Stroke

NINDS

NEJM 1995; 333:1581

Benefit

tPA: minimal/no deficit at 3 months: 39%

Placebo: 26%

Absolute benefit increase (39-26) = 13%

Relative benefit increase (13/26) = 50%

NNT = 8

Risk

tPA: symptomatic hemorrhage*: 6.4%

Placebo: 0.6%

Absolute risk increase (6.4-0.6) = 5.8%

Relative risk increase (5.8/0.6) = 900%

NNH = 17

*No difference in mortality

Stroke Trials (adapted from thennt.com)

1. MAST-Italy, 1995 (n = 622) Lancet 1995; 346: 1509-14
   • Time to treatment: < 6 hours
   • Results: Increased early death (OR 2.7), Slight decrease 6 m disability (OR 0.5)
   • Overall: No benefit
2. ECASS, 1995 (n = 620) JAMA 1995; 274(13): 1017-25
   • Time to treatment: < 6 hours, Notable inclusion: Moderate - severe hemispheric stroke
   • Results: No difference in disability or death
   • Overall: No benefit
3. NINDS-1, tPA 1995 (n = 291) New Engl J Med 1995; 333:1581-7
   • Time to treatment: < 3 hours
   • Results: No difference NIHSS improvement by 4 pts or resolution of deficits at 24 hours
   • Overall: No benefit
4. NINDS-2, tPA 1995 (n = 333) N Engl J Med 1995; 333:1581-7
   • Time to treatment: < 3 hours
   • Results: Planned primary outcome was to be improvement in functional and stroke scores (of 20%). This was changed, post-hoc, to dichotomous favorable vs. unfavorableoutcome. Original primary outcome result not reported.
   • Overall: Benefit = NNT of 8 for post-hoc ‘favorable’ outcome measure
5. MAST-Europe, 1996 (n = 310***) N Engl J Med 1996;335:145.
   • Time to treatment: < 6 hours Notable Inclusion: Mod-severe stroke, MCA territory only Outcome: No difference combined disability/death at 6 months; increased ICH (21% vs. 3%) and statistically nonsignificant increased mortality (47% vs. 38%)
   • Overall: Harmful
   • ***STOPPED EARLY DUE TO ICH AND MORTALITY, n of 600 planned
6. ASK, 1996 (n = 340***) JAMA 1996; 279: 961.
   • Time to treatment: <4h (small % 4-5h)
   • Outcome: No difference combined disability/death at 3 months; slightly decreased disability and increased mortality at 3 months, OR 1.83 (1.14-2.93)
   • Overall: Harmful
   • ***STOPPED EARLY DUE TO MORTALITY, n of 600 planned
7. ECASS-II, tPA 1998 (n = 800) Lancet 1998; 352: 1245-51
   • Time to treatment: <6h (20% < 3 hours)
   • Outcome: No difference in favorable outcomes (modified Rankin Scale) at 3 months
   • Overall: No benefit
8. ATLANTIS-B, tPA 1999 (n = 613*) JAMA 1999; 282(21): 2019-26
   • Time to treatment: 20% 3-4 h, 70% 4-5
   • Outcome: No difference, favorable outcome at 3 months; increased ICH (7% vs. 1%) and nonsignificant increase in mortality (11% vs. 7%)
   • Overall: Harmful
   • ***STOPPED EARLY BECAUSE “unlikely to prove beneficial” - n of 968 planned
9. ATLANTIS-A, tPA 2000 (n = 142*) Stroke 2000; 31(4): 811-16
   • Time to treatment: Initially 0-6 hours, stopped enrolling 0-3 based on NINDS result
   • Outcome: Improvement in NIHSS score (4 pts) at 24h favored lytics (40% vs. 21%, p=0.02) but at 1 month favored placebo (75% vs. 60%, p=0.05). Increased ICH with tPA (11% vs. 0%) and increased mortality at 3 months (23% vs. 7%)
   • Overall: Harmful
   • ***STOPPED EARLY FOR HARM - n of 300 planned
10. DIAS-2, desmoteplase 2008 (n = 193) Lancet Neurology 2009; 8(2), 141-150
    • Time to treatment: 3-9 hours Notable inclusion: reversible ischemic penumbra on MR or CT
    • Outcome: No difference in favorable outcomes; Statistically nonsignificant increase in mortality for high dose desmoteplase group (stopped early for harm, analyzed, restarted)
    • Overall: No benefit
11. ECASS-III, tPA 2008 (n = 821) N Engl J Med 2008; 359: 1317-29
    • Time to treatment: 3-4.5 h
    • Outcome: More favorable outcomes with tPA (OR 1.34, 1.02-1.76), mortality no difference
    • Overall: Benefit = NNT of 15 for ‘favorable’ outcome
12. IST-3, tPA 2012 (n = 3035) Lancet 2012; 379(9834): 2352-2363
    • Time to treatment: 0-6 h
    • Outcome: No difference alive and independentat 6 mo with tPA (OR 1.13, 0.95-1.35), mortality no difference at 6mo
    • Overall: No benefit