- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00735280
Reduced Dose of Unfractionated Heparin in Patients Undergoing PCI (ISAR-REACT-3A)
January 3, 2012 updated by: Deutsches Herzzentrum Muenchen
Non-randomized, Open-label, Historical Control, Single Group Assignment Trial of a Reduced Dose of Unfractionated Heparin in Patients Undergoing Percutaneous Coronary Interventions
The aim of this trial is to evaluate whether a reduction in the heparin dose from 140 to 100 U/kg is associated with a better net clinical outcome in patients undergoing PCI after pretreatment with 600mg clopidogrel
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Percutaneous coronary interventions, mostly with implantation of bare-metal or drug-eluting stents, are commonly used to treat patients with coronary artery disease.
Various periprocedural adjunct antithrombotic therapies have been investigated and are being used.
Unfractionated heparin (UFH) has been the standard adjunctive antithrombin therapy during PCI for more than 25 years.
Combined antiplatelet treatment consisting of aspirin and a thienopyridine has significantly reduced early ischaemic events following coronary stenting (1).
Thienopyridines act by irreversibly inhibiting the platelet adenosine diphosphate (ADP) P2Y12 receptor.
Compared to ticlopidine, clopidogrel has the advantage of a more favourable side effect profile (2) and more rapid onset of action.(3,4)
Pretreatment with a loading dose of 300mg clopidogrel improved outcomes (5-7) and is recommended by current guidelines for patients undergoing PCI.
(8) More recently, trials have shown that the larger loading dose of 600mg achieves more rapid and more potent inhibition of platelet aggregation than 300 mg do.(9-11)
The results of several randomized controlled trials suggest that pretreatment with 600mg clopidogrel might obviate the need for IIb/IIIa inhibitors in a broad spectrum of patients undergoing PCI (12-14) although no formal direct comparison of different clopidogrel doses has been assessed by trials sufficiently powered for clinical endpoints.
The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial showed that after pretreatment with 600mg clopidogrel for at least 2 hours before the intervention, additional use of abciximab was not associated with any clinically measurable benefit among low-to-intermediate risk patients who underwent PCI.(12)
Even in higher risk settings such as small vessel size (14) and the presence of diabetes (13)additional use of abciximab was not associated with a measurable clinical benefit in patients pretreated with 600mg clopidogrel.
An important exception is the group of patients with non-ST-segment elevation ACS.
In the ISAR-REACT-2 trial that enrolled this category of patients those with an elevated troponin level did benefit from abciximab even after pretreatment with 600mg clopidogrel.(15)
The recently completed ISAR-REACT-3 trial compared unfractionated heparin with the direct thrombin inhibitor bivalirudin in biomarker negative patients with stable and unstable angina undergoing contemporary PCI.
Bivalirudin did not provide "net clinical benefit" - did not reduce the quadruple endpoint - at 30 days compared to unfractionated heparin.
However, there was a significant reduction in bleeding with bivalirudin (16) The heparin dose regimen used in ISAR-REACT-3 diverges from current US practice insofar as the majority of patients received a bolus dose of 140 U/kg with no follow up ACT measurement and no additional heparin doses.
Although heparin has been the standard antithrombin therapy in interventional cardiology for decades, its optimal dose is still not known.
During the last years there has been a trend towards using lower heparin doses.
In most interventional trials in the United States it is now current practice to use a bolus of not more than 100 U/kg.
(8) Many interventionalists believe that a dose lower than 140 U/kg is associated with a better clinical outcome.
However, no studies have been performed to identify the most appropriate dose of heparin.
Since pretreatment with clopidogrel has proven to reduce ischemic events, a heparin dose of 140U/kg might conceivably be too high.
A lower dose might prove to be as effective in preventing ischemic endpoints while reducing the risk of bleeding if patients were pretreated with 600mg clopidogrel prior to the intervention.
Therefore the aim of this trial is to evaluate whether a reduction in the heparin dose from 140 to 100 U/kg is associated with a better net clinical outcome in patients undergoing PCI after pretreatment with 600mg clopidogrel.
The hypothesis to be tested is whether a reduced dose of 100U/kg heparin is superior to the higher dose of 140U/kg used in the ISAR-REACT-3 trial (historical control) regarding the combined incidence of death, myocardial infarction, urgent target vessel revascularization within 30 days and in hospital major bleeding.
The ISAR-REACT-3a trial will enroll a patient population with a similar risk profile to that of patients included in ISAR-REACT-3.
Biomarker negative patients with stable or unstable angina undergoing PCI will receive a reduced dose heparin bolus of 100U/kg.
Results will be compared with the ISAR-REACT-3 trial (historical control).
Primary comparison will be with the heparin arm of ISAR-REACT-3 regarding the primary endpoint ("Net clinical benefit", the combined incidence of death, myocardial infarction, urgent target vessel revascularization within 30 days and in hospital major bleeding).
A secondary aspect will be the comparison with the historical bivalirudin group of the ISAR-REACT-3 trial.
Study Type
Interventional
Enrollment (Actual)
2505
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
-
Bad Krozingen, Germany, 79189
- Herz-Zentrum
-
München, Germany, 81675
- Klinikum rechts der Isar der Technischen Universitat Munchen
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München, Germany, 81541
- Deutsches Herzzentrum München
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Patients older than 18 years undergoing a PCI procedure
- Pretreatment with 600mg clopidogrel at least 2 hours before the intervention
- Informed, written consent by the patient or her/his legally-authorized representative for participation in the study.
Exclusion Criteria:
- Recent ST-elevation myocardial infarction within the last 48 hours
- Acute coronary syndromes with positive biomarkers (Troponin T > 0.03 μg/L or CK-MB > ULN)
- Cardiogenic shock
- Malignancies or other comorbid conditions (for example severe liver, renal and pancreatic disease) with life expectancy less than one year or that may result in protocol non-compliance
- Active bleeding; bleeding diathesis
- History of gastrointestinal or genitourinary bleeding within the last 6 weeks
- Presence of diseases which have a high probability of vascular lesions and subsequent bleeding such as active gastric ulcer or active ulcerous colitis
- Recent trauma or major surgery in the last month
- Ophthalmic surgery or brain surgery in the last month
- Retinopathies or vitreous body bleeding in the last month
- History of intracranial bleeding or structural abnormalities (for example aneurysm of cerebral arteries)
- Suspected aortic dissection; pericarditis and subacute bacterial endocarditis
- Patient's refusal to blood transfusion.
- Oral anticoagulation therapy with coumarin derivative within the last 7 days
- Treatment with UFH within 6 hours unless an ACT is less than 150 sec or low-molecular weight heparin within 8 hours before enrollment
- Treatment with bivalirudin within 24 hours before enrollment
- Severe uncontrolled hypertension >180/110 mmHg unresponsive to therapy
- Planned staged PCI procedure within 30 days from index procedure or prior PCI within the last 30 days.
- Relevant hematologic deviations: hemoglobin < 100 g/L, platelet count < 100 x 109 /L.
- Glomerular filtration rate (GFR) < 30 ml/min or serum creatinine > 30 mg/L or dependence on renal dialysis.
- Known allergy to the study medications: aspirin, clopidogrel, UFH, true anaphylaxis after prior exposure to contrast media.
- Known heparin-induced thrombocytopenia (Typ II)
- Previous enrollment in this trial.
- Pregnancy (present, suspected or planned) or positive pregnancy test.
- Spinal, peridural and epidural anesthesia
- Patient's inability to fully cooperate with the study protocol.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Reduced dose of unfractionated heparin
|
bolus of 100 U/kg of unfractionated heparin
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The primary outcome measure will be a composite of death, MI, urgent TVR after 30 days or in hospital bleeding (quadruple endpoint, "net clinical benefit").
Time Frame: 30 days
|
30 days
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Composite of death, MI or urgent TVR (Triple endpoint to assess ischemic complications)
Time Frame: 30 days
|
30 days
|
Composite of death, MI or TVR
Time Frame: 1 year after the index procedure
|
1 year after the index procedure
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Julinda Mehilli, MD, Deutsches Herzzentrum München
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. doi: 10.1001/jama.288.19.2411. Erratum In: JAMA. 2003 Feb 26;289(8):987.
- Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig A; Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006 Apr 5;295(13):1531-8. doi: 10.1001/jama.295.13.joc60034. Epub 2006 Mar 13.
- Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH; CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000 Aug 8;102(6):624-9. doi: 10.1161/01.cir.102.6.624.
- Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996 Apr 25;334(17):1084-9. doi: 10.1056/NEJM199604253341702.
- Thebault JJ, Kieffer G, Cariou R. Single-dose pharmacodynamics of clopidogrel. Semin Thromb Hemost. 1999;25 Suppl 2:3-8.
- Gawaz M, Seyfarth M, Muller I, Rudiger S, Pogatsa-Murray G, Wolf B, Schomig A. Comparison of effects of clopidogrel versus ticlopidine on platelet function in patients undergoing coronary stent placement. Am J Cardiol. 2001 Feb 1;87(3):332-6, A9. doi: 10.1016/s0002-9149(00)01369-2.
- Chan AW, Moliterno DJ, Berger PB, Stone GW, DiBattiste PM, Yakubov SL, Sapp SK, Wolski K, Bhatt DL, Topol EJ; TARGET Investigators. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol. 2003 Oct 1;42(7):1188-95. doi: 10.1016/s0735-1097(03)00944-6.
- Assali AR, Salloum J, Sdringola S, Moustapha A, Ghani M, Hale S, Schroth G, Fujise K, Anderson HV, Smalling RW, Rosales OR. Effects of clopidogrel pretreatment before percutaneous coronary intervention in patients treated with glycoprotein IIb/IIIa inhibitors (abciximab or tirofiban). Am J Cardiol. 2001 Oct 15;88(8):884-6, A6. doi: 10.1016/s0002-9149(01)01897-5. No abstract available.
- Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB 3rd, Morrison DA, O'Neil WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention. 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 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 2006 Feb 21;113(7):e166-286. doi: 10.1161/CIRCULATIONAHA.106.173220. No abstract available.
- Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, Beygui F, Drouet L; ALBION Trial Investigators. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006 Sep 5;48(5):931-8. doi: 10.1016/j.jacc.2006.04.090. Epub 2006 Aug 17.
- Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein PS. Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers. Am J Cardiol. 2006 Sep 1;98(5):681-4. doi: 10.1016/j.amjcard.2006.03.054. Epub 2006 Jul 7.
- von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005 Nov 8;112(19):2946-50. doi: 10.1161/CIRCULATIONAHA.105.559088. Epub 2005 Oct 31.
- Kastrati A, Mehilli J, Schuhlen H, Dirschinger J, Dotzer F, ten Berg JM, Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schomig A; Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med. 2004 Jan 15;350(3):232-8. doi: 10.1056/NEJMoa031859.
- Mehilli J, Kastrati A, Schuhlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schomig A; Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation. 2004 Dec 14;110(24):3627-35. doi: 10.1161/01.CIR.0000148956.93631.4D. Epub 2004 Nov 7.
- Hausleiter J, Kastrati A, Mehilli J, Schuhlen H, Pache J, Dotzer F, Glatthor C, Siebert S, Dirschinger J, Schomig A; ISAR-SMART-2 Investigators. A randomized trial comparing phosphorylcholine-coated stenting with balloon angioplasty as well as abciximab with placebo for restenosis reduction in small coronary arteries. J Intern Med. 2004 Nov;256(5):388-97. doi: 10.1111/j.1365-2796.2004.01398.x.
- 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; ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med. 2008 Aug 14;359(7):688-96. doi: 10.1056/NEJMoa0802944. Erratum In: N Engl J Med. 2008 Aug 28;359(9):983.
- Schulz S, Mehilli J, Neumann FJ, Schuster T, Massberg S, Valina C, Seyfarth M, Pache J, Laugwitz KL, Buttner HJ, Ndrepepa G, Schomig A, Kastrati A; Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3A Trial Investigators. ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention. Eur Heart J. 2010 Oct;31(20):2482-91. doi: 10.1093/eurheartj/ehq330. Epub 2010 Aug 30.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
August 1, 2008
Primary Completion (Actual)
March 1, 2010
Study Completion (Actual)
March 1, 2011
Study Registration Dates
First Submitted
August 12, 2008
First Submitted That Met QC Criteria
August 13, 2008
First Posted (Estimate)
August 14, 2008
Study Record Updates
Last Update Posted (Estimate)
January 5, 2012
Last Update Submitted That Met QC Criteria
January 3, 2012
Last Verified
January 1, 2012
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- GE IDE No. A01408
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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