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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

Field	Combination Therapy	Control
Intervention	Low-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)
Duration	Single treatment	Single treatment

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Symptomatic intracranial hemorrhage within 36 hours	Primary	2/25 (8.0%)	1/69 (1.4%)	6.55%	0.17
mRS 0–1 or return to baseline at 90 days	Secondary	12/25 (48%)	21/69 (30%)	Adjusted OR 0.56 (0.19–1.63)	0.14 (unadjusted); 0.29 (adjusted)
Barthel Index ≤95 at 90 days	Secondary	18/25 (72%)	32/69 (46%)	Adjusted OR 0.46 (0.14–1.53)	0.04 (unadjusted); 0.20 (adjusted)
Glasgow Outcome Score 0 at 90 days	Secondary	13/25 (52%)	28/69 (41%)	Adjusted OR 1.03 (0.36–3.00)	0.35 (unadjusted); 0.95 (adjusted)
NIHSS decrease ≥4 at 24 hours	Secondary	11/25 (44%)	29/69 (42%)	Adjusted OR 0.61 (0.20–1.86)	1.0 (unadjusted); 0.38 (adjusted)
NIHSS ≤2 at 24 hours	Secondary	5/25 (20%)	9/69 (13%)	Adjusted OR 0.70 (0.17–2.87)	0.51 (unadjusted); 0.62 (adjusted)
Symptomatic ICH (36 h)	Adverse	2/25 (8.0%)	1/69 (1.4%)		0.17
Asymptomatic ICH	Adverse	3/25 (12.0%)	7/69 (10.3%)
Any ICH	Adverse	5/25 (20%)	8/69 (12%)	Adjusted OR 0.28 (0.06–1.23)	0.32 (unadjusted); 0.09 (adjusted)
Death at 7 days	Adverse	1/25 (4%)	9/69 (13%)		0.28
Death at 90 days	Adverse	3/25 (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)