T-PA: Beyond thrombolysis

Benarroch EE. Neurology 2007;69: 799-802.

Author discusses basic science oo t-PA. t-PA is serine protease that cleaves plassminogen into plasmin that digests fibrin. It is widely distributed in CNS and is involved in synaptic regulation, synaptic plasticity and neural injury. Clinically may wish to neutralize the extravascular neurotoxic effects of t-PA. Neuroserpin is a candidate that inhibits the actions of tPA in the CNS.

Mutations of the neuroserpin gene are linked to familial encephalopathy with neuroserpin inclusion bodies (degenerative disease).

t-PA is present in dense core granules in dendritic spines and axon terminals and is released via calcium dependent exocytosis in response to depolarization or activation of NMDA receptors. The gene encoding for t-PA is induced with neuronal activity involving translation of mRNA. It maybe released from injured blood vessels and microglia, suggesting a role for it in neuroplasticity.

Stroke and amyloidosis

Zubkov AY et al. Primary systemic amyloidosis with ischemic stroke as a presenting sign.

Neurology 2007 69:1136-1141.

Widjicks most patients (37/49) had light chain disease rather than primary or secondary systemic amyloidosis. In AL (amyloid due to light chain) the amyloid sheets are made by clonal expansion of the bone marrow rather than the liver as in the other types. Most strokes were large vessel, single arterial territory. 2 patients had cardiac amyloid and recurrent strokes. Most patients had abnormal ECHO c/w amyloid. There was no gender preference and the average age was 70. The median time to death was 7 months. A few patients presented with stroke (or TIA). The average delay of diagnosis was over nine months, that could be shortened by discovering amyloid on ECHO. The cardiac disease is a constrictive cardiomyopathy with CHF. The classic finding with increased echogenicity, valvular infiltration, and biventricular thickening is seen only in cardiac amyloidosis. LVEF is normal but strain and strain rate imaging are abnormal with long axis dysfunction and disproportionate impairment of longitudinal contraction. 70 % had cardioembolic strokes. Amyloid is actually common in atrial appendage (40/259 in surgical specimens) and may be associated with Atrial fibrillation. Clues thickened valves and septum can lead to diagnostic myocardial biopsy or referral to hematologist for additional evaluation.

Risk of bleeding with ASA-Plavix combination

MATCH trial Diener et al. Took 7599 high risk patients with TIA or stroke, on Plavix, and added ASA 75 mg. Followed patients for 18 months. The results wre highly statistically significant with more major and minor bleeding of all types among patients receiving combination therapy. However, in the combined group, the actual risk of symptomatic intracranial hemorrhage was 1 % in each group; major bleeding of all types combined two percent v. one percent; and minor bleeding of all types combined was 3 % v. 1 %. Thus the overall complication rate is relatively low. The trial was based on the previous CURE trial that showed an acceptable safety profile of combined therapy among patients with acute coronary syndrome.

By contrast, the vascular risk reduction from antiplatelet therapy after TIA or stroke (reduction in stroke, MI or vascular death) was, absolute. 0.72 percent (NTT about 100/.72 or 138) with a relative risk reduction of 5.9 %. Thus by comparison the 3 % risk of hemorrhage is large.

OTHER EVIDENCE
CHARISMA trial supported results of MATCH.

CARESS trial in symptomatic carotid stenosis showed less embolic signals, but not less clinical events in patients on dual therapy.
FASTER trial suggested a role for dual therapy after clopidogrel loading for brief trial (90 days) after TIA. Not conclusive.

intravenous v intrarterial (bridging) lysis therapy

data of IMS investigators, reported in Stroke 2004. The outcomes overtly appear the same. Percent with modified Rankin of 0-1 at 90 days was 30 % in IMS group, 32 % in iv tpa group. The respective percentages for NIHSS less than 1 at 90 days was 28 and 25 %; Barthel index 95 or 100 46 and 42 %; these data favor intravenous therapy. However patients in the IMS trial were not equivalent at baseline. They had persistent major vascular occlusions despite early iv tpa treatment and greater clot burden than those in the NINDS trial, and were treated later. This suggests greater benefit in selected patients.

diabetes and stroke risk

Stroke Risk Doubles Within 5 Years After Diabetes Diagnosis

The risk for stroke is twice as high in patients with newly diagnosed diabetes as in the general population, according to a study in Stroke.

Using health databases of a Canadian province, researchers identified some 12,200 adults aged 30 and older with recent diagnoses of type 2 diabetes. During a mean follow-up of about 5 years, 9.1% of the patients had hospital admissions with a stroke-related diagnosis. The rate ratio for stroke was 2.1 for diabetes patients, compared with the general population.

The authors write that their results "will help to dispel the notion that macrovascular consequences of diabetes occur only in the long term" and may motivate "both patients and providers to aggressively control cardiovascular risk factors soon after diagnosis."

Stroke article (Free)

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Pillcam contraindicated in stroke alert

I have been asked twice this week regarding the safety and efficacy of the PillCam used to evaluate the esophagus and/or the intestinal track. These devices are highly contraindicated for any MRI procedure. Being within the vicinity of an MR system alters the operation, patient are at risk for RF burns if put inside an MR system.  I have included information from the manufacturers website (contraindications in bold and underlined). I will be forwarding this information to all the techs corporately as well.

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Clinical Trials: DIAS

DIAS-- desmoteplase in acute ischemic stroke -- placebo controlled, double blind, dose-finding randomized Phase II trial designed to evaluate safety and efficacy of desmoteplase. Looked at patients presenting 3-9 hours, enrolled 2001-2003 104 patients with NIHSS of 4-20 and mismatch on perfusion/diffusion imaging. Doses were 25, 37.5, and 50 mg of drug given as an iv bolus over two minutes. Due to excess symptomatic ICH lower doses were investigated in part 2 (62.5, 90 and 125 ug/kg). Safety outcome was rate of sICH, efficacy outcome measures were rate of reperfusion after 4-8 hours and NIHSS, mRS and Barthel at 90 days. In part excess s ICH was seen (23-30 % all within 24 hours). In part 2, the rate of sICH was 2.2%. In part 2 rates of reperfusion UP TO 71.4 % were seen at 125 ug dose compared to 19.2 % with placebo. Good clinical outcome was seen in 22 % of placebo treated patients and 13.3-60 % of drug treated patients (proportional to higher dose) also corresponding with early reperfusion. Overall 52 % of patients with reperfusion had favorable outcome v 24.6 % without.

Conclusions-- DIAS showed iv lysis is safe at 3-9 hours in patients with mismatch on MRI and dose dependent reperfusion correlated with clinical outcome. Outcome at 6-9 hours was as good as 3-6 hours. A phase 3 trial comparing 90 and 125 ug / kg doses in ongoing.

Clinical trials ECASS III and IST III

Background-- pooled data from earliir ATLANTIS ECASS AND NINDS trials, published in 2002 suggested good outcomes for subjects treated within 180 minutes, with a trend to improved outcomefrom 180-270 minutes, and little benefit beyond 270 minutes.

ECASS III (European Cooperative Acute Stroke Study) in an ongoing trial begun in 2003 of alteplase started from 3-4 hours after stroke onset. Leader Werner Hacke. Later changed to 3-4.5 hours to help recruitment. Primary endpoints are mRS, Barthel and NIHSS at 90 days. Will end in summer of 2007?

IST III (International Stroke Trial) plans to enroll 6000 patients to see if alteplase within six hours increases proportion of independent survivors at six months. It also wants to see which categories benefit most from treatment. Placebo controlled.

Stroke Trials CLOTBUST

Ultrasound enhanced thrombolysis-- u/s can help diagnose clot, monitor thrombolysis and increase t-Pa binding to thrombin. CLOTBUST-- combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic rt-PA. 2001-4 Texas-Houston, 126 patients enrolled. All patients received alteplase within guidelines and half got TCD monitoring, the other half placebo monitoring. Half (49 %) of treatment group reached endpoint of complete recanalization or dramatic clinical recovery (NIHSS of 3 or less) within 2 hours, compared to 30 % of controls. At 3 months 42-29 % favoring treatment had mRankins of 0 or 1. Three subjects in each group had ICH. Authors concluded that arterial recanalization was augmented by TCD.

Complications of Rx for Subclavian stenosis

( a benign disease)
transthoracic or extrathoracic bypass

Horner's s
phrenic palsy
pleural effusion
chylothorax
cervical lymph fistula
infection
hemorrhage

In a revie of 2496 patients, the surgical complication rate was 16 %, stroke rate 3 %, mortality rate of 2 %.

Angioplasty is better in this disease with major technical success and low rate of complications.

Clinical trials for stenting: CAVATAS, SAPPHIRE

CAVATAS carotid and vertebral artery transluminal angioplasty study-- large prospective randomized trial oo CEA v. carotid angioplasty. Criteria-- symptommtic stenosis > 70 %. Surgical candidates were randomized to angioplasty or stent. Nonsurgical candidates were randomized to angioplasty v. best medical treatment. In first group, 504 patients were randomized and the differences were nonexistent. In both the surgical and angioplasty group, the rate of any stroke lasting more than a week or death in first 30 days was 10 % The rate of disabling stroke or death in first 30 days was 6 % for each. The rate of restenosis was twice as great in the endovascular cohort v. the surgical group, 18 v. 9 %.

SAPHIRE-- stenting and angioplasty with protection in patients at high risk for endarterectomy-- compared stenting with protection v. CEA in surgically high risk patients with comorbidities. Enrolled 747 patients with > 50 % symptomatic stenosis or > 80 % asymptomatic stenosis. Stenting with a dis: tal protection device was not inferior and narrowly missed superiority. The risk of stroke, death oo MI was 39 % lower with stenting at 30 days. The risk of ipsilateral stroke was 7.9 % lower at one year. Critiques: 1) a high number, 55 % were excluded due to "surgical risk." 2) 20 % had restenosis after prior CEA 3) Inclusion of MIi as an endpoint obscures cerebrovascular data.

Ongoing trials:
EVA 3S Endarterectomy v. angioplasty in severe carotid stenosis
ARCHeR-2 (Acculink)
ICSS= CAVATAS 2 compares stent v. CEA in high risk group
SPACE -Stent protected percutaneous angioplasty of the carotid v endarterectomy 1900 patients, German study
CREST

Who is at risk for further stroke? MRI factors

Minor stroke or TIA with a lesion on DWI and and large artery stenosis had a 32 % chance of recurrence within 90 days (v. 11% with DWI alone and 4 % with neither finding) (Coutts SB et al. Ann Neurol 2005; 57:848-854)

Patients imaged within 24 hours who had DWi lesions with differing ADC values (implying different lesion ages) were more likely to develop recurrent stroke at 30 days v. those with DWIi lesions but nonvariable ADC (relative risk 3.6). Patients with cardioembolic source had a higher probability of having new DWI lesions on followup MRI (odds ratio 3.2). ( Sylaja et al. Neurology 2007; 68:415-419.

Subarachnoid hemorrhage scales

Hunt Hess (Neurosurgery 1998)
Grade Clinical Condition
0 Unruptured
1 asymptomatic or minimal headache/nuchal rigidity
2 Mod/severe headache, nuchal rigidity, no neuro deficit except CN palsy
3 drowsy confused, mild focal deficit
4 stupor, moderate/severe hemiparesis, possible early decerebrate
5 deep coma


Fisher scale (based on CT) (Neurology 1980)
Score Description
1 No blood
2 diffuse deposition or vertical layers <1 mm thick, no clots
3 localized clot and/or vertical layers > 1 mm thick
4 intracerebral or intraventricular clots with diffuse or no blood


Ogilvy Carter System for prognosis (Neurosurgery 1998; 42:959-970)

Points Description
1 Hunt Hess grade > 3
1 Fisher score > 2
1 Aneurysm size > 10 mm
1 Age > 50
1 Giant (> 25 mm) posterior circulation location

Stroke protocols per AAN meetings

Candidate selection for intervention level 2 evidence

 

1) Patients  inelegible for iv tPA within 6 hours use lytics, within 8 hours, MERCI

2) Consider longer duration for posterior circulation disease

3)  Use of DWI'PWI mismatch for patients beyond standard time windows.

 

Within 3 hours patients with ICA, MCA, BA occlusion, patients that fail to respond to IV tPA, or are excluded by NINDS iv exclusion criteria are candidates for intervention

 

3-6 hours patients with DWI/PWI mismatch are candidates for arterial

 

6-8 hours MERCI candidates

>8 hours for posterior circulation

 

Intervention

10 % vessels are open

first use 22-25 mg tPA inside clot

then go to stenting if reperfuse great

 

if don't reperfuse go to clot retrieval.

 

 

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Recanalization after iv tpa-- MCA v. ICA

(Beth Israel, Boston) Lanfante et al, Stroke 2002.

 

This is not a summary of the article but presentation of a few facts pulled out from it.  With initial NIHSS score of 16 or above most do not recanalize with iv tpa.  At NIH of 14 or below, MCA strokes recanalize much better than ICA strokes.Outcome correlates closely with recanlization. 

 

Christou et al showed that recanalization after iv tpa in 60 patients  with TIMI 2 or 3, 80 % MCA recanalized, 25 % ICA, 19% MCA-ICA, 7 % BA recanalized.

 

Frequency of iv tpa use:  national estimate is 1-2%.  30,000 ischemic strokes per month, 500 get iv tpa, 29,500 do not.

 

There are 3 categories of patients to consider.  1)  Those excluded from iv tpa (time,recent stroke, 2 weeks surgery, trauma, coagulopathy or INR>1.7)   2)  Nonresponders   3)  Reooclusion after initial reperfusion.

 

Mechanical reperfusion-- no thrombolytics used to reduce chance of bleeding (MERCI 1st and 2d generation, angioplasty and stenting). "Requires a learning curve."  Soft clots don't respond as well.

 

MultiMERCI

use of iv tPA allowed, newer device MERCI 1.5

mean age 66, baseline NIHSS 19, 34 %mRS <2 90 days, 30 % mortality at 90 days, 9 % SICH, 10 % procedure related SAE's (dissection, vessel perforation, distal embolization).  Comment one third get better whereas they had been doomed to death or disability previously.  Across trials all had about one third good outcome by mRS.

 

Patient selection:

How to select patients better.

MR rescue up to 8 hours

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MERCI 1 notes

mean age 67 NIHSS 20, mean time stroke onset to groin puncture 4.3 hours, 38 % enrolled within 3 hours, mean procedure time 2 hours, device passes 2.9 7.8 % SICH, 11 device fractures, 2 contributing to mortality. Mortality was 43 %, partly due to perforation with device malfunction.

 

MERCI I subgroup anal	Post circ n=14	ICA n=47	Mca n=80
Revasc	50%	53	45
Favorable 90 day mRS	36	24	29
Favorable 90 day NIHSS	50	33	29
Mortality	43	51	39

 

 

Clinical Trials Comparison

	NINDS	Controls	PROACT 2	Controls	IMS	MERCI
Patients	168	165	121	59	80	141
Window (hours)	0-3	0-3	0-6	0-6	0-3	0-8
BaseNIHSS	14	15	17	17	18	20
Timi 2-3			66	18	56	46
sICH	6	1	10	2	6	8
mRS 0-1	31	26	26	7	30
mRS 0-2	39	28	40	25	43	23
Death %	21	24	25	27	16	43

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Trials of interventional therapies for stroke (select)

Proact 2    ia prourokinase

474 screening angiograms, 180 randomized, mean age 64, NIHSS 17, all MCA occlusions 2:1 ratio placebo controlled,all patients received low dose heparin.  MRS<=2 at 90 days was 40 % in pro UK group v. 25 % placebo, 15 % absolute benefit, mortality (pro UK) 25 % v. (placebo) 27 %. NTT for 1 benefit =7.  Not approved due to high rate of ICH.

 

IMS  Study  Bridging therapy  eg. .6 mg/kg iv tpa (15 % bolus) followed by ia tpa up to 22 mg over 2 hours, ages 18-80, NIHSS>=10 within 3 hours.  Primary outcome safety SICH, clinical outcome mRS 0-1 at 3 months.  28/77 (36%) had major occlusion or high grade ICA stenosis, but 56 % were TIMI 2 or 3 at end of 2 hours of infusion.

 

IMS 2 - 3 ongoing multicenter randomized trial with similar design except that coull use iv tPA.endovascular (IA, MERCI, or ultrasound lysis) v. iv tPA alone.

 

 

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New stroke reccomendations

In reviewing the new ASA guidelines regarding acute stroke treatment they basically say you should give IV rtPA to all eligible patients. They recommend IA thrombolysis only for patients with a significant MCA occlusion with a last time normal < 6 hours who are otherwise not candidates for IV rtPA. It appears that no IR procedures are recommended for posterior circulation strokes at this time. I have copy and pasted the specific recommendations below. For all other interventional approaches they recommend further evaluation within the context of clinical trials. Note the new language regarding the qualifications of interventionalists that has been added.

Class I Recommendations
Intra-arterial thrombolysis is an option for treatment of selected patients who have major stroke of <6 hours’ duration due to occlusions of the MCA and who are not otherwise candidates for intravenous rtPA (Class I, Level of Evidence B). This recommendation has not changed since previous guidelines.
Treatment requires the patient to be at an experienced stroke center with immediate access to cerebral angiography and qualified interventionalists. Facilities are encouraged to define criteria to credential individuals who can perform intra-arterial thrombolysis (Class I, Level of Evidence C). This recommendation has been added since previous guidelines.
Class II Recommendation
Intra-arterial thrombolysis is reasonable in patients who have contraindications to use of intravenous thrombolysis, such as recent surgery (Class IIa, Level of Evidence C). This recommendation was not included in the previous guideline.
Class III Recommendation
The availability of intra-arterial thrombolysis should generally not preclude the intravenous administration of rtPA in otherwise eligible patients (Class III, Level of Evidence C). This recommendation has not changed from previous guidelines.
Also, here are the new recommendations regarding imaging in acute stroke:

Class I Recommendations
Imaging of the brain is recommended before initiating any specific therapy to treat acute ischemic stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
In most instances, CT will provide the information to make decisions about emergency management (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
The brain imaging study should be interpreted by a physician with expertise in reading CT or MRI studies of the brain (Class I, Level of Evidence C). This recommendation has been added since the previous guideline.
Some findings on CT, including the presence of a dense artery sign, are associated with poor outcomes after stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.
Multimodal CT and MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A). This recommendation has been added since the previous guideline.
Class II Recommendations
Nevertheless, data are insufficient to state that, with the exception of hemorrhage, any specific CT finding (including evidence of ischemia affecting more than one third of a cerebral hemisphere) should preclude treatment with rtPA within 3 hours of onset of stroke (Class IIb, Level of Evidence A). This recommendation has not changed from the previous guideline.
Vascular imaging is necessary as a preliminary step for intra-arterial administration of pharmacological agents, surgical procedures, or endovascular interventions (Class IIa, Level of Evidence B). This recommendation has not changed from the previous guideline.
Class III Recommendations
Emergency treatment of stroke should not be delayed in order to obtain multimodal imaging studies (Class III, Level of Evidence C). This recommendation has been added since the previous guideline.
Vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago and who have acute ischemic stroke (Class III, Level of Evidence B). This recommendation has been added since the previous guideline.

Timing of TIA's preceding stroke, and ABCD score,

Time window for prevention is very short. Neurology 2005; 64:817-820. Study involved 2416 European subjects in trials or a database. 23 % of patients overall gave a history of prior TIA. 17 % occurred on the day of the stroke, 9 % on previous day,and 43 % during the previous week. A risk of 1-2 % at seven days and 2-4 % at one month is usually quoted but omits fact that patients were not recruited until 2 weeks were up. The true early risk may be much higher, even tenfold higher.

Risk of stroke after TIA (cf slide by Brott) average of about 12 studies was about 5 % in first 2 days, 12 % in first 90 days. Kaiser and California studies were cited specifically. 1702 patients presented to California ED's received a diagnosis of TIA and were followed for three months, from record review. ABCD score was derived age > 60 (1 point), bp > 140/90 (1 point), clinical (unilateral weakness 2 points, speech disturbance without weakness one point) and duration (> 60 min, 2 points; 15 m to 60 m, 1 point) Final score 0-6 (Lancet 2005 Rothwell). OR California ABCD score (age> 60 one point, DM 1 pt, duration > 10 min 1 point,any weakness 1 pt, any speech impairment 1 pt, 0-5 score, Johnston JAMA 2000). ABCD (2) score Lancet 2007: age 1 pt, bp 1 pt, weakness/speech impairment 2/1 pts, dur >60 2 pt, 15-60 1 pt, dm 1 pt, 0-7 scale).

ABCD(2) score was validated and is ready for clinical use. 2 day risks for score (0-3) 1 %; score 4-5 (4%), score 6-7 (8%). Pct of patients in low medium and high risk groups were respectively34, 45, 21 respectively.

From Lancet article(2007) 90 day risk appears 0-3 (4 %?), score 4-5 9-13 %, and 6-7, 18-22 % (estimates off chart).

Benign recurrent tia's sensory only may have more tia's but < 3 % risk of stroke.

Consults for Stroke risk and timing of surgery

Blacker Dj et al The preoperative cerebrovascular consultation. Common cerebrovascular questions before general or cardiac surgery. Mayo Clin Proc 2004;79: 223-229.


Table one described stroke risk in various scenarios. CABG + valve surgery led with 4-13 % risk. CABG after prior stroke/TIA 8 %, CABG with carotid occlusion, 7 %, surgery with symptomatic VB stenosis, 6 %, CABG with bilateral > 50 % stenosis 5 %, unilateral 3%, after prior stroke 2.9 %, all surgery stroke risk 0.2 %. Other important factors are PVD, cardiac arrythmias, and chronic airway disease.

For CABG, prior stroke or TIA is very risky, worse with advanced age, recent MI, angina, DM smoking, impaired renal function. Authors suggest carotid surgery before CABG if dual disease, if carotid disease is symptomatic. and if carotid is not symptomatic, avoiding dual procedure (ie not doing CABG and CEA together). They also suggest waiting one month after stroke to do carotid surgery.

Why not trial intra-arterial lytics in basilar artery thrombosis

Article by Powers WJ. Intrarterial thrombolysis for basilar artery thrombosis. Trial it. Stroke. 2007; 38: 704-706. This article stresses the lack of current evidence in favor of arterial lytics therapy for ba thrombosis and the need for clinical trials. Macleod et al.(2005; 20: 12-17)Cerebrovascular Disease) is only randomized trial and it was prematurely terminated due to shortage of urokinase. Authors comment: "However, not every treatment requires a randomized clinical
trial to establish efficacy. Observational studies may provide
compelling evidence of treatment efficacy if treatment effects
are sufficiently large and consistent.6 Thus, the following 2
conditions must be met: (1) outcomes in untreated patients
are consistent; and (2) outcomes in treated patients are
consistently superior by a large margin. "". Lindsberg and Mattle have recently reviewed data on
344 patients from 11 different publications who were treated
with intra-arterial thrombolytic therapy for acute basilar
artery occlusion.5 Good outcome was achieved in 17% to
40% cases with a mean value of 24%. Those treated within
6 hours did not have a better outcome than those treated
after 6 hours.18,19 These values are not superior to the 30% to
67% good outcomes in patients who did not receive intraarterial
therapy reported in 4 recent hospital-based series
cited above. However, such comparisons across observational
studies are problematic because of differences in eligibility
criteria and in definitions of favorable outcome among the
different studies. In 1988, Hacke et al published an observational
study in which they compared 43 patients who receive
intra-arterial thrombolytic therapy for vertebral basilar thrombosis
to 22 historical controls from their center using the same outcome definition. significant benefit of intra-arterial thrombolysis in producing
favorable outcome (P[1]0. 017) and survival (P[1]0.0005).11
However, this conclusion was based on a flawed comparison
of 22 controls to only those 19 patients in whom successful
recanalization was achieved, not to the total group of 43 who
underwent thrombolytic therapy. This analytic approach is
not valid. Spontaneous recanalization of basilar artery occlusion
occurs in a substantial number of patients.20 Patients with
high levels of plasminogen activator inhibitors have both
reduced recanalization to exogenous thrombolytic agents and
reduced endogenous thrombolysis.21,22 Thus, selecting only
those patients with successful recanalization to exogenous
thrombolytic agents will also select those with the best
chance for spontaneous endogenous thrombolysis. Comparing
this selective subgroup to the full spectrum of control
patients will yield an invalid, overestimation of the treatment
effect. The more appropriate analysis based on the intentionto-
treat principle reveals that favorable outcome was
achieved in 10 of 43 treated patients and 3 of 22 untreated
patients (P[1]0.22). This study actually failed to demonstrate,
even with the use of historical controls, any significant benefit for intra-arterial thrombolytic therapy in this condition. "
Unfortunately, this therapy is not without either risk
or expense. The risk of symptomatic hemorrhage is 8% and
these may be fatal.5,23 Costs for thrombolytic drugs ($1000 to
$3000), cerebral arteriography ($4000 to $8000) and an intensive
care unit bed ($2300 to $3000/day) add substantial burdens
to a healthcare system that is already strained with no room to
grow.24,25,26 These procedural risks and expenses can be justified
only if the treatment is sufficiently effective to provide an
improvement in clinical outcome to outweigh the procedural
risks and a reduction in long-term costs to outweigh the
procedural expenses. In the absence of evidence for efficacy, the
procedural risks and expenses remain with nothing to outweigh
them.

Lack of utility of MERCI device

2007 AAN poster p06.127 p.A286 in neurology supplementBarreto et al. Adjunctive MERCI catheter utilization during intraarterial therapy does not benefit unselected ischemic stroke patients. Compared 22 patients receiving MERCI to 144 who received intraarterial therapy without merci at their center (Houston). Results-- patients receiving merci had higher recanalization but did not achieve better outcome.conclusion-- the results remain suboptimal in unselected patients indicating the need for better patient selection.

Encephalopathy,stroke & MI with DMSO stem cell

Chen-Plotkin et al. Neurology 2007; 68:859-861. Cases identify patients with stem cell transplantation and simultaneous MI and stroke. Stroke were fairly small. DMSO 10% was used as cryopreservative. Event occurred during or towards the end of the infusion.

Cholesterol goals and stroke

A high level of LDL cholesterol (160 mg/dL and above) reflects an increased risk of heart disease. Patients with a diagnosis of heart disease should aim for a target LDL cholesterol of less than 100 mg/dL. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) issued an evidence-based set of guidelines on cholesterol management in 2001 (Grundy, 2004) Since the publication of the ATP III, five major clinical trials of statin therapy with clinical endpoints have been published: HPS: Heart Protection Study (Collins, 2004) o Simvastatin significantly reduced the first event rate of stroke versus placebo (444 versus 585, P<0.0001) o There was no significant difference in strokes attributed to hemorrhage (51 versus 53, P=0.8) o Simvastatin also reduced the number of patients having TIAs alone compared with placebo (2.0% versus 2.4%, P=0.02) or requiring CEA or angioplasty (0.4% versus 0.8%, P=0.0003) PROSPER: Prospective Study of Pravastatin in the Elderly (Shepherd, 2002) o Statistically significant reduction in major vascular events in patients using pravastatin versus placebo (408 versus 473, P=0.014) o Death from CHD and nonfatal MI was significantly reduced by 24% (P=0.043) and CHD events were reduced by 19% in patients receiving active therapy (P=0.006) o Stroke risk was unaffected by pravastatin (P=0.8) and TIAs were decreased by 25% (P=0.51) ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Trial (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002) o Patients treated with chlorthalidone had a 15% lower risk for stroke (P=0.02) and a 10% lower risk of combined CVD (P=0.001) ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes—Lipid Lowering Arm (Sever, 2003) o The trial was stopped early because atorvastatin had resulted in a statistically significant reduction in CVD events: stroke (89 versus 121, P=0.024); total CV events (389 versus 486, P=0.0005); total coronary events compared with placebo (178 versus 247, P=0.0005) PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (Rouleau, 2005) o Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductants receiving active therapy (P=0.006) o Stroke risk was unaffected by pravastatin (P=0.8) and TIAs were decreased by 25% (P=0.51) ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Trial (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002) o Patients treated with chlorthalidone had a 15% lower risk for stroke (P=0.02) and a 10% lower risk of combined CVD (P=0.001) ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes—Lipid Lowering Arm (Sever, 2003) o The trial was stopped early because atorvastatin had resulted in a statistically significant reduction in CVD events: stroke (89 versus 121, P=0.024); total CV events (389 versus 486, P=0.0005); total coronary events compared with placebo (178 versus 247, P=0.0005) PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection—Thrombolysis in Myocardial Infarction 22 (Rouleau, 2005) o Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/d) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/d) o At two years, a relative risk reduction of 16% (95% CI, 5%-26%; P = 0.005) in the primary endpoint rate (death, MI, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The trials confirmed the benefit of cholesterol-lowering therapy in high-risk patients and support the following: ATP III treatment goal of LDL cholesterol <100 mg/dL Inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL cholesterol lowering therapy in these patients Inclusion of older persons benefiting from therapeutic lowering of LDL cholesterol More recently, tn) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/d) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/d) o At two years, a relative risk reduction of 16% (95% CI, 5%-26%; P = 0.005) in the primary endpoint rate (death, MI, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The trials confirmed the benefit of cholesterol-lowering therapy in high-risk patients and support the following: ATP III treatment goal of LDL cholesterol <100 mg/dL Inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL cholesterol lowering therapy in these patients Inclusion of older persons benefiting from therapeutic lowering of LDL cholesterol More recently, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated that when compared with placebo, atorvastatin 80 mg/d significantly reduced the risk of recurrent stroke in patients with recent stroke or TIA and no history of CHD, while substantially decreasing the risk of major coronary and CHD events and revascularization procedures (Welch, 2006). Table 7 provides the updated ATP III guidelines for cholesterol management (Grundy, 2004). Therapeutic lifestyle changes remain an essential modality in clinical management. Lifestyle changes, which include a healthy diet and exercise, must be an integral part of risk reduction therapy. When an LDL-cholesterol-lowering drug is employed in a person at high risk or moderately high risk, a reduction in LDL cholesterol levels of at least 30% to 40% beyond dietary therapy should be achieved, if feasible. Very high risk patients consider LDL <> If HDL is low consider niacin or gemfibrozil

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Hypertension recommendations after stroke

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) provided several new guidelines for hypertension prevention and management (Chobanian, 2004; Table 6). Some of the updates included:

• Thiazide-type diuretics should be used to treat most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers)
• Most patients with hypertension will require two or more antihypertensive medications to achieve goal blood pressure (<140/90 mm Hg or <130/80 mm Hg for patients with diabetes or chronic kidney disease)
• If blood pressure is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic
• even in normotensive patients, further reduction of blood pressure should be contemplated unless they have a high grade arterial stenosis.

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Modifiable risk factors for stroke

In 2001, the Stroke Council of the American Heart Association (AHA) issued a scientific statement on the primary prevention of ischemic stroke (Goldstein, 2001). The statement was based on the findings of an ad hoc writing group formed by the AHA council to review pertinent literature, published guidelines, and expert opinions regarding risk factors for ischemic stroke. 

According to the AHA council, each recommendation was based on five different levels of evidence. Further classification within the AHA scientific statement included the potential for modification (nonmodifiable, modifiable, or potentially modifiable) of the identified risk factor and the strength of evidence (well documented or less well documented).

Nonmodifiable risk factors included age, sex, race/ethnicity, and family history of stroke or TIA. Well-documented modifiable risk factors (all level I [data from randomized trials with low false-positive and low false-negative errors], grade A [supported by level I evidence]) included hypertension, smoking, diabetes/hyperinsulinemia/insulin resistance, asymptomatic carotid stenosis, atrial fibrillation, other cardiac disease (eg, valvular heart disease, intracardiac congenital defects), sickle cell disease, and hyperlipidemia. Less well-documented or potentially modifiable risk factors included hyperhomocysteinemia, obesity, physical inactivity, alcohol and drug abuse, hypercoagulability, hormone replacement therapy, oral contraceptive use, and inflammatory processes.

Hypertension was considered a major risk factor for stroke, as it remains underdiagnosed and inadequately treated. The relationship between stroke and systolic and diastolic blood pressures is direct, continuous, and apparently independent. More than 30 years of evidence reveals that adequately controlled hypertension is a factor in preventing stroke, as are beta-blocker and high-dose diuretic therapy. Particularly in elderly persons, isolated systolic hypertension is considered an important risk factor for stroke (systolic blood pressure of more than 160 mm Hg and diastolic blood pressure of less than 90 mm Hg). One trial involving 4,695 elderly patients with isolated systolic hypertension was terminated when a stroke reduction rate of 42% was reached in the patients who were actively treated with antihypertensive therapies (a long-acting dihydropyridine calcium antagonist as initial therapy and other drugs as part of step-two drug titration) compared with those taking placebo (Staessen, 1997).  The AHA recommends that adult patients undergo routine screening for hypertension at least once every two years. 

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MATCH trial

the Management of Atherothrombosis with Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke (MATCH) trial, 7,599 high-risk patients with a recent history of TIA or ischemic stroke were randomized to receive either clopidogrel 75 mg plus aspirin 75 mg once daily or clopidogrel 75 mg plus placebo once daily.  Eligible patients had experienced a TIA or ischemic stroke within the last three months and had evidence of at least one additional risk factor within the last three years (prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic PAD). The primary endpoint was the composite of ischemic stroke, MI, vascular death, and rehospitalization for an acute ischemic event. The duration of treatment and follow-up was 18 months for each patient (Diener, 2004a; Diener, 2004b).

In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50her clopidogrel 75 mg plus aspirin 75 mg once daily or clopidogrel 75 mg plus placebo once daily.  Eligible patients had experienced a TIA or ischemic stroke within the last three months and had evidence of at least one additional risk factor within the last three years (prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic PAD). The primary endpoint was the composite of ischemic stroke, MI, vascular death, and rehospitalization for an acute ischemic event. The duration of treatment and follow-up was 18 months for each patient (Diener, 2004a; Diener, 2004b).

In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).

Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. Thng (defined as any fatal bleeding event, a drop in hemoglobin of  ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).

Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. The MATCH trial demonstrated that monotherapy with clopidogrel is as effective as combination therapy with clopidogrel plus aspirin in specific high-risk cerebrovascular patients, and that the risk of life-threatening or major bleeding was clinically and statistically significantly increased by the addition of aspirin to clopidogrel.

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established CAD, PAD, or cerebrovascular disease, or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event (ie, primary stroke prevention)(Bhatt, 2006a).  This randomized, international, multicenter, double-blinded, placebo-controlled study enrolled a total of 15,603 patients worldwide. The rate of the primary efficacy endpoint (a composite of MI, stroke, or death from cardiovascular causes) was 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin (relative risk, 0.93; 95% CI, 0.83-1.05; P=0.22). Overall, the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of the primary endpoint; however, statistically significant decreases were shown for individual secondary endpoints, including hospitalizations for ischemic events and nonfatal stroke.

In a pre-specified subgroup analysis, the rate of the primary endpoint among asymptomatic patients with multiple risk factors was 6.6% with clopidogrel plus aspirin and 5.5% with placebo plus aspirin (relative risk, 1.2; 95% CI, 0.91-1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with combination treatment with clopidogrel plus aspirin (3.9% versus 2.2%, P=0.01). In the subgroup with clinically evident atherothrombosis (ie, symptomatic), the rate was 6.9% with clopidogrel plus aspirin and 7.9% with placebo plus aspirin (relative risk, 0.88; 95% CI, 0.77 -0.998; P=0.046).

The rate of the primary safety endpoint (severe bleeding according to the Global Utilization of Strategies To Open Occluded Arteries [GUSTO] definition) was 1.7% in the clopidogrel plus aspirin group and 1.3% in the placebo plus aspirin group (relative risk, 1.25; 95% CI, 0.97-1.61; P=0.09).The rate of moderate bleeding was 2.1% in the clopidogrel plus aspirin group, as compared with 1.3% in the placebo plus aspirin group (relative risk, 1.62; 95% CI, 1.27-2.10; P<0.001). The rate of intracranial hemorrhage was similar in the two treatment groups. Hence, in CHARISMA, the rate of severe bleeding was not significantly greater with clopidogrel than with placebo, but clopidogrel was associated with a significant increase in the rate of moderate bleeding.

Overall, CHARISMA suggested some benefit may be observed with combination clopidogrel and aspirin treatment in patients with symptomatic atherothrombosis, but that the risks of bleeding may outweigh these benefits especially in patients with multiple risk factors.

Conversely, the combination of clopidogrel plus aspirin has been demonstrated to be superior to treatment with aspirin alone for patients with acute coronary syndromes and after coronary stenting (Ault,1999; Mehta, 2003; Steinbuhl, 2003; Mehta, 2001; Steinhubl, 2002; Peters, 2003). Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk secondary prevention (ie, after TIA/stroke) requires further investigation.

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Mechanisms of antiplatelet drugs

Aspirin inhibits the cyclooxygenase enzyme, preventing the production of prostaglandin and thromboxane A2 (TXA2) from arachidonic acid. TXA2 activates the GP IIb/IIIa binding site on the platelet, allowing fibrinogen to bind (Physician's Desk Reference, 2004)(Aggrenox^® PI). Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of TXA2, a powerful inducer of platelet aggregation and vasoconstriction. Paradoxically, aspirin blocks synthesis of prostacyclin by endothelial cells, resulting in an effect that promotes platelet aggregation.

Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to more than 20 hours (Physician's Desk Reference, 2004; Aggrenox^® PI). 

Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation (Plavix^® PI). Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible and lasts for the duration of platelet life, about seven to ten days. The inhibition is specific and does not significantly affect cyclooxygenase or arachidonic acid metabolism.

The mechanism of action of clopidogrel is different from that of aspirin. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma. The elimination half-life of the main circulating metabolite was eight hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.

Both low- and high-affinity ADP receptors are present on platelets, and the active metabolite of clopidogrel binds to the low-affinity receptors. ADP binding to this site is necessary for activation of the GP IIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate. Clopidogrel thus ultimately inhibits the activation of the GP IIb/IIIa receptor and its binding with fibrinogen (Figure 2).
 
Dipyridamole has been suggested to act as an antiplatelet drug by several possible mechanisms (Aggrenox^® PI).  It directly stimulates prostacyclin synthesis, potentiates the platelet inhibitory actions of prostacyclin, and inhibits phosphodiesterase to raise platelet cyclic AMP levels. However, these effects may not occur at therapeutic levels of the drug; hence, the mechanism of action of dipyridamole remains to be elucidated. Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide (which has low pharmacodynamic activity) is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin/extended-release dipyridamole, which is 13.6 hours.

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