EXTEND

Clinical Question

Does the use of alteplase in patients with acute ischemic stroke between 4.5 and 9 hours from stoke onset (or woke up with stroke with time from midpoint of sleep < 9 hours) improve clinical outcome?

Bottom Line

The use of t-PA was associated with improved clinical outcome (35.4% attained mRS of 0 or 1 compared with 29.5% in the placebo group)

Major Points

Current guidelines recommend the use of t-PA in acute ischemic stroke up to 4.5 hours from onset, based on prior studies that used CT head to select candidates. EXTEND trial looked at using perfusion studies instead of CT head to select more patients up to 9 hours from stroke onset with salvageable penumbra on CT/MR perfusion.

Guidelines

No guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, randomized, controlled trial
• N=225
  • alteplase (n=112)
  • placebo (n=113)
• Setting: 16 centers in Australia, 1 center in New Zealand, 10 centers in Taiwan, and 1 center in Finland
• Enrollment: August 2010 through June 2018
• Mean follow-up: 90 days
• Analysis: Intention-to-treat
• Primary outcome: score of 0 or 1 on the modified Rankin scale at 90 days

Population

Inclusion Criteria

1. Hemispheric acute ischemic stroke 2. Informed consent was given. 3. Age is ≥18years 4. Treatment can commence between 4.5 and 9 hours after stroke onset 5. Patients who wake with stroke if time from midpoint of sleep is less than or equal 9 hours. Midpoint of sleep is the midpoint between going to sleep (r last known well) and waking up. 6. NIHSS is between 4-26 7. Penumbral mismatch, with mismatch ratio > 1.2 and penumbra more than 10 mL. 8. An ischemic core < 70 ml using MR-DWI or CT-CBF

Exclusion Criteria

- ICH on CT or MRI - Rapidly improving symptoms (NIHSS is expected to be < 4 at time of randomization). - Endovascular thrombectomy candidates - Pre-stroke mRS score of ≥ 2 - Contraindication to contrast agents - Ischemic core>1/3 MCA territory qualitatively - Terminal illness with expected survival < 1 year - Pregnant women (clinically evident) - Usual contraindications for tPA use, including recent stroke within past 3 months, history of recent ICH, SAH, AVM, aneurysm or neoplasm, current use of warfarin with INR > 1.7, use of therapeutic heparin within 48 hours with prolonged PTT, use of glycoprotein IIb - IIIa inhibitors within the past 72 hours, hypoglycemia, uncontrolled HTN with SBP > 185 or DBP > 110 mmHg, recent GI bleeding within past 3 weeks or recent major surgery within past 14 days

Baseline Characteristics

• Mean age: 72 years
• Mean BMI: 28
• Mean HbA1c: 8.8%
• Units of insulin: 14 units/day

Interventions

• Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

  • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
  • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
• Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
• Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Modified Rankin scale score of 0 or 1

35.4% vs 29.5% (adjusted risk ratio, 1.44; 95% CI, 1.01 to 2.06; P = 0.04)

Secondary Outcomes

Modified Rankin scale score of 0 to 2

49.6% vs 42.9% (adjusted risk ratio 1.36; 95% CI 1.06 to 1.76)

Percentage of reperfusion of atleast 50% at 24 hours

71.7% vs 52.3% (adjusted risk ratio 1.35; 95% CI 1.09 to 1.67)

Percentage of reperfusion of atleast 90% at 24 hours

50.0% vs 28.4%(adjusted risk ratio 1.73; 95% CI 1.22 to 2.46)