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CLEAR Eptifibatide

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke: The CLEAR Stroke Trial

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Year of Publication: 2008

Authors: Arthur M. Pancioli, Joseph Broderick, Thomas Brott, ..., for the CLEAR Trial Investigators

Journal: Stroke

Citation: Stroke. 2008;39(12):3268–3276. doi:10.1161/STROKEAHA.108.517656

Link: https://doi.org/10.1161/STROKEAHA.108.517656

PDF: https://www.ahajournals.org/doi/reader/1...EAHA.108.517656

Clinical Question

Is combination therapy with low-dose rt-PA and eptifibatide safe in acute ischemic stroke patients treated within 3 hours of onset?

Bottom Line

Low-dose rt-PA plus eptifibatide was safe and did not increase symptomatic ICH compared to standard-dose rt-PA, despite higher risk baseline features.

Major Points

  • Randomized 3:1 trial of 69 patients on combination therapy vs 25 on standard rt-PA
  • Dose-escalation design: rt-PA 0.3 mg/kg (Tier 1) and 0.45 mg/kg (Tier 2) + eptifibatide
  • Symptomatic ICH: 1.4% in combo group vs 8.0% in rt-PA-only group
  • No significant efficacy benefit; Barthel Index slightly favored standard rt-PA
  • Trial halted early due to acceptable safety profile

Design

Study Type: Multicenter, randomized, double-blind, dose-escalation safety trial

Randomization: 1

Blinding: Double-blind (drug preparation and administration)

Enrollment Period: July 2003 – April 2007

Follow-up Duration: 90 days

Centers: 9

Sites: 9 US centers (19 hospitals)

Countries: USA

Sample Size: 94

Analysis: Logistic regression with covariate adjustment; intention-to-treat for safety

Inclusion Criteria

  • Age 18–80 years
  • NIHSS >5
  • Initiation of therapy within 3 hours of symptom onset
  • Serious, measurable neurologic deficit

Exclusion Criteria

  • History of stroke in past 3 months
  • Previous ICH, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation
  • Hypertension at treatment: SBP >185 mm Hg or DBP >110 mm Hg (or requiring aggressive lowering)
  • Recent (within 30 days) surgery or biopsy of parenchymal organ
  • Recent (within 30 days) trauma with internal injuries or ulcerative wounds
  • Severe head trauma within 90 days
  • Active or recent (within 30 days) serious systemic hemorrhage
  • Anticoagulant therapy with PT >15 or INR >1.4
  • Glucose <50 or >400 mg/dL
  • Platelets <100,000/mm³
  • Hematocrit <25%
  • Creatinine >4 mg/dL
  • Heparin within 48 hours (unless normal PTT)
  • Arterial puncture at noncompressible site or lumbar puncture within 7 days
  • CT hypodensity >1/3 of MCA territory, or hemorrhage/mass effect
  • Seizure at onset of stroke
  • Known amyloid angiopathy
  • Pregnancy

Baseline Characteristics

Age: 71.4 (62, 77) combo vs 61.2 (55, 74) control years; P=0.01

NIHSS Score: 14 (10, 20) combo vs 10 (6, 14) control; P=0.04

Baseline mRS = 0: 52/69 (75%) combo vs 24/25 (96%) control; P=0.04

Baseline mRS 0–1: 61/69 (88%) combo vs 25/25 (100%) control; P=0.10

Prior stroke: 13/69 (19%) combo vs 4/25 (16%) control; P=0.58

History of diabetes: 17/69 (25%) combo vs 4/25 (16%) control; P=0.31

History of hypertension: 49/69 (71%) combo vs 15/25 (60%) control; P=0.31

Time to Treatment: Median 2.5 h (2.2, 2.8) combo vs 2.6 h (2.4, 2.8) control (text: 2.53 vs 2.62 h); P=0.28

Systolic BP (mm Hg): 153 (139, 175) combo vs 154 (137, 178) control

Diastolic BP (mm Hg): 83 (74, 93) combo vs 82 (77, 101) control

Glucose (mg/dL): 117 (100, 141) combo vs 116 (99, 146) control

Arms

FieldCombination TherapyControl
InterventionLow-dose rt-PA (0.3 or 0.45 mg/kg) + eptifibatide (75 μg/kg bolus, 0.75 μg/kg/min for 2h)Standard rt-PA (0.9 mg/kg per NINDS protocol)
DurationSingle treatmentSingle treatment

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Symptomatic intracranial hemorrhage within 36 hoursPrimary2/25 (8.0%)1/69 (1.4%)6.55%0.17
mRS 0–1 or return to baseline at 90 daysSecondary12/25 (48%)21/69 (30%)Adjusted OR 0.56 (0.19–1.63)0.14 (unadjusted); 0.29 (adjusted)
Barthel Index ≤95 at 90 daysSecondary18/25 (72%)32/69 (46%)Adjusted OR 0.46 (0.14–1.53)0.04 (unadjusted); 0.20 (adjusted)
Glasgow Outcome Score 0 at 90 daysSecondary13/25 (52%)28/69 (41%)Adjusted OR 1.03 (0.36–3.00)0.35 (unadjusted); 0.95 (adjusted)
NIHSS decrease ≥4 at 24 hoursSecondary11/25 (44%)29/69 (42%)Adjusted OR 0.61 (0.20–1.86)1.0 (unadjusted); 0.38 (adjusted)
NIHSS ≤2 at 24 hoursSecondary5/25 (20%)9/69 (13%)Adjusted OR 0.70 (0.17–2.87)0.51 (unadjusted); 0.62 (adjusted)
Symptomatic ICH (36 h)Adverse2/25 (8.0%)1/69 (1.4%)0.17
Asymptomatic ICHAdverse3/25 (12.0%)7/69 (10.3%)
Any ICHAdverse5/25 (20%)8/69 (12%)Adjusted OR 0.28 (0.06–1.23)0.32 (unadjusted); 0.09 (adjusted)
Death at 7 daysAdverse1/25 (4%)9/69 (13%)0.28
Death at 90 daysAdverse3/25 (12%)15/69 (22%)Adjusted OR for survival 0.41 (0.04–4.05)0.38 (unadjusted); 0.45 (adjusted survival)

Subgroup Analysis

Trend toward lower symptomatic ICH in combination group despite older age and higher stroke severity

Criticisms

  • Significant baseline imbalance in NIHSS and age
  • Small sample size limits efficacy interpretation
  • Complex blinding protocol caused treatment delays
  • Trial not powered for clinical outcome comparison

Funding

NINDS Specialized Programs of Translational Research in Acute Stroke; rt-PA and eptifibatide supplied by Genentech and Schering Plough

Based on: CLEAR Eptifibatide (Stroke, 2008)

Authors: Arthur M. Pancioli, Joseph Broderick, Thomas Brott, ..., for the CLEAR Trial Investigators

Citation: Stroke. 2008;39(12):3268–3276. doi:10.1161/STROKEAHA.108.517656

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