Within 3 hours – within 4.5 hours – beyond 4.5 hours
Within 3 hours but thrombolysis contraindicated
Within 4.5 hours but thrombolysis contraindicated
Proximal artery vs distal artery occlusions
Ischemic penumbra model:
Cerebral artery occlusion – hypoperfused braintissue at risk for infarction salvageable by restoration of blood flow (ischemic penumbra) reversible – irreversible infarction; – brain titssue with irreversible damage (ischemic core); – decreased perfusion but no infarction risk regardless of treatment (benign oligemia)
Reperfusion leads to better outcomes
Time to irreversible infarction? What predicts?
Every minute artery occluded – 2M neurons die
10 hours = neuronal loss occurring with 26 years of normal aging
Coil retrievers – wraps around clot and pulls it back
Stent retrievers – expands site of occlusion by stent, traps and extracts thrombus
Aspiration devices – sucks thrombus
Challenge: distinguish penumbra from core infarct from benign oligemia
National Institute of Neurological Disorders and Stroke (NINDS) 1990s[i] – 1995 sponsored 2 RCTs of IV rtPA vs placebo: 624 patients with ischemic stroke within 3 hours – 16% inc in favorable outcome (mRS0-1) at 3 monthes (42.6% vs 26.6% p<0.01 NNT 6), inc risk for Sxic brain hemorrhage (6.4% vs 0.6% p<0.001) – FDA approval
European Cooperative Acute Stroke Study III (ECASS-3)[ii] – 2008 821 patients with stroke <80y/o present within 3-4.5hours, (mRS 0-1 52.4% vs 45.2% p=0.04 NNT 14)
*dichotomous analysis – compelling; if analyzed for shift towards improved outcomes across full range – even more strongly associated with benefit (NNT 3 in 0-3h, NNT 7 in 3-4.5h)
*IV rtPA established as standard therapy for AIS within 3 hours; still not approved by FDA for use I 3-4.5 although recommended for moderately severe Sx <80y and without C/I
Stroke diagnostic tests: CT, MRI, CTA, MRA, echo, telemetry, outpatient cardiac monitoring, HbA1C, lipid panel; in select patients (inflammatory markers, hypercoag work-up, US lower ex, LP, blood cultures)
Meta-analysis of 2775 patients undergoing IV rtPA – odds of good outcome dependent on time – 0-90 mins OR 2.55, 91-180mins OR 1.64; 181-270 minutes OR 1.34, no benefit beyond 4.5 hours; confirmed similar risk of symptomatic brain hemorrhage seen in NINDS trial (5.2 vs 1.0% OR 5.37)
Outcomes are better overall
However: after tPA aone – only 10-15% ICA occlusions and 25-50% prox MCA occlusions recanalize; on 35-40% achieve functional independence
*prox artery occlusions (1/3 of all AIS) may be resistant to IV rtPA alone; goal: improve recanalization rates with other methods
Catheter based treatment
Early trials (first generation approaches) failed to show clinical benefit despite successful recanalization
Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial[iii] – 1999 180 patients within 6h + angio confirmed MCA occlusions, IA recombinant prourokinase (r-proUK) with heparin (2000 U bolus + 500 U/H x4h) vs heparin alone – (mRS 0-2 at 90 days: 39.4% vs 25.4% OR 2.13 p=0.04 NNT7) (higher risk of symptomatic brain hemorrhage (10.2% vs 1.9% p=0.06
*benefits marginal, offset by increased risk of harm, not approved for IA thrombolysis in AIS
Japanese study using urokinase vs best medical care supported findings of PROACT II (mRS 0-1 42.1 vs 22.8% p=0.045, sxic hemorrhage 8.8 vs 1.8% p=0.21)
Mechanical thrombectomy devices approved by FDA based on technical efficacy and safety reports from large multicenter case registries – acceptable complication rates: 7-19% experience device and procedure-related complications (device fracture, vessel perforation and hemorrhage, nontarget artery embolization
Coil retriever / aspiration devices – approved by FDA based on single-group studies showing improved revascularization for prox artery occlusions, results were compared to historical control (from PROACT II)
Interventional Management of Stroke (IMS) III trial[iv] – 2013 standard dose IV rtPA vs low dose IV rtPA and IA rtPA or mechanical thrombectomy; only 1% stent retrievers; no preprocedure vascular imaging selection in 46.6% (so 21% did not have proximal artery occlusion in IA treatment group); 656 patients over 6 years, stopped for futility (mRS0-2 at 90d 40.8% vs 38.7%; mortality 19.1% vs 21.6% p=0.52) or symptomatic brain hemorrhage (6.2% vs 5.9% p=0.83)
Intra-arterial vs Systemic Thrombolysis for AIS (SYNTHESIS EXP) study[v] – 2010 2 groups of 181 patients; IV rtPA vs mech thrombectomy or IA therapy within 4.5h; of IA patients, 60% treated with rtPA infusion and microguidewire thrombus fragmentation, 31% with thrombectomy devices, 13% with stent retrievers; no benefit observed, no disability at 90d (30.4% vs 34.8% p=0.037) no safety differences symptomatic ICH (5.5% vs 5.5% p=0.99) and mortality 7.7% vs 6.1% p=0.53.
2 studies[vi][vii]: both 2012 newer stent retriever devices vs earlier coil retriever – improve recanalization, reduced mortality, better functional outcomes; established superiority but no direct comparison with control group with IV rtPA
4 RCTS of stent retrievers vs medical treatment
Multicenter RCT of Endovascular Treatment for AIS (MR CLEAN)[viii] phase 3 – 2015 mech thrombectomy within 6h vs standard treatment improved improved 90d clinical outcomes; 90.6% received IV rtPA within 4.5h; 16 stroke centers in Holland; stroke patients with confirmed prox artery occlusions – randomized to std (267) or standard + IA (pred stent retriever) treatment; mRS0-2 32.6% vs 19.1% p<0.01 NNT8; no hemorrhagic safety concerns! (symptomatic ICH 7.7% vs 6.4%; 30d mortality 18.4 vs 18.9); increased risk of new ischemic stroke within 90d (5.6 vs 0.4 p<0.01) likely procedure-related embolization
Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial[ix] – 2015 n=316; within 12h, 22 global sites; prox artery occlusions identified with CT angio randomized to best medical therapy (IV rtPA in 78%) vs IA (86% stent retrievers) – stopped early for efficacy (mRS0-2 53% vs 29.3% p<0.01 NNT4) – improved workflow and enhanced patient selection emphasized – onset to reperfusion time of 241 minutes; only 15.5% treated beyond 6h
Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra arterial (EXTEND-IA)[x] – 2015 Australian, used CT perfusion imaging, randomized patients with favorable mismatch patterns to IV rtPA vs IVrtPA + stent retriever within 4.5h – stopped early for technical efficacy after 35 patients in each group; mRS 0-2 71.4% vs 40% p<0.01 NNT3
SOLITAIRE with intention for Thrombectomy as Primary Endovascular Treatment (SWIFET PRIME)[xi] – 2015 stopped early after 196 patients; rtPA able to undergo cath within 6h with ant circulation occlusion – thrombectomy superior (mRS0-2 60.2 vs 35.5% p<0.01 NNT4)
Imaging-based patient selection
Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE-2)[xii] – 2012 uncontrolled, prospective cohort study, n=99, acute stroke; favorable penumbral pattern (penumbra to infarct core ratios >1.8) better 90d outcomes with successful reperfusion vs no reperfusion (mRS0-2 56.5 vs 31.3% p=0.04); no benefit in patients without a favorable penumbra pattern (mRS0-2 25% vs 22% p>0.99)
MR RESCUE study[xiii] – 2013 phase 2b open-label RCT with blinded outcome, 118 patients with AIS – no benefit of mech thrombectomy in favorable penumbral patterns (20.6 vs 26.5% p=0.78)
*DEFUSE-2 used only MRI-based selection; MR RESCUE included CT perfusion in 20% of analyzed patients
*DEFUSE-2 defined penumbra to core ratio as >1.8 with max core infarct vol 70ml; MR RESCUE used smaller penumbra to core ratio of >1.4 and larger max core infarct vol of 90ml
*led to greater rates of futile reperfusion in MR RESCUE
*EXTEND-IA used similar algorithm as MR RESCUE but at earlier time points (<4.5h)
- Pragmatic and simple – CT angio to identify prox art occlusions; enroll based on time (<6h) as in MR CLEAN
- Assess early infarct signs (core infarct) with noncontrast CT and time window as in ESCAPE (<12h) and in SWIFT PRIME (<6h)
- CT angio assessment of collaterals as in ESCAPE
- Penumbra imaging with CT or MRI perfusion imaging with angio to confirm occluded artery within 4.5h as in EXTEND-IA and some in SWIFT PRIME
*which is superior? Not clear but all 3 shown to select patients who benefit from adjunctive IA therapy
Need more accurate and reliable measurement of brain ischemia
Penumbral imaging may take up to 30 minutes – will this negate any efficacy advantage?
Endovascular Trial Comparisons
Interventional Management of Stroke (IMS III), SYNTHESIS EXP, MR RESCUE – tested first-gen strategies for IA treatment of prox occlusions
*differences cf more recent trials: rates of reperfusion, time to reperfusion, selection
*SYNTHESIS EXP used clot fragmentation with IA rtPA in 60%
*MR CLEAN ESCAPE EXTEND IA SWIFT PRIME used stent retrievers
*rates of substantial reperfusion (TICI grades 2b or 3) lower in IMS III (40%) and MR RESCUE (27%) cf stent retriever trials (58-88%)
*time to reperfusion lower in recent trials – 4h in ESCAP, 4.1h in EXTEND-IA, 4.2h in SWIFT PRIME, 5.4 in IMSIII
*MR CLEAN ESCAPE EXTEND IA SWIFT PRIME required confirmation of prox artery occlusion on baseline CT angio – more homogenous cohort, selects more likely to benefit, decreases rate of futile reperfusion
AMBULYSIS – ambulances staffed by stroke experts fitted with CT scanners – thrombolysis in ambulance
Current AHA/ASA guidelines – IV rtPA administer to all eligible patients as quickly as possible (door-to-needle time <60 mins) in the 0-3h window (Class 1-A), in the 3-4.5 window (class I-B) and even if considering other adjunctive therapies (Class 1-A). Reduce and avoid delays to reperfusion (Class 1-A); IA thrombolyssi with rtPA in carefully selected patients with MCA occlusion within 6h onset (Class 1-B), based on MELT and PROACT II). Recommend stent retrievesr over earlier generation coil retrievers (Class I-A). Weak recommendations for clinical efficacy of mechanical thrombectomy (Class IIa-B) – does not include the 4 new trials in 2015.
MCA Embolism Local Fibrinolytic Intervention Trial (MELT)
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[ii] Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
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[x] Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018.
[xi] Saver JL, Goyal M, Bonafe A, et al. SOLITAIRE FR with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke. Paper presented at: International Stroke Conference; February 2015; Nashville, TN.
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