Stable Coronary Artery Disease (CAD), Unstable Angina (Troponin Negative)
Conditions
Brief summary
To determine change of QTc interval during intravenous argatroban infusion in patients undergoing percutaneous coronary intervention (PCI)
Detailed description
Primary objective: To determine change of corrected QT interval (QTc) during intravenous argatroban infusion in patients undergoing percutaneous coronary intervention (PCI). Secondary objectives: * Determination of the QTc interval after sufficient wash-out period by ECG-3 which needed to be performed \> 8 but ≤ 28 hours after termination of prolonged argatroban infusion. * Investigation of dependence of QTc interval on gender and applied doses. * Determination of coagulation status during argatroban therapy. * Assessment of safety-related events within the scope of anticoagulation with argatroban, for example bleeding events or thromboembolic events.
Interventions
DRUGArgatroban
Patients received an intravenous (i.v.) bolus of 300 μg/kg argatroban administered over a span of 3 to 5 minutes followed by the i.v. infusion of argatroban at 20 μg/kg/min until the end of the procedure. ACT was checked 5 minutes after bolus dose. If ACT remained below the target of 300 s, the patient received an additional i.v. bolus injection of 150 μg/kg and the infusion dose was raised up to 30 μg/kg/min. In cases ACT \> 450 s, the infusion was reduced to 15 μg/kg/min and the value was checked again after 5 minutes. As soon as the target ACT (between 300 s and 450 s) was reached, infusion dose remained unchanged during the PCI procedure. Depending on clinical relevancy further ACT assessments were possible.
Sponsors
Tanabe Pharma GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of stable CAD or unstable angina (troponin negative, i.e. within the normal range for the study site) with low to moderate anatomic risk. * Patient required elective percutaneous coronary angioplasty or stent insertion with an approved device in one or more de novo-treated or re-stenotic lesions in native vessels. * Patient was on adequate platelet inhibition therapy after having received a loading dose with ASA and clopidogrel before start of intervention (this additional inclusion criterion was introduced with study protocol version 1.6, dated 14.12.2018) * Willingness to give written informed consent, written consent for data protection (legal requirement in Germany datenschutzrechtliche Einwilligung) and willingness to participate and to comply with the requirements of the study protocol. * The patient (female/male) was at least 18 years of age. * Baseline ECG without changes that impair assessment of QTc interval.
Exclusion criteria
* Patient was indicated for highly complex 3-vessel intervention. * The female patient was pregnant (exclusion by routine urine test) or was nursing during therapy period. * Patients who were currently participating in another clinical trial or patients who participated in another clinical trial during the last 3 months prior to study start (date of treatment visit). * History of drug, alcohol or chemical abuse within 6 months prior to study start. * Planned surgical intervention other than study procedure within 7 days after study start. * Any condition, which contraindicated the use of argatroban, or endangered the patient if he/she participated in this study. Factors influencing QTc interval: * Marked baseline prolongation of QTc interval (repeated demonstration of a QTc interval \> 450 ms at baseline ECG). * A history of risk factors of Torsade de pointes (e.g. heart failure, hypokalemia, family history of Long QT Syndrome). * Known intraventricular conduction disturbance. * Bradycardia: heart rate \< 45 min-1. * Electrolyte level outside normal range (according to laboratory's reference values). * The use of concomitant medications that interfered with the QTc interval. * Intake of digitalis within the last 2 weeks before study start. * Acute myocardial infarction or troponin-positive unstable angina. Factors inhibiting use of argatroban in this study: * Intolerance to ingredients of Argatra® (sorbitol). * Known cirrhosis, hepatitis, clinically significant hepatic disorder at study start and/or history of clinically relevant hepatic disorder. * Current hepatic disorder indicated by laboratory liver profile at screening: Bilirubin, AST/SGOT, ALT/SGPT, gammaGT \> 3.0 times upper limit of the normal (ULN). * Renal insufficiency indicated by laboratory renal profile at study start: GFR \< 35 ml/min. * Uncontrolled hypertension (defined as blood pressure \>180/120 mmHg). * If any form of heparin was taken prior to study start and aPTT ≥ 35 s. * Intake of direct oral anticoagulants (DOAC) within 1 month prior to study start. * If anticoagulants of type of vitamin K antagonists (VKA) were taken prior to study start and INR \>1.2. * Platelet count \<125 x 109/l. * Documented coagulation disorder or bleeding diathesis. * Uncontrolled haemorrhage within the past 3 months. * Uncontrolled peptic ulcer disease or gastrointestinal bleeding within the past 3 months. * Cerebral aneurysm. * Haemorrhagic stroke or ischaemic stroke in the past 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population) | ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status). | It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1 |
| Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Subgroup Male or Female) | ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status). | It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1 |
| Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Centre 01 or Centre 02) | ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status). | It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With a Prolongation of QTc Interval to >500 ms at ECG-2 | ECG-2 immediately after argatroban infusion | Number of patients of ITT population exhibiting QTc interval of \> 500 ms |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion i.v. bolus of 300 μg/kg argatroban administered over a span of 3 to 5 minutes followed by the i.v. infusion of argatroban at 20 μg/kg/min until the end of the procedure. | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Argatroban Intravenous (i.v.) Bolus & i.v. Infusion |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 26 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 49 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 50 |
| other Total, other adverse events | 4 / 50 |
| serious Total, serious adverse events | 3 / 50 |
Outcome results
Primary
Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population)
It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1
Time frame: ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population) | Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population) | 0.94 milliseconds | Standard Deviation 46.37 |
Primary
Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Centre 01 or Centre 02)
It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1
Time frame: ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population) | Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Centre 01 or Centre 02) | 15.0046 milliseconds | Standard Deviation 44.9538 |
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population/Sub Group Female) | Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Centre 01 or Centre 02) | -13.1343 milliseconds | Standard Deviation 44.2363 |
Primary
Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Subgroup Male or Female)
It was investigated if a mean QTc prolongation of more than 10 ms occurred between ECG-2 and ECG-1
Time frame: ECG-2 was recorded immediately after cardiac intervention when patient was fully anticoagulated with argatroban and ECG-1 was recorded at baseline prior to first bolus dose of argatroban (argatroban-free status).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population) | Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Subgroup Male or Female) | -5.8936 milliseconds | Standard Deviation 46.4072 |
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population/Sub Group Female) | Mean Difference in QTc Interval Between ECG-2 and ECG-1 (ITT Population/Subgroup Male or Female) | 25.1460 milliseconds | Standard Deviation 39.0616 |
Secondary
Proportion of Patients With a Prolongation of QTc Interval to >500 ms at ECG-2
Number of patients of ITT population exhibiting QTc interval of \> 500 ms
Time frame: ECG-2 immediately after argatroban infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban Intravenous (i.v.) Bolus & i.v. Infusion (ITT Population) | Proportion of Patients With a Prolongation of QTc Interval to >500 ms at ECG-2 | 1 Participants |