What's the Evidence Tuesdays

HHH and aSAH - All Hype(rtension) and no HHelp?

30/6/2020

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Background and Rationale

Delayed cerebral ischaemia (DCI) is a major contributor to poor outcome after aSAH
Hypertension, haemodilution, hypervolaemia has been suggested as a potential therapeutic strategy based on the theory that this should improve perfusion (autoregulation impaired)
Hypertension aims to increase cerebral blood flow (CBF) by increasing perfusion pressure
Haemodilution; lower haemoatocrit/viscosity may increase laminar flow through spastic vessels
Hypervolaemia; SAH results in contraction of extracellular/vascular spaces (+/-cerebral salt wasting) so additional fluid required – also increases cardiac output and facilitates hypertension (htn)

Advantages and Disadvantages

Advantages
- Relatively cheap, easy, no specialist services/equipment required
- Reasonably physiologically plausible
Disadvantages
- Hypervolaemia potential for greater harm, in particular if pre-existing cardiac disease, or co-existing stress induced cardiomyopathy (SIC) or neurogenic pulmonary oedema
- Haemodilution counterintuitive as Hb essential for oxygen carriage/delivery to ishcaemic tissue; ?should transfuse - small studies with conflicting outcomes… enter SAHaRA…
- Hypertension and high dose vasopressors undesirable in SIC / IHD & unclear BP targets
- Risk in patients with other co-existing cerebral aneurysms (unruptured, unsecured)

Key studies

Kassell, Neurosurgery 1982 (treatment of angiographically confirmed vasospasm)
- Retrospective analysis of 58 consecutive patients with angiographic evidence of vasospasm; intervention included PRBC to Hct 40, volume expansion with dextran / albumin, fludrocortisone/desoxycortisone given, fluids til daily positive fluid balance and CVP>10 or PAWP 18-20mmHg. Vagal response ablated with atropine 1mg IM 3-4hrly to keep HR 80-120bpm and diuresis effect ablated by vasopressin IM to keep UO<200ml/h. Minimal vasopressors/inotropes needed with this, but were added if no improvement in neurological impairment 20-100torr increase in arterial sBP from baseline (lowest possible increase needed for neurological improvement) for 12h-8d (max allowed BPs 240, MAP 150; if unsecured BPs 160)
- 47/58 had reversal of neurological deterioration (43 pts - 74% permanent improvement, 9 pts - 16% transient improvement, 6 - 10% deterioration with therapy)
- Concluded ‘safe’ if meticulous attention to parameters (?external validity) except potentially hazardous if unsecured aneurysm (22 patients), advocate properly designed trial
Awad, Stroke 1987 (treatment of clinical /radiological vasospasm)
- 118 consecutive patients admitted with SAH (113 aneurysms, no trauma) within 2/52 to ICU, with early surgery advocated and HHH therapy if signs of clinical AND radiological vasospasm postoperatively (normotensive haemodilution and surgery only if resolution of spasm if preoperatively). 42 patients developed vasospasm (35.6%). Treatment included targeting HCT 33-38%, CVP 10-12 (PAWP 15-18) ad BPs 160-200 (or 120-150mmHg if unclipped) for duration of clinical vasospasm
- 60% had sustained improvement (by at least one grade; Hunt and Hess), 24% stable neurology, 19% major neurological deficit or dead
- 22/42 ‘required adjunctive CSF diversion’
Levy, Neurosurgery 1993 (hypervolaemia prophylaxis and hyperdynamic-hypervol as treatment)
- 160 patients presenting with SAH were induced with hypervolaemia on admission to ICU, of these 45 patients (34%) went on to exhibit vasospasm despite hypervolaemia; these were given albumin and dobutamine (5-10mcg/kg/min) with mean 52% change in cardiac index but only 11% increase in BP
- Clinical reversal of ischaemic symptoms occurred in 18/23 (78%) patients
Egge, Neurosurgery 2001 (prophylactic HHH)
- RCT surgically fixed <72h, Hunt and Hess 1-3, <75y. Stratified by Fisher grade. Prophylactic (post-op) 12d HHH therapy (target; volume CVP 8-12, Hct; 30-35%, MAP; >20 above preoperative MAP) vs standard. No change to Mx if DCI clinically or on transcranial doppler (TCD; done daily). N=32
- Significant difference in MAP/CVP/Hct. No difference in vasospasm (clinically or TCD), no difference in regional cerebral blood flow on SPECT at d12 and 1y. No difference in neurophysiological parameters (including GOS) at 1y
- Statistically significantly more complications in HHH group (<0.001) e.g. extradural haematomas, cardiac failure/arrhythymia; and more expensive (additional $250/d)
Dankbaar, Critical care 2010
- Systematic review of individual components of HHH therapy (both prophylactic and treatment) on cerebral perfusion in patients with aSAH. Total of 11 studies (each only 4-51 pts) included cerebral blood flow (CBF) analyses before and after intervention
- Meta-analysis not possible due to heterogeneity of studies
- No good evidence for HHH or separate components on CBF in controlled studies. In uncontrolled studies hypertension (htn) showed to be most effective of the 3 strategies
HIMALAIA, Stroke 2018 (hypertension alone as treatment)
- MC RCT. Secured aneurysm with symptomatic DCI (GCS <1 or new focal neurological deficit; exclusion of other causes by CT, bloods +/- EEG) & spontaneous MAP<120; hypertension group max MAP130/BPs230 (fluids and norad) if resolution in 24h, continued for 48h then tapered (with plan if recurred on tapering), 24h if no resolution, ceased earlier if complications. No hypertension group MAP>80 with fluids +/- vasopressors. N=41 (of 240)
- Outcome adjusted for WFNS at admission and time of DCI (both higher in Htn group), Hijdra score (blood load) via poisson regression analysis
- Stopped early; slow recruitment and lack of effect on CT perfusion (secondary outcome)
- Primary outcome; poor outcome at 3m (mRS >3) 57% (htn) vs 40% (no-htn) OR 1.4 (CI 0.7-2.7). In first 24h, difference in MAP 11mmHg (baseline in both groups 99mmHg -both htn!) Improvement in neurology at 24h 57% vs 30% but not upheld at 3m. More adverse events

Summary (my practice)

There is lack of high-quality evidence supporting any component of HHH therapy as either prevention or treatment of clinical or radiological vasospasm
I target euvolaemia in all patients (and closely monitor and respond rapidly to hypovolaemia)
Unless polycythaemic there is no role for haemodilution and I await the results of SAHaRA to better understand optimal Hb targets / transfusion thresholds in this specific population
In a secured aneurysm, in patients exhibiting vasospasm (other causes excluded) and in absence of contraindication (e.g. cardiac failure) I may induce gentle hypertension as part of treatment (not prophylaxis). This is however not to the levels often described in the above studies where risks of harm are significant (e.g. may aim MAP 80-100mmHg / BPs 160-180mmHg; specific target will be dependent on response and pt risks). I never induce hypertension in an unsecured aneurysm
Some pts may drive their own hypertension in response to vasospasm and again unless there is evidence of harm I will not interfere to treat this (allow permissive hypertension) if secured

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aSAH & CCB - prevention is better than a cure

23/6/2020

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Background and Rationale

Aneurysmal subarachnoid haemorrhage (aSAH) is a disease that predominantly affects the young. Those that survive the initial event can go on to experience complications to include cerebral artery spasm (vasospasm), leading to ischaemic neurological deficits (delayed cerebral ischaemia, DCI) that yet further increase morbidity and mortality
Vasospasm risk in particular correlates with Fisher grade (blood load on CT) and can be diagnosed clinically (focal neurological deficit of no other cause) or radiographically (CT angiogram)
Smooth muscle relaxants that cross the blood brain barrier (BBB) may be useful in preventing vasospasm. Ideally an agent that does not cause systemic hypotension would be ideal
Extracellular calcium is the main source of calcium for contraction in large cerebral arteries (unlike systemic arteries which rely on intracellular calcium). Animal studies showed nimodipine was more potent than other centrally acting calcium channel blockers (CCBs) e.g. nidefipine which was initially studied in more detail. Amlodipine does not cross the BBB
Nimodipine is a highly protein bound (95%) lipid soluble CCB with rapid enteral absorption (1h peak concentration), low bioavailability (predominantly first-pass hepatic metabolism) of 13%, which is rapidly eliminated with a half life of 1-2h (terminal elimination half life 8-9h). Bioavailability is further reduced by co-ingestion of food. Increased bioavailability with co-ingestion of drugs that inhibit CYP-450. Importantly there is a significant reduction in bioavailability of nimodipine with many antiepileptics (seizures also complicate aSAH) to include phenytoin and carbamazepine

Advantages and Disadvantages

Advantages
- Simple, cheap, effective
- Reasonable physiological rationale, no other proven effective treatment for prevention
Disadvantages
- May cause systemic hypotension (independent risk factor for poor neurological outcome if untreated, otherwise co-administering vasopressors with unclear benefit-harm)
- Degree of enteral absorption often unknown, drug interactions, GI perfusion in particular if stress-induced cardiomyopathy
- Route; why would enteral administration be more efficacious over intravenous?
- Not dose titrated; one size fits all? Very rarely dose adjustments made (interactions, hypotension)

Key studies

Nimodipine enterally
- Allen (US) 1983 NEJM
  - MC RCT DB and stratified to center/surgeon; near normal neurology on entry to trial; enteral nimodipine (0.7mg/kg loading then 0.35mg/kg 4hrly thereafter) vs placebo for 21d, start <96h (preoperatively) aSAH; n=116
  - Persistent (d21) severe neurological deficit or death attributable to vasospasm 8/60 in placebo vs 1/56 in Rx group P=0.03(similar baseline neurology and fisher grade)
- Philippon (Fr) 1986
  - MC RCT DB aSAH <72h, Hunt and Hess 1-3 and without early complications (eg hydrocephalus) 60mg 4hrly vs placebo for 21d (NB use of TXA); n=70
  - Neurological deficit caused by vasospasm at d21 in 12.9% (nimodipine) vs 28.2% (placebo), P<0.05; non-statistically significant reduction in vasospasm on angio
- Pertruk (Ca) 1988 J Neurosurg
  - MC RCT DB of enteral nimodipine 90mg 4hrly vs placebo <96h (preoperatively) aSAH with significant presenting neurology (grade 3-5 on Hunt and Hess) n=154
  - Good outcome at 3m (on Glasgow outcome score, GOS) 29.2% nimodipine vs 9.8% placebo P<0.001; (note whilst large increase in mortality with nimodipine, mostly from grade 3 group; 28% vs 4.8% these were predominantly explained by other causes such as rebleed, higher fisher score etc… hypotension was not implicated)
- Pickard (UK) 1989 BMJ
  - MC RCT DB; nimodipine 60mg 4hrly versus placebo (note did not specify aneurysmal cause of SAH) <96h of onset of bleed for 21d (NB. 130 discontinued early; mainly due to no vasospasm on angiogram; 70 nimodipine, 60 placebo); n=554
  - Nimodipine reduced cerebral infarction; 22% vs 33% (RRR 34%) and reduced poor outcomes (dead, vegetative state & severe disability) 20% vs 33% (RRR 40%) at 90d
Nimodipine intravenously
- Ohman 1988 (Fin) Neurosurg
  - MC RCT DB; IV placebo vs nimodipine (up-titrated to 0.5mcg/kg/min continuously for up to 7-10d immediately post aSAH diagnosis; if operated late could be continued for further 2-3d post-op) then oral (60mg 4hrly vs placebo) for 21d. Hunt & Hess 1-3; (NB in both groups 4mg dexamethasone 6hrly given); n=213
  - Significant reduction in mortality with early surgery (looked at <72h, 4-7d vs =/>8d). At 3m 83.7% of nimodipine group were independent vs 78.9% in placebo. Mortality by ischaemic deterioration was significantly lower p=0.01 (1% vs 8.3%)
- Numerous small RCTs IV vs oral nimodipine
  - e.g. Kronvall (2009, J neurosurg) n=106, Soppi (2012, World Neurosurg) n=174
  - No difference in clinical efficacy in the studies I found
Nimodipine intra-arterially
- I can find no prospective RCTs specifically looking at this… (mostly case series etc)
Nicardipine intravenously (no IV nimodipine in north America)
- Haley 1993 (US) J Neurosurg
  - MC RCT DB; <7d from onset of aSAH, high dose IV nicardipine (0.15mg/kg/h) vs placebo for up to 14d following haemorrhage; n=906
  - Symptomatic vasospasm during treatment period less (32% vs 46%, P<0.001) in treatment group, but no difference in outcomes at 3m (death or good outcome)
  - More HHH therapy in placebo group; questioned whether HHH as effective for DCI

Summary (my practice)

Nimodipine is the only treatment with high-level evidence to prevent vasospasm and DCI in aSAH
I routinely give nimodipine early (<72h) to all patients with aSAH presenting for active management as soon as initial haemodynamic stability has been achieved, irrespective of timing of aneurysm fixation. I preferentially use the enteral route (60mg 4hrly), but where vomiting or concerns re absorption exist I use continuous IV infusion. I continue treatment for 21d, changing to enteral when able. I do not use Nimodipine in pregnancy (cat C; teratogenic) rather treat early if DCI occurs
Where hypotension exists (post fixation of aneurysm in euvolaemic patient) I consider potential causes of high plasma concentrations (cirrhosis, CYP450 inhibitors) that may require personalised approach to dosing. However overall in this group I will administer low dose vasopressors (noradrenaline) in order to tolerate ongoing nimodipine administration, but review benefit-harm at moderate-high levels
Intraarterial vasodilators seem to be effective in treatment of symptomatic radiological vasospasm

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Hypertension and (i)CVA - To let be or not to let be?

16/6/2020

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Background and Rationale

In patients with acute ischaemic stroke, hypertension is an independent predictor of poor outcome. Whether this is an association (stroke severity) or causation is unclear
Management of hypertension is important for primary and secondary prevention of stroke, but its role acutely is less well established with reasonable physiological rationale that it may be an appropriate response in an attempt to perfuse ischaemic (salvageable) penumbra
Nimodipine initially was of particular interest following on from promising neurological outcomes in aneurysmal subarachnoid haemorrhage (by preventing vasospasm). Early studies in ischaemic stoke suggested a potential benefit but these (premise leading to the INWEST trial below) were not upheld by later studies
Studies have either predominantly looked at the effect of lowering blood pressure per se, or prioritised assessing the potential benefits of specific agents (unrelated to BP target)

Advantages and Disadvantages

Advantages of treating hypertension;
- Easy, simple, cheap, does not require specialist center (can be done anywhere)
- May reduce haemorrhagic transformation
- Likely to be protective of myocardial function by reducing afterload (risk factors for ischaemic heart disease overlap with those of stroke)
Disadvantages of treating hypertension;
- May compromise CPP, in particular of ischaemic (salvageable) tissue
- May overshoot and cause hypotension -with consequences to both neurological outcome but similarly may cause multiorgan hypoperfusion and dysfunction
- No clarity as to what is an optimum blood pressure target is; one sized fits all unlikely to be correct. Is systolic more important than mean arterial pressure?
- Crossover of patients e.g. primary ischaemic CVA with small haemorrhage; what target?

Key studies

Many many small trials exist! Here are just some of the more major studies;
INWEST Cerebrovasc Dis 1994 (Intravenous Nimodipine West European Stroke Trial)
- MC RCT (DB) of ischaemic stroke in the carotid artery territory <24h; n= 295 (of 600); intavenous nimodipine for 5d at either 1mg/h (n=101) or 2mg/h (n=94) or placebo (n=100) each followed by oral (120mg vs placebo) up to 21d
- Primary end-points; neurological outcome by Orgogozo scale (neurological status 0-100) and functional outcome outcome according to the Barthel scale (ADLs 0-100) at day 21. Significant (dose related) worse outcome with nimodipine P <0.001 & 0.0033
- Terminated early for safety concerns (incl mortality). Subgroup with a stable MAP and BPd on nimodipine showed trend towards improved neurological outcome
CATIS JAMA 2014 (China Antihypertensive Trial in acute Ischaemic Stroke)
- MC RCT (SB) =/>22y/o with CVA <48h with BPs >140 and <220 (and BPd <120) (exclud. severe heart failure, acute myocardial infarction, thrombolysis) randomised to reduce BP by 10-25% in 24h and BP <140/90 by day 7 and for remainder of inpatient admission vs ‘control’ (no antihypertensives). Any choice of drugs, n=4071
- Primary endpoint; death or major disability (mRS 3-5) by d14 / hospital discharge; 33.6% in both arms (OR 1.0, P=0.98), held at 3m. no difference in mRS seen
SCAST-IS Int J Stroke 2015 (Scandinavian Candesartan Acute Stroke Trial Study group)
- Original SCAST; DB MC RCT of all stroke (schaemic/haemorrhage) BPs>140 <30h, increasing candesartan dose vs placebo for 7d (rationale; small positive study -terminated early- suggested benefit); n=2029; composite endpoint -no difference
- Sub-study of ischaemic group of moderate-severe carotid artery stenosis, n=187, hypothesized harm; composite outcome (vascular death, stroke, MI, mRS) no difference but trend towards worse outcomes in severe stenosis
VENTURE Int J Stroke 2015 Valsartan Efficacy oN modesT blood pressure Reduction in AIS
- S Korean MC RCT (open label; valsartan to target 15% reduction / BPs<145 vs no Rx) >18y/o, <24h acute ischaemic stroke, BPd 150-185mmHg excl. thrombolysis, hypertensive emergencies etc. N=372 (stopped early)
- Primary outcome (blinded); death or dependency (mRS 3-5) at 90d 24.6% vs 22.6% (OR 1.11 CI 0.69-1.79; no difference) with a similar rate of death between groups
ENCHANTED-BP Lancet 2019 (incl. Au)
- MC RCT; Intensive (BPs 130-140 within 1h) versus guideline-recommended (BPs <180) BP lowering treatment for up to 72h after thrombolysis for ischaemic CVA in patients with BPs >150mmHg randomised within 6h of symptom onset; n=2196
- Primary endpoint (blinded); functional outcome (shift in mRS) at 90d; no difference. Note less ICHg in intensive group (14.8% vs 18.7% P=0.0137) however symptomatic ICHg was not significantly different (1.3% vs 2% P0.2143)

Summary (my practice)

Nearly 40 years on we are still debating whether there is a role for lowering BP in ischaemic CVA
Cannot extrapolate specific drug effects e.g. from aSAH group to stroke patients (tend to be older, more prone to hypotension and drop in CPP with nimodipine, role of cortical collaterals important)
In the absence of high-quality evidence; AHA/ASA guidelines for acute ischaemic stroke 2018 are a reasonable starting point:
- If eligible for thrombolysis reduce BP to <185/110 before treatment and maintain <180/105 for 24h post (based on inclusion criteria into thrombolysis RCTs) class 1
- After thrombectomy maintain BP <180/105 irrespective of success (class 2a/2b)
- In other ischaemic stroke (not eligible for intervention) and hypertension treatment not acutely indicated by comorbid condition (acute cardiac event, dissection, eclampsia – class 1) it may be reasonable to lower BP by 15% in first 24h if BP =/> 220/120. Class 2b only
- Treat hypotension and hypovolaemia (class 1); however induced hypertension not well established (2b)
- Antihypertensives recommended; IV labetalol, nicardipine and clevidipine
My usual practice is to treat BP >220/120 in all-comers with ischaemic CVA and target <180/105 if undergoing/underwent intervention <24h. However I do this gently (avoid hypotension) and with drugs I am most familiar with -initially titratable IV agents (hydralazine bolus → clevidipine infusion; avoiding SNP which may increase ICP, negatively inotropic agents where possible and GTN ), if persistent/refractory, reduced doses of patient’s usual antihypertensive agents (if no contraindications exist eg ARB/ACE-I and AKI)
Where invasive monitoring exists I translate BPs/BPd targets to MAPs for continuous trends, but continue to corroborate this intermittently with NIBP (in particular if intervention indicated)
Whilst I do not usually induce mild hypertension, I may consider this in a usually hypertensive patient who has had a fall in BP associated with reduction in conscious level (with other likely causes excluded e.g. hypoglycaemia, haemorrhagic transformation) in discussion with the treating neurologist; a trial of gentle titratable short-acting vasopressor (e.g. noradrenaline) is reasonable to target a BPs 140 (or MAP 70) for example in a place where the effects can be closely monitored

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Decompression & CVA - Feeling the pressure?

9/6/2020

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Background and Rationale

Despite advances in stroke management, patients with MCA (middle cerebral artery) infarct who have a seemingly good response to treatment may go on to deteriorate neurologically and die or be severely disabled
Malignant MCA (mMCA) syndrome is life threatening space-occupying brain oedema following a large MCA territory infarct (CT, perfusion or MRI) usually occurring day 2-5 post stroke. The patient develops focal or global raised pressures secondary to this oedema → reduced focal or global perfusion → increased morbidity and mortality despite optimal medical therapy (mortality up to 88% with medical therapy alone). Untreated main mode of death is brain death from herniation
Early decompressive craniectomy (<48h of CVA) may improve perfusion of infarct and penumbra due to reduced effect on pressures of local oedema → improved survival and neurological recovery (aim is good functional survivors)

Advantages and Disadvantages

Advantages;
- Improved survival, reduced morbidity (higher extended Glasgow outcome scale -GOS E and lower modified rankin scale – mRS) in selected cases
- Neurosurgery may potentially be indicated anyway e.g. if haemorrhagic transformation and indications for clot evacuation present
Disadvantages;
- Highly invasive; associated risks (in particular if thrombolysis recently)
- Resource intensive (neurosurgical center), associated skill and cost, if survive require further surgery to replace bone
- Evidence potentially weak – potential controversies / conflicting opinion
- May increase survival of heavily disabled individuals in unselected groups

Key studies

Animal studies and case reports suggested substantial benefit with decompression … hence;

DESTINY: Stroke 2007
- German MC RCT, n=32 (power calc 188); hemicraniectomy vs conservative for >1/3 MCA territory infarct in 18-60y/o, symptoms >12h but <36h after stroke with associated drop in conscious level
- 88% surgical vs 47% conservative survival at 30d (P=0.01, almost all died <8d); mRS (modified rankin score) at 6m showed positive results in favour of surgery
- Higher NIHSS (24 vs 21 P<0.01) and more dominant hemisphere stroke (73% vs 53% P<0.23) in the conservative arm
- Stopped early due to interim analysis for mortality at 30d
DECIMAL: Stroke 2007
- French MC RCT, n=38, 18-55y/o, <24h mMCA, infarct volume >145cm3 on MR DWI
- Craniectomy as large as possible (temporal, frontal, parietal +/- occipital)
- Primary outcome (mRS =/<3 at 6m) 25% in surgical group vs 5.6% in non-surgical group (P=0.18), and at 12m 50% and 22.2% respectively (P=0.10)
- Large mortality difference (absolute reduction 52.8% with surgery); brain death from herniation main modality in non-surgical group. Life worth living all/most of the time in 8/10 interviewed craniectomy patients at 1y
- Stopped early for; slow recruitment, high difference in mortality and meta-analysis results
HAMLET: Lancet Neurol 2009
- Dutch MC RCT, n=64 (of 112); 18-60y/o with CVA >2/3 MCA territory , drop in GCS to =/<13
- Wanted to look at later decompression (up to 4d) MCA infarct with life threatening oedema
- Primary outcome mRS good (0-3) vs poor (4-6) at 1y. Poor outcome in 75% of both arms (P=1.0), death however 22% in surgical group vs 59% in medical group at 1y (P=0.002)
- ?Worse outcomes than Decimal and destiny as median time to randomisation 41h (longer)
- Stopped early, due to poor likelihood of reaching statistical significance of primary outcome
Meta-analysis: Lancet Neurol 2007
- Pooled analysis of all 3 studies led to them being stopped early
- <48h of 16-80y/o with space occupying MCA infarction treated within 48h; n=93
- Primary outcome; mRS 0-4 (favourable) vs 5-6 (unfavourable) at 1 year; favourable outcome in surgical grp vs control grp 75% vs 24% (ARR 51%, CI 34-69)
- Secondary outcome (more in keeping with trial designs!) mRS 0-3 vs 4-6; 43% vs 21% (ARR 23%, CI 5-41), and survival 78% vs 29% (ARR 50%, 33-67). No specific subgroup differences
- NNT=2 for survival and mRS =/<4, NNT=4 for survival and mRS =/<3, survival alone NNT=2
DESTINY 2: NEJM 2014
- German MC RCT non-blinded, >60y/o (median 70y) mMCA <48h, n=112; craniectomy compared to standard (ICU) care. Stopped early (for efficacy of primary endpoint)
- Primary outcome; survival without severe disability (mRS 0-4) at 6m; 38% (surgical) vs 18%, P=0.04, however this was predominantly from improved mortality (33% vs 70%) -no patients had mRS 0-2, 7% vs 3% mRS=3, 32% vs 15%, mRS=4 28% vs 13%
- Increased survival with hemicraniectomy but substantial disability at 6 and 12 months

Summary (my practice)

Decompressive hemicraniectomy should be considered early (<48h) in the young (<60y/o) at risk mMCA population, with a reasonable chance of a good functional neurological outcome. Medical consensus on this should involve consultation and consensus between neurosurgeons (risks re doing the procedure), neurology (treating team; rehabilitation potential) and intensive care (impact of global morbidity). Should there be consensus that this is a reasonable treatment to offer this should discussed with patient and/or family and a personalised decision made in the interests of the patient around realistic functional recovery.

Taken from Vehadi et al (meta analysis, Lancet Neurol 2007

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Thrombolysis for CVA - When is it wise to lyse?

2/6/2020

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Background and Rationale

Stroke continues to contribute towards significant morbidity and mortality
Degree of reversibility and recovery often time critical. Therapies that can be delivered early are therefore desirable
Initial premis was high quality evidence for thrombolysis in myocardial infarction – why not for CVA?
More recent evidence supporting neurointervention describes a therapy still not accessible everywhere. Similarly compared usual care +/- ECR (endovascular clot retrieval) and so does not negate the need for knowing the ongoing indications for thrombolysis

Advantages and Disadvantages

Advantages
- Simple and cheap therapy, minimal skills required to administer
- Offers an intervention to those geographically isolated from major stroke centers (CT brain, IV cannula, monitoring) in particular with evolving telemedicine to assist in specialist examination and decision making
Disadvantages
- Time critical; therapeutic window narrow
- Not suitable to all; contraindications (e.g. therapeutic anticoagulation, uncontrolled hypertension, CVA or head injury <3/12, ) and no benefit in non-thrombotic CVA (calcium emboli, injectable material in IVDU with PFO)
- Increase in intracranial haemorrhage (ICHg) and other major bleeding, increases early death (<7d)

Evidence

NINDS (US) 1995 NEJM
- Part 1; alteplase (tPA) versus placebo in two subgroups (0-90mins and 91-180mins) to see whether clinical improvement (improvement in NIHSS by 4 or more at 24h), n=291, no statistically significant difference between the groups
- Part 2; sustained increase in patient with minimal/no deficit at 3m (assessors blinded from part one results) n=333, 12% absolute (32% relative) increase in patients with minimal or no disability (95-100 on Barthel index, BI), similar improvements in GOS, mRS, NIHSS
- ICHg at 36h occurred in 6.4% of tPA group compared to 0.6% of placebo (n<0.001)
ECASS-1 1995 JAMA
- European large double blind RCT; acute ischaemic hemispheric stroke, moderate-severe neurological deficit, no major early infarct signs on CT randomised to tPA (alteplase 1.1mg/kg upto 100mg) versus placebo within 6h from onset of symptoms, n=620,
- ITT analysis and target population (TP) analysis (expected 20% major protocol violations and indeed 17.4% occured eg randomised but not treated, concomitant heparin use etc)
- No statistically significant difference in Barthel Index at 90d (+/-14d) in both ITT and TP
MAST-I (I=Italy) 1995 Lancet
- Aspirin (300mg daily for 10d) vs streptokinase (1.5MU over 1h) vs both vs neither; in acute stroke <6h
- Streptokinase associated with increased early mortality (in particular when combined with aspirin) at 10d, at 6m streptokinase and/or aspirin arms marginally reduced severe disability
MAST-E (E=Europe) 1996 NEJM
- RCT streptokinase (1.5M) vs placebo within 6h of MCA stroke with moderate to severe ischaemia, n=310; primary outcome was RS =/>3 (severe disability) or death at 6m
- Similar death and severe disability at 6m (79.5% vs 81.8%) with more deaths in treatment arm
- Higher mortality at 10d in streptokinase group (34% vs 18.2% P=0.002) due to haemorrhagic transformation (symptomatic ICHg in hospital 21.25 vs 2.6%)
ASK (Australian StreptoKinase) 1996 JAMA
- DB RCT; 1.5MU streptokinase vs placebo for ischaemic stroke <3h and 3-4h, primary outcome reduction in morbidity (defined as BI <60) and mortality at 3m. N=340, stopped early for harm
- Nonsignificant trend towards unfavourable outcomes with streptokinase arm (RR 1.08 95% CI 0.74-1.58) including increased mortality – poor outcomes confined to those >3h
- Only a trend towards improvement in streptokinase arm in <3h group (RR unfavourable outcome 0.6 95% CI 0.28-1.58)
ECASS-2 1998 Lancet
- European-Australasian DB RCT acute ischaemic stroke without major infarct on CT stratified to 0-3h or 3-6h post symptom onset, randomised to 0.9mg/kg alteplase vs placebo. Primary endpoint mRS at 90d dichotomized favourable (0-1) vs unfavourable (2-6) outcome
- Favourable outcome in 40.3% of alteplase vs 36.6% placebo groups (no statistical difference)
- Post-hoc analysis of new dichotomised mRS of 0-2 as favourable outcome showed 54.3% vs 46% (p=0.024)
ATLANTIS B (JAMA 1999) and A (Stroke 2000)
- Part B: DB RCT alteplase versus placebo in acute ischaemic stroke between 3-5h post symptom onset n=613 (547 3-5h, 39 <3h, 24 >5h)
- Excellent neurological outcome at 90d (NIHSS =/<1) – no difference (34% vs 32% p=0.65)
- Increased mortality and ICHg at 90d
- Part A: (initial study, halted early then recommenced as part B as above) 0-6h window; halted early for safety, n=142, increased ICHg (11% vs 0%) and mortality at 90d (23% vs 7%)
EPITHET 2008 Lancet neurol
- RCT alteplase vs placebo at 3-6h post stroke onset, with diffusion and perfusion imaging repeated at day 90 to see if tPA attenuates infarct growth (radiologically), n=101
- Less infarct growth with tPA (p=0.001) and improved mRS 0-1 (36% vs 12%)
ECASS-3 2008 NEJM
- Following a pooled analysis of studies that suggested favourable outcome between 3-4.5h and that this was not associated with increased ICHg compared to <3h
- DB parallel-group RCT initially 3-4h but early on extended to 4.5h; 1:1 0.9mg/kg (up to 90mg) alteplase vs placebo, n=821
- More favourable outcome (mRS 0-1) with alteplase 52.4% vs 45.2% P=0.04, no significant increase in mortality, but more ICHg in alteaplse group 27% vs 17.6% P=0.001)
DIAS-2 2009 Lancet neurol
- DB RCT desmoteplase 90mcg/kg vs 125mcg/kg vs placebo at 3-9h with at risk tissue demonstrated on CT or MRI; n=193
- Composite endpoint at 90d (improved NIHSS of =/>8, or NIHSS =/<1, mRS 0-2, BI 75-100)
- No benefit with desmetoplase but less severe stroke (NIHSS and core size) in placebo group
IST-3 2012 Lancet
- International MC RCT (open label), rt-PA (0.9mg/kg up to 90mg) versus control for stroke up to 6h post symptom onset where no local indication or contraindication was met. Initial 276 patients double blinded, then open label
- At 6m 37% (rt-PA) versus 35% (control) were alive and independent (as per the Oxford Handicap Score OHS 0-2) – non statistically significant. But a significant shift in OHS was seen
- Elderly cohort (53% >80y/o) -no disadvantage in elderly, ICHg risk 7% vs 1%, as per other studies higher early mortality 11% vs 7% at 7d) but no difference by 6m with rt-PA
WAKE-UP 2018 NEJM
- MC RCT where unknown duration of stroke (and not planned for thrombectomy), ischaemia on DW-MRI but no hyperintensity on MRI FLAIR (suggesting likely <4.5h); alteplase vs placebo, n=503 (planned 800 but stopped early due to cessation of funding)
- Primary outcome was mRS at 90d 0-1; 53.3% in treatment arm vs 41.8% in placebo P=0.02 (ICHg 2% vs 0.4%)
EXTEND 2019 NEJM
- MC RCT alteplase vs placebo 4.5-9h post stroke (or on awakening with stroke if within 9h from midpoint of sleep) in patients with hypoperfused but salvageable tissue on perfusion imaging, n=225 (of planned 310; terminated due to loss of equipoise from WAKE-UP trial)
- Primary outcome mRS of 0-1 at 90d; 35.4% (alteplase) vs 29.5% P=0.04 (symptomatic ICHg 6.2% vs 0.9% P=0,05)

Summary (my practice)

Controversial – many negative studies, total number of patients across all studies is low, positive studies difficult to pool due to diverse choice of end points and stroke severity scores. Not endorsed by all societies (but is by ASA/AHA)
Do not use Streptokinase. Thrombolytic of choice is alteplase (at dose of 0.9mg/kg up to 90mg with 10% given as a bolus over one minute, remainder over 60mins), no aspirin for at least first 24h after thrombolysis (usually give 24-48h)
Positive studies seemed to show no initial benefit in neurological outcome at 24h, but more favourable outcomes at 3m
Thrombolyse if clinical picture in keeping with stroke, where available perfusion imaging suggestive of ischaemia and no contraindications -thrombolyse 0-3h, extended criteria up to 4.5h as per ECASS-3 (best evidence in <80y/o no DM/CVA no oral anticoagulants and CVA not involving >1/3 MCA territory on imaging) +/- beyond this in select patients as per ASA/AHA with stroke specialist input and discussion with patient/family of risks
Open and honest discussions; improves functional outcome, but increases early death (<7d) and symptomatic ICHg up to 10x
In centers with no close access to perfusion imaging; non haemorrhage on CT, clinical picture in keeping with CVA, euglycaemic state, in absence of contraindications is all that is required according to ASA/AHA guidelines (do not delay)
Refer for ECR if appropriate without delay (do not wait to assess success of thrombolysis)

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