Abstract

Aims

Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable with bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome.

Methods and results

A total of 2505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pre-treatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome—a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2281 patients). In a second analysis, we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group compared with 8.7% in the higher UFH dose group [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.67–1.00; P = 0.045]. The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR 0.79; 95% CI 0.59–1.05; P = 0.11). The lower UFH dose met the criterion of non-inferiority compared with bivalirudin (P < 0.001).

Conclusion

In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared with the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding.

Clinical trial registration information

URL www.clinicaltrials.gov; Unique identifier NCT00735280.

See page 2447 for the editorial comment on this article (doi:10.1093/eurheartj/ehq344)

Since the first percutaneous coronary intervention (PCI) was performed in 1977,1 unfractionated heparin (UFH) has been the standard antithrombin agent in interventional cardiology and the reference against which new antithrombotic agents have been tested. Two UFH dosing regimens are currently recommended for PCI: an initial UFH bolus dose of 70–100 units (U)/kg followed by additional boluses if required under activated clotting time (ACT) guidance2 and the other consisting of a single bolus dose of 100 U/kg of UFH without ACT monitoring.3 The first UFH regimen is more common in the USA and the second is typically employed in Europe.

In fact, recommendations regarding UFH dose to use during PCI are based on evidence level C that reflects the lack of sufficient data from randomized trials. Vainer et al.4 found no significant difference in outcomes among 404 patients randomly assigned to either 5000 or 20 000 U of UFH during PCI. Boccara et al.5 also found no difference in outcomes among 400 patients randomly assigned to either 100 U/kg or 15 000 U of UFH. In a British survey in 2001, 53% of practitioners used UFH doses of 10 000 U or higher during PCI.6 In an analysis of four randomized clinical trials on adjunct antithrombotic treatment where UFH dosing was done under ACT guidance, total UFH dose during PCI ranged on average between 67 and 89 U/kg.7 However, 43–100% of the patients included in these trials also received glycoprotein IIb/IIIa inhibitors, a situation which requires halving of the dose of UFH.

A single bolus dose of 140 U/kg of UFH led to net clinical outcome comparable with that achieved with bivalirudin—a direct thrombin inhibitor8–10—in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, but it was associated with a higher risk of bleeding.11

The aim of the prospective, multicentre, single-arm, open-label ISAR-REACT 3A trial was to evaluate whether a reduction in the UFH dose from 140 to 100 U/kg is associated with better net clinical outcome in biomarker negative patients undergoing PCI after pre-treatment with 600 mg clopidogrel. Results were to be primarily compared with those achieved in the higher (140 U/kg) UFH dose arm of the ISAR-REACT 3 trial (historical control).

Methods

Study population

Patients were enrolled in three German centres—the Deutsches Herzzentrum, Munich, the 1. Medizinische Klinik, Klinikum rechts der Isar, Munich, and the Herz-Zentrum Bad Krozingen—from August 2008 until February 2010. The eligibility, inclusion, and exclusion criteria were the same as that used for the ISAR-REACT 3 trial.11 Briefly, biomarker negative patients with stable and unstable angina undergoing PCI after pre-treatment with 600 mg clopidogrel for at least 2 h before the intervention were enrolled.

Data collection was performed by the ISAResearch Center in Munich. There was no industry involvement in the design, conduct, analysis, or interpretation of the data. Ethics committee approval was obtained and informed consent received from the subjects (or their guardians).

Study protocol

Eligible patients were included consecutively after establishing the indication for PCI. All patients enrolled in ISAR-REACT 3A received one open label bolus of 100 U/kg bodyweight UFH before the guide wire had crossed the lesion. Monitoring of ACT was not required and no additional boluses of UFH were administered. As in ISAR-REACT 3 trial, patients received 325–500 mg aspirin as well as 600 mg clopidogrel prior to PCI, the latter within a time interval of at least 2 h before the intervention. Sheath was removed and manual compression applied as soon as the aPTT was <50 s. Post-interventional antithrombotic therapy consisted of aspirin 80–325 mg indefinitely and clopidogrel 75–150 mg daily for the remainder of the hospitalization (but not more than 3 days) followed by 75 mg a day for at least 1 month after bare metal stent implantation and at least 6 months after deployment of a drug-eluting stent. More details of the study protocol were reported in the primary publication.11

Follow-up

Electrocardiograms and laboratory measurements (including cardiac enzymes, haemoglobin, and platelet count) were performed every 8 h for the first 24 h after the procedure and daily afterwards, until discharge. All patients were interviewed by phone at 30 days. Those with cardiac complaints underwent a complete clinical, electrocardiographic, and laboratory evaluation. If patients suffered a qualifying event at another hospital, the appropriate source documents were solicited (including discharge summaries, laboratory values, and angiograms). Family doctors, referring cardiologists, patients, or their relatives were contacted for additional information if necessary.

Study endpoints and definitions

In ISAR-REACT 3A, identical endpoints and definitions as used in ISAR-REACT 3 were applied.11 The primary net clinical outcome endpoint was the combined incidence of death from any cause, myocardial infarction (MI), urgent target vessel revascularization (TVR; coronary bypass surgery or PCI) at 30 days after inclusion, or major bleeding during the index hospitalization. Myocardial infarction was defined as the development of pathologic Q waves (≥30 ms in duration and ≥0.1 mV in depth) in two or more contiguous precordial or adjacent limb leads, or an elevation of CK-MB isoenzyme levels (or total CK if measures of CK-MB were not available) to at least two times the upper limit of the normal. Major bleeding was defined according to Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial criteria: intracranial, intraocular, or retroperitoneal haemorrhage; clinically overt blood loss resulting in a decrease in haemoglobin of more than 3 g per decilitre; any decrease in haemoglobin of more than 4 g per decilitre; or transfusion of two or more units of packed red cells or whole blood.8 The secondary ‘ischaemic’ endpoint was a combined incidence of death from any cause, MI, or urgent TVR at 30 days after inclusion. In addition, major and minor bleeding were assessed according to the Thrombolysis in Myocardial Infarction criteria.12 Stent thrombosis was considered to have occurred when the Academic Research Consortium criteria for definite stent thrombosis were met.13 All events were adjudicated and classified by the event-adjudication committee.

Statistical analysis

The hypothesis to be tested was that the reduced dose of 100 U/kg UFH provides net clinical benefit compared with the higher heparin dose of 140 U/kg used in the ISAR-REACT 3 trial (historical control). In ISAR-REACT 3, the incidence of the primary quadruple endpoint was 8.7% in the UFH arm and 8.3% in the bivalirudin arm.11 Assumptions of a 25% relative reduction (2.2% in absolute) in the incidence of the primary endpoint with the lower vs. the higher UFH dose, a power of 80%, and a two-sided α-level of 0.05 required the inclusion of 2367 patients. To account for possible losses to follow-up it was planned to enrol a total number of 2500 patients. This number of patients also provides the trial with 74% power for checking the non-ineriority of treatment with lower dose UFH vs. treatment with bivalirudin in the ISAR-REACT 3 trial with a margin of non-inferiority of 1.8% and a one-sided α-value of 0.05. The margin of non-inferiority aimed at preserving 80% of the superiority assumption of bivalirudin over UFH 140 U/kg of 2.2% in ISAR-REACT 3.11 Sample size calculation was performed with nQuery Advisor (version 4.0, Statistical Solutions).14

Categorical data are presented as counts (%) and compared with the use of a chi-square test and Fisher's exact test when expected cell values were less than 5. Continuous data were presented as median (25th and 75th percentiles) and compared by means of the Wilcoxon's test, because they were not normally distributed (Kolmogorov–Smirnov's test).

Because part of the patients received interventional treatment in multiple lesions, generalized estimation equation (GEE) models were employed to consider for repeated measurements (lesions) per subject within the analysis of group differences. The GEE approach properly reflects the structure of clustered data and takes within-subject dependencies (autocorrelation) into account.15

Cumulative incidences of events were estimated by the Kaplan–Meier method. The hazard ratios (HRs) with 95% confidence intervals (CIs) associated with treatment assignment were calculated with the use of Cox proportional hazards models. The proportional hazards assumption was checked by the method of Grambsch and Therneau16 and was fulfilled in all cases in which the Cox proportional hazards model was used.

In order to balance covariates and thus reduce bias, we used propensity score methodology. The propensity score is the probability that a patient would have been treated with UFH 100 U/kg vs. UFH 140 U/kg and UFH 100 U/kg vs. bivalirudin, respectively, given the patient's observed pre-treatment characteristics. The propensity score was estimated using a logistic regression model including baseline clinical and angiographic characteristics as predictor variables and treatment category as an outcome variable. The obtained propensity scores were used in two subsequent types of analysis. First, we created samples of patients matched for propensity scores within a calliper of ±0.002. Matching was performed with the use of an internet-based software based on a Euclidean nearest neighbour metric method.17 In patients with multilesion interventions, only one lesion at random was selected for matching. Comparison of the parameters in the matched groups was done with the use of Wilcoxon's (continuous variables) and McNemar's (discrete variables) tests for paired samples. The risk for adverse outcomes was assessed by calculating the odds ratio (OR) with the McNemar's test. Second, the individual propensity scores were entered into all multivariable models used for assessment of outcomes.

Pre-specified subgroups were defined by median age, sex, the presence or absence of diabetes, the median baseline serum creatinine value, and stable or unstable angina. No formal adjustment for multiple testing was performed. Heterogeneity of treatment differences across the levels of a baseline variable were checked by assessing the interaction between the assigned treatment and the baseline variable with respect to the primary endpoint. This was done by entering the interaction term into the respective Cox proportional hazards model with adjustment for propensity score.

For non-inferiority testing, a one-sided P-value < 0.05 was considered significant; otherwise, a two-tailed P-value < 0.05 was considered to indicate statistical significance. The program EquivTest (Statistical Solutions) was used for non-inferiority testing (according to the method of Chow and Liu).18 In all other cases, S-PLUS software, version 4.5 (Insightful) was used.

Results

A total of 2505 eligible patients (1052 patients in the Deutsches Herzzentrum Munich; 1004 in the Herz-Zentrum Bad Krozingen, and 449 in the 1. Medizinische Klinik, Klinikum rechts der Isar, Munich) were consecutively included in this study and received a reduced single bolus dose of 100 U/kg UFH. These three centres had provided 93% of the patients enrolled in the previous ISAR-REACT 3 trial.11 None of the patients required administration of glycoprotein IIb/IIIa inhibitors. Thirty-day follow-up was complete in all but 21 patients, whose data were censored at the last available contact date (range 2–8 days after enrolment).

Baseline characteristics of the patients that received the lower heparin dose are shown in Tables 1 and 2 and compared with the higher heparin dose group and the bivalirudin group of ISAR-REACT 3.11 The analysis revealed significant differences in baseline variables.

Table 1

Baseline characteristics of the patientsa

Characteristic UFH 100 U/kg UFH 140 U/kg Bivalirudin P-value* P-value** 
No. of patients 2505 2281 2289   
Age (year) 67.9 (60.0–74.4) 67.5 (60.2–74.2) 67.8 (60.4–73.8) 0.55 0.45 
Women, n (%) 554 (22.1) 530 (23.2) 545 (23.8) 0.36 0.16 
Diabetes, n (%) 758 (30.3) 636 (27.9) 618 (27.0) 0.07 0.013 
 Insulin-treated, n (%) 247 (9.9) 191 (8.4) 176 (7.7) 0.07 0.008 
Current smoker, n (%) 374 (14.9) 337 (14.8) 328 (14.3) 0.88 0.56 
Arterial hypertension, n (%) 2283 (91.1) 2044 (89.6) 2034 (88.9) 0.07 0.008 
Hypercholesterolaemia, n (%) 1791 (71.5) 1795 (78.7) 1850 (80.8) <0.001 <0.001 
Angina, n (%)    <0.001 <0.001 
 Unstable 566 (22.6) 415 (18.2) 421 (18.4)   
 Stable 1939 (77.4) 1866 (81.8) 1868 (81.6)   
No. of diseased coronary vessels, n (%)    <0.001 <0.001 
 One vessel 339 (13.5) 459 (20.1) 452 (19.7)   
 Two vessels 617 (24.6) 658 (28.8) 633 (27.7)   
 Three vessels 1549 (61.8) 1164 (51.0) 1204 (52.6)   
Prior myocardial infarction, n (%) 858 (34.3) 689 (30.2) 734 (32.1) 0.003 0.11 
Prior aortocoronary bypass surgery, n (%) 346 (13.8) 248 (10.9) 286 (12.5) 0.002 0.18 
Body weight (kg) 81 (73–91) 81 (72–90) 80 (72–90) 0.32 0.005 
Body mass index (kg/m227.4 (24.9–30.1) 27.2 (24.9–29.8) 27.1 (24.8–29.8) 0.43 0.049 
Serum creatinine (mg/dL) 1.0 (0.8–1.1) 0.9 (0.8–1.1) 0.9 (0.8–1.1) <0.001 <0.001 
Left ventricular ejection fraction (%) 58 (50–62) 60 (52–65) 60 (52– 65) <0.001 <0.001 
Characteristic UFH 100 U/kg UFH 140 U/kg Bivalirudin P-value* P-value** 
No. of patients 2505 2281 2289   
Age (year) 67.9 (60.0–74.4) 67.5 (60.2–74.2) 67.8 (60.4–73.8) 0.55 0.45 
Women, n (%) 554 (22.1) 530 (23.2) 545 (23.8) 0.36 0.16 
Diabetes, n (%) 758 (30.3) 636 (27.9) 618 (27.0) 0.07 0.013 
 Insulin-treated, n (%) 247 (9.9) 191 (8.4) 176 (7.7) 0.07 0.008 
Current smoker, n (%) 374 (14.9) 337 (14.8) 328 (14.3) 0.88 0.56 
Arterial hypertension, n (%) 2283 (91.1) 2044 (89.6) 2034 (88.9) 0.07 0.008 
Hypercholesterolaemia, n (%) 1791 (71.5) 1795 (78.7) 1850 (80.8) <0.001 <0.001 
Angina, n (%)    <0.001 <0.001 
 Unstable 566 (22.6) 415 (18.2) 421 (18.4)   
 Stable 1939 (77.4) 1866 (81.8) 1868 (81.6)   
No. of diseased coronary vessels, n (%)    <0.001 <0.001 
 One vessel 339 (13.5) 459 (20.1) 452 (19.7)   
 Two vessels 617 (24.6) 658 (28.8) 633 (27.7)   
 Three vessels 1549 (61.8) 1164 (51.0) 1204 (52.6)   
Prior myocardial infarction, n (%) 858 (34.3) 689 (30.2) 734 (32.1) 0.003 0.11 
Prior aortocoronary bypass surgery, n (%) 346 (13.8) 248 (10.9) 286 (12.5) 0.002 0.18 
Body weight (kg) 81 (73–91) 81 (72–90) 80 (72–90) 0.32 0.005 
Body mass index (kg/m227.4 (24.9–30.1) 27.2 (24.9–29.8) 27.1 (24.8–29.8) 0.43 0.049 
Serum creatinine (mg/dL) 1.0 (0.8–1.1) 0.9 (0.8–1.1) 0.9 (0.8–1.1) <0.001 <0.001 
Left ventricular ejection fraction (%) 58 (50–62) 60 (52–65) 60 (52– 65) <0.001 <0.001 

UFH, unfractionated heparin.

aData are presented as n (%) or median (25–75th percentile).

*P for the comparison of the lower dose UFH group (100 U/kg) with the higher dose UFH group of ISAR-REACT 3 (140 U/kg).

**P for the comparison of the lower dose UFH group (100 U/kg) with the bivalirudin group of ISAR-REACT 3.

Table 2

Lesion and procedural characteristicsa

Characteristic UFH 100 U/kg UFH 140 U/kg Bivalirudin P-value* P-value** 
No. of lesions 4252 3886 3869   
Target vessel, n (%)    0.19 0.25 
 Left main coronary artery 172 (4.0) 134 (3.4) 159 (4.1)   
 Left anterior descending coronary artery 1629 (38.3) 1507 (38.8) 1568 (40.5)   
 Left circumflex coronary artery 1158 (27.2) 1004 (25.8) 986 (25.5)   
 Right coronary artery 1208 (28.4) 1172 (30.2) 1086 (28.1)   
 Venous bypass graft 85 (2.0) 69 (1.8) 70 (1.8)   
Complex (type B2 or C) lesions, n (%) 3031 (71.3) 2636 (67.8) 2610 (67.5) 0.003 0.001 
Chronic total occlusions, n (%) 364 (8.6) 266 (6.8) 268 (6.9) 0.004 0.006 
Lesion length (mm) 13.4 (8.7–20.6) 11.9 (7.9–18.1) 12.0 (8.1–18.0) <0.001 <0.001 
Vessel size (mm) 2.8 (2.4–3.2) 2.8 (2.4–3.2) 2.8 (2.4–3.2) 0.70 0.76 
Diameter stenosis prior to procedure (%) 66.4 (56.3–76.5) 61.3 (53.6–71.3) 61.6 (53.8–71.4) <0.001 <0.001 
Maximal balloon pressure (atm) 16 (13–18) 15 (12–18) 15 (12–18) <0.001 0.001 
Balloon-to-vessel ratio 1.09 (1.04–1.17) 1.09 (1.04–1.15) 1.09 (1.04–1.15) <0.001 <0.001 
Type of intervention, n (%)    <0.001 <0.001 
 Drug-eluting stent 3865 (90.9) 3383 (87.1) 3416 (88.3)   
 Bare-metal stent 68 (1.6) 238 (6.1) 198 (5.1)   
 Balloon angioplasty 319 (7.5) 265 (6.8) 255 (6.6)   
Length of stented segment (mm) 24 (18–30) 20 (16–28) 20 (16–28) <0.001 <0.001 
Diameter stenosis after procedure (%) 11.3 (7.8–16.0) 10.8 (7.3–14.9) 10.9 (7.3–14.9) <0.001 <0.001 
Characteristic UFH 100 U/kg UFH 140 U/kg Bivalirudin P-value* P-value** 
No. of lesions 4252 3886 3869   
Target vessel, n (%)    0.19 0.25 
 Left main coronary artery 172 (4.0) 134 (3.4) 159 (4.1)   
 Left anterior descending coronary artery 1629 (38.3) 1507 (38.8) 1568 (40.5)   
 Left circumflex coronary artery 1158 (27.2) 1004 (25.8) 986 (25.5)   
 Right coronary artery 1208 (28.4) 1172 (30.2) 1086 (28.1)   
 Venous bypass graft 85 (2.0) 69 (1.8) 70 (1.8)   
Complex (type B2 or C) lesions, n (%) 3031 (71.3) 2636 (67.8) 2610 (67.5) 0.003 0.001 
Chronic total occlusions, n (%) 364 (8.6) 266 (6.8) 268 (6.9) 0.004 0.006 
Lesion length (mm) 13.4 (8.7–20.6) 11.9 (7.9–18.1) 12.0 (8.1–18.0) <0.001 <0.001 
Vessel size (mm) 2.8 (2.4–3.2) 2.8 (2.4–3.2) 2.8 (2.4–3.2) 0.70 0.76 
Diameter stenosis prior to procedure (%) 66.4 (56.3–76.5) 61.3 (53.6–71.3) 61.6 (53.8–71.4) <0.001 <0.001 
Maximal balloon pressure (atm) 16 (13–18) 15 (12–18) 15 (12–18) <0.001 0.001 
Balloon-to-vessel ratio 1.09 (1.04–1.17) 1.09 (1.04–1.15) 1.09 (1.04–1.15) <0.001 <0.001 
Type of intervention, n (%)    <0.001 <0.001 
 Drug-eluting stent 3865 (90.9) 3383 (87.1) 3416 (88.3)   
 Bare-metal stent 68 (1.6) 238 (6.1) 198 (5.1)   
 Balloon angioplasty 319 (7.5) 265 (6.8) 255 (6.6)   
Length of stented segment (mm) 24 (18–30) 20 (16–28) 20 (16–28) <0.001 <0.001 
Diameter stenosis after procedure (%) 11.3 (7.8–16.0) 10.8 (7.3–14.9) 10.9 (7.3–14.9) <0.001 <0.001 

UFH, unfractionated heparin.

aData are presented as n (%) or median (25th–75th percentile).

*P for the comparison of the lower dose UFH group (100 U/kg) with the higher dose UFH group of ISAR-REACT 3 (140 U/kg).

**P for the comparison of the lower dose UFH group (100 U/kg) with the bivalirudin group of ISAR-REACT 3.

Thirty-day clinical outcomes

Table 3 shows the cumulative incidences of ischaemic and bleeding events in the lower heparin dose group. Results were compared with outcomes of the higher heparin dose group of the ISAR-REACT 3 trial.11

Table 3

Primary quadruple endpoint, secondary triple endpoint, and their components in the two unfractionated heparin groupsa

Event UFH 100 U/kg (n = 2505) UFH, 140 U/kg (n = 2281) Unadjusted HR (95% CI) Adjusted HR (95% CI) 
Quadruple endpoint of death, myocardial infarction, urgent target vessel revascularization, or major bleeding 183 (7.3) 199 (8.7) 0.81 (0.67–1.00) 0.75 (0.60–0.92) 
Triple endpoint of death, myocardial infarction, urgent target vessel revascularization 111 (4.4) 115 (5.0) 0.87 (0.67–1.13) 0.82 (0.62–1.08) 
 Death 5 (0.2) 4 (0.2)   
 Myocardial infarction 99 (4.0) 110 (4.8)   
  Q wave myocardial infarction 8 (0.3) 9 (0.4)   
 Urgent target vessel revascularization 22 (0.9) 17 (0.7)   
 Major bleeding 91 (3.6) 104 (4.6) 0.79 (0.59–1.05) 0.71 (0.53–0.97) 
 Bleeding according to TIMI definition     
  Major 16 (0.6) 24 (1.1)   
  Minor 27 (1.1) 51 (2.2)   
Event UFH 100 U/kg (n = 2505) UFH, 140 U/kg (n = 2281) Unadjusted HR (95% CI) Adjusted HR (95% CI) 
Quadruple endpoint of death, myocardial infarction, urgent target vessel revascularization, or major bleeding 183 (7.3) 199 (8.7) 0.81 (0.67–1.00) 0.75 (0.60–0.92) 
Triple endpoint of death, myocardial infarction, urgent target vessel revascularization 111 (4.4) 115 (5.0) 0.87 (0.67–1.13) 0.82 (0.62–1.08) 
 Death 5 (0.2) 4 (0.2)   
 Myocardial infarction 99 (4.0) 110 (4.8)   
  Q wave myocardial infarction 8 (0.3) 9 (0.4)   
 Urgent target vessel revascularization 22 (0.9) 17 (0.7)   
 Major bleeding 91 (3.6) 104 (4.6) 0.79 (0.59–1.05) 0.71 (0.53–0.97) 
 Bleeding according to TIMI definition     
  Major 16 (0.6) 24 (1.1)   
  Minor 27 (1.1) 51 (2.2)   

Hazard ratios were adjusted for the propensity scores.

HR, hazard ratio; TIMI, thrombolysis in myocardial infarction; UFH, unfractionated heparin.

aData are presented as n (%).

The primary endpoint of the study—the composite of death, MI, urgent TVR, or major bleeding—occurred in 183 patients in the lower dose heparin group (7.3%) and 199 patients in the higher heparin dose group (8.7%) (HR 0.81; 95% CI 0.67–1.00; P = 0.045) (Figure 1).

Figure 1

Cumulative incidence of the primary endpoint in the lower (100 U/kg) unfractionated heparin dose group of the ISAR-REACT 3A trial and in the higher (140 U/kg) unfractionated heparin dose group as well as in the bivalirudin group of the ISAR-REACT 3 trial (historical control). The primary, quadruple endpoint of the study was the 30-day composite of death, myocardial infarction, urgent target-vessel revascularization, or in hospital major bleeding. UFH denotes unfractionated heparin.

Figure 1

Cumulative incidence of the primary endpoint in the lower (100 U/kg) unfractionated heparin dose group of the ISAR-REACT 3A trial and in the higher (140 U/kg) unfractionated heparin dose group as well as in the bivalirudin group of the ISAR-REACT 3 trial (historical control). The primary, quadruple endpoint of the study was the 30-day composite of death, myocardial infarction, urgent target-vessel revascularization, or in hospital major bleeding. UFH denotes unfractionated heparin.

There was no significant interaction between any of the variables defining the pre-specified subgroups of interest and treatment effect on the primary endpoint (Figure 2).

Figure 2

Incidences and adjusted hazard ratios of the primary endpoint (30-day composite of death, myocardial infarction, urgent target-vessel revascularization, or in hospital major bleeding) in pre-specified subgroups. Hazard ratios associated with the use of the lower unfractionated heparin dose (100 U/kg) are shown with their 95% confidence intervals. All hazard ratios were adjusted for the propensity scores. UFH indicates unfractionated heparin.

Figure 2

Incidences and adjusted hazard ratios of the primary endpoint (30-day composite of death, myocardial infarction, urgent target-vessel revascularization, or in hospital major bleeding) in pre-specified subgroups. Hazard ratios associated with the use of the lower unfractionated heparin dose (100 U/kg) are shown with their 95% confidence intervals. All hazard ratios were adjusted for the propensity scores. UFH indicates unfractionated heparin.

The secondary, ischaemic endpoint of the study—the composite of death, MI, or urgent TVR—was reached in 111 patients in the lower heparin dose group (4.4%) and 115 patients in the higher heparin dose group (5.0%; HR 0.87; 95% CI 0.67–1.13; P = 0.29) (Figure 3).

Figure 3

Incidence of events in the lower (100 U/kg) unfractionated heparin dose group of the ISAR-REACT 3A trial and in the higher (140 U/kg) unfractionated heparin dose group as well as in the bivalirudin group of the ISAR-REACT 3 trial (historical control). The secondary endpoint (30-day composite of death, myocardial infarction, urgent target-vessel revascularization) is shown on the left side of the graph; in-hospital major bleeding is shown on the right side of the graph.

Figure 3

Incidence of events in the lower (100 U/kg) unfractionated heparin dose group of the ISAR-REACT 3A trial and in the higher (140 U/kg) unfractionated heparin dose group as well as in the bivalirudin group of the ISAR-REACT 3 trial (historical control). The secondary endpoint (30-day composite of death, myocardial infarction, urgent target-vessel revascularization) is shown on the left side of the graph; in-hospital major bleeding is shown on the right side of the graph.

After entering the propensity score in the multivariable Cox proportional hazards model, the HR associated with the use of the lower heparin dose was 0.75 (95% CI 0.60–0.92; P = 0.007) for the primary endpoint and 0.82 (95% CI 0.62–1.08; P = 0.15) for the secondary endpoint.

Definite stent thrombosis was observed in nine patients (0.4%) in either heparin group.

Major bleeding was observed in 91 patients in the lower heparin dose group (3.6%) and 104 patients (4.6%) in the higher heparin dose group (unadjusted HR 0.79; 95% CI 0.59–1.05; P = 0.11; adjusted HR 0.71; 95% CI 0.53–0.97; P = 0.03; Figure 3). According to TIMI criteria, major bleeding occurred in 16 patients (0.6%) in the lower heparin dose group and 24 patients (1.1%) in the higher heparin dose group; minor bleeding occurred in 27 patients (1.1%) in the lower heparin dose group and 51 patients (2.2%) in the higher heparin dose group.

When the ISAR-REACT 3A study period was divided in tertiles containing similar numbers of patients, there was no significant difference regarding the primary quadruple endpoint, the secondary triple endpoint, and the REPLACE-2 major bleeding within the lower heparin dose group across the tertiles.

As part of the secondary analysis, Table 4 tabulates ischaemic and bleeding events in the lower heparin dose group of the present study and in the bivalirudin group of the ISAR-REACT 3 trial. The difference regarding the primary quadruple endpoint between the lower heparin dose group and the bivalirudin group was −1% (upper one-sided 95% CI: 0.3%). This difference was significantly within the pre-specified non-inferiority margin of 1.8% (P < 0.001). The non-inferiority of the lower heparin dose compared with bivalirudin regarding the primary endpoint was also confirmed by the Cox proportional hazards model including the individual propensity scores. A HR of 0.78 (90% CI 0.65–0.93) was calculated. The upper limit of the 90% CI (one-sided test) did not exceed the threshold value of 1.21 (translated from the predefined non-inferiority margin for the difference in incidences of 1.8%).

Table 4

Primary quadruple endpoint, secondary triple endpoint, and their components in the 100 U/kg unfractionated heparin and in the bivalirudin groupa

Event UFH 100 U/kg (n = 2505) Bivalirudin (n = 2289) Pnon-inferiorityb 
Quadruple endpoint of death, myocardial infarction, urgent target vessel revascularization or major bleeding 183 (7.3) 190 (8.3) <0.001 
Triple endpoint of death, myocardial infarction, urgent target vessel revascularization 111 (4.4) 134 (5.9)  
 Death 5 (0.2) 3 (0.1)  
 Myocardial infarction 99 (4.0) 128 (5.6)  
  Q-wave myocardial infarction 8 (0.3) 14 (0.6)  
 Urgent target vessel revascularization 22 (0.9) 19 (0.8)  
 Major bleeding 91 (3.6) 70 (3.1)  
 Bleeding according to TIMI definition    
  Major 16 (0.6) 12 (0.5)  
  Minor 27 (1.1) 29 (1.3)  
Event UFH 100 U/kg (n = 2505) Bivalirudin (n = 2289) Pnon-inferiorityb 
Quadruple endpoint of death, myocardial infarction, urgent target vessel revascularization or major bleeding 183 (7.3) 190 (8.3) <0.001 
Triple endpoint of death, myocardial infarction, urgent target vessel revascularization 111 (4.4) 134 (5.9)  
 Death 5 (0.2) 3 (0.1)  
 Myocardial infarction 99 (4.0) 128 (5.6)  
  Q-wave myocardial infarction 8 (0.3) 14 (0.6)  
 Urgent target vessel revascularization 22 (0.9) 19 (0.8)  
 Major bleeding 91 (3.6) 70 (3.1)  
 Bleeding according to TIMI definition    
  Major 16 (0.6) 12 (0.5)  
  Minor 27 (1.1) 29 (1.3)  

TIMI, thrombolysis in myocardial infarction; UFH, unfractionated heparin.

aData are presented as n (%).

bNon-inferiority testing was performed for the primary quadruple endpoint only. Differences in other events were not tested for statistical significance.

It was not intended to test differences in other events for statistical significance; thus no non-inferiority margins were pre-specified for them.

Propensity score-matched cohorts

Propensity score matching algorithm identified 1000 closely matched patients for the comparisons between the 100 and 140 U/kg UFH groups as well as the 100 U/kg UFH and bivalirudin groups (Table 5).

Table 5

Baseline characteristics in the matched cohortsa

Characteristic UFH 100 U/kg UFH 140 U/kg P-value UFH 100 U/kg Bivalirudin P-value 
No. of patients 1000 1000  1000 1000  
Age (year) 67.5 (59.7–73.6) 67.4 (59.6–74.7) 0.42 67.9 (60.5–74.2) 67.8 (60.2–74.3) 0.54 
Women, n (%) 226 (22.6) 222 (22.2) 0.83 224 (22.4) 230 (23.0) 0.75 
Diabetes, n (%) 295 (29.5) 305 (30.5) 0.62 284 (28.4) 280 (28.0) 0.84 
 Insulin-treated, n (%) 91 (9.1) 102 (10.2) 0.40 89 (8.9) 82 (8.2) 0.58 
Current smoker, n (%) 148 (14.8) 142 (14.2) 0.70 159 (15.9) 143 (14.3) 0.33 
Arterial hypertension, n (%) 913 (91.3) 910 (91.0) 0.81 899 (89.9) 906 (90.6) 0.61 
Hypercholesterolaemia, n (%) 745 (74.5) 746 (74.6) 0.96 755 (75.5) 735 (73.5) 0.29 
Angina, n (%)   0.36   0.26 
 Unstable 222 (22.2) 205 (20.5)  215 (21.5) 195 (19.5)  
 Stable 778 (77.8) 795 (79.5)  785 (78.5) 805 (80.5)  
No of diseased coronary vessels, n (%)   0.74   0.86 
 One vessel 153 (15.3) 143 (14.3)  150 (15.0) 142 (14.2)  
 Two vessels 266 (26.6) 278 (27.8)  254 (25.4) 252 (25.2)  
 Three vessels 581 (58.1) 579 (57.9)  596 (59.6) 606 (60.6)  
Prior myocardial infarction, n (%) 324 (32.4) 335 (33.5) 0.60 332 (33.2) 363 (36.3) 0.16 
Prior aortocoronary bypass surgery, n (%) 136 (13.6) 137 (13.7) 0.95 130 (13.0) 138 (13.8) 0.60 
Body mass index (kg/m227.2 (24.8–30.1) 27.1 (24.9–29.8) 0.76 27.2 (24.7–29.7) 27.2 (24.8–30.0) 0.49 
Serum creatinine (mg/dL) 0.9 (0.8–1.1) 0.9 (0.8–1.1) 0.42 0.9 (0.8–1.1) 0.9 (0.8–1.1) 0.96 
Left ventricular ejection fraction (%) 58 (52–62) 58 (49–64) 0.19 58 (52–62) 57 (48–63) 0.04 
Target vessel, n (%)   0.90   0.91 
 Left main coronary artery 28 (2.8) 29 (2.9)  26 (2.6) 30 (3.0)  
 Left anterior descending coronary artery 369 (36.9) 382 (38.2)  390 (39) 374 (37.4)  
 Left circumflex coronary artery 274 (27.4) 261 (26.1)  265 (26.5) 265 (26.5)  
 Right coronary artery 303 (30.3) 297 (29.7)  288 (28.8) 302 (30.2)  
 Venous bypass graft 26 (2.6) 31 (3.1)  31 (3.1) 29 (2.9)  
Complex (type B2 or C) lesions, n (%) 684 (68.4) 682 (68.2) 0.92 651 (65.1) 683 (68.3) 0.13 
Chronic total occlusions, n (%) 80 (8.0) 89 (8.9) 0.47 98 (9.8) 84 (8.4) 0.27 
Lesion length (mm) 12.7 (8.4–19.2) 13.2 (8.6–19.4) 0.29 12.8 (8.5–19.5) 13.1 (9.0–19.5) 0.19 
Vessel size (mm) 2.8 (2.4–3.1) 2.8 (2.5–3.2) 0.08 2.8 (2.4–3.1) 2.8 (2.5–3.2) 0.09 
Diameter stenosis prior to procedure (%) 65.6 (56.8–75.4) 63.5 (55.4–73.7) 0.07 66.4 (56.7–75.7) 63.8 (55.8–73.9) 0.02 
Type of intervention, n (%)   0.14   0.55 
 Drug-eluting stent 904 (90.4) 916 (91.6)  892 (89.2) 890 (89.0)  
 Bare-metal stent 8 (0.8) 2 (0.2)  10 (1.0) 6 (0.6)  
 Balloon angioplasty 88 (8.8) 82 (8.2)  98 (9.8) 104 (10.4)  
Characteristic UFH 100 U/kg UFH 140 U/kg P-value UFH 100 U/kg Bivalirudin P-value 
No. of patients 1000 1000  1000 1000  
Age (year) 67.5 (59.7–73.6) 67.4 (59.6–74.7) 0.42 67.9 (60.5–74.2) 67.8 (60.2–74.3) 0.54 
Women, n (%) 226 (22.6) 222 (22.2) 0.83 224 (22.4) 230 (23.0) 0.75 
Diabetes, n (%) 295 (29.5) 305 (30.5) 0.62 284 (28.4) 280 (28.0) 0.84 
 Insulin-treated, n (%) 91 (9.1) 102 (10.2) 0.40 89 (8.9) 82 (8.2) 0.58 
Current smoker, n (%) 148 (14.8) 142 (14.2) 0.70 159 (15.9) 143 (14.3) 0.33 
Arterial hypertension, n (%) 913 (91.3) 910 (91.0) 0.81 899 (89.9) 906 (90.6) 0.61 
Hypercholesterolaemia, n (%) 745 (74.5) 746 (74.6) 0.96 755 (75.5) 735 (73.5) 0.29 
Angina, n (%)   0.36   0.26 
 Unstable 222 (22.2) 205 (20.5)  215 (21.5) 195 (19.5)  
 Stable 778 (77.8) 795 (79.5)  785 (78.5) 805 (80.5)  
No of diseased coronary vessels, n (%)   0.74   0.86 
 One vessel 153 (15.3) 143 (14.3)  150 (15.0) 142 (14.2)  
 Two vessels 266 (26.6) 278 (27.8)  254 (25.4) 252 (25.2)  
 Three vessels 581 (58.1) 579 (57.9)  596 (59.6) 606 (60.6)  
Prior myocardial infarction, n (%) 324 (32.4) 335 (33.5) 0.60 332 (33.2) 363 (36.3) 0.16 
Prior aortocoronary bypass surgery, n (%) 136 (13.6) 137 (13.7) 0.95 130 (13.0) 138 (13.8) 0.60 
Body mass index (kg/m227.2 (24.8–30.1) 27.1 (24.9–29.8) 0.76 27.2 (24.7–29.7) 27.2 (24.8–30.0) 0.49 
Serum creatinine (mg/dL) 0.9 (0.8–1.1) 0.9 (0.8–1.1) 0.42 0.9 (0.8–1.1) 0.9 (0.8–1.1) 0.96 
Left ventricular ejection fraction (%) 58 (52–62) 58 (49–64) 0.19 58 (52–62) 57 (48–63) 0.04 
Target vessel, n (%)   0.90   0.91 
 Left main coronary artery 28 (2.8) 29 (2.9)  26 (2.6) 30 (3.0)  
 Left anterior descending coronary artery 369 (36.9) 382 (38.2)  390 (39) 374 (37.4)  
 Left circumflex coronary artery 274 (27.4) 261 (26.1)  265 (26.5) 265 (26.5)  
 Right coronary artery 303 (30.3) 297 (29.7)  288 (28.8) 302 (30.2)  
 Venous bypass graft 26 (2.6) 31 (3.1)  31 (3.1) 29 (2.9)  
Complex (type B2 or C) lesions, n (%) 684 (68.4) 682 (68.2) 0.92 651 (65.1) 683 (68.3) 0.13 
Chronic total occlusions, n (%) 80 (8.0) 89 (8.9) 0.47 98 (9.8) 84 (8.4) 0.27 
Lesion length (mm) 12.7 (8.4–19.2) 13.2 (8.6–19.4) 0.29 12.8 (8.5–19.5) 13.1 (9.0–19.5) 0.19 
Vessel size (mm) 2.8 (2.4–3.1) 2.8 (2.5–3.2) 0.08 2.8 (2.4–3.1) 2.8 (2.5–3.2) 0.09 
Diameter stenosis prior to procedure (%) 65.6 (56.8–75.4) 63.5 (55.4–73.7) 0.07 66.4 (56.7–75.7) 63.8 (55.8–73.9) 0.02 
Type of intervention, n (%)   0.14   0.55 
 Drug-eluting stent 904 (90.4) 916 (91.6)  892 (89.2) 890 (89.0)  
 Bare-metal stent 8 (0.8) 2 (0.2)  10 (1.0) 6 (0.6)  
 Balloon angioplasty 88 (8.8) 82 (8.2)  98 (9.8) 104 (10.4)  

aData are presented as n (%) or median (25–75th percentile).

The primary quadruple endpoint occurred in 6.1% of patients in the lower heparin dose group compared with 8.8% of patients in the higher heparin dose group (OR 0.69; 0.51–0.94; P = 0.02). The secondary endpoint was encountered in 3.5% of patients in the lower heparin dose group compared with 5.2% of patients in the higher heparin dose group (OR 0.67; 0.45–1.02; P = 0.06). Major bleeding was observed in 3.5% of patients in the lower and 4.4% of patients in the higher heparin dose groups, respectively (OR, 0.80; 0.52–1.23; P = 0.30).

The primary quadruple endpoint occurred in 6.1% of patients in the lower heparin dose group compared with 8.5% of patients in the bivalirudin group. The non-inferiority of the lower heparin dose compared with bivalirudin regarding the primary endpoint was established by an estimated HR of 0.70 (90% CI 0.53–0.93). This conclusion is justified by the result that the upper limit of the 90% CI (one-sided test) did not exceed the threshold value of 1.21 (see above).

Discussion

This prospective, multicentre, open-label, single-group assignment trial of biomarker negative patients undergoing PCI after clopidogrel pre-treatment suggests that a single bolus dose of 100 U/kg UFH may provide net clinical benefit compared with the higher bolus dose of 140 U/kg UFH used in the ISAR-REACT 3 trial (historical control). The lower UFH dose was associated with a significant reduction in the combined quadruple endpoint of 30-day ischaemic events (death, MI, and urgent TVR) and in-hospital major bleeding complications.

The design of the ISAR-REACT 3A trial bears several limitations. Although we applied the same eligibility criteria and protocol procedures as those used in the ISAR-REACT 3 trial, due to different recruitment periods temporal changes in the patients' risk profile and their management may have occurred and considerably influenced the outcomes observed. The patients enrolled in ISAR-REACT 3A trial were clearly sicker patients with more complex lesions and interventions. This shows how important the parallel random assignment design is in eliminating an uneven distribution of entry characteristics and related bias in the observed outcomes. The degree of this potential bias might be difficult to quantify and fully eliminate by multivariable modelling and propensity score matching methods. Another limitation of the ISAR-REACT 3A trial design when compared with the predecessor ISAR-REACT 3 trial is its open-label nature of treatment assignment. In view of these limitations, the results of the present trial should be seen as hypothesis generating regarding the clinical value of a reduced UFH dose. Definition of the optimal UFH dose still awaits the conduct of large randomized clinical trials. In addition, the applicability of the results of the ISAR-REACT 3A trial should be confined to the setting of the predominant use of the femoral access approach with manual compression after sheath removal. Finally, the comparison between the lower UFH dose and bivalirudin was only done as a secondary exploratory analysis, acknowledging that the trial lacked sufficient power for this aspect.

Although heparin has been the standard antithrombin since the inception of PCI, there is currently no solid evidence to guide its dosing during contemporary PCI. During the history of PCI, the dosing regimen of UFH has undergone significant evolution. Initially, dosing regimens for PCI were adopted from experiences gained from cardiopulmonary bypass circuitry.19 With improved results of PCI over time, concerns about haemorrhagic complications led to an empirical reduction in the strength of anticoagulation,4,5,20–22 especially in the setting of adequate platelet inhibition. These efforts recently culminated in the hypothesis that in a very low-risk setting, the omission of any antithrombin agent could be safely performed against the background of aggressive platelet inhibition, achieved either by the use of glycoprotein IIb/IIIa inhibitors23,24 or thienopyridines in addition to aspirin.25 In the randomized, double-blind Coronary Interventions Antiplatelet-based Only (CIAO) trial of 700 selected patients undergoing very low-risk procedures, the additional use of anticoagulant therapy with heparin was not found to be required in patients on dual antiplatelet therapy with aspirin and clopidogrel.25 Even if these results can be confirmed by adequately powered trials in the future, there is less doubt concerning the need for combined antiplatelet and antithrombotic therapy in more complex patients and/or procedures. The lowest heparin dose required, however, has not yet been determined.

There are currently two dosing regimens in use: one that uses a weight adjusted bolus of 100 U/kg without monitoring of ACT (most common in Europe) and one that uses ACT guidance to maintain an ACT level of 250–350 s (most common in the USA).2,3

At first glance, the use of a single bolus dose of 140 U/kg UFH as used in the ISAR-REACT 3 trial as part of our long institutional practice seems to be higher than the currently recommended dosing regimens with ACT measurement. However, in a pooled analysis of more than 6000 patients undergoing PCI with ACT guidance, the mean total dose of heparin administered was >14 000 U, which is higher than the total dose administered in the ISAR-REACT 3 trial.26

Numerous analyses of the impact of different levels of anticoagulation measured by ACT on the ensuing haemorrhagic and ischaemia outcomes have been performed but yielded mostly conflicting results. Since none of them used a prospective randomized design, the optimal level of anticoagulation to achieve remains unclear. Although several trials found a correlation of higher ACT levels with increased bleeding rates,7,26,27 others failed to find any association.28,29 Current evidence for the impact of ACT levels on ischaemic outcomes is even more confusing, with several trials suggesting reduced ischaemic events with higher levels of ACT,28–30 and several others finding no association.7,22 A plateau at higher ACT levels has also been described27 as well as a U-shaped correlation, with more ischaemic events at very high ACT levels.26 Uncertainties about the optimal time point of ACT measurement, device-dependent variability in ACT levels, the low predictability of ACT after fixed UFH doses, and the fact that advised levels are achieved only in a minority of patients27 make current recommendations even more complicated.

New anti-IIa and anti-Xa agents with the advantage of a more homogeneous dose response are currently undergoing testing in clinical trials.31,32 The ISAR-REACT 3A study adds valuable information to the existing evidence. It shows that a simple reduction in the heparin dose from a single bolus of 140 U/kg to a single bolus of 100 U/kg without ACT monitoring or additional boluses may provide net clinical benefit in biomarker negative patients undergoing PCI after clopidogrel pre-treatment. The results with this approach also appeared to be non-inferior to those achieved with bivalirudin in the ISAR-REACT 3 trial.

Additional analysis revealed that the net clinical benefit of the lower UFH dose was achieved by a non-significant reduction in both bleeding and ischaemic events. This is important, since it shows that the reduction in bleeding is not achieved at the expense of an increased risk of thrombotic events. Both of these events are of important prognostic value.33 Although low doses of heparin are more apt to reduce platelet aggregation, and high doses are more likely to increase it in vitro,34 it is not known whether this mechanism might have had an impact on the numerically lower ischaemic complication rate in the 100 U/kg UFH dose group of the ISAR-REACT 3A trial. Moreover, it has been shown that bleeding also influences the occurrence of ischaemic events.35

In conclusion, the present trial shows that in biomarker negative patients, a reduced dose of UFH may represent a simple and safe method of lowering the bleeding risk after PCI without compromising the risk of ischaemic complications.

Funding

The ISAR-REACT 3 trial was supported in part by Nycomed Pharma GmbH, Unterschleißheim, Germany (distributor of bivalirudin in Europe at the time in which patients were recruited), and the grant KKF 1.1-05 (984323) from Deutsches Herzzentrum, Munich, Germany. The ISAR-REACT 3A trial was a non-sponsored trial.

Conflict of interest: none declared.

Acknowledgements

We gratefully acknowledge the precious contribution of Maria de Fátima Maimer Rodrigues da Cunha, Martina Schulz, Heike Paul, and Christine Peteler to patient event monitoring.

References

1
Gruntzig
AR
Senning
A
Siegenthaler
WE
Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty
N Engl J Med
 , 
1979
, vol. 
301
 (pg. 
61
-
68
)
2
Smith
SC
Jr
Feldman
TE
Hirshfeld
JW
Jr
Jacobs
AK
Kern
MJ
King
SB
3rd
Morrison
DA
O'Neill
WW
Schaff
HV
Whitlow
PL
Williams
DO
Antman
EM
Smith
SC
Jr
Adams
CD
Anderson
JL
Faxon
DP
Fuster
V
Halperin
JL
Hiratzka
LF
Hunt
SA
Jacobs
AK
Nishimura
R
Ornato
JP
Page
RL
Riegel
B
ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention)
J Am Coll Cardiol
 , 
2006
, vol. 
47
 (pg. 
e1
-
e121
)
[PubMed]
3
Silber
S
Albertsson
P
Aviles
FF
Camici
PG
Colombo
A
Hamm
C
Jorgensen
E
Marco
J
Nordrehaug
JE
Ruzyllo
W
Urban
P
Stone
GW
Wijns
W
Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
804
-
847
)
[PubMed]
4
Vainer
J
Fleisch
M
Gunnes
P
Ramamurthy
S
Garachemani
A
Kaufmann
UP
Meyer
BJ
Luscher
TF
Meier
B
Low-dose heparin for routine coronary angioplasty and stenting
Am J Cardiol
 , 
1996
, vol. 
78
 (pg. 
964
-
966
)
5
Boccara
A
Benamer
H
Juliard
JM
Aubry
P
Goy
P
Himbert
D
Karrillon
GJ
Steg
PG
A randomized trial of a fixed high dose vs a weight-adjusted low dose of intravenous heparin during coronary angioplasty
Eur Heart J
 , 
1997
, vol. 
18
 (pg. 
631
-
635
)
[PubMed]
6
Swanson
N
Hogrefe
K
Stephens Lloyd
A
Gershlick
A
Current perspectives on British use of adjunctive therapies during coronary interventions
Int J Cardiol
 , 
2001
, vol. 
79
 (pg. 
119
-
125
(discussion 126-117).
7
Brener
SJ
Moliterno
DJ
Lincoff
AM
Steinhubl
SR
Wolski
KE
Topol
EJ
Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention
Circulation
 , 
2004
, vol. 
110
 (pg. 
994
-
998
)
8
Lincoff
AM
Bittl
JA
Harrington
RA
Feit
F
Kleiman
NS
Jackman
JD
Sarembock
IJ
Cohen
DJ
Spriggs
D
Ebrahimi
R
Keren
G
Carr
J
Cohen
EA
Betriu
A
Desmet
W
Kereiakes
DJ
Rutsch
W
Wilcox
RG
de Feyter
PJ
Vahanian
A
Topol
EJ
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
, vol. 
289
 (pg. 
853
-
863
)
9
Stone
GW
McLaurin
BT
Cox
DA
Bertrand
ME
Lincoff
AM
Moses
JW
White
HD
Pocock
SJ
Ware
JH
Feit
F
Colombo
A
Aylward
PE
Cequier
AR
Darius
H
Desmet
W
Ebrahimi
R
Hamon
M
Rasmussen
LH
Rupprecht
HJ
Hoekstra
J
Mehran
R
Ohman
EM
Bivalirudin for patients with acute coronary syndromes
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2203
-
2216
)
10
Stone
GW
Witzenbichler
B
Guagliumi
G
Peruga
JZ
Brodie
BR
Dudek
D
Kornowski
R
Hartmann
F
Gersh
BJ
Pocock
SJ
Dangas
G
Wong
SC
Kirtane
AJ
Parise
H
Mehran
R
Bivalirudin during primary PCI in acute myocardial infarction
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
2218
-
2230
)
11
Kastrati
A
Neumann
FJ
Mehilli
J
Byrne
RA
Iijima
R
Buttner
HJ
Khattab
AA
Schulz
S
Blankenship
JC
Pache
J
Minners
J
Seyfarth
M
Graf
I
Skelding
KA
Dirschinger
J
Richardt
G
Berger
PB
Schomig
A
Bivalirudin versus unfractionated heparin during percutaneous coronary intervention
N Engl J Med
 , 
2008
, vol. 
359
 (pg. 
688
-
696
)
12
The TIMI Study Group
Definitions used in TIMI trials
 
Available at: http://www.timi.org, (last accessed April 10, 2010)
13
Cutlip
DE
Windecker
S
Mehran
R
Boam
A
Cohen
DJ
van Es
GA
Steg
PG
Morel
MA
Mauri
L
Vranckx
P
McFadden
E
Lansky
A
Hamon
M
Krucoff
MW
Serruys
PW
Clinical end points in coronary stent trials: a case for standardized definitions
Circulation
 , 
2007
, vol. 
115
 (pg. 
2344
-
2351
)
14
Fleiss
JL
Tytun
A
Ury
HK
A simple approximation for calculating sample sizes for comparing independent proportions
Biometrics
 , 
1980
, vol. 
36
 (pg. 
343
-
346
)
15
Liang
KY
Zeger
L
Longitudinal data analysis using generalized linear models
Biometrika
 , 
1986
, vol. 
73
 (pg. 
13
-
22
)
16
Grambsch
P
Therneau
T
Proportional hazards tests and diagnostics based on weighted residuals
Biometrika
 , 
1994
, vol. 
81
 (pg. 
515
-
526
)
17
FinnDiane
Match controls to cases
 
available at: http://www.artemis.kll.helsinki.fi/misc/match.php (last accessed 11 August 2010)
18
Chow
S-C
Liu
J-P
Design and Analysis of Bioavailability and Bioequivalence Studies
 , 
1992
New York
Marcel Dekker
19
Bull
BS
Korpman
RA
Huse
WM
Briggs
BD
Heparin therapy during extracorporeal circulation. I. Problems inherent in existing heparin protocols
J Thorac Cardiovasc Surg
 , 
1975
, vol. 
69
 (pg. 
674
-
684
)
[PubMed]
20
Koch
KT
Piek
JJ
de Winter
RJ
David
GK
Mulder
K
Tijssen
JG
Lie
KI
Safety of low dose heparin in elective coronary angioplasty
Heart
 , 
1997
, vol. 
77
 (pg. 
517
-
522
)
[PubMed]
21
Kaluski
E
Krakover
R
Cotter
G
Hendler
A
Zyssman
I
Milovanov
O
Blatt
A
Zimmerman
E
Goldstein
E
Nahman
V
Vered
Z
Minimal heparinization in coronary angioplasty—how much heparin is really warranted?
Am J Cardiol
 , 
2000
, vol. 
85
 (pg. 
953
-
956
)
22
Tolleson
TR
O'Shea
JC
Bittl
JA
Hillegass
WB
Williams
KA
Levine
G
Harrington
RA
Tcheng
JE
Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial
J Am Coll Cardiol
 , 
2003
, vol. 
41
 (pg. 
386
-
393
)
23
Valencia
R
Price
MJ
Sawhney
N
Lee
SS
Wong
GB
Gollapudi
RR
Banares
M
Schatz
RA
Teirstein
PS
Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial)
Am J Cardiol
 , 
2007
, vol. 
100
 (pg. 
1099
-
1102
)
24
Denardo
SJ
Davis
KE
Tcheng
JE
Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy
Am Heart J
 , 
2005
, vol. 
149
 (pg. 
138
-
144
)
25
Stabile
E
Nammas
W
Salemme
L
Sorropago
G
Cioppa
A
Tesorio
T
Ambrosini
V
Campopiano
E
Popusoi
G
Biondi Zoccai
G
Rubino
P
The CIAO (Coronary Interventions Antiplatelet-based Only) Study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention
J Am Coll Cardiol
 , 
2008
, vol. 
52
 (pg. 
1293
-
1298
)
26
Chew
DP
Bhatt
DL
Lincoff
AM
Moliterno
DJ
Brener
SJ
Wolski
KE
Topol
EJ
Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials
Circulation
 , 
2001
, vol. 
103
 (pg. 
961
-
966
)
[PubMed]
27
Montalescot
G
Cohen
M
Salette
G
Desmet
WJ
Macaya
C
Aylward
PE
Steg
PG
White
HD
Gallo
R
Steinhubl
SR
Impact of anticoagulation levels on outcomes in patients undergoing elective percutaneous coronary intervention: insights from the STEEPLE trial
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
462
-
471
)
28
Pinto
DS
Lorenz
DP
Murphy
SA
Marble
SJ
DiBattiste
PM
Demopoulos
LA
Cannon
CP
Gibson
CM
Association of an activated clotting time < or =250 sec with adverse event rates after percutaneous coronary intervention using tirofiban and heparin (a TACTICS-TIMI 18 substudy)
Am J Cardiol
 , 
2003
, vol. 
91
 (pg. 
976
-
978
)
29
Bertrand
OF
Rodes-Cabau
J
Rinfret
S
Larose
E
Bagur
R
Proulx
G
Gleeton
O
Costerousse
O
De Larochelliere
R
Roy
L
Impact of final activated clotting time after transradial coronary stenting with maximal antiplatelet therapy
Am J Cardiol
 , 
2009
, vol. 
104
 (pg. 
1235
-
1240
)
30
Narins
CR
Hillegass
WB
Jr
Nelson
CL
Tcheng
JE
Harrington
RA
Phillips
HR
Stack
RS
Califf
RM
Relation between activated clotting time during angioplasty and abrupt closure
Circulation
 , 
1996
, vol. 
93
 (pg. 
667
-
671
)
[PubMed]
31
Rao
SV
Melloni
C
Myles-Dimauro
S
Broderick
S
Kosinski
AS
Kleiman
NS
Dzavik
V
Tanguay
JF
Chandna
H
Gammon
R
Rivera
E
Alexander
JH
Fier
I
Roach
J
Becker
RC
Evaluation of a new heparin agent in percutaneous coronary intervention: results of the phase 2 evaluation of M118 IN pErcutaNeous Coronary intErvention (EMINENCE) Trial
Circulation
 , vol. 
121
 (pg. 
1713
-
1721
)
32
Cohen
M
Bhatt
DL
Alexander
JH
Montalescot
G
Bode
C
Henry
T
Tamby
JF
Saaiman
J
Simek
S
De Swart
J
Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial
Circulation
 , 
2007
, vol. 
115
 (pg. 
2642
-
2651
)
33
Ndrepepa
G
Berger
PB
Mehilli
J
Seyfarth
M
Neumann
FJ
Schomig
A
Kastrati
A
Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
690
-
697
)
34
Xiao
Z
Theroux
P
Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor
Circulation
 , 
1998
, vol. 
97
 (pg. 
251
-
256
)
[PubMed]
35
Vavalle
JP
Rao
SV
Impact of bleeding complications on outcomes after percutanous coronary interventions
Int Cardiol
 , 
2009
, vol. 
1
 (pg. 
51
-
62
)

Supplementary data

Comments

0 Comments