Hemorrhagic transformation in patients with acute ischaemic stroke and an indica

Hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation; Marsh EB, Llinas RH, Hillis AE, Gottesman RF; European Journal of Neurology (Mar 2013)

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) can occur in patients following acute ischaemic stroke in the form of hemorrhagic transformation, and results in significant long-term morbidity and mortality. Anticoagulation theoretically increases risk. We evaluated stroke patients with an indication for anticoagulation to determine the factors associated with hemorrhagic transformation. METHODS: Three-hundred and forty-five patients with ICD-9 codes indicating: (i) acute ischaemic stroke; and (ii) an indication for anticoagulation were screened. One-hundred and twenty-three met inclusion criteria. Data were collected retrospectively. Neuroimaging was reviewed for infarct volume and evidence of ICH. Hemorrhages were classified as: hemorrhagic conversion (petechiae) versus intracerebral hematoma (a space occupying lesion); symptomatic versus asymptomatic. Using multivariable logistic regression, we determined the hypothesized factors associated with intracerebral bleeding. RESULTS: Age [odds ratio (OR) = 1.50 per 10-year increment, 95% confidence interval (CI) 1.07-2.08], infarct volume (OR = 1.10 per 10 ccs, 95% CI 1.06-1.18) and worsening category of renal impairment by estimated glomerular filtration rate (eGFR; OR = 1.95, 95% CI 1.04-3.66) were predictors of hemorrhagic transformation. Ninety- nine out of 123 patients were anticoagulated. Hemorrhage rates of patients on and off anticoagulation did not differ (25.3% vs. 20.8%; P = 0.79); however, all intracerebral hematomas (n = 7) and symptomatic bleeds (n = 8) occurred in the anticoagulated group. CONCLUSIONS: The risk of hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation is multifactorial, and most closely associated with an individual's age, infarct volume and eGFR.

MR Rescue NEJM 2013

Background
Whether brain imaging can identify patients who are most likely to benefit from
therapies for acute ischemic stroke and whether endovascular thrombectomy improves
clinical outcomes in such patients remains unclear.
Methods
In this study, we randomly assigned patients within 8 hours after the onset of largevessel,
anterior-circulation strokes to undergo mechanical embolectomy (Merci
Retriever or Penumbra System) or receive standard care. All patients underwent
pretreatment computed tomography or magnetic resonance imaging of the brain.
Randomization was stratified according to whether the patient had a favorable
penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral
pattern (large core or small or absent penumbra). We assessed outcomes
using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead).
Results
Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment
was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization
in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality
was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate
differed across groups. Among all patients, mean scores on the modified Rankin
scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P = 0.99).
Embolectomy was not superior to standard care in patients with either a favorable
penumbral pattern (mean score, 3.9 vs. 3.4; P = 0.23) or a nonpenumbral pattern
(mean score, 4.0 vs. 4.4; P = 0.32). In the primary analysis of scores on the 90-day
modified Rankin scale, there was no interaction between the pretreatment imaging
pattern and treatment assignment (P = 0.14).
Conclusions
A favorable penumbral pattern on neuroimaging did not identify patients who would
differentially benefit from endovascular therapy for acute ischemic stroke, nor was
embolectomy shown to be superior to standard care. (Funded by the National Institute
of Neurological Disorders

 

Blogger comment:  key point here is mean time to vascularization has to be less than 8 hours.  MR rescue should be done within six or preferably four hours.

IMS 3 article

Endovascular Therapy after Intravenous
t-PA versus t-PA Alone for Stroke
Joseph P. Broderick, M.D., Yuko Y. Palesch, Ph.D., Andrew M. Demchuk, M.D., et al NEJM 2013

 

BACKGROUND
Endovascular therapy is increasingly used after the administration of intravenous tissue
plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic
stroke, but whether a combined approach is more effective than intravenous t-PA
alone is uncertain.
METHODS
We randomly assigned eligible patients who had received intravenous t-PA within
3 hours after symptom onset to receive additional endovascular therapy or intravenous
t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified
Rankin scale score of 2 or less (indicating functional independence) at 90 days
(scores range from 0 to 6, with higher scores indicating greater disability).
RESULTS
The study was stopped early because of futility after 656 participants had undergone
randomization (434 patients to endovascular therapy and 222 to intravenous t-PA
alone). The proportion of participants with a modified Rankin score of 2 or less at
90 days did not differ significantly according to treatment (40.8% with endovascular
therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage
points; 95% confidence interval [CI], −6.1 to 9.1, with adjustment for the National
Institutes of Health Stroke Scale [NIHSS] score [8–19, indicating moderately severe
stroke, or ≥20, indicating severe stroke]), nor were there significant differences for
the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8
percentage points; 95% CI, −4.4 to 18.1) and those with a score of 19 or lower (−1.0
percentage point; 95% CI, −10.8 to 8.8). Findings in the endovascular-therapy and
intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively;
P = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage
within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 0.83).
CONCLUSIONS
The trial showed similar safety outcomes and no significant difference in functional
independence with endovascular therapy after intravenous t-PA, as compared with
intravenous t-PA alone. (Funded by the National Institutes of Health and others;
ClinicalTrials.gov number, NCT00359424.)

 

Blogger comment

 

There's a lot of issues with the studies:

IMS III:

1) IMS III only included patients that arrived in <3 hours and could get IV tPA.

2) Patients that are not candidates for IV tPA (recent surgery, coumadin, etc) undergo endovascular mechanical thrombectomy.

3) 5197 patients were screened for IMS III, but only 656 patients randomized, which typically means the confined scope of a PRCT does not generalize to the real world.

4) For most of IMS III, noncontrast CT was the only imaging (CTA was only added later) which means there were likely a significant number of patients withOUT an occlusion that were randomized in the study (in the Ciccone study, 10% of patients did not have an occlusion!).

5) IMS III included a hodge-podge of endovascular treatments including EKOS, which no one uses, and IA tPA, which is rarely used now that we have mechanical thrombectomy devices.

6) The study was halted because of futility, thus the number of patients studied was not enough for the study to be adequately powered to demonstrate a difference.

7) IMS III was a comparison of IV tPA versus IV tPA plus endovascular therapy. What the study shows is maybe IV tPA is our best treatment. However, the way we practice, and most high-volume stroke centers are the same, is we give IV tPA to eligible candidates and only perform endovascular therapy in patients that are not eligible for IV tPA, or who receive IV tPA and the IV tPA does not work.

8)  Current devices in past year are much more effective and current protocols stress earlier door to needle.

Synthesis trial

SYNTHESIS N Engl J Med 2013

Background
In patients with ischemic stroke, endovascular treatment results in a higher rate of
recanalization of the affected cerebral artery than systemic intravenous thrombolytic
therapy. However, comparison of the clinical efficacy of the two approaches is
needed.
Methods
We randomly assigned 362 patients with acute ischemic stroke, within 4.5 hours
after onset, to endovascular therapy (intraarterial thrombolysis with recombinant
tissue plasminogen activator [t-PA], mechanical clot disruption or retrieval, or a
combination of these approaches) or intravenous t-PA. Treatments were to be given
as soon as possible after randomization. The primary outcome was survival free of
disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6, with
0 indicating no symptoms, 1 no clinically significant disability despite symptoms,
and 6 death) at 3 months.
Results
A total of 181 patients were assigned to receive endovascular therapy, and 181 intravenous
t-PA. The median time from stroke onset to the start of treatment was
3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P<0.001).
At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the
intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for
age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence
interval, 0.44 to 1.14; P = 0.16). Fatal or nonfatal symptomatic intracranial
hemorrhage within 7 days occurred in 6% of the patients in each group, and there
were no significant differences between groups in the rates of other serious adverse
events or the case fatality rate.
Conclusions
The results of this trial in patients with acute ischemic stroke indicate that endovascular
therapy is not superior to standard treatment with intravenous t-PA. (Funded
by the Italian Medicines Agency, ClinicalTrials.gov number, NCT00640367.)

 

Blogger comment-- endovascular v tpa does not represent real world since current protocol is patients get iv if eligible and both if iv does not work,and endovascular alone if not eligible for iv. Also hodgepodge of old interventional methods were used.

SYNTHESIS (Italian Study):

1) This study only randomized patients that arrived in < 4.5 hours and were eligible candidates for IV tPA. For same reasons as above, this is a very narrow scope of patients.

2) This study was a comparison of IV tPA versus IA tPA (additional devices could be used). IA tPA is rarely used as an endovascular therapy now that we have mechanical devices.

3) No CTA was allowed in this study. Only noncontrast head CT. 10% of patients randomized to IA therapy had no occlusion on angiogram, and these patients because the protocol dictated, were given IA tPA anyways even if they had no occlusion!

4) In his presentation, Ciccone showed that the time-to-treatment was significantly different: >60 minutes longer in the IA treatment arm of the study.

5) It is not clear how many patients were screened to arrive at the final enrollment of 362.

Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients wit

Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF and ATRIA Study Cohorts; Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM; Circulation (Dec 2012)BACKGROUND: We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS: In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R(2)CHADS(2)) improved net reclassification index (NRI) by 6.2% when compared with CHA(2)DS(2)VASc (C-statistic=0.578) and 8.2% when compared with CHADS(2) (C-statistic=0.575). The inclusion of estimated glomerular filtration rate<60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R(2)CHADS(2) in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS(2). CONCLUSIONS: In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Unique identifier: NCT00403767.

8

FDA: Don't use dabigatran with mechanical valves

ROCKVILLE, Md -- December 20, 2012 -- The US Food and Drug Administration (FDA) is informing healthcare professionals and the public that the anticoagulant dabigatran etexilate mesylate (Pradaxa) should not be used to prevent stroke or blood clots in patients with mechanical prosthetic heart valves.

A clinical trial in Europe (RE-ALIGN) was recently stopped because dabigatran users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were warfarin users. There was also more bleeding after valve surgery in the dabigatran group versus the warfarin group.

Dabigatran is not approved for patients with atrial fibrillation caused by heart valve problems.

The FDA is requiring a contraindication of dabigatran in patients with mechanical heart valves. Health care professionals should promptly transition any patient with a mechanical heart valve who is taking dabigatran to another medication.

The use of dabigatran in patients with bioprosthetic valves has not been evaluated and cannot be recommended.

Patients with all types of prosthetic heart valve replacements taking dabigatran should talk to their health care professional as soon as possible to determine the most appropriate anticoagulation treatment.

Data Summary
In the RE-ALIGN trial, patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrolment) were randomised to receive warfarin or dabigatran (150, 220, or 300 mg twice-daily). Initial dosing of dabigatran was determined by renal function. In the warfarin group, the target international normalized ratio (INR) was 2 to 3 or 2.5 to 3.5, depending on the presence of risk factors and the position of the mechanical prosthetic heart valve.

The study was terminated early because the dabigatran arm had significantly more thromboembolic events (valve thrombosis, stroke, and myocardial infarction) and major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) than did the warfarin arm. These bleeding and thromboembolic events were reported in patients who were initiated on dabigatran postoperatively within 3 days after mechanical bileaflet valve implantation and in patients whose valves had been implanted more than 3 months previously.

Adverse events should be reported to the FDA's MedWatch program:
1-800-332-1088
1-800-FDA-0178 Fax
Report a Serious Problem
MedWatch Online
Download Forms
Regular Mail: Use postage-paid
Mail to: MedWatch 5600 Fishers Lane
Rockville, MD 20857

Atenolol improves outcome in ICH

Is beta-blocker (atenolol) a preferred antihypertensive in acute intracerebral hemorrhage?; Kalita J, Misra UK, Kumar B; Neurological Sciences (Oct 2012)

 

The mortality in intracerebral hemorrhage (ICH) is mainly due to raised intracranial pressure, and its complications mediated by sympathetic overactivity. There is paucity of studies evaluating the role of beta-blockers in the outcome of ICH. This study reports the role of atenolol in reducing mortality, pneumonia, systemic inflammatory response syndrome (SIRS), and 3 months outcome in the patients with hypertensive ICH. 138 consecutive patients with hypertensive ICH were included and their stroke risk factors and clinical details were recorded. Consciousness was assessed by Glasgow Coma Scale and severity of stroke by Canadian Neurological Scale. Volume of hematoma was measures on CT scan and occurrence of SIRS and pneumonia were noted. 3 months outcome was categorized into good (Barthel index>12) and poor (BI < 12). The patients were categorized into those receiving atenolol and nonatenolol. The effects of atenolol on stroke outcome parameters were evaluated. Seventy-nine patients received atenolol and 59 did not and they mainly received amlodipine. There was no difference in the base line clinical characteristics between the two groups except smoking (P = 0.01) and baseline blood pressure (P = 0.007). Atenolol significantly reduced the mortality (11.4 vs 37.3 %, P < 0.0001), SIRS (16.4 vs 40.9 %, P = 0.007), and pneumonia (8.9 vs 30.5 %, P = 0.002) compared to those not receiving atenolol. At 3 months, patients with atenolol had insignificantly better outcome compared to nonatenolol group (49.1 vs 31.9 %, P = 0.11). Use of atenolol in hypertensive ICH results in reduction in mortality, SIRS, and pneumonia which may be due to its β-adrenergic blocking effect.

warfarin v. dabigatran RE-LY trial

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran: The RE-LY Trial; Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf S; Stroke (Apr 2012)

BACKGROUND AND PURPOSE: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. METHODS: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). RESULTS: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). CONCLUSIONS: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.

212 Stars

Star

(no subject)

Dose-dependent effect of early antiplatelet therapy in acute ischaemic stroke; Meves SH, Overbeck U, Endres HG, Krogias C, Neubauer H; Thrombosis and Haemostasis 107 (1), (Dec 2011)

Antiplatelet agents are essential in treating patients with acute ischaemic stroke (AIS) to prevent recurrent ischaemic events. The aim of this study was to evaluate the effectiveness of early antiplatelet therapy with different aspirin (ASA) dosages in patients with AIS. This observational study included 454 patients with AIS in whom antiplatelet treatment was initiated. The antiplatelet effect was determined by whole blood aggregometry within 48 hours after antplatelet therapy was initiated. An impedance change exceeding 0 Ω after stimulation with arachidonic acid was defined as ASA low response (ALR) and ≥5 Ω in ADP-stimulated specimen as clopidogrel LR. Of the study group 53.5% patients were treated with 200 mg ASA orally, 27.5% with 500 mg ASA intravenously, 8.6% with 100 mg ASA orally, and 7.7% with 75 mg clopidogrel. A dose-dependent antiplatelet effect of ASA treatment was found: 18.4% of patients with 500 mg ASA intravenously were ALR, in contrast to 32.5% on 200 mg and 35.9% on 100 mg ASA orally. Clopidogrel treatment without a loading dose resulted in a high proportion of LR (45.7%). Using the propensity score method revealed a three times higher risk for ALR for patients treated with ASA 200 mg [odds ratio 2.99 (1.55-5.79)] compared to treatment with ASA 500 mg. In conclusion, initiating antiplatelet therapy in patients with AIS resulted in a dose-dependent insufficient platelet inhibitory effect. Our findings suggest using a loading dose of 500 mg ASA intravenously as this seems to be favourable when a sufficient early platelet inhibitory effect is wanted.

comment- debate over aspirin dose never ends.  However, we treat patients, not lab tests and it would be interesting to know if there were any clinical effects or side effects of high v. low dose aspirin

dual antiplatelet therapy for 7 days in intracranial occlusive disease

The effectiveness of dual antiplatelet treatment in acute ischemic stroke patients with intracranial arterial stenosis: a subgroup analysis of CLAIR study; the CLAIR Study Investigators; International Journal of Stroke (Aug 2012)

BACKGROUND: Dual antiplatelet therapy with clopidogrel and aspirin reduces the presence and number of microembolic signals in patients with large artery disease. However, whether it is effective in patients with intracranial disease alone remains uncertain. We performed a subgroup analysis of the The CLopidogrel plus Aspirin for Infarction Reduction (CLAIR in acute stroke or transient ischemic attack patients with large artery stenosis and microembolic signals) study of only patients with intracranial occlusive disease, excluding those with extra cranial disease. METHODS: CLAIR was a randomized-controlled, open-label, multicenter clinical trial with blinded outcome evaluation, which recruited patients with symptoms of ischemic stroke or transient ischemic attack within seven-days of onset, with large artery stenosis verified by transcranial Doppler and carotid ultrasound, and with microembolic signals detected by transcranial Doppler recording. All patients were randomized to receive clopidogrel plus aspirin daily for seven-days (dual treatment), or aspirin alone for seven-days (monotherapy). Repeated transcranial Doppler recordings for microembolic signals were made on day one, two, and seven. This subgroup study only analyzed the patients with purely intracranial large artery disease and excluded those with extra cranial stenosis. RESULTS: There were 70 patients recruited with purely intracranial stenosis, 34 in the dual treatment group and 36 in the monotherapy group. The proportion of the patients with positive emboli at day seven in the dual treatment group was significantly lower than that in the monotherapy group (relative risk reduction 56·5%, 95% confidence interval 2·5-80·6; P = 0·029). The number of emboli in the dual treatment group decreased significantly at day two (P = 0·043) and day seven (P = 0·018) compared with the monotherapy group. After adjustment for the number of emboli at day one, the effect of dual treatment was still significant for the reduction of presence (relative risk reduction 56·0%; 95% confidence interval 5·4-79·6; P = 0·036) and number (adjusted mean difference -0·9; 95% confidence interval -1·5 to -0·3; P = 0·004) of positive emboli at day seven. CONCLUSIONS: Dual treatment with clopidogrel and aspirin for seven-days is more effective than aspirin alone to reduce microembolic signals in patients with intracranial arterial stenosis.

Suggestion AGAINST warfarin after 3 months post maze procedure

The impact of CHADS(2) score on late stroke after the Cox maze procedure; Pet M, Robertson JO, Bailey M, Guthrie TJ, Moon MR, Lawton JS, Rinne A, Damiano RJ, Maniar HS; Journal of Thoracic and Cardiovascular Surgery (Jul 2012)

OBJECTIVE: The Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society jointly recommend indefinite warfarin anticoagulation in patients with CHADS(2) (congestive heart failure, hypertension, age, diabetes, and stroke) score of at least 2 who have undergone ablation for atrial fibrillation. This study determined the impact of CHADS(2) score on risk of late stroke or transient ischemic attack after the performance of a surgical Cox maze procedure. METHODS: A retrospective review of 433 patients who underwent a Cox maze procedure at our institution was conducted. Three months after surgery, warfarin was discontinued regardless of CHADS(2) score if the patient showed no evidence of atrial fibrillation, was off antiarrhythmic medications, and had no other indication for anticoagulation. A follow-up questionnaire was used to determine whether any neurologic event had occurred since surgery. RESULTS: Follow-up was obtained for 90% of the study group (389/433) at a mean of 6.6 ± 5.0 years. Among these patients, 32% (125/389) had a CHADS(2) score of at least 2, of whom only 40% (51/125) remained on long-term warfarin after surgery. Six patients had late neurologic events (annualized risk of 0.2%). Neither CHADS(2) score nor warfarin anticoagulation was significantly associated with the occurrence of late neurologic events. Among the individual CHADS(2) criteria, both diabetes mellitus and previous stroke or transient ischemic attack were predictive of late neurologic events. CONCLUSIONS: The risk of stroke or transient ischemic attack in patients after a surgical Cox maze procedure was low and not associated with CHADS(2) score or warfarin use. Given the known risks of warfarin, we recommend discontinuation of anticoagulation 3 months after the procedure if the patient has no evidence of atrial fibrillation, has discontinued antiarrhythmic medications, and is without any other indication for systemic anticoagulation.

19

asa + plavix decreased MI's, increases fatal hemorrhages, no effect on mortality

Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials; Palacio S, Hart RG, Pearce LA, Benavente OR; Stroke 43 (8), 2157-62 (Aug 2012)

 

BACKGROUND AND PURPOSE In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials. METHODSRandomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported. RESULTSTwelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days-3 months; OR, 0.93; 95% CI, 0.87-0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91-1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97-1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74-0.91). CONCLUSIONSThe addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction. Clinical Trial Registration- URL: http//www.clinicaltrials.gov. Unique identifier: NCT00059306.

 

Comment -- metaanalysis improves our knowledge over SPS3 results which are outliers

Need for extended clopidofrel therapy after intracranial stenting

Incidence of cerebral ischemic events after discontinuation of clopidogrel in patients with intracranial aneurysms treated with stent-assisted techniques; Rossen JD, Chalouhi N, Wassef SN, Thomas J, Abel TJ, Jabbour PM, Kung DK, Hasan DM; Journal of Neurosurgery (Sep 2012)

 

Object: The optimal antiplatelet medication protocol for prevention of thrombotic complications after stent-assisted coil embolization of cerebral aneurysms is unclear. Early cessation of antiplatelet agents may be associated with an increased risk of cerebral ischemic events. In this study, the authors assess the incidence of stroke or transient ischemic attack (TIA) following discontinuation of a 6-week course of clopidogrel in patients with cerebral aneurysms treated with stent-assisted techniques. Methods A retrospective review was conducted in all patients with cerebral aneurysms undergoing stent-assisted coil embolization or stent-in-stent flow diversion at the University of Iowa during a 24-month period. The antiplatelet protocol was 81 mg aspirin and 75 mg clopidogrel daily for 6 weeks, followed by 325 mg aspirin daily indefinitely. The incidence of stroke or TIA was determined by a retrospective review of medical records generated during a 3-month period following discontinuation of clopidogrel. Results A total of 154 patients underwent aneurysm treatment with stent techniques during this interval. Documentation of neurological follow-up 3 months after discontinuation of a 6-week clopidogrel treatment was available in 121 (78.6%) of 154 patients. Of these 121 patients, 114 were treated with stent-assisted coil embolization and 7 with stent-in-stent flow diversion. Six patients (5%) suffered an ischemic event after cessation of clopidogrel, with 2 events occurring within the first 2 weeks. Specifically, the rate of ischemic events was 5 (4.3%) of 114 in the"stent-coil"treatment group and 1 (14.3%) of 7 in the stent-in-stent group. Treatment had been performed in the setting of a subarachnoid hemorrhage in 1 patient. Atypical aneurysm features and technical factors predisposing to thrombotic events were found in all but one of these patients. Similarly, cardiovascular risk factors were present in 5 of the 6 patients in whom ischemic events developed after clopidogrel discontinuation. Conclusions Clopidogrel discontinuation is associated with a 5% risk of ischemic events in patients treated with stent techniques. Any stroke related to clopidogrel discontinuation is avoidable, and longer treatment is therefore clearly necessary. Patients with cardiovascular risk factors, high-risk aneurysm features, and those undergoing stent-in-stent flow diversion might benefit the most from longer clopidogrel therapy.

details of preiprocedural strokes in SAMMPRIS

Detailed Analysis of Periprocedural Strokes in Patients Undergoing Intracranial Stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS); Fiorella D, Derdeyn CP, Lynn MJ, Barnwell SL, Hoh BL, Levy EI, Harrigan MR, Klucznik RP, McDougall CG, Pride GL, Zaidat OO, Lutsep HL, Waters MF, Hourihane JM, Alexandrov AV, Chiu D, Clark JM, Johnson MD, Torbey MT, Rumboldt Z, Cloft HJ, Turan TN, Lane BF, Janis LS, Chimowitz MI, for the SAMMPRIS Trial Investigators; Stroke (Sep 2012)

 

BACKGROUND AND PURPOSE: Enrollment in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial was halted due to the high risk of stroke or death within 30 days of enrollment in the percutaneous transluminal angioplasty and stenting arm relative to the medical arm. This analysis focuses on the patient and procedural factors that may have been associated with periprocedural cerebrovascular events in the trial. METHODS: Bivariate and multivariate analyses were performed to evaluate whether patient and procedural variables were associated with cerebral ischemic or hemorrhagic events occurring within 30 days of enrollment (termed periprocedural) in the percutaneous transluminal angioplasty and stenting arm. RESULTS: Of 224 patients randomized to percutaneous transluminal angioplasty and stenting, 213 underwent angioplasty alone (n=5) or with stenting (n=208). Of these, 13 had hemorrhagic strokes (7 parenchymal, 6 subarachnoid), 19 had ischemic stroke, and 2 had cerebral infarcts with temporary signs within the periprocedural period. Ischemic events were categorized as perforator occlusions (13), embolic (4), mixed perforator and embolic (2), and delayed stent occlusion (2). Multivariate analyses showed that higher percent stenosis, lower modified Rankin score, and clopidogrel load associated with an activated clotting time above the target range were associated (P≤0.05) with hemorrhagic stroke. Nonsmoking, basilar artery stenosis, diabetes, and older age were associated (P≤0.05) with ischemic events. CONCLUSIONS: Periprocedural strokes in SAMMPRIS had multiple causes with the most common being perforator occlusion. Although risk factors for periprocedural strokes could be identified, excluding patients with these features from undergoing percutaneous transluminal angioplasty and stenting to lower the procedural risk would limit percutaneous transluminal angioplasty and stenting to a small subset of patients. Moreover, given the small number of events, the present data should be used for hypothesis generation rather than to guide patient selection in clinical practice.Clinical Trial Registration Information

 

Comment

high risk for hemorrhagic stroke: higher percent stenosis, lower modified Rankin score, and clopidogrel loading dose.n=13

high risk for ischemic stroke:  nonsmoker, BA stenosis, DM, and older age n=19

Clinical Outcomes Using a Platelet Function-Guided Approach for Secondary Preven

Depta JP, Fowler J, Novak E, Katzan I, Bakdash S, Kottke-Marchant K, Bhatt DL; Stroke (Jun 2012)BACKGROUND AND PURPOSE: Antiplatelet therapy nonresponse is associated with worse clinical outcomes. We studied the clinical outcomes associated with platelet function-guided modifications in antiplatelet therapy in patients with ischemic stroke or transient ischemic attack. METHODS: From January 2005 to August 2007, 324 patients with ischemic stroke underwent platelet function testing using platelet aggregometry. Aspirin nonresponse was defined as a mean platelet aggregation ≥20% with 0.5 mg/mL arachidonic acid and/or ≥70% with 5 μmol/L adenosine diphosphate. Clopidogrel nonresponse was defined as a mean platelet aggregation ≥40% with 5 μmol/L adenosine diphosphate. A modification was any increase in antiplatelet therapy occurring after testing. Clinical outcomes were compared between patients with and without platelet function-guided antiplatelet therapy modifications using univariate and propensity score-adjusted analyses. RESULTS: In patients with ischemic stroke or transient ischemic attack, 43% (n=128) and 35% (n=54) were nonresponders to aspirin and clopidogrel, respectively. After platelet function testing, antiplatelet therapy was increased in 23% of patients (n=73). After propensity score matching (n=61 in each group), antiplatelet therapy modification was associated with significantly increased rates of death, ischemic events, or bleeding (hazard ratio, 2.24; 95% CI, 1.12-4.47; P=0.02) compared with no modification in antiplatelet therapy and a trend toward increased bleeding (hazard ratio, 3.56; 95% CI, 0.98-12.95; P=0.05). No differences in ischemic events were observed. CONCLUSIONS: Platelet function-guided modification in antiplatelet therapy after an ischemic stroke or transient ischemic attack was associated with significantly higher rates of adverse clinical outcomes.

32

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation W

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran: The RE-LY Trial

Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf S; Stroke (Apr 2012)

BACKGROUND AND PURPOSE: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. METHODS: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). RESULTS: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). CONCLUSIONS: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.

 

Comment:  warfarin use by itself was more of a risk than dabagitran + asa, although the combination also increased risk.  Age was not a major risk factor. Fall risk was not looked at.

Old studies that panned the use of anticoagulation in stroke, including WASID might need to be restudied, with dabagatran, since in Wasid the real problem was keeping the INR's in range.  This point is likely to be incredibly controversial, yet the facts speak:  dabagatran has not been studied in the group of intracranial stensosis and the results of warfarin studies cannot be generalized as is clear from this trial.

Glaucoma and obstructive sleep apnea

Faridi O, Park SC, Liebmann JM, Ritch R; Clinical and Experimental Ophthalmology (Feb 2012)

 

Glaucoma is increasingly becoming recognized as a manifestation of both ocular and systemic risk factors. Risk factors in addition to intraocular pressure (IOP) are increasingly being identified and play a critical role in the development and/or progression of glaucoma. Particularly in the lower ranges of IOP, a number of disorders associated with reduced blood flow and ischemia, collectively termed vascular risk factors, such as migraine, Raynaud's phenomenon, atrial fibrillation, and reduced nocturnal blood pressure, lead to decreased ocular perfusion pressure. During sleep, alterations occur in cardiovascular physiology that are balanced by auto-regulatory mechanisms to maintain homeostasis. However, in obstructive sleep apnea (OSA), the normal physiologic balance is upset, leading to hypoxia and sympathetic activation. OSA can range from mild to severe, and, therefore, its associations and their severity may depend on the severity of the sleep apnea. A potentially modifiable systemic risk factor, OSA has recently been increasingly associated with glaucoma, is independent of IOP. Through hypoxia-mediated damage to blood vessels and their compensatory mechanisms, OSA may alter blood flow to the optic nerve head and, in combination with other predisposing factors, lead to decreased ocular perfusion pressure. This in turn may directly affect the optic nerve or it may indirectly increase its susceptibility to other insults. The purpose of this review is to shed light on the association between OSA and glaucoma. © 2012 The Authors. Journal compilation © 2012 Royal Australian and New Zealand College of Ophthalmologists.

Dragon score for predicting success of thrombolysis pub in neurology

Objective: To develop a functional outcome prediction score, based on immediate pretreatment parameters, in ischemic stroke patients receiving IV alteplase.

Methods: The derivation cohort consists of 1,319 ischemic stroke patients treated with IV alteplase at the Helsinki University Central Hospital, Helsinki, Finland. We evaluated the predictive value of parameters associated with the 3-month outcome and developed the score according to the magnitude of logistic regression coefficients. We assessed accuracy of the model with bootstrapping. External validation was performed in a cohort of 330 patients treated at the University Hospital Basel, Basel, Switzerland. We assessed the score performance with area under the receiver operating characteristic curve (AUC-ROC).

Results: The DRAGON score (0–10 points) consists of (hyper)Dense cerebral artery sign/early infarct signs on admission CT scan (both = 2, either = 1, none = 0), prestroke modified Rankin Scale (mRS) score >1 (yes = 1), Age (≥80 years = 2, 65–79 years = 1, <65 years = 0), Glucose level at baseline (>8 mmol/L [>144 mg/dL] = 1), Onset-to-treatment time (>90 minutes = 1), and baseline National Institutes of Health Stroke Scale score (>15 = 3, 10–15 = 2, 5–9 = 1, 0–4 = 0). AUC-ROC was 0.84 (0.80–0.87) in the derivation cohort and 0.80 (0.74–0.86) in the validation cohort. Proportions of patients with good outcome (mRS score 0–2) were 96%, 88%, 74%, and 0% for 0–1, 2, 3, and 8–10 points, respectively. Proportions of patients with miserable outcome (mRS score 5–6) were 0%, 2%, 5%, 70%, and 100% for 0–1, 2, 3, 8, and 9–10 points, respectively. External validation showed similar results.

Conclusions: The DRAGON score is valid at our site and was reliable externally. It can support clinical decision-making, especially when invasive add-on strategies are considered. The score was not studied in patients with basilar artery occlusion. Further external validation is warranted.

Risk of warfarin association with bleeding with antibiotics

Baillergeon J. et al.  Am J Med 2012; 125:183-9.

 

Antibiotic (class)          odds ratio of bleeding (univariate/multivariate)

 

Azole antifungals             6.49/4.57

macrolides                      2.09/1.86

quinolones                      2.20/1.69

cotrimoxazole                 3.06/2.70

penicillins                       1.89/1.92

cephalosporins                2.85/2.45

 

Use of other meds

 

SSRI                               1.45/1.34

SNRI                               1.34/1.17

corticosteroid                   2.58/2.30

antiplatelet                       1.57/1.43

CYP2CP                          1.11/1.07

 

 

sICH after alteplase, on v. not on warfarin

Seet RCS et al.  Stroke 2011; 42:2333-2335

Authors highlight increased risk of alteplase in warfarin patients treated at a single site, irrespective of htn or stroke etiolgy, or INR . 

NNT and NNH with t-pa by time administered

Lansberg et al. Stroke 2009  meta-analysis of 6 stroke trials of t-pa.

Time to treat      NNT            NNH   (NNT= number needed to treat or number needed to harm)

0-90 minutes       3.6                65
90-180 minutes   4.3                38
180-270 min       5.9                30
270-360 min       19.3              14

Debates on Intracranial artery disease (ICAD) at ISC 2012, and imaging

Lessons from Sampris-- Wingspan stent trial was stopped due to more deaths in stent group.  However, issues that were brought out include that sites had inexperienced interventionalists with an average enrollment of 2 per site, total enrollment fairly small, plus criteria for enrollment was not (necessarily) ideal since we don't know who best candidates are.  One comment was that randomized trials if done too early (as here) retard innovation.

 

An  important finding of Sammpris ties in with the theme of the year, which is that medical management has improved. 2 year mortality of ICD declined from 20 percent in earlier trials to about 12 % in Sammpris.  The putative hero is aggressive 2011 medical management, with all it entails for tighter blood pressure control, tighter LDL-c reduction, attention to so called minor risk factors including metabolic syndrome, HDL, CRP and others.

 

One woman commented on her own "no metal " experience with angioplasty and made a case for a clinical trial with "no metal."  The main risk of failure was not seen in her series of series. (Thanh Nguyen).  Thereupon a discussion ensued about whether or not brain arteries are like coronary arteries where we already have learned so much.  Brain arteries have no external lamina are smaller caliber and more prone to perforation. 

 

Tom Brott opined that future trials of ICAD will need to compare procedures with new "best medical."

 

IMAGING

 

Debate again, is over what is best imaging protocol for stroke.  Data was presented that CT-P does NOT improve 90 day modified Rankin scores over regular noncontrast CT as a stratifier.  CT-P does add to time to catheter.  Time to order is a major delay point.  Whatever is used should be comfortable at facility. 

 

Purpose of extra procedures (advanced MRI or CT) is to exclude futile procedures and cases likely to hemorrhage (do no harm) as well as tell anatomy of occlusion to guide procedure. D-P mismatch, as last year, is not key, core infarct size is much more important (can tell best on MRI diffusion studies or possibly CBV). Exceptions are malignant pattern (see DEFUSE trial)  Evaluation of collateral flow is gaining prominence. One speaker commented that they still intervene on the ten percent that imaging says are futile. 

 

 

Dissection and i-v alteplase treatment

Quereshi et al.  Arch Neurol 2011; 68: 1536-42

Authors reviewed database finding about 1 % of 48,000 stroke patients had an underlying dissection. Alteplase was less effective in this stroke type in lowering disability, but the rates of hemorrhage were similar to other stroke types, and the lower outcome was not due to alteplase therapy.

Cognitive and Neurologic Outcomes after CABG

Selnes, Gottesman, ....McKhann.  NEJM 2012; 366: 250-7  Review article

Bullet points  STROKE
1.  1.6 % rate overall, but rate may increase 10x if radiographic/clinically silent CVA's included

2.  Mechanism of micro/macroemboli with cross clamping needs to be modified to include hypotension and inflammatory response.  Caplan et al , proposed the combination of hypotension and microemboli leads to more injury because microemboli aren't washed out as readily.

3.  risk factors for neurologic morbidity: age, DM, HTN, history of stroke  Others:  PREOPERATIVE FACTORS (and odds ratio) :  athero of ascending aorta (2.0), h/o of TIA/CVA (2.1); h/o of subcortical disease (4.1), carotid stenosis (5.3); PVD (2); DM (1.2 or 2.8);HTN (1.8 or 1.3);  high pulse pressure (1.1);prior cardiac surgery (1.4); smoking history (1.6).     OPERATIVE FACTORS:  Hypotension (8.4); manipulation of aorta (1.8); bypass time > 2 hours (1.4).    POSTOP FACTORS: AD (.8 to 2.6). (article gives references for each risk factor).

4.  PREVENTION:  Use of individualized factors, and use of preop or postop ASA which are both controversial.  Use of eipaortic ultrasound to guide decision to cross clamp.  Use of carotid screening preop.  Avoiding combined carotid/coronary procedures.  All of these ideas have limited data.  Operative monitoring with TCD or near infraredspectroscopy has been used. 

COGNITIVE DECLINE

Factors include:
1.  preop cognitive abilities/disabilities
2,  

Recovery after spinal cord infarcts; long term outcomes in 115 patients

Neurolgy 2012;;78: 114-121  Robertson, Brown, Wijdicks, and Rabinstein.  Mayo Clinic

Authors debunk myths of spinal cord infarcts.  Retrospective study of patients show many improved over time.  Among their findings

1.  Gradual improvement was common after hospital dismissal. More than half walked aided or unaided eventually.

2. One third of those catheterised at dismissal did not require catheter long term

3. MRI's were frequently normal initially and even occassionally on followup MRI

4.  ASIA A/B predicted a poor outcome, but not invariably.  Other predictors of poor outcome included absent Babinski sign, sensory level, longitudinally extensive MRI, and lesions in highest thoracic level.  NON RISK FACTORS included age, mechanism, gender were not predictive of a poor functonal outcome

5.  There was a fairly high early mortality, around 26 % that was associated with HTN, DM, smoking, PVD, severity of impairment, and age (ie traditional risk factors mostly).

6.  Pain especially back pain was a common initial finding and a common longterm problem of survivors.

Lacune subtypes and risk factors

Authors divided lacunes into very small (<3 mm) and small (3-7 mm) and larger (8-20 mm).  The hypothesized mechanism for very small lacunes and small lacunes was lipohyalinosis and larger lacunes was microatheroma. 

Risk factors for small lacunes (lipohyalinosis) in 1548 patients analyzed included age, African American race, HTN, diabetes, ever smoking.   HBA1C could be substituted for DM. 

Very small lacunes had similar risk factors as small lacunes.  Diabetes was key risk factor here.

8-20 mm lacunes (microatheroma) were associated with ever smoking, age, and LDL levels.

Conclusion is that diabetes leads to disorder of systemic microcirculation leading to very small lacunes.  LDL and smoking lead to microatheroma

Opioids: Might depress cerebral perfusion pressure

 

Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trials; Roberts DJ, Hall RI, Kramer AH, Robertson HL, Gallagher CN, Zygun DA; Critical Care Medicine 39 (12),

 

OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury. DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles. STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury. DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results. DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure. CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

 

Blogger note:  take home message is in bold above.  Until the definitive study is done, pay attention if, to nothing else, that one sentence.

Bevacizumab, metastasis, and brain hemorrhage, True, true and unrelated?

Intracranial hemorrhage in patients treated with bevacizumab: Report of two cases; Nishimura T, Furihata M, Kubo H, Tani M, Agawa S, Setoyama R, Toyoda T; World Journal of Gastroenterology 17 (39), 4440-4 (Oct 2011)

Treatment with bevacizumab, an antiangiogenic agent, in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan. Bevacizumab improves the survival of patients with metastatic colorectal cancer; however, it may lead to complications such as bleeding, which are sometimes fatal. Bevacizumab should be administered only after careful consideration because the potential risks of therapy outweigh its benefits. Therefore, pharmaceutical companies do not recommend bevacizumab therapy for patients with brain metastases. While some reports support the cautious use of bevacizumab, others report that it is not always necessary to prohibit its use in patients with metastases to the central nervous system (CNS), including the brain. Thus, bevacizumab therapy in colorectal cancer patients with brain metastases is controversial, and it is unclear whether brain metastases are a risk factor for intracranial hemorrhage during anti-vascular endothelial growth factor (VEGF) therapy. We report a 64-year-old man and a 65-year-old man with recurrent colorectal cancer without brain metastases; these patients developed multifocal and solitary intracranial hemorrhage, respectively, after the administration of bevacizumab. Our findings suggest that intracranial hemorrhage can occur even if the patient does not have brain metastases prior to bevacizumab treatment and also suggest that brain metastases are not a risk factor for intracranial hemorrhage with bevacizumab treatment. These findings also question the necessity of excluding patients with brain metastases from clinical trials on anti-VEGF therapy.

Blogger note:  Paper intrigues but any number of conclusions could be drawn out of it.  Larger experience is required.

Stroke centers and survival

Does primary stroke center certification change ED diagnosis, utilization, and disposition of patients with acute stroke?; Ballard DW, Reed ME, Huang J, Kramer BJ, Hsu J, Chettipally U; American Journal of Emergency Medicine (Nov 2011)

BACKGROUND AND PURPOSE: We examined the impact of primary stroke center (PSC) certification on emergency department (ED) use and outcomes within an integrated delivery system in which EDs underwent staggered certification. METHODS: A retrospective cohort study of 30 461 patients seen in 17 integrated delivery system EDs with a primary diagnosis of transient ischemic attack (TIA), intracranial hemorrhage, or ischemic stroke between 2005 and 2008 was conducted. We compared ED stroke patient visits across hospitals for (1) temporal trends and (2) pre- and post-PSC certification-using logistic and linear regression models to adjust for comorbidities, patient characteristics, and calendar time, to examine major outcomes (ED throughput time, hospital admission, radiographic imaging utilization and throughput, and mortality) across certification stages. RESULTS: There were 15 687 precertification ED visits and 11 040 postcertification visits. Primary stroke center certification was associated with significant changes in care processes associated with PSC certification process, including (1) ED throughput for patients with intracranial hemorrhage (55 minutes faster), (2) increased utilization of cranial magnetic resonance imaging for patients with ischemic stroke (odds ratio, 1.88; 95% confidence interval, 1.36-2.60), and (3) decrease in time to radiographic imaging for most modalities, including cranial computed tomography done within 6 hours of ED arrival (TIA: 12 minutes faster, ischemic stroke: 11 minutes faster), magnetic resonance imaging for patients with ischemic stroke (197 minutes faster), and carotid Doppler sonography for TIA patients (138 minutes faster). There were no significant changes in survival. CONCLUSIONS: Stroke center certification was associated with significant changes in ED admission and radiographic utilization patterns, without measurable improvements in survival.

 

Blogger note:  Small select group of stroke patients, those given alteplase, may be less than 5 percent of the total and are the only ones who would be expected to do better in primary stroke centers.  However, the target group is likely to be buried in the statistics of 15,000 patients reviewed.  This type of stroke center evaluation might be better suited for evaluating specific populations receiving specific treatments.

Which antihypertensive? Beta blockers risky

Webb et al.  Lancet 2010 375:905-915

Idea  BP variability is worse than absolute measurement of a high BP.  Certain drugs such as Beta blockers are associated with high variability and therefore higher risk, whereas Calcium channel blockers have less variability in BP and are therefore better for stroke prevention.  ACE inhibitors trend bad, ARBs slightly better.

lifestyle choices and stroke prevention risk

Chiuve et al. Circulation 2008; 118:947-954

43,685 men Health professionals followup study

71,243 women Nurses health study

Five factors:

1.  Not smoking

2.  healthy diet

3.  30 minutes per day vigorous activity

4.  Weight BMI< 25

5.  one alcoholic drink per day for women, 1-2 for men

80 percent reduction in risk, dose dependent on how many followed.

Partly related to secondary effects of above on blood pressure.  Amount of BP reduction per lifestyle aspect adopted

10 kg weight reduction= 5-20 mm HG

DASH eating plan 8-14 mm

dietary sodium restriction  5-8

physical activity 4-9 mm

moderate alcohol consumtpion 2-4 mm

Chobanian JAMA 2003; 289:2560

Every 10 mm   reduction in BP leads to a 31 % stroke risk

Lawes et al. Stroke 2004; 35:776

Carrascal and Guerrero- Stroke and CABG part II

from the Neurologist

Perioperative risk factors:
1.  CPB use and factors that are uncontrollable including low flow
2.  Type of procedure-- 3 fold risk in patients undergoing open chamber procedure.Combined procedures eg. CABG + valve causes baseline increase from 5 to 16 % or so
3.  Duration-- number of emboli increase by 90.5 % for every hour
4.  Postoperative complications including low CO (due to MI eg.) or postoperative AFIB which is common in first 4 days.

III Preventive Procedures--
 Operatively
A.  Minimize aortic manipulation -- one cross clamp not multiple, or even zero with pediculate anastomoses
B.  Heart Port Clamp-- instead of external clamp, use a saline filled balloon and clamp internally avoiding manipulation
C.  Identify aortic disease with epiaortic ultrasound; if needed use femoral or axillary catheterization and / or profound hypothermia.
D.  Use side hole not end hole cannulas-- less displacement of particle
E.  Use intraaortic filtration-- not shown to be beneficial YET
F.Dispersion aortic cannulas when friable valves are diagnosed
G.  Carotid surgery according to above criteria
H.  Prophylactic resection of atrial appendage in patients with preexisting AF who also need MVR

Reduce microemboli in CPB Circuit
A. heparin bound CPB circuit
B. Membrane rather than bubble oxygenator
C. CO2 sufflation into thoracic wound to decrease air bubbles
D.  Filter in arterial line; leukocyte filter to decrease inflammatory response
E.  Decrease CPB time
F.  Decrease cardiotomy suction to prevent lipid microemboli and improve cognitive; us ultrasound to help
G.  Early slow rewarming 0.2 degrees C per minute
H.  Alphastat protocol for pH and CO2
I.    Reduce perfusionists' interventions which are directly tied to cognitive decline
J.  Avoid collecting/reinfusing mediastinal blood
K.  Emblocker ultrasound transducer on aorta redirects debris to descending aorta, tried in animals so far

Prevention of ischemic injury
A.  Keep MAP> 50
B.  Avoid maneuvers that increase CVP (CPP = MAP-CVP)
C.  Avoid cardiac luxation during off pump procedures which can lower CO
D.  Pulsatile flow not shown to be superior to continuous flow
E.  Substitute Aprinin for amicar or transxemic acid
F.  Avoid profound hemodilution especially in octagenerarians

Metabolic
A.  Avoid hyperglycemia
B.  Keep HCT over 30

Neuroprotection
Summary
Many have been studied none have shown effective

Bypass and stroke Pt !

also see blog post regarding Lou Caplan's opinion regarding the issue http://strokenotes.blogspot.com/search?q=cabg

Carrascal Y, Guerrerro AL.  Neurological damage related to cardiac surgery; pathophysiology, diagnostic tools, and prevention strategies. Using actual knowledge for planning the future.  The Neurologist 2010; 16:152-164.

Summary-- the population undergoing cardiac surgery is older and sicker.  Prevention efforts should include improvements in surgical techniques and cerebral protection, pharmacotherapy, and adequate neuropsychologic assessments. 

Bullet points: Intro
1. 1-6 % of patients have neurologic complications, but number is up to 15 % in high risk group and up to 50 % if you count cognitive dysfunction.  Neurologic complications increase one year mortality tenfold in first year, and doubles ICU care time.  31 % of patients with neurologic damage return home, 75 % with "minor" cognitive damage, 85 % without neurologic damage. 

I.  Mechanism of damage in cardiopulmonary bypass:  emboli (micro or macro), inflammatory response, metabolic response to hypoxemia or vasogenic or cytotoxic edema, and cerebral hypoperfusion

A.  Emboli
1) Macro, > 200 um, related to manipulation of aorta, calcium, valvular debris.  Causes focal deficits. 
2) Micro, <200 um, due to a) air, related to opening chambers of heart, generation in CPB machine, and during patient rewarming   b)  lipids, especially due to cardiotomy suction especially with lipid reinfusion into CPB circuit   c)  cellular aggregate esp platelets     d)  Exogenous material from heart lung machine such as silicon.  Microemboli go to border zone, to basal ganglia and white matter tracts.  TCD detection of microemboli over 60 correlates with a 70 % risk of cognitive damage.  TCD does not detect type of particle.
Intraoperative TEE detects air bubbles in chambers and diseased arteries that can be avoided for cross clamping.  Aortic intimal thickening over 3 mm, especially with rounded, protruberant or ulcerated plaque is associated with a 4.5 x risk of neurologic sequelae.  Post op stroke is 25 % with a mobile plaque, 8 % with a fixed plaque, and 1.8 % if there is no plaque. 

B.  Inflammatory response activation-- duet to CPB, leads to a coagulation cascade and damage to blood brain barrier. 

C.  Disorders in Neuronal Metabolism secondary to hypoxemia or vasogenic or cytotoxic edema-- related to hypothermia during procedure, which has good and bad points, although mild hypothermia seems to benefit.  Severe may lead to brain edema.

D.  Hypoperfusion--

II Detection
A..Biochemical markers of neuropsychological damage-- adenylate kinase (good), CK-BB (bad marker, totally nonspecific), neuronal specific enolase (good marker, raised levels over 35 ng/ml after 48 hours correlates with bad prognosis, S100 B is a white matter marker, good marker more than 24 hours out (early rise occurs during CPB and is not prognostic) Level of > .5 ug/mL at 48 hours have a 78 % mortality compared to 18 % with a level under .5.  S100B < 1.1 24 hours after surgery has a 97 % specificity to exclude stroke. 
B. Imaging- DWi and NIRS (near infrared spectroscopy) show clinically silent events in a MAJORITY of patients or at least 50 %.  Fluroescein retinal angiography can detect clinically silent retinal events.  and disappear 7 days postop
C.  Neuropscyh-- Studies not clear.  Risk factors (incremental) include DM, CRF, ascending aortic atherosclerosis, CVD, PVD, or previous severe neurologic disease. 

III Major risk factors for complications
A. Age
B.  Carotid disease (controversial)-- this author suggests there is a 10 % reduction of stroke risk if the artery is symptomatic and stenosis is > 50 %.  For asymptomatic , procedure only if patient has life expectancy > 5 years, is 40-70, mortality of procedure < 3 %. 
C.  Prior stroke confers 13-15 % risk no matter when the prior stroke
D.  PVD increases risk of perioperative stroke by 4.5 %, and affects 33 % of octagenarians.
E. Severe LV dysfunction and poor EF
F. Indirect risk factors : DM, RF, HTN, COPD
G. Baseline intellectual function
H.  Genetic factors (apoE) unsettled
I Gender-- women do worse

see next post

Reconsidering MI as a contraindication for IV thrombolysis for stroke

De Silva DA et al.  Neurology 2011; 76:1838-1840. 

General points

1.  Some guidelines suggest 90 days not to use t-pa, but risk exists only in those with transmural MI (for cardiac rupture) and in those cases the wall is healed within 7 weeks, or at least healing, with fibrosis and scarring maximized by then,  to  mitigate risk in younger stroke patients without transmural rupture. 

2.  There are only 3 reports of 5 elderly women with tamponade after stroke thrombolysis. 

3.  In cardiac literature, wall rupture occurs in first 48 hours in those with transmural MI. 

Atraumatic convexal subarachnoid hemorrhage

Clinical presentations, imaging patterns and etiologies.  Kumar S. et al.  Neurology 2010; 74: 893-399

Authors include LR Caplan

Convexal SAH is about 8 percent of all SAH.  Authors found 29 patients at Beth Israel, about two thirds were women.  There was a dichotomy in presentation by age.  The under 60's had a strong tendency to present with a severe headache, whereas that was rare in the over 60's, who presented with TIA-like presentations, migraine creeping numbness mimic (even repetitively) or lethargy.  Angiography/MRA/CTA was almost always negative.  The under 60's were most likely to have reversible cerebral vasoconstriction syndrome (formerly Call syndrome), whereas the over 60's were more likely to have amyloid angiopathy. The latter group tends to have recurrent disease, but this study does not have good followup.  Headaches often were prolonged, associated with retching or vomiting, and described as "thunderclap" in younger patients.  Surface eeg's were always negative for seizures among those presenting with repetitive sensory phenomena.  They were more likely to have superficial siderosis on imaging.

The differential of the presentation includes, in addition to the two above causes, cortical vein occlusion, PRES, coagulopathy, cocaine, lupus vasculitis, cavernoma, brain aneurysm, ephedra, HELLP syndrome, post LP headache, and arterial dissection.

Activated prothrombin complex for dabigratan bleed? one opinion

We recently had a 67-year-old man with atrial fibrillation who was
admitted from the EP lab after developing pericardial hemorrhage during
the procedure.  He had been taking dabigatran and had received his last
dose seven hours prior to the procedure.  He was undergoing an ablation
when a transseptal perforation occurred and hypotension ensued.  He had
received  5000 units of heparin prior to the start of the procedure.
Pericardiocentesis was undertaken and 4500 cc of blood was withdrawn.  He
was given two units of FFP  & Protamine 100 mg  with persistent bleeding.
He was then given  FEIBA (activated prothrombin complex) 3159 units (26
units per kilogram over 15 minutes).   One minute after initiating FEIBA
infusion slowing of the bleeding was observed.  Bleeding stopped from
pericardiocentesis within minutes of administration of FEIBA.  His PTT the
prior to the procedure was 53.  ACT prior to administration of heparin was
233. The PTT decreased to 35 after protamine infusion but prior to the
FEIBA administration, and decreased further to 29 following FEIBA. ACT
decreased to 131 following FEIBA.

Our single experience would suggest that FEIBA was effective in reversing
the anticoagulant effect of dabigatran.  I wonder if any others have had
an opportunity to use this treatment and what their experience has been?
Has anyone used other ways of reversing dabigatran and with what success?

normal thrombin time and dabagitan

(reprinted not practice in our facility)

A normal thrombin time essentially rules out any anticoagulant effect due to Dabigatran. Thrombin time is a widely available and inexpensive test. For patients known or suspected to be on Dabigatran, our stroke team policy is to consider treatment with IV-t-PA only when thrombin time is normal.

CADASIL typical temporal lobe imaging involving temporal pole

SAMMPRIS trial stopped

CLINICAL ALERT

The National Institute of Neurological Disorders and Stroke (NINDS) has stopped enrollment in a clinical trial that is evaluating whether intracranial angioplasty combined with stenting adds benefit to aggressive medical therapy alone for preventing stroke in patients with symptomatic intracranial arterial stenosis. The Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) study is the first prospective randomized multicenter trial to compare aggressive medical management alone versus aggressive medical management plus angioplasty combined with stenting in patients with symptomatic high grade (70-99%) stenosis of a major intracranial artery (intracranial carotid, middle cerebral artery, intracranial vertebral artery, and basilar artery).

Full NINDS Alert (PDF)

billing code for administering alteplase by MS

You can use the CPT code 37195 if you are personally at the bedside while
> the tPA is given by a physician. 

Lambl's excrescences and fibrous strands

The serpentine mitral valve and cerebral embolism

James Ker

Cardiovascular Ultrasound 2011, 9:7 

 

Vilem Dusan Lambl, a Bohemian physician (1824-1895) were the first to describe the occurrence of small, filiform processes he observed on the aortic valve in 1856[5] . Today, these Lambl's excrescences are also referred to as valvular strands and have been observed on all native and prosthetic valves[5] . These strands may occur as single strands, in rows or even in clusters[5] . They can vary in length from 1 mm to 10 mm and are usually less than 1 mm in thickness[5] .

Valvular strands are composed of a fibroelastic, avascular core, covered by a layer of endothelial cells[5,6] .

The exact pathogenesis of formation of these structures are still unclear, however current opinion is that the initiating factor is that of an endocardial lesion in areas of trauma and/or high shear stress[5,6] . These denuded areas are then covered by fibrin with subsequent covering by an endothelial layer[5,6] . The prevalence of valvular strands has been estimated as 5.5% in a general population referred for transesophageal echocardiography and 40% in patients with stroke of unknown cause[1,2] .

The differential diagnosis for valvular strands includes the following[5] : a myxoma, thrombi, valvular vegetations, nonbacterial thrombotic (marantic) endocarditis, cardiac metastases, a fibroelastoma and other primary cardiac neoplasms.

Of all of the above, the most difficult distinction is that between a valvular strand and a fibroelastoma[5,7] . Histologically, these two entities are very similar with both containing a central core of elastic connective tissue, covered by endothelium. However, valvular strands are covered by a single layer of endothelial cells, but fibroelastomas contain regions of multiple layers of endothelial cells[5,7] .

Echocardiographically, fibroelastomas are more bulky, with stalks or pedestals sometimes present and multiple, fingerlike projections on their surface[5] . As fibroelastomas are usually found on the mechanically less strained parts of valves and endocardium they tend to be larger than valvular strands[5] . Valvular strands (Lambl's excrescences) are always found on the affected valve's line of closure and this limits their growth[5] .

Several published case reports have shown that valvular strands are associated with emboli to the coronary, pulmonary, spinal, retinal and cerebral circulation[1] .

Specifically regarding stroke, numerous reports have demonstrated an association with valvular strands, particularly in young patients[3,4,8,9] . The mechanism for embolic events is either that of thrombi forming on the strands which then embolize or it is possible that the valvular strand itself can embolize[2] . Direct visualization of thrombus on a valvular strand have indeed been described before[10] .

In conclusion, a case of a valvular strand, attached to the coapting edge of the mitral valve is presented, giving a serpentine appearance to the mitral valve. This valvular strand was the cause for a cerebral embolism which presented with a transient right sided hemiparesis. This is the only current case in the literature, where the combination of aspirin and clopidogrel is used for the prevention of further episodes of cerebral embolism. In the only randomized treatment study to date, no difference in relation to efficacy of warfarin compared to aspirin was found in patients with valvular strands and previous embolic episodes[2] . For this reason a combination of antiplatelet therapy was initiated as a therapeutic trial.

It is proposed that a randomized controlled study involving the combination of aspirin and clopidogrel is warranted in patients with valvular strands presenting with a first episode of cerebral embolism.

1. Wolf RC, Spiess J, Vasic N, Huber R: Valvular strands and ischemic stroke.

   Eur Neurol 2007, 57:227-231.

   Homma S, Di Tullio MR, Sciacca RR, Sacco RL, Mohr JP: Effect of aspirin and warfarin therapy in stroke patients with valvular strands.

2. Stroke 2004, 35:1436-1442.

   Freedberg RS, Goodkin GM, Perez JL, Tunick PA, Kronzon I: Valve strands are strongly associated with systemic embolization: A transesophageal echocardiographic study.

3. J Am Coll Cardiol 1995, 26:1709-1712.

   Roberts JK, Omarali I, Di Tullio MR, Sciacca RR, Sacco RL, Homma S: Valvular strands and cerebral ischemia. Effect of demographics and strand characteristics.

4. Stroke 1997, 28:2185-2188.

   Jaffe W, Figueredo VM: An example of Lambl's excrescences by transesophageal echocardiogram: A commonly misinterpreted lesion.

5. Echocardiography 2007, 24:1086-1089.

   Roldan CA, Shively BK, Crawford MH: Valve excrescences: Prevalence, evolution and risk for cardioembolism.

6. J Am Coll Cardiol 1997, 30:1308-1314.

   Gowda RM, Khan IA, Nair CK: Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases.

7. Am Heart J 2003, 146:404-410.

   Lee RJ, Bartzokis T, Yeoh TK, Grogin HR, Choi D, Schnittger I: Enhanced detection of intracardiac sources of cerebral emboli by transesophageal echocardiography.

8. Stroke 1991, 22:734-739.

   Tice FD, Slivka AP, Walz ET, Orsinelli DA, Pearson AC: Mitral valve strands in patients with focal cerebral ischemia.

9. Stroke 1996, 27:1183-1186.

   Nighoghossian N, Derex L, Loire R, Perinetti M, Honnorat J, Riche G, Barthelet M, Ninet J, Chazot G, Chassignolle J, Trouillas P: Giant Lambl excrescences.

10. Arch Neurol 1997, 54:41-44.