowest quartile of duration (<45 minutes). Patients undergoing shorter procedures were younger and less likely to be hypertensive and smokers. Shorter procedures were less complicated with fewer stents implanted, less multivessel stenting, less thrombus, and less Author Affiliations: Division of Cardiology, Beth Israel Deaconess no-reflow. An increased risk of definite AST was associated with shorter than with longer Medical Center, Boston, procedures with bivalirudin (7 [2.1%] vs 7 [0.7%]; relative risk, 2.87; 95% CI, 1.01-8.17; P = .04) Massachusetts (Tamez, Pinto, Yeh, but not with heparin plus GPI (0 vs 3 [0.3%]; P = .30). Ortiz, Gibson); Columbia University Medical Center/New York- Presbyterian Hospital and the CONCLUSIONS AND RELEVANCE Despite less procedural complexity, shorter primary Cardiovascular Research Foundation, percutaneous coronary intervention time was associated with an increased risk of AST in New York, New York (Kirtane, patients treated with bivalirudin but not patients treated with heparin plus GPI, possibly Litherland, Stone); Associate Editor, JAMA Cardiology (Kirtane); Mount because of the rapid offset of bivalirudin’s antithrombotic effect during a window of limited Sinai Medical Center, New York, oral antiplatelet action. New York (Dangas, Mehran); The Medicines Company, Parsippany, TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00433966 New Jersey (Deliargyris). Corresponding Author: Duane S. Pinto, MD, MPH, Department of Cardiology, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, JAMA Cardiol. 2017;2(6):673-677. doi:10.1001/jamacardio.2016.5669 Palmer 415, Boston, MA 02215 Published online March 1, 2017. ([email protected]).

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n the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) ran- Key Points domized clinical trial, bivalirudin, compared with heparin I Question Do “fast” procedures (<45 minutes) have a higher risk of and glycoprotein IIb/IIIa receptor inhibitor (GPI), had similar acute stent thrombosis? rates of ischemic complications and reduced bleeding and mor- Findings In this ad hoc analysis of the Harmonizing Outcomes tality after primary percutaneous coronary intervention (PPCI) with Revascularization and Stents in Acute Myocardial Infarction for ST-segment elevation myocardial infarction (STEMI).1 Defi- (HORIZONS-AMI) clinical trial, patients who were randomized to 2-4 nite stent thrombosis was more common with bivalirudin. bivalirudin, underwent stent placement, and had shorter (<45 Preprocedural heparin and high-dose clopidogrel therapy re- minutes) procedures were at statistically higher risk of acute stent duced subacute stent thrombosis but not acute stent throm- thrombosis than patients who underwent longer procedures. bosis (AST).2 It was postulated that (1) in shorter procedures sup- Meaning Short-acting medications, such as bivalirudin, may not ported by procedural bivalirudin, AST rates would be higher allow for adequate antithrombotic effect of oral antiplatelets in than in longer procedures because the therapeutic antiplate- fast procedures; additional studies are needed to evaluate let effect was not achieved before antithrombin inhibition re- antithrombotic therapies with different pharmacokinetics. solves, and (2) this phenomenon would not be observed with heparin plus GPI because of longer antithrombin and more potent antiplatelet effect.1,2 Results

Methods Baseline Characteristics Median (interquartile range [IQR]) procedure time was 55 (49- The HORIZONS-AMI randomized clinical trial, conducted be- 77) minutes and was similar in the bivalirudin group and the tween March 25, 2005, and May 7, 2007, was a prospective, heparin-plus-GPI group (median [IQR], 58 [45-76] minutes; open-label, multicenter trial that included 3602 patients with P = .35). Median (IQR) procedure time was 38 (32-42) min- STEMI, aged 18 years or older, who were undergoing PPCI and utes in the shorter procedure quartile, while the other quar- presenting fewer than 12 hours from symptom onset. The study tiles had a pooled median (IQR) of 68 (56-85) minutes. Base- design and primary results of this trial have been published.1 line clinical characteristics are shown in Table 1. Patients who The trial was approved by the institutional review board or eth- underwent shorter procedures were younger and less likely to ics committee at each participating site, and all participants be hypertensive and smokers. provided written informed consent prior to participation. Pa- tients were randomized 1:1 to bivalirudin or heparin plus GPI Procedural Characteristics and then 3:1 to the TAXUS-Express paclitaxel-eluting stent (Bos- Shorter procedures in both treatment groups were associated ton Scientific Corporation) or identical bare metal stents. Clini- with shorter door-to-balloon times, less frequent use of ra- cal follow-up occurred at 30 days, 6 months, 1 year, 2 years, dial access, and more frequent use of a 600-mg (rather than and 3 years. This ad hoc analysis was conceived and prepared 300-mg) clopidogrel loading dose (Table 2). Rates of prepro- between March 1, 2015, and April 30, 2016. cedure heparin administration were similar for shorter and longer procedures. Shorter procedural times were associated with Study Design and Patient Population less complex procedures and less multivessel PPCI. There were Procedure time, defined as the difference between the patient’s no substantial differences between pre-PCI and post-PCI arrival at the catheterization laboratory and the patient’s final thrombolysis in myocardial infarction flow or peak activated angiogram, was identified in all patients (bivalirudin, n = 1286; clotting time measurements according to procedure time. Bail- heparin plus GPI, n = 1412) (eFigure in the Supplement). Total out use of GPI in patients treated with bivalirudin was more procedure time was divided into shorter (shortest procedure frequent among patients with longer procedures (Table 2). The quartile) and longer (other 3 quartiles) procedures. Patients were most common indications for bailout use of GPI were sus- excluded for bivalirudin or heparin infusion postprocedure tained no-reflow (47 [32.1%]) and giant thrombus (39 [26.7%]). (n = 185) (eFigure in the Supplement), missing procedure times (n = 16), or no stent implantation (n = 703). Stent Thrombosis Among patients treated with bivalirudin, definite AST was more Primary Outcome frequent after shorter procedures than after longer proce- The primary outcome was clinical events committee– dures (7 [2.1%] vs 7 [0.7%]; 95% CI, 1.01-8.17; P =.04)(Table 3). adjudicated definite AST (occurring ≤24 hours after percuta- All stent thromboses occurred postprocedure. The median neous coronary intervention), according to Academic (IQR) procedure time for bivalirudin-treated patients with AST Research Consortium criteria.5 Core laboratory angiographic was 49 (30-67) minutes and for bivalirudin-treated patients analysis confirming stent thrombosis was performed. Pro- without AST was 60 (45-79) minutes (P = .04). Most AST oc- pensity score matching (eTable in the Supplement) was curred among patients treated with bivalirudin, with proce- employed to address known confounding factors and to dure times faster than 60 minutes. Among patients treated with quantify the time-dependence odds of AST according to heparin plus GPI, no AST occurred in shorter procedures com- treatment. pared with longer procedures (0 vs 3 [0.3%]; P = .30) (Table 3).

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Table 1. Baseline Characteristics by Procedure Time in Patients Treated With Bivalirudin or Heparin Plus GPI

Bivalirudin, No. (%) Heparin + GPI, No. (%) Quartile 1 Quartiles 2-4 Quartile 1 Quartiles 2-4 Variable (n = 333)a (n = 953)b P Value (n = 370)a (n = 1042)b P Value Age, median (IQR), y 57.5 (50.2-65.5) 60.0 (52.3-69.7) <.001 57.9 (50.6-67.8) 60.8 (53.2-69.6) <.001 Male 274 (82.3) 732 (76.8) .04 274 (74.1) 801 (76.9) .27 BMI, median (IQR) 27.0 (24.5-29.7) 27.2 (24.5-30.5) .42 27.4 (24.8-30.5) 27.0 (24.6-29.8) .18 Hypertension, No. (%) 158 (47.4) 473 (49.6) .49 177 (47.8) 568 (54.5) .03 Hyperlipidemia, No. (%) 141 (42.3) 395 (41.4) .78 153 (41.4) 440 (42.2) .77 Any prior smoking, No. (%) 221 (66.6) 650 (68.6) .50 237 (64.2) 643 (61.8) .40 Current 178 (53.6) 457 (48.2) .09 175 (47.4) 478 (45.9) .62 Former 43 (13.0) 193 (20.4) .00 62 (16.8) 164 (15.8) .64 Diabetes, No. (%) 46 (13.8) 148 (15.5) .45 61 (16.5) 168 (16.1) .87 Diet only 12 (3.6) 30 (3.1) .69 10 (2.7) 30 (2.9) .86 Oral medications 27 (8.1) 91 (9.5) .43 38 (10.3) 101 (9.7) .75 Insulin 10 (3.0) 39 (4.1) .37 19 (5.1) 46 (4.4) .57 Prior myocardial infarction, No. (%) 26 (7.8) 86 (9.0) .50 35 (9.5) 108 (10.4) .62 Prior PCI, No. (%) 27 (8.1) 87 (9.1) .57 34 (9.2) 95 (9.1) .97 Prior CABG, No. (%) 2 (0.6) 28 (2.9) .01 2 (0.5) 24 (2.3) .03 Prior angina, No. (%) 69 (20.7) 211 (22.1) .59 85 (23.0) 228 (21.9) .66 Prior congestive heart failure, No. (%) 7 (2.1) 22 (2.3) .83 6 (1.6) 35 (3.4) .09 Killip class 1 310 (93.4) 869 (91.3) .23 348 (94.1) 943 (90.6) .04 2 17 (5.1) 74 (7.8) .10 21 (5.7) 82 (7.9) .16 3 2 (0.6) 6 (0.6) >.99 0 7 (0.7) .20 4 3 (0.9) 3 (0.3) .18 1 (0.3) 9 (0.9) .47 Abbreviations: BMI, body mass index (calculated as weight in kilograms divided a The median (IQR) for quartile 1 was 38 (32-42) minutes. by height in meters squared); CABG, coronary artery bypass graft; b The median (IQR) for quartiles 2 to 4 was 68 (58-85) minutes. GPI, glycoprotein IIb/IIIa receptor inhibitor; IQR, interquartile range; PCI, percutaneous coronary intervention.

There were no substantial differences in stent thrombosis antiplatelet effect is achieved with heparin plus GPI; no rela- between the treatment groups from 1 to 30 days (subacute) and tionship between procedural duration and AST was found. from 1 to 3 years (very late) (Table 3). Results of propensity score Whether this phenomenon occurs with the use of unfraction- analysis (eTable in the Supplement) indicated most AST oc- ated heparin without GPI is unknown. curred in procedures faster than 60 minutes. There was an in- These findings also provide insight into differential out- teraction of treatment assignment and procedure duration in- comes reported among STEMI trials comparing bivalirudin dicating this relationship was observed in patients treated with with heparin. Pooled results of the HORIZONS-AMI and bivalirudin but not for those treated with heparin plus GPI. EUROMAX (European Ambulance Acute Coronary Syndrome Angiography)7 studies demonstrated reduced rates of car- diac death (2.0% vs 2.9%; relative risk [RR], 0.70; 95% CI, 0.50- Discussion 0.97; P = .03) and less major bleeding (4.2% vs 7.8%; RR, 0.53; 95% CI, 0.43-0.66; P < .0001).7 Similarly, among patients with Compared with the use of heparin plus GPI, bivalirudin use in STEMI in the MATRIX (Minimizing Adverse Hemorrhagic PPCI was associated with less major bleeding, thrombocyto- Events by Transradial Access Site and Systemic Implementa- penia and mortality, and an increased risk of AST.1,3,4 Shorter tion of Angiox) study,4 the 30-day rate of all-cause mortality procedural duration (≤45 minutes) among patients treated with was lower with bivalirudin treatment compared with heparin bivalirudin was associated with more definite AST despite being (2.1% vs 3.1%; RR, 0.68; 95% CI, 0.46-1.01; P = .05).2,4 How- less complex than longer procedures. These findings were spe- ever, among patients treated with procedural-only bivaliru- cific to patients treated with bivalirudin because this associa- din in these trials (or with a low-dose post-PCI bivalirudin in- tion was not observed in patients receiving heparin plus GPI. fusion of 0.25 mg/kg/h), AST was increased, compared with The pharmacokinetics of bivalirudin and clopidogrel of- heparin with or without GPI; this is a finding also observed in fer insight. When the PPCI procedure is completed rapidly, ad- the HEAT-PPCI (Unfractionated Heparin vs Bivalirudin in equate antiplatelet effect may not have been achieved with oral Primary Percutaneous Coronary Intervention) trial.8 agents, particularly if gastrointestinal tract absorption has been In the EUROMAX and BRIGHT (Bivalirudin vs Heparin With slowed in STEMI.6 In this setting, the short half-life of bivali- or Without Tirofiban During Primary Percutaneous Coronary In- rudin (25 minutes) leaves the newly implanted stent rela- tervention in Acute Myocardial Infarction) trials,7-9 prolonga- tively unprotected against AST for short procedures. Con- tion of the 1.75–mg/kg/h bivalirudin infusion for 3 to 4 hours af- versely, the duration of antithrombin effect is longer and rapid ter PCI appeared to mitigate the risk of AST regardless of whether

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Table 2. Procedural Characteristics by Procedure Time in Patients Treated With Bivalirudin or Heparin Plus GPI

Procedure Time: Bivalirudin, No. (%) Procedure Time: Heparin + GPI, No. (%) Quartile 1 Quartiles 2-4 P Quartile 1 Quartiles 2-4 P Variable (n = 333)a (n = 953)b Value (n = 370)a (n = 1042)b Value Preprocedure heparin received, No. (%) 214 (64.3) 609 (63.9) .91 250 (67.6) 669 (64.2) .24 Clopidogrel loading dose, No. (%) 300 mg 85 (25.5) 373 (39.1) <.001 105 (28.4) 385 (36.9) .003 600 mg 247 (74.2) 579 (60.8) <.001 265 (71.6) 655 (62.9) .002 Total stent length implanted, 20.0 (16.0-28.0) 28.0 (20.0-40.0) <.001 20.0 (16.0-28.0) 28.0 (20.0-40.0) <.001 median (IQR), mm Poststent dilatation, No. (%) 72 (22.9) 377 (43.2) <.001 81 (22.8) 414 (43.0) <.001 Multiple vessels treated, No. (%) 3 (0.9) 48 (5.1) .00 2 (0.5) 58 (5.6) <.001 Multiple lesions treated, No. (%) 12 (3.6) 119 (12.5) <.001 12 (3.3) 132 (12.7) <.001 Direct stenting attempted, No. (%) 118 (35.4) 264 (27.7) .01 158 (42.7) 312 (29.9) <.001 Total fluoroscopy time, median (IQR), min 7.0 (5.0-9.0) 13.0 (9.0-19.0) <.001 7.0 (5.0-10.0) 13.0 (9.0-18.0) <.001 Total amount of contrast, median (IQR), mL 190.0 (150.0-225.0) 246.0 (200.0-300.0) <.001 180.0 (145.0-220.0) 240.0 (195.0-300.0) <.001 Any side branch treated, No. (%) 5 (1.5) 72 (7.6) <.001 3 (0.8) 79 (7.6) <.001 Index PCI vessel, No. (%) LAD 132 (38.8) 410 (39.2) .91 160 (42.8) 483 (41.6) .69 LCX 54 (15.9) 181 (17.3) .55 49 (13.1) 183 (15.8) .21 RCA 153 (45.0) 439 (41.9) .32 165 (44.1) 484 (41.7) .41 LM 0 5 (0.5) .34 0 1 (0.1) >.99 SVG 0 11 (1.1) .08 0 10 (0.9) .13 Bailout GPI, No. (%) 22 (6.6) 124 (13.0) .00 NA NA NA Reason for bailout GPI, No. (%) Giant thrombus 5 (1.5) 34 (3.6) .06 NA NA NA Sustained no-reflow 2 (0.6) 45 (4.7) .00 NA NA NA Angiographic complication 6 (1.8) 13 (1.4) .60 NA NA NA Distal embolization or side branch loss 2 (0.6) 4 (0.4) .65 NA NA NA Acute closure 0 1 (0.1) >.99 NA NA NA Residual thrombus 0 5 (0.5) .34 NA NA NA TIMI flow pre-PCIc, No. (%) TIMI 0/1 219 (64.6) 680 (64.9) .91 237 (63.4) 731 (63.0) .90 TIMI 2 58 (17.1) 169 (16.1) .68 56 (15.0) 203 (17.5) .26 TIMI 3 62 (18.3) 198 (18.9) .80 81 (21.7) 226 (19.5) .36 Final TIMI flow post-PCIc, No. (%) TIMI 0/1 0 7 (0.7) .20 1 (0.3) 13 (1.1) .21 TIMI 2 15 (4.4) 51 (4.9) .73 18 (4.8) 56 (4.8) >.99 TIMI 3 325 (95.6) 988 (94.5) .42 354 (94.9) 1092 (94.1) .54 Symptom onset-to-balloon, 204.5 (144.0-305.0) 229.0 (166.0-346.0) <.001 210.0 (151.0-320.0) 221.0 (162.0-331.5) .11 median (IQR), min Door-to-balloon, median (IQR), min 81.0 (59.0-125.0) 102.5 (78.0-135.0) <.001 91.0 (63.0-123.0) 101.0 (75.0-136.5) <.001 Abbreviations: GPI, glycoprotein IIb/IIIa receptor inhibitor; IQR, interquartile a The median (IQR) for quartile 1 was 38 (32-42) minutes. range; LAD, left anterior descending artery; LCX, left circumflex artery; LM, left b The median (IQR) for quartiles 2 to 4 was 68 (58-85) minutes. main; NA, not applicable; PCI, percutaneous coronary intervention; RCA, right c Operator assessed. coronary artery; SVG, saphenous vein graft; TIMI, thrombolysis in myocardial infarction.

clopidogrel or a more potent and rapid-acting oral antiplatelet mately 50% reduction in AST compared with periprocedural agent, such as ticagrelor or prasugrel, was used. Similarly, AST clopidogrel use, although few of these were patients with occurred in 0.6%, 0.8%, and 0.2% of patients in the MATRIX STEMI.12 Bolus GPI led to rapid and sustained platelet inhibi- trial4 with no, low-dose, and high-dose postprocedural bivali- tion with prasugrel in the FABOLUS-PRO (Facilitation Through rudin infusions, confirming that prolongation of infusion likely Aggrastat by Dropping or Shortening Infusion Line in Pa- does reduce the excess risk of stent thrombosis.4,9-11 Thus, the tients With ST-Segment Elevation Myocardial Infarction Com- US Food and Drug Administration has recently revised the in- pared to or on Top of Prasugrel Given at Loading Dose) trial.13 structions for use of bivalirudin to strongly recommend this pro- Furthermore, preloading with ticagrelor has also shown to longed high-dose infusion after PPCI. decrease risk of thrombotic events.14,15 Whether use of a rapid-acting potent intravenous antiplatelet agent lowers AST risk with procedural-only bivaliru- Limitations din for short procedures requires further study. A 2-hour in- Our findings should be interpreted with care given the low fusion of cangrelor in bivalirudin-treated patients undergoing event rates. Although HORIZONS-AMI was one of the largest percutaneous coronary intervention resulted in approxi- PPCI trials ever, there was not sufficient statistical power to

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Table 3. Proportion of Patients With Definite Stent Thrombosis by Procedure Time in Patients Treated With Bivalirudin or Heparin Plus GPIa

Procedure Time: Procedure Time: Bivalirudin, No. (%) Heparin + GPI, No. (%) Abbreviations: GPI, glycoprotein Quartile 1 Quartiles 2-4 P Quartile 1 Quartiles 2-4 P IIb/IIIa receptor inhibitor; Variable (n = 333)b (n = 953)c Value (n = 370)b (n = 1042)c Value IQR, interquartile range. Acute stent thrombosis, <24 h 7 (2.1) 7 (0.7) .04 0 3 (0.3) .30 a Data are given as number of events Subacute stent thrombosis, 1-30 d 4 (1.2) 8 (0.9) .56 4 (1.1) 13 (1.3) .79 (event rates [Kaplan-Meier Early stent thrombosis, 30 d 11 (3.3) 15 (1.6) .05 4 (1.1) 16 (1.6) .52 estimates]). Late stent thrombosis, 1-12 mo 2 (0.6) 9 (1.0) .56 3 (0.8) 9 (0.9) .92 b The median (IQR) for quartile 1 was 38 (32-42) minutes. Stent thrombosis, 1 y 13 (3.9) 23 (2.5) .15 7 (1.9) 24 (2.4) .63 c The median (IQR) for quartiles 2 to 4 Very late stent thrombosis, 12-36 mo 4 (1.3) 11 (1.2) .94 15 (0.5) 22 (2.3) .36 was 68 (58-85) minutes.

evaluate differences in various patient characteristics and technical factors for a low-frequency outcome such as AST, espe- Conclusions cially when stratifying by procedure time. However, most of the observed factors confounding the association of proce- Shorter procedure time among patients with STEMI is associ- dure time with AST, such as complexity of patients and pro- ated with an increased risk of AST after PPCI with procedural cedures, would have biased toward negating the results ob- bivalirudin, but not with heparin plus GPI. Additional studies served in this study. Similarly, interpretation of the effect of evaluating strategies aimed at mitigating this effect, includ- nonrandomized treatments, such as bailout or upstream GPI ing a high-dose prolonged bivalirudin infusion or intrave- use and prerandomization unfractionated heparin use, is lim- nous cangrelor, are warranted in order to achieve the benefits ited. Differences in procedural duration may also reflect less of bivalirudin during PPCI, including reducing major bleed- meticulous technique, resulting in AST. ing and mortality, without an increased risk of AST.

ARTICLE INFORMATION REFERENCES 9. Han Y, Guo J, Zheng Y, et al; BRIGHT Investigators. Accepted for Publication: December 3, 2016. 1. Stone GW, Witzenbichler B, Guagliumi G, et al; Bivalirudin vs heparin with or without tirofiban HORIZONS-AMI Trial Investigators. Bivalirudin during primary percutaneous coronary intervention Published Online: March 1, 2017. during primary PCI in acute myocardial infarction. in acute myocardial infarction: the BRIGHT random- doi:10.1001/jamacardio.2016.5669 N Engl J Med. 2008;358(21):2218-2230. ized clinical trial. JAMA. 2015;313(13):1336-1346. AuthorContributions:DrPintohadfullaccesstoallthe 2. Dangas GD, Caixeta A, Mehran R, et al; Harmonizing 10. Schömig A. Ticagrelor—is there need for a new data in the study and takes responsibility for the integ- Outcomes With Revascularization and Stents in Acute player in the antiplatelet-therapy field? N Engl J Med. rity of the data and the accuracy of the data analysis. Myocardial Infarction (HORIZONS-AMI) Trial Investiga- 2009;361(11):1108-1111. Study concept and design: Tamez, Pinto, Kirtane, tors. Frequency and predictors of stent thrombosis 11. Clemmensen P, Wiberg S, Van’t Hof A, et al. Dangas, Mehran, Deliargyris, Gibson, Stone. afterpercutaneouscoronaryinterventioninacutemyo- Acute stent thrombosis after primary percutaneous Acquisition, analysis, or interpretation of data: cardial infarction. Circulation. 2011;123(16):1745-1756. Tamez, Pinto, Kirtane, Litherland, Yeh, Mehran, coronary intervention: insights from the EUROMAX 3. Cavender MA, Sabatine MS. Bivalirudin versus trial (European Ambulance Acute Coronary Deliargyris, Ortiz, Stone. heparin in patients planned for percutaneous Draftingofthemanuscript:Tamez,Pinto,Kirtane,Ortiz. Syndrome Angiography). JACC Cardiovasc Interv. coronary intervention: a meta-analysis of 2015;8(1 Pt B)(1, pt B):214-220. Critical revision of the manuscript for important randomised controlled trials. Lancet. 2014;384 intellectual content: Tamez, Pinto, Kirtane, (9943):599-606. 12. BhattDL,StoneGW,MahaffeyKW,etal;CHAMPION Litherland, Yeh, Dangas, Mehran, Deliargyris, PHOENIXInvestigators.Effectofplateletinhibitionwith 4. Valgimigli M, Frigoli E, Leonardi S, et al; MATRIX Gibson, Stone. cangrelor during PCI on ischemic events. N Engl J Med. Investigators. Bivalirudin or unfractionated heparin Statistical analysis: Tamez, Pinto, Litherland. 2013;368(14):1303-1313. in acute coronary syndromes. N Engl J Med. 2015; Obtained funding: Stone. 373(11):997-1009. 13. Valgimigli M, Tebaldi M, Campo G, et al; FABOLUS Administrative, technical, or material support: 5. Cutlip DE, Windecker S, Mehran R, et al; PROInvestigators.Prasugrelversustirofibanboluswith Tamez, Kirtane, Deliargyris. Academic Research Consortium. 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