Angiomax
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Angiomax - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Angina, Percutaneous Coronary Intervention
Class: Thrombin inhibitors
Form: Liquid solution, Intravenous (IV)
Ingredients: bivalirudin, mannitol, sodium hydroxide, trifluoroacetate

Pharmaceutical information

Drug Substance

Bivalirudin is a synthetic peptide with the following attributes:

Proper name: Bivalirudin
Chemical name: D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine trifluoracetate (salt) hydrate
Molecular formula and molecular mass: C98H138N24O33•(C2HF3O2)x•(H2O)y
2180 daltons (anhydrous free base peptide)

Structural formula:


Physicochemical properties: Bivalirudin is a white to off-white powder, with a pH of approximately 3 when dissolved in water without buffering.

The compound’s solubility is ≥ 140 mg/mL at pH 4.6-5.6.

Bivalirudin is insoluble (≤0.1 mg/mL) in acetonitrile, chloroform, octanol and ethyl acetate. It is sparingly soluble (≥0.1 mg/mL, ≤1.0 mg/mL) in acetone and sec- butanol, and soluble (≥1.0 mg/mL, ≤10.0 mg/mL) in water, pH 3.3-4.0. It is freely soluble (≥10.0 mg/mL) in methanol (gels), ethanol (gels), and water at pH of 2.2 (gels), 2.4-3.1, 4.3-4.5, 4.6-5.6.

Clinical trials

ACUITY (UA/NSTEMI)

Study demographics and trial design

The ACUITY trial was carried out in 13,819 patients with moderate or high risk acute coronary syndromes due to unstable angina or non-ST-segment elevation myocardial infarction who were undergoing an early invasive strategy using a PROBE design (Prospective Randomized Open- label Blinded Endpoint) to determine the non-inferiority and/or superiority of ANGIOMAX with or without glycoprotein IIb/IIIa inhibitors (GPI) to heparin or enoxaparin with GPI. Additional anti-platelet therapy utilised in the study included aspirin and clopidogrel.

Patients were equally randomized to treatment in one of three arms: ANGIOMAX alone, ANGIOMAX plus planned use of GPI (abciximab, eptifibatide, or tirofiban), or heparin (either UFH or enoxaparin) plus planned use of GPI. Rescue GPIs were used during PCI for procedural complications in 6.6% of patients who were randomized to ANGIOMAX alone due to any of the following circumstances:

  1. new or persistent thrombus formation during or after PCI;
  2. slow or no reflow;
  3. distal embolization;
  4. side branch closure;
  5. other reasons for which the operator feels patient safety requires a GPI.
  • There were no significant differences in baseline characteristics between the three treatment groups. Patients ranged in age from 20-95 years (median 63 years); 45% were ≥65 years; weight ranged from 34-195 kg (median 83 kg); 30.1% were female; 59% had abnormal cardiac markers (Creatine Kinase –MB [CK-MB], troponin T or I); and 38% had ST segment deviations. In the ANGIOMAX arm, 2078 patients had received prior heparin (UFH, LMWH) prior to being randomized to receive ANGIOMAX. Angiography was performed in 99% of the patients. Patients were subsequently triaged to either PCI (56%), CABG (11%) or medical management (33%). Stents were deployed in 85% of patients who underwent PCI (drug-eluting stents in 60%). Ninety-six percent of patients received ASA.

    ANGIOMAX was administered as a 0.1 mg/kg bolus followed by an infusion of 0.25 mg/kg/hr. For the patients who underwent PCI, an additional bolus of 0.50 mg/kg was administered and the infusion rate increased to 1.75 mg/kg/hr for the duration of the procedure. At investigator discretion, the infusion was continued following the procedure at a dose of 0.25 mg/kg/hr. For patients being medically managed or planned for CABG, a dose of 0.25 mg/kg/hr was continued at physician discretion. Heparin was administered as a 60 U/kg bolus followed by a 12 U/kg/hr infusion through angiography; dosing was adjusted appropriately for PCI and CABG. Enoxaparin and GPIs were administered according to manufacturers’ instructions.

    Study results

    The primary analysis and results for ACUITY at 30-days and 1 year for the overall (ITT) population and for the patients that received aspirin and clopidogrel as per protocol (pre- angiography or pre-PCI) are shown in Tables 1 and 2.

    Table 1. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic endpoint and its components for the overall population (ITT)
    Overall population (ITT)
    Arm A
    UFH/enox
    +GPI
    (N=4,603)
    %*
    Arm B
    bival +GPI
    (N=4,604)
    %*
    B–A
    Risk diff.
    (95% CI)
    Arm C
    bival
    alone
    (N=4,612)
    %*
    C–A
    Risk diff.
    (95% CI)
    30-day
     Composite
     ischemia
    7.3
    7.7
    0.48
    (-0.60, 1.55)
    7.8
    0.55
    (-0.53, 1.63)
     Death 1.3
    1.5
    0.17
    (-0.31, 0.66)
    1.6
    0.26
    (-0.23, 0.75)
     MI 4.9
    5.0
    0.04
    (-0.84, 0.93)
    5.4
    0.45
    (-0.46, 1.35)
     Unplanned
     revasc.
    2.3 2.7 0.39
    (-0.24, 1.03)
    2.4 0.10
    (-0.51, 0.72)
    1-year
     Composite
     ischemia
    15.3
    15.9
    0.65
    (-0.83, 2.13)
    16.0
    0.71
    (-0.77, 2.19)
     Death 3.9
    3.8
    0.04
    (-0.83, 0.74)
    3.7
    -0.18
    (-0.96, 0.60)
     MI 6.8
    7.0
    0.19
    (-0.84, 1.23)
    7.6
    0.83
    (-0.22, 1.89)
     Unplanned
     revasc.
    8.1 8.8 0.78
    (-0.36, 1.92)
    8.4 0.37
    (-0.75, 1.50)

    UFH=unfractionated heparin; enox=enoxaparin; bival=bivalirudin; GPI=glycoprotein IIb/IIIA inhibitor; revasc=revascularization

    * % represents the incidence of observed events


    Table 2. ACUITY trial; 30-day and 1-year risk differences for the composite ischaemic endpoint and its components for patients that received aspirin and clopidogrel as per protocol**
    Patients receiving aspirin and clopidogrel as per protocol**
    Arm A
    UFH/enox
    +GPI
    (N=2,842)
    %*
    Arm B
    bival +GPI
    (N=2,924)
    %*
    B–A
    Risk diff.
    (95% CI)
    Arm C
    bival
    alone
    (N=2,911)
    %*
    C–A
    Risk diff.
    (95% CI)
    30-day
     Composite
     ischemia
    7.4
    7.4
    0.03
    (-1.32, 1.38)
    7.0
    -0.35
    (-1.68, 0.99)
     Death 1.4
    1.4
    0.00
    (-0.60, 0.60)
    1.2
    -0.14
    (-0.72, 0.45)
     MI 4.8
    4.9
    0.04
    (-1.07, 1.14)
    4.7
    -0.08
    (-1.18, 1.02)
     Unplanned
     revasc.
    2.6 2.8 0.23
    (-0.61, 1.08)
    2.2 -0.41
    (-1.20, 0.39)
    1-year
     Composite
     ischemia
    16.1
    16.8
    0.68
    (-1.24, 2.59)
    15.8
    -0.35
    (-2.24, 1.54)
     Death 3.7
    3.9
    0.20
    (-0.78, 1.19)
    3.3
    -0.36
    (-1.31, 0.59)
     MI 6.7
    7.3
    0.60
    (-0.71, 1.91)
    6.8
    0.19
    (-1.11, 1.48)
     Unplanned
     revasc.
    9.4 10.0 0.59
    (-0.94, 2.12)
    8.9 -0.53
    (-2.02, 0.96)

    UFH=unfractionated heparin; enox=enoxaparin; bival=bivalirudin; GPI=glycoprotein IIb/IIIA inhibitor; revasc=revascularization

    * % represents the incidence of observed events

    **clopidogrel pre-angiography or pre-PCI

    ACUITY major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥5 cm diameter haematoma at puncture site, reduction in haemoglobin concentration of ≥4 g/dl without an overt source of bleeding, reduction in haemoglobin concentration of ≥3 g/dl with an overt source of bleeding, re-operation for bleeding or use of any blood product transfusion. Minor bleeding was defined as any observed bleeding event that did not meet the criteria as major.

    Major bleeding rates are shown in Table 3 for the IIT population (patients receiving clopidogrel and aspirin). Both major and minor bleeds were significantly less frequent with bivalirudin alone than the heparin plus GP IIb/IIIa inhibitor and bivalirudin plus GP IIb/IIIa inhibitor groups.Similar reductions in bleeding were observed in patients who were switched to bivalirudin from heparin-based therapies (N = 2,078).

    The incidence of both ACUITY-scale and TIMI-scale bleeding events to day 30 for the per protocol population are presented in Table 4.

    The advantage of bivalirudin over UFH/enoxaparin plus GP IIb/IIIa inhibitor in terms of bleeding events was only observed in the bivalirudin monotherapy arm.

    Table 3. ACUITY Trial: Major bleeding rates at 30 days for intent-to-treat population Bivalirudin (%) UFH/Enox1 + GPI
    Bivalirudin (%) Bival + GPI (%) UFH/Enox1 + GPI (%)
    N = 4,612 N = 4,604 N = 4,603
    Protocol defined major
    bleeding
    3.0 5.3 5.7
    TIMI
    Major (non-CABG)
    Bleeding
    0.9
    1.8
    1.9

    UFH=unfractionated heparin; enox=enoxaparin; bival=bivalirudin; GPI=glycoprotein IIb/IIIA inhibitor; revasc=revascularization

    *% represents the incidence of observed events


    Table 4. ACUITY trial; bleeding events up to day 30 for the population of patients who received aspirin and clopidogrel as per protocol**
    UFH/enox + GPI
    (N= 2,842) %*
    Bival + GPI
    (N=2,924) %*
    Bival alone
    (N=2,911) %%
    ACUITY scale major
    bleeding
    5.9 5.4 3.1
    TIMI scale major bleeding 1.9 1.9 0.8

    UFH=unfractionated heparin; enox=enoxaparin; bival=bivalirudin; GPI=glycoprotein IIb/IIIA inhibitor; revasc=revascularization

    * % represents the incidence of observed events

    **clopidogrel pre-angiography or pre-PCI

    HORIZONS (STEMI undergoing primary PCI)

    Study demographics and trial design

    The HORIZONS trial was a prospective, dual arm, single blind, randomised, multi-centre trial to establish the safety and efficacy of ANGIOMAX in patients with STEMI undergoing a primary PCI strategy with stent implantation with either a slow release paclitaxal-eluding stent (TAXUSTM) or an otherwise identical uncoated bare metal stent (Express2TM). A total of 3,602 patients were randomised to receive either ANGIOMAX (1,800 patients) or unfractionated heparin plus a GP IIb/IIIa inhibitor (1,802 patients). All patients received aspirin and clopidogrel, with twice as many patients (approximately 64%) receiving a 600 mg loading dose of clopidogrel than a 300 mg loading dose of clopidogrel. Approximately 66% of patients were pre-treated with unfractionated heparin.

    The dose of ANGIOMAX used in HORIZONS was the same as that used in the REPLACE-2 study (0.75 mg/kg bolus followed by 1.75 mg/kg/hr infusion). A total of 92.9% of patients treated underwent primary PCI as their primary management strategy.

    Study results

    In the HORIZONS study, the key efficacy endpoint of MACE (Major Adverse Ischaemic Cardiac Events) included any death, reinfarction, ischaemic TVR, or stroke. The primary analysis and results for HORIZONS at 30 days and 1 year for the overall (ITT) population are shown in Table 5. Results at 1 year were consistent with results at 30 days.

    Table 5. HORIZONS trial: 30-day and 1-year results for the composite endpoint (MACE) and its components for the overall population (ITT)
    Overall population (ITT)
    n/N (%) of patients Estimate [95% CI]
    ANGIOMAX UFH + GP
    IIb/IIIa
      Difference     Relative Risk           P-valuea
    30-day
     MACE

      Death

      Reinfarction

      Ischemic TVR
      Stroke

    98/1800 (5.4)
    37/1800 (2.1)
    34/1800 (1.9)
    45/1800 (2.5)
    14/1800 (0.8)

    100/1802 (5.5)
    56/1802 (3.1)
    32/1802 (1.8)
    35/1802 (1.9)
    12/1802 (0.7)

    -0.1 [-1.6, 1.4]

    -1.1 [-2.1, 0.0]

    0.1 [-0.8, 1.0]

    0.6 [-0.5, 1.6]

    0.1 [-0.5, 0.7]

    0.98
    [0.75, 1.29]
    0.66
    [0.44, 1.00]
    1.06
    [0.66, 1.72]
    1.29
    [0.83, 1.99]
    1.17
    [0.54, 2.52]

    0.8901

    0.0465

    0.8003

    0.2561

    0.6917
    1-year
     MACE

      Death

      Reinfarction

      Ischemic TVR
      Stroke

    209/1800 (11.6)
    61/1800 (3.4)
    62/1800 (3.4)
    123/1800 (6.8)
    20/1800 (1.1)

    210/1802 (11.7)
    86/1802 (4.8)
    76/1802 (4.2)
    100/1802 (5.5)
    20/1802 (1.1)

    -0.0 [2.2, 2.1]

    -1.4 [-2.7, 0.0]

    -0.8 [-2.1, 0.5]

    1.3 [-0.3, 2.9]

    0.0 [-0.7, 0.7]

    1.00
    [0.83, 1.19]
    0.71
    [0.51, 0.98]
    0.82
    [0.59, 1.13]
    1.23
    [0.95, 1.59]
    1.00
    [0.54, 1.85]

    0.9682

    0.0359

    0.2268

    0.1099

    0.9972

    a Superiority p-value.

    REPLACE-2 (Randomized Evaluation of PCI Linking ANGIOMAX Reduced Clinical Events)

    Study demographics and trial design

    ANGIOMAX (bivalirudin) has been evaluated in five interventional cardiology trials reporting 19,211 patients. Stents were deployed over 13,224 of the patients in these trials - mainly in trials performed since 1995. PTCA, atherectomy or other procedures were performed in the remaining patients.

    ANGIOMAX plus provisional platelet GPIIb/IIIa inhibition was evaluated versus heparin plus planned GPIIb/IIIa inhibition in 6010 patients undergoing PCI in the double-blind, randomized, multi-centre REPLACE-2 trial (Randomized Evaluation in PCI linking ANGIOMAX to reduced Clinical Events).

    Patients were aged 25-95 years with body weights 35-199 kg. Indications for PCI included unstable angina (35% of patients), myocardial infarction (MI) within 7-days prior to intervention (8%), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients, balloon angioplasty, atherectomy and other procedures were performed in 15%. Pretreatment with ASA (given in 99%) and thienopyridines (86%) was based on protocol recommendations. Pretreatment with other anticoagulants was allowed by protocol.

    ANGIOMAX was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hr infusion for the duration of the procedure. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 minutes. Heparin was administered as a 65 U/kg bolus. Abciximab and eptifibatide were given according to manufacturers  instructions. Both randomised groups could be given "provisional" treatments with GPIIb/IIIa inhibitors during the PCI at investigator discretion, but under double-blind conditions. Provisional treatment with GPIIb/IIIa inhibitors was requested in 5.2% of patients randomised to heparin plus GPIIb/IIIa (they were given placebo) and in 7.2% patients randomised to ANGIOMAX (they were given abciximab or eptifibatide according to pre- randomisation investigator choice and patient stratification). Reasons for provisional treatment included new or suspected thrombus, dissection with decreased flow and decreased Thrombosis In Myocardial Infarction (TIMI) flow (0-2) or slow reflow.

    The ACT (measured by a Hemochron device) was checked 5 minutes after the first bolus of study medication. For patients randomised to ANGIOMAX, the median 5-minute ACT was 358 seconds (interquartile range 320-400 seconds) and the ACT was <225 seconds in 3%. For patients randomised to heparin plus GPIIb/IIIa inhibitors, the median 5-minute ACT was 317 seconds (interquartile range 263-373 seconds) and the ACT was <225 seconds in 12%. At the end of the procedure, median ACT values were 344 seconds (ANGIOMAX group) and 276 seconds (heparin plus GPIIb/IIIa inhibitor group).

    ANGIOMAX was also evaluated in patients with unstable angina undergoing PTCA in two randomised, double-blind, multicenter studies with identical protocols (the BAT trial, Bivalirudin Angioplasty Trial). Overall, 4312 patients with unstable angina, including 741 patients (17%) with post-MI angina, were treated in a 1:1 randomised fashion with ANGIOMAX or heparin. Patients evaluated had a median age of 63 years (range 29-90 years) and a median weight of 80 kg (range 39-120 kg), with 68% male, and 91% Caucasian. Twenty-three percent of patients were treated with open-label heparin within one hour prior to randomisation. All patients were administered ASA 300-325 mg prior to PTCA, and daily thereafter.

    Patients randomised to ANGIOMAX were started on an i.v. infusion of ANGIOMAX of 2.5 mg/kg/hr in a double-blind fashion. Within 5 minutes after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an i.v. bolus. The infusion was continued for 4 hours, then the infusion was changed, under double-blind conditions, to ANGIOMAX at 0.2 mg/kg/hr for up to an additional 20 hours, with patients receiving this infusion for an average of 14 hours. The ACT was checked at 5 minutes and at 45 minutes following commencement of the ANGIOMAX infusion. If on either occasion the ACT was < 350 seconds, an additional double-blinded bolus of placebo was administered. The ANGIOMAX dose was not titrated to ACT. Median ACT values (and observed values between the 5th and 95th percentile) were: 345 seconds (240-595 seconds) at 5 minutes, and 346 seconds (269-583 seconds) at 45 minutes after initiation of dosing.

    Patients randomised to heparin were given a loading dose of 175 IU/kg in a double-blind fashion as an i.v. bolus 5 minutes before the planned procedure, after commencement of an initial infusion of heparin at 15 IU/kg/hr. The infusion was continued for 4 hours. After 4 hours, the heparin infusion was changed, under double-blind conditions, to remain at heparin 15 IU/kg/hr for up to 20 additional hours. The ACT was checked at 5 minutes and at 45 minutes following commencement of the infusion. If on either occasion the ACT was < 350 seconds, an additional double-blind bolus of heparin at 60 IU/kg was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event, pre-defined as “procedural failure”, had occurred. The use of open-label heparin after administration of test drug was similar between ANGIOMAX and heparin treatment groups, at about 20% in both groups.

    Study results

    In the REPLACE-2 trial, the primary protocol endpoint was a composite of three efficacy variables measured 30 days post-procedure, (death, MI, and urgent revascularization), and one safety variable, (in-hospital major hemorrhage), adjudicated under double-blind conditions. The rates of this composite endpoint were similar in the ANGIOMAX and heparin plus GPIIb/IIIa inhibitor treatment groups. The secondary composite ischemic endpoint of death, MI or urgent revascularisation was reported with similar incidence in both groups. Major hemorrhage was reported significantly less frequently in patients randomised to ANGIOMAX. Study outcomes are shown in Table 6.

    Table 6: Incidences of Clinical Endpoints at 30 days for REPLACE-2 in patients undergoing PCI
    Intention-to-treat population Per-protocol population
    Angiomax
    (N=2994)
    [%]
    Heparin +
    GPIIb/IIIa
    inhibitor
    N=3008)
    [%]
    O.R(95% C.I.)              Angiomax
    (N=2902)
    [%]
    Heparin +
    GPIIb/IIIa
    inhibitor
    (N=2882)
    [%]
    O.R.(95% C.I.)             
    Primary (quadruple) endpoint
    9.2

    10.0

    0.92
    (0.77-1.09)

    9.2

    10.0

    0.91
    (0.77-1.09)
    Secondary (triple) endpoint
    7.6

    7.1

    1.09
    (0.90-1.32)

    7.8

    7.1

    1.10
    (0.90-1.34)
    Endpoint components
     Death
     
     Myocardial Infarction

     Urgent revascularization

     Major bleeding


    0.2

    7.0


    1.2


    2.4#


    0.4

    6.2


    1.4


    4.1


    0.59
    (0.23-1.49)
    1.13
    (0.92-1.39)

    0.84
    (0.53-1.31)

    0.57
    (0.42-0.77)


    0.2

    7.1


    1.2


    2.2#


    0.4

    6.4


    1.3


    4.0


    0.5
    (0.19-1.32)
    1.12
    (0.91-1.37)

    0.91
    (0.57-1.46)

    0.56
    (0.41-0.76)

    #: p<0.001 vs. heparin + GPIIb/IIIa inhibitor

    BAT (Bivalirudin Angioplasty Trial)

    In the BAT trial, the studies were designed to demonstrate the safety and efficacy of ANGIOMAX in patients undergoing PTCA as a treatment for unstable angina. The primary pre- specified endpoint was a composite endpoint called “procedural failure”, which included both clinical and angiographic elements measured during hospitalisation. The clinical elements were the occurrence of death, MI, or urgent revascularisation, while the angiographic elements were identified as impending or abrupt vessel closure. The pre-specified safety endpoint was major hemorrhage.

    The median duration of hospitalisation was 4 days for both the ANGIOMAX and heparin treatment groups. The rates of so-called procedural failure were similar in the ANGIOMAX and heparin treatment groups. Study outcomes are shown in Table 7 below for the intent-to-treat population.

    Table 7: Incidence of In-hospital Clinical Endpoints in BAT Trial Occurring within 7 Days
    All Patients ANGIOMAX
    n = 2161
    HEPARIN
    n = 2151
    P Value
    Efficacy Endpoints:
    Procedural Failure1 7.9% 9.3% 0.108
    Death, MI, Revascularisation 6.2% 7.9% 0.039
    Death 0.2% 0.2% 0.987
    MI2 3.3% 4.2% 0.126
    Revascularisation3 4.2% 5.6% 0.030
    Safety Endpoint:
    Major Hemorrhage4 3.5% 9.3% < 0.001

    1 The protocol specified primary endpoint (a composite of death or MI or clinical deterioration of cardiac origin requiring revascularisation or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure).

    2 Defined as: Q-wave MI; CK-MB elevation ≥2xULN, new ST- or T-wave abnormality, and chest pain ≥30 min; OR new LBBB with chest pain ≥30 min and/or elevated CK-MB enzymes; OR elevated CK-MB and new ST- or T-wave abnormality without chest pain; OR elevated CK-MB.

    3 Defined as: any revascularisation procedure, including angioplasty, CABG, stenting, or placement of an intra-aortic balloon pump.

    4 Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥

    3g/dL or leading to a transfusion of 2 units of blood.

    In evaluating the efficacy and safety of ANGIOMAX in these clinical studies, the relatively high initial bolus dose of heparin (175 IU/kg) used in the comparator group should be noted. This is reflected by the mean ACT values reported in these studies of 377 seconds for ANGIOMAX- treated patients at 5 minutes after initiation of therapy, compared to 414 seconds with heparin; and 380 seconds for ANGIOMAX-treated patients at 45 minutes after initiation, compared to 418 seconds in those treated with heparin. Mean baseline ACT values were virtually identical for both groups at 145 and 144 seconds, respectively.

    CHOOSE (CABG/HIT/TS On- and Off-pump Safety and Efficacy) and EVOLUTION (EValuation of patients during coronary artery bypass graft Operation: Linking UTilization of bivalirudin to Improved Outcomes and New anticoagulant strategy)

    Study demographics and trial design

    The results of four trials provided clinical substantiation that ANGIOMAX is a safe and effective anticoagulant for use in patients with or at risk of HIT/TS undergoing cardiac surgery. Each of the two CHOOSE efficacy studies in patients with or at risk of HIT/TS undergoing on- or off- pump cardiac surgery included 50 prospective patients administered bivalirudin compared to approximately 50 historical control patients. Patients were considered to be with or at risk of HIT/TS if they had a new diagnosis or a documented history of HIT/TS. This was defined by a positive platelet aggregation assay, functional assay, or immunoassay for HPF-4 antibodies, and/or thrombocytopenia (platelet count decreased 50% or more from baseline) associated with heparin use. In addition patients with HIT plus any evidence of arterial or venous thrombosis (HITTS) were eligible for inclusion. The two EVOLUTION safety studies were each conducted in 150 non-HIT/TS patients undergoing on- or off-pump cardiac surgery, randomized 2:1, bivalirudin to heparin/protamine.

    Patients in the CHOOSE and EVOLUTION studies had a median age ranging from 64-67 years, 69-74% were male and 87-93% were Caucasian in the two treatment groups. The median weight ranged from 77-88 kg with a corresponding Body Mass Index (BMI) of 27-29.

    In the on-pump studies, patients were dosed with a bivalirudin i.v. bolus of 1.0 mg/kg followed by an i.v. infusion of 2.5 mg/kg/hr; patients undergoing off-pump surgery were dosed with an i.v. bolus of 0.75 mg/kg followed by an i.v. infusion of 1.75 mg/kg/hr.

    Study results

    In the CHOOSE and EVOLUTION trials, the primary endpoint was procedural success, defined as the absence of death, Q-wave MI, repeat coronary revascularization, and stroke at Day 7 or discharge, whichever occurred first. Procedural success rates were similar in the ANGIOMAX and the comparator groups in the CHOOSE and EVOLUTION studies at Day 7/discharge and at Day 30 (see Table 8). The incidences of death, Q-wave MI, revascularization and stroke were few and were similar in the treatment groups. The clinical trial data indicated that any of the commonly used activated clotting tests may be used to ensure that the patient is adequately anticoagulated following administration of ANGIOMAX.

    Table 8: Procedural Success for the CHOOSE (patients with or at risk of HIT/TS) and EVOLUTION (non- HIT/TS patients) Studies in Cardiac Surgery (ITT Population)
    Parameter CHOOSE Studies (HIT/TS)1 EVOLUTION Studies (Non-HIT/TS)2
    On-pump Off-pump On-pump Off-pump
    ANGIOMAX

    n/N (%)
    HISTORICAL
    CONTROL
    n/N (%)
    ANGIOMAX

    n/N (%)
    HISTORICAL
    CONTROL
    n/N (%)
    ANGIOMAX

    n/N (%)
    HEPARIN/
    PROTAMINE
    n/N (%)
    ANGIOMAX

    n/N (%)
    HEPARIN/
    PROTAMINE
    n/N (%)
    Procedural success3:
    Day 7/ discharge 46/50
    (92.0)
    69/75
    (92.0)
    50/52
    (96.2)
    35/36
    (97.2)
    96/101
    (95.0)
    47/49
    (95.9)
    101/105
    (96.2)
    49/52
    (94.2)
    Day 30 45/50
    (90.0)
    68/75
    (90.7)
    48/51
    (94.1)
    32/36
    (88.9)
    95/101
    (94.1)
    47/49
    (95.9)
    97/104
    (93.3)
    48/52
    (92.3)

    1Investigator-reported Q-wave MI data were used for the CHOOSE studies because data from the historical cohort could not be adjudicated

    2Q-wave MI data adjudicated by an independent Clinical Events Committee are used for these studies

    3Defined as absence of death, Q-wave MI, stroke and revascularization

    Detailed pharmacology

    Human Pharmacokinetics

    In healthy volunteers, ANGIOMAX (bivalirudin) was administered as a 15 minute i.v. infusion at a range of doses.

    Table 9: ANGIOMAX i.v. Infusion in Healthy Volunteers over 15 minutes
    Infusion Dose
    (mg/kg/hr)
    Mean Volume of
    Distribution (L/kg)
    Mean Clearance
    (mL/min/kg)
    Mean Half-Life (min) Mean Percentage
    Urinary Excretion
    (%)
    0.2 N/D N/D N/D N/D
    0.3 N/D N/D N/D N/D
    0.6 N/D N/D N/D N/D
    02-01-15 0.24 7.79 05-22-15 09-09-15
    04-02-15 0.24 6.74 06-24-15 04-13-15

    N/D: not detectable

    Bivalirudin plasma concentrations were measured using an ELISA antibody based assay that detected bivalirudin and some bivalirudin metabolites.

    Further studies have been carried out in patients with varying degrees of renal impairment undergoing PTCA at the dose of 1.0 mg/kg i.v. bolus, plus 2.5 mg/kg/hr i.v. infusion for 4 hours followed by 0.5 mg/kg/hr for a further 4 hours, and in severely renally impaired patient volunteers where a bolus of 1.0 mg/kg and infusion of 0.5 mg/kg/hr for 10 hours was given, see Table 10 below. Plasma and urine levels of bivalirudin were detected by an LC/MS based method validated to quantify only intact bivalirudin.

    Table 10: Pharmacokinetics of ANGIOMAX in Healthy Volunteers and Patients with Renal Impairment
    Renal Function i.v. Infusion Dose
    (mg/kg/hr)
    Mean Clearance
    (mL/min/kg)
    Elimination
    Half-Life
    (min)
    Normal Renal Function
    GFR ≥90 mL/min
    2.5 (4 hr) 3.4 ± 0.5 24.9 ± 12.1
    (modeled)
    0.5 (4 hr) 3.7 ± 1.0
    Mild Renal Impairment
    GFR 60-89 mL/min
    2.5 (4 hr) 3.4 ± 0.7 22.2 ± 8.0
    (modeled)
    0.5 (4 hr) 3.2 ± 0.9
    Moderate Renal Impairment
    GFR 30-59 mL/min
    2.5 (4 hr) 2.7 ± 0.4 33.5 ± 6.8
    (modeled)
    0.5 (4 hr) 2.5 ± 0.2
    Severe Renal Impairment
    GFR <30 mL/min
    0.5 (10 hr) 2.8 ± 0.7 56.8 ± 24.0

    These data indicate that patients with moderate and severe renal impairment exhibit about 20% reduction in renal clearance. The half-life was prolonged in these patients. Therefore, in patients with severe renal impairment (GFR <30 mL/min), ACT should be monitored and a reduction in the infusion dose should be considered (see DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Renal Impairment).

    An additional study of subjects with normal to severely impaired renal function (as determined by insulin clearance), demonstrated that plasma clearance of ANGIOMAX is proportional to glomerular filtration rate at all levels of renal function. The study also demonstrated that ANGIOMAX is hemodialysable.

    Toxicology

    Bivalirudin was administered to animals for up to 28 days by continuous i.v. infusion at dose levels of up to 80 times the clinically recommended dose of 15 mg/kg/day. Toxicological effects observed were directly related to the route of administration and to the anticoagulant activity of bivalirudin, such as local injection site phlebitis and hemorrhage, and internal organ hemorrhage. Bivalirudin caused no signs of toxicity at clinically relevant doses administered by either repeated i.v. injection or continuous infusion for up to 28 days.

    The relative anticoagulant activity of various species is reported below in Table 11.

    Table 11: Estimates in Several Species of Bivalirudin Concentration Required to Prolong aPTT to 3 Times Baseline
    Species Effective Conc. (Вµg/mL)* Relative to Human
    Human 0.82 1
    Baboon 0.35 0.4
    Monkey 0.9 1.1
    Rat 1.8 2.3
    Dog 3.5 4.3
    Rabbit 14 17.1
    Pig 24 29.3

    *Required to prolong aPTT to 3 times baseline.

    Acute Toxicity:

    Mouse: No overt toxicity was observed within a 14-day observation period at i.v. and subcutaneous (s.c.) doses up to and including 200 mg/kg.

    Rat: An acute single dose i.v. study in rats assessed doses up to 200 mg/kg, when administered in 10 mL/kg saline infusion, and included a 14-day observation period. This study showed enlargement of the thymus gland and submandibular lymph nodes in both sexes. Acute toxicity was also observed, including death, respiratory distress, piloerection and vascular congestion of the lungs. Findings were observed at all dose levels.

    Another study, examining a 100 mg/kg single i.v. dose, administered in 2 mL/kg saline infusion, with a 14-day follow-up observation period, reported no adverse effects.

    Monkey: No mortality or adverse effects attributable to bivalirudin were observed in two monkeys administered doses up to 42 mg/kg over a four hour period by i.v. infusion.

    Subchronic and Chronic Toxicity:

    Rat: Continuous i.v. infusion for 7 to 28 days at doses from 25 to 1200 mg/kg/day caused no adverse effects at 25 mg/kg/day. Mortality was observed at doses of 250 mg/kg/day for 28 days (2 of 30 animals) and 500 mg/kg/day for 28 days (2 of 10 animals) and above. At 500, 1000, and 1200 mg/kg/day, in addition to mortality, hemorrhage of internal organs was observed. A dose of 75 mg/kg/day and above for 28 days produced phlebitis at the injection site accompanied by effects in the spleen (enlargement), liver (sinusoidal histiocytosis/necrosis), and bone marrow (myeloid hypercellularity).

    Monkey: Clinical signs, body weight, and food consumption appeared normal in cynomolgus monkeys following continuous i.v. infusion for 14 or 28 days at doses of 15 and 45 mg/kg/day. Internal organ hemorrhage was identified in some animals receiving 150 mg/kg/day over 14 days. Anticoagulant activities maintained during the study were approximately 85, 200, and 350 percent above baseline levels at the three doses tested, respectively. In a 28-day study, myocardial degeneration and/or necrosis were noted in 2 monkeys receiving the highest dose of 150 mg/kg/day. The lesions were associated with mild hemorrhage and appeared to occur during the last 7 to 10 days of the 28-day treatment period. No cardiac lesions were evident in monkeys treated with bivalirudin at 150 mg/kg/day for 14 days.

    Special Studies:

    Bivalirudin, when administered subcutaneously once/week at 1 mg/kg for 3 weeks was considered non-antigenic in guinea pigs.

    No antibodies cross-reacting with bivalirudin were detected in monkeys receiving i.v. doses up to 100 mg/kg and up to 150 mg/kg/day for 14 days by continuous infusion.

    Bivalirudin at 10 mg/mL did not cause hemolysis or plasma protein flocculation of human blood in vitro.

    Carcinogenesis and Genotoxicity:

    No long-term studies in animals have been performed to evaluate the carcinogenic potential of bivalirudin. Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay.

    Reproductive and Developmental Toxicity:

    Rat: Reproductive toxicity, as defined by adverse effects on mating and fertility indices, was observed only at dose levels associated with toxicity, i.e. 150 and 500 mg/kg/day.

    Developmental toxicity, i.e. adverse fetal effects, was observed only at maternally toxic doses of 150 and 500 mg/kg/day.

    No teratogenic effects were evident at any doses evaluated.

    Rabbit: Neither maternal nor developmental adverse effects were observed up to and including bivalirudin doses of 150 mg/kg/day.