Tenecteplase v altepalse

Campbell BCV et al. Tenecteplase versus altepalse before thrombectomy for ischemic stroke.  NEJM 378: 1573-1582.

Tenecteplase is more fibrin specific and has longer activity than alteplase.  101 patients were assigned to .25 mg/kgof tenecteplase and 101 to 0.9 mg/kg alteplase within 4.5 hours of onset.  . The primary outcome was repercussion of more than 50 percent of the involved ischemic territory or absent retrievable thrombus at time of angiography.  Secondary outcome was mRS at ninety days.  

Primary outcome was achieved in 22 % of tenecteplase patients, ten percent of altepalse patients p= 0.002, clinical difference of twelve percentage points.  sICH occurred in  1 percent of each group.  90 day mRS was also better , 2 v. 3 (p=0.04).  

EXTEND 1A, NIH sponsored trial.  

editorial  Baird AE. Paving the way for improved treatment of acute stroke with tenecteplase. NEJM  378:  1635-6.  

Notes that alteplase helps only a small portion of the patients with large clots, so time between tap and groin puncture is key.  Drug has a long half life, can be administed as a bolus,  doubled the rate of recanalization and averted the need for some thrombectomies. This is a second phase two trial and a phase 3 trial is needed.

In a study of patients with mild stroke who were not expected to proceed to thrombectomy,  superiority of tenecteplase at a dose of .4 mg/kg  v. alteplase was NOT shown.    Additional ongoing trials including TASTE and ATTEST2  have not reported.  Campbell also did NOT show a decrease between thrombolysis and thrombectomy in tenecteplase treated patients in another trial.

Management of antiphospholipid syndrome-- pearls

from Garcia D. and Erkan D. Diagnosis and management of the antiphospholipid syndrome. NEJM 378; 2010:2021.  

1.  Ten percent of healthy blood donors are positive for apl  antibodies and one percent are positive for lupus anticoagulant; however after one year, only one percent remain positive, so rechecking titers is key. Its rare for a truly healthy person to  remain positive. Transient apl is common during infections.

2.  Prevalence by underlying condition of persisting moderate to high risk apl antibody profiles:  SLE, 20-30 percent;  women with pregnancy complications, six percent;  patients with venous thrombosis, ten percent;  MI, 11 percent; patients less than fifty with stroke, 17 percent.  

3.  Clinical presentation pearls: among pregnant women, most occur after ten weeks of pregnancy (those in earlier period more likely have genetic anomalies causing miscarriage).  Patients with venous thromboembolism most likely have lower extremity or pulmonary emboli.  

4.  Other clinical features include pulmonary hypertension, livedo reticularis, thrombocytopenia, hemolytic anemia, acute or chronic renal vascular lesions, and moderate or severe cognitive impairment.  

5.  Other lab features to note:  LA test best correlates with clinical events, but may be misleading among patients on warfarin or DOACs.  For ELISA, moderate to high titers ( greater than 40 GPL or 99th percentile of cal or anti B2GP1correlate better with outcomes than lower titers; IgG is more strongly associated with bad clinical events than IgA.  

6. Treating traditional risk factors and avoiding estrogen  is very important.

7.  Anticoagulation for primary prevention or use of aspirin for primary prevention is still controversial.  For patients with persistent apl syndrome and provoked thrombosis, eg. by surgery, or for those with impersistent apl ab's, the benefit of prolonged anticoagulation is "less certain."  

8. Treatment of "warfarin failures" is not known, but options include high intensity warfarin to INO 3-4, addition of aspirin or plaquenil or statin, use of a different anticoagulant such as a  LMWH or a combination.  There is insufficient evidence about DOACs.  

9. Catastrophic apl syndrome includes ARF, ARDS and adrenal hemorrhage.  Diagnosis is definite with involvement of three or more organs and a persistently positive test.  Early treatment with anticoagulants, steroids, IVIG and PLEX is indicated.  

10. Treatment in pregnancy is with low quality evidence, use of low dose aspirin and LMWH,  

if platelets are more than 50 K, no acute therapy

if platelets are more than 20 K, first line is steroids and IVIG not splenectomy

for warm mediated HA steroids are used first

ARF with thrombotic microangiopathy is usually treated with PLEX

Valve disease with high risk use ASA or warfarin for high risk vegetations

APS criteria-- once clinical event (venous or arterial) and/or fetal loss after ten weeks and/or 3 sequential miscarriages before 10 weeks  AND either present LA, ACL ab, or antiB2glycoprotein

Rivaroxabin for stroke prevention after embolic stroke of undetermined source

Hart RG. Rivaroxabin for stroke prevention after embolic stroke of undetermined source.  NEJM; 378: 2191-2201.  

Study tested  15 MG rivaroxaban v. 100 mg of aspirin with presumed embolic but undetermined source, with no arterial stenosis,lacunae or identified cardioembolic source.7213 patients were enrolled at 459 sites. Study was halted at eleven months with non superiority. Primary outcome was recurrent ischemic or hemorrhage stroke and primary safety measure was bleeding.   Recurrent stroke was 4.7 percent is both groups.  Bleeding occurred in 1.8 percent of rivaroxaban group, 0.7 percent of aspirin group ( p<0 .001="" a="" and="" bleeding.="" div="" effective="" had="" higher="" more="" nbsp="" not="" of="" onclusion:="" rate="" rivaroxaban="" was="">

NAVIGATE ESUS trial-- New approach rivaroxaban inhibition of factor Xa in a global trial versus aspirin to prevent embolism in embolic stroke of undetermined source.

The primary outcome of any stroke or systemic embolism slightly and non significantly favored rivaroxaban (5.1 v. 4.8 percent) There were hemorrhagic strokes in 0.4 v. 0.1 in respective groups (statistically significant but low effect size).  

Atrial fibrillation was not excluded prior to randomization.  About 12 percent of patients with cryptogenic stroke have undiagnosed atrial fibrillation.  PFO's were excluded. 

Comment-- Study is conclusive for unselected group, but what about for selected group with an educated guess of etiology? That could happen through selection of patients with certain ECHO characteristics , for example  left atrial hypertrophy or intracranial stenosis.  While one may argue that would be overkill to do the study, in the prior negative warfarin studies (WASID) patients never maintained their INR's within range..  

Power was very high to determine outcome.  Risk of stroke in first 11 months was about five percent.  

Risk of stroke after a TIA

Amarenco P., et al.  Five year risk of stroke after TIA or Minor ischemic stroke. NEJM; 378: 2182-2190.

Methods: TIA registry from 2009-2011, 21 countries, 4789 patients.  Outcome was composite ischemic brain or heart or death.  

results rate of stroke,coronary syndrome or death was 6.4 percent in the first year, 6.4 percent infers 2-5.  ABCD2 score predicted a higher rate of stroke if score was greater than or equal to 4.  The presence of a brain lesion on imaging was not important. 

POINT trial

Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high risk TIA.  NEJM; 379:215-225  

Gotta, JC.  Antiplatelet therapy after ischemic stroke or TIA. NEJM 379:291 (editorial)

Chinese trial (CHANCE) previously showed a benefit of dual anti platelets in a Chinese population for a short period after stroke.  This study was a  RCT 1:1 of minor ischemic stroke  (NIHSS of 3 or less) or high risk TIA (ABCD2>4) to receive clopidorel loading dose (600 mg on day one, then 75 mg per day) plus aspirin 50-325 mg po daily (dual anti platelets or DAP), v. aspirin alone.  Primary outcome was the risk of composite ischemic events (Stroke, MI, or CV death). 4881 patients at 269 sites internationally.  After 84 percent enrollment, the trial was halted when trial showed less major ischemic events AND higher risk of major hemorrhage at 90 days than mono therapy.  The effect size was fairly small, with 6.5 % risk in DAP, 5.0 % in aspirin alone.  Major hemorrhage occurred in 0.9 % of DAP, 0.4 percent of aspirin alone. This was a ninety day trial.  

Commment- basic math shows 1.5 percent less major ischemic events, 0.5 percent more major hemorrhage with DAP.  Previously Chinese trial (CHANCE) showed 32 % decreased stroke recurrence with DAP and no increased hemorrhages.

James Grotta- Most of the prevented events were ischemic strokes arguably the most important outcome after TIA/minor stroke.  Most of the bleeding were systemic, nonfatal,nonintracranial hemorrhages.  Most of the benefit occurred int he first week, most of the hemorrhages occurred later.  DAP should be confined to a limited time, eg. the first three weeks.  

Candidates for neuroprotective trials

1. Hypothermia
2. Caspace inhibitors (none tried yet due to irreversibility)
3. Hypoxic preconditioning (how would this study be done?)
4. Magnesium antiexcitotoxin, inhibits inflammation, reduces infarct volume six hours late
5. Minocycline
6. Enlimomab
7. FK506
8.

Clinical trials: DEDAS

DEDAS dose escalation study of desmoteplase in acute ischemic stroke -- twin study to DIAS. phase 2 trial for safety and efficacy among patients with P/D mismatch on mRI 3-9 hours after onset of acute ischemic stroke. (Tony Furlan). 39 patients, doses 90 and 125 ug/kg, NIHSS baseline 4-20. There were no sICH cases Reperfusion occurred in 37.5 %, including 18 % of lower dose patients and 53% of higher dose patients. Good outcome occurred in 25 % of placebo, 28 % of lower dose patients, and

Clinical trials LIFE

Losartan v. atenolol-- looked at hypertensive stroke patients with LVH. Losartan prevented morbidity and mortalityin the group, but the effects were small.

CONTINUUM STROKE PREVENTION risk factors, AF

This next series of posts designates pearls taken from Continuum education series and designed to assist preparation for vascular neurology boards. Again, many commonly understood ideas won't be blogged, only those on the fringe or confused commonly need to be blogged, so the posts may seen disjointed, but it has a purpose.

Nonmodifiable risk factors for stroke: age (doubles per decade after 55), sex (24-30% greater in men), race (2.4 fold increase for African Americans, 2 fold in Hispanics, increased in Chinese), and heredity (1.9 fold with positive family history).


Modifiable risk factors

Hypertension affects 50 million people in US, and population-attributable risk for stroke is 40 % depending on age group. In Framingham, htn > 160/95 had an age adjusted relative risk of stroke of 3.1 for men, 2.9 for women (Kannel 1970). Isolated systolic htn is also a risk factor. Dutch study showed similar. Linear relationship of stroke to bp occurs down to 115/75. JNC created a category of "prehypertension." Its defined as 120-139/80-89. These should be treated.

Atrial fibrillation
Prevalence of stroke in age>65 is 6 %. Attributable risk increases with age. In Framingham the relative risk was 20 x in patients with valvular disease + AF and 5 x in patients with AF alone. (Wolf et al 1991), which is independent of age hypertension, and other cardiac abnormalities. SPAF (Stroke in AFIB) trials clarified. SPAF studied nonvalvular afib only. SPAF I randomized to placebo, ASA or warfarin. Placebo stroke risk was 6 % per year. High risk patients were those with htn, chf, prior stroke or tia, systemic emboli, or women over 75, or LV dysfunction or increase left atrial size. SPAF III found low risk patients as defined above had stroke risk of 2 % per year on ASA and a disabling stroke risk of .8% per year. Patients with htn who were moderate risk had intermediate risk (3.6 per year). Framingham derived study based on new AF not treated with warfarin created a risk stratification model to predict 5 year risk of stroke. from JAMA 2003:
Assign points for different conditions
age <59>Points Five year risk,%

0-1 5
2-3 6
4 7
5 8
6-7 9
8 11
9 12
10 13
11 14
12 16
13 18
14 19
15 21
16 24
17 26
18 28
19 31
20 34
21 37
22 41
23 44
24 48
25 51
26 55
27 59
28 63
29 67
30 71
31 75

African Americans have less atrial fibrillation

Von Willebrand's disease and other bleeding disorders

VWD

Ristocetin induces platelet activity and is used to diagnose von Willebrand's disease, which is most common inherited bleeding/coagulability disorder. Reduced levels of platelet aggregation are seen in vwd in association with ristocetin antibiotic presence.

type 1, 3 -- quantitative defect of VWF
type 2- qualitative defect of VWF

Rx: desmopressin or plasma concentrates c Factor VII and VWF

Bernard Soulier- May Hegglin's anomaly, gray platelet syndrome, inherited giant platelet disorder with thrombocytopenia and bleeding

Hemohilia A-- deficient factor VIII (more common)
Hemophilia B (deficient factor IX ) Christmas disease

spot sign

DVT prophylaxis in cerebral hemorhage

Zubkov AY, Wijdicks EFM Reviews in Neurological Diseases 2009; 6:21-25.

DVT occurs in 55 % of patients with acuts stroke and 5 % of early deaths in this group. Clinically apparent DVT occurs in 1.8 to 5 % of patients with ischemic stroke, subclinical in 28-73 %. In ICH, risk is similar; 15.9 % had DVT at 10 days among those wearing stockings. LE doppler is insensitive (misses many cases). 30 % of patients with PE do not show signs of lower extremity DVT. ACCP (2004) suggested mechanical means to prevent DVT, discouraged LMWH, and left heparin at discretion of practitioner. A meta-analysis in 2000 showed 45 % RR among neurosurgical patients receiving heparin. Only one RCT done shows 85 % reduction in DVT in heparinized patients (J Neurosurg 1978).

Statins enhance collateralization in acute stroke

Ovbiagele B Saver JL, Starkman S et al. Neurology 2007; 68: 2129-2131.

Mendelsohn maneuver for stroke

The Mendelsohn maneuver is taught by having the patient place


their fingers lightly over the thyroid cartilage and then trying to

swallow. When the thyroid cartilage reaches the top part of its

elevation during the swallow the patient is supposed to try to keep it

in this position for a second or two. The crycopharyngeus upper

esophageal sphincter is stretched by this excursion and is mechanically

opened. There may also be some reflex inhibition of the sphincter, but

the benefit is probably mostly mechanical. Logeman's book on dysphagia

has a much better description.