IVTPA. In 1996 IVtPA was approved by FDA, this is the only FDA approved medication for the setting of acute stroke but only around 5% of patients with acute ischemic stroke receive IVtPA. Why? Several reasons: delay to come to ER, delay in evaluation by ER physician, delay in radiology and labs, liability concerns by physicians, and lack of confidence regarding correct diagnosis by physicians without having MRI. In fact, with more education of general population, not giving IVtPA in appropriate settings could cause liability for the managing physician. Multiple studies confirmed IVtPA is beneficial; 39% achieved minimal or no disability at 3 months, although survival is basically the same in both groups (due to higher risk of ICH in tPA group). Giving the medication faster has a better outcome (even within th first three hours). There are some contraindications, which you can see AHA website, but some of these are relative contraindication. For example a patient with stroke after minor surgey or heart cath still can have thrombolytic therapy if one makes sure he/she is able to control bleeding. Some stroke syndromes such as isolated aphasia, hemianopia or hemineglect are not minor symptoms and they could cause severe disability if they persist. Minor stroke means pure sensory symptoms, isolated facial droop, and isolated disarthria. Also age is not a contraindication. Stroke patients with recent major surgery may have Intra-arterial tPA or MERCI device, they should be transferred to the facilty with this equipments within 6 hours. In case of patient with acute stroke and seizure, if one is sure the weakness is not a Todd's paralysis, still IVtPA can be given safely. Regarding CT exclusions, subtle changes should not be used for exclusion based on current evidence, changes should be clear in a large area (such as greater than one-third MCA territory). Do we need consent for IVtPA? Consent is not required for IV tPA as it is considered the standard of care. However, discussion with the patient and/or family is important.
How to give tPA? First, make sure you have Alteplase not [r-PA (reteplase) or TNK (tenecteplase)]. Rapid access to the drug is recommended. Preferably tPA should be stored in the ER. The drug is mixed in a 1:1 dilution with provided sterile water (normal saline is acceptable as well) with gentle swirling, but not shaking. Dosing for acute ischemic stroke is 0.9 mg/kg (maximum of 90 mg). Ten percent is administered as a bolus over 1 minute, and the remainder is given infusion over 60 minutes. It should be noted that this is lower than the MI dose of 1.1 mg/kg, as there is concern that the risk of symptomatic intracranial hemorrhage would be high with the cardiac dose.
Patient Monitoring During/After Treatment: Prevention of bleeding both during the tPA infusion and in the first 24 hours after administration. Frequent monitoring of vital signs, clinical and neurologic status is recommended. Typically, the patient is assessed every 15 minutes during the t-PA infusion, every 30 minutes for the next 7 hours, and every hour for the next 16 hours. Blood pressure greater than 180/105 mm Hg after tPA must be treated aggressively. Changes in clinical status of particular concern are worsening of the neurologic deficit, a new neurologic deficit, new or worsening headache, or nausea/vomiting. These symptoms should lead to prompt discontinuation of t-PA (if still infusing) and emergent CT scan to rule out bleed. If there is no bleed, the t-PA infusion may be reinitiated and efforts to provide symptomatic relief are appropriate.
IVtPA beyond 3 hours (<4.5h) Exclusion criteria included age greater than 80 years (2) Severe stroke (NIHSS score greater than 25) and history of taking coumadin/anticoagulation, in addition to general exclusion for IVtPA below 3 hours. Even in this group tPA was significantly associated with a favorable outcome at 3 months . Symptomatic intracranial hemorrhage was more frequent in the treatment group (2.4% Vs. 0.2%). Mortality was similar for both groups. IV tPA given 3 to 4.5 hours after the onset of stroke symptoms was associated with a modest but significant improvement in clinical outcomes. The findings of the ECASS III trial confirm the safety and efficacy of IV tPA for acute ischemic stroke. The emphasis should remain on treating patients with acute ischemic stroke as quickly as possible.
High dose albumin after IV tPA, IV/PO Minocycline (3-10 mg/kg) in acute ischemic stroke with or without tPA, IV Mg in acute stroke, IV/PO Citicholin, Hypothermia, Sonothrombolysis (tPA and TCD). These are very exciting but needs more time to discuss.
CASE 1 : A 59 y-old man, with a hx of DM, HTN and obesity, OSA, woke up at 7.00 AM with dense right sided weakness. His wife called EMS and was brought to hospital in one hour. Immediately head CT was done andwas negative for any bleed. Patient is progressively getting worse. On exam his BP 210/110, very agitated having conduction aphasia, left gaze deviation with right homonymous hemianopia dense right hemiplegic (0/5 upper and lower) with right upgoing toe. His glu was 250. What would you do next?ž
1. Order Brain MRI stat
2. Since he woke up with stroke, the onset is unknown, no TPA is indicated. Start him on ASA +/- Plavix
3. Transfer him to higher level of care for possible intra-arterial tPA
4. Aggressive control of BP with IV labetalol and nicardipin, if BP<=180/110, consider IVtPA
Although all of the above answers could be correct, MRI of the brain most likely will show an ischemic stroke at the distribuation of left MCA, but will waste more time. Although the actual onset of stroke is unclear, but the CT of the head is negative, that means most likely stroke was less than 4-5 hours. Also the option of intra-arterial tPA is correct, though another 1-2 hours delay may occur. After explaining the risks and benefits of the IVtPA in this particular setting, first his BP successfully was controlled Alteplase was given with very close monitoring. He had a CT immediately after infusion with no interval bleed. First, his gaze deviation resolved in 1 hour, his aphasia resolved in 3 hours, his right leg weakness was 4/5 at 24h, and right hand weakness was 2/5 at 48 h. Patient was discharged to rehab 3 days later. In support of this case, in a recent study of Dr. Grotta in forty-six thrombolysed and 34 nonthrombolysed Wake-Up-Stroke (WUS) patients, sixty-one percent (28/46) of the treated WUS patients underwent intravenous thrombolysis alone whereas 30% (14/46) were given only intra-arterial thrombolysis. Four patients received both intravenous and intra-arterial thrombolysis (9%). Two symptomatic intracerebral hemorrhages occurred in treated WUS (4.3%). Controlling for NIHSS imbalance, treated WUS had higher rates of excellent (14% vs 6%; P=0.06) and favorable outcome (28% vs 13%; P=0.006), but higher mortality (15% vs 0%) compared to nontreated WUS. A second comparison controlling for baseline NIHSS between treated WUS and 174 intravenous tissue plasminogen activator patients treated within 3 hours of symptoms showed no significant differences in safety and clinical outcomes. Conclusion— Thrombolysis may be safe in WUS patients. Our center’s experience supports considering a prospective, randomized trial to assess the safety and outcome of thrombolysis for this specific patient population.
When do we need intervention in Asymptomatic Carotid Stenosis (ACS)?
CASE 2 . Patient a 57 year old woman with a history of diabetes, DM neuropathy, HTN and CAD presented with acute slurred speech and visual disturbance. She has alexia without agraphia. Her CT was unremarkable, brain MRI was ordered 2 days later due to persistence of her symptoms, it showed a DWI abnormal signal at splenium of corpus callosum. As part of work-up for stroke a carotid doppler was done and showed a moderate 60% stenosiss of the right carotis artery. Would you do CEA or stent in this patient based on her symptoms? Even though patient did have a stroke, but that was not related to her carotid system (splenium of corpus callosum blood supply is from posterior cerebral artery (PCA), so this case is an asymptomatic carotid stenosis. Other examples, patient with vertigo and unilateral carotid stenosis of 80% is still asymptomatic. In a recent and interesting study regarding the best treatment for asymptomatic carotid stenosis (ACS), (Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis J. David Spence, et al, Arch Neurol. 2010;67(2):180-186.) Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity were evaluated. Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm2 (SD, 96 mm2) to 23 mm2 (SD, 86 mm2) (P < .001). In summary,cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD. Arch Neurol. 2010;67(2):143-144
CREST, STENT or CEA ? Now the question is if we really need intervention (mostly in cases of symptomatic carotid disease) what intervention is the best? Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) had the answer. CREST compared the safety and effectiveness of CEA and CAS in symptomatic and asymptomatic patients. The overall efficacy of the two procedures was similar. There was more MI in the surgical group, 2.3 percent compared to 1.1 percent in the stenting group; and more strokes in the stenting group, 4.1 percent versus 2.3 percent for the surgical group in the weeks following the procedure. Role of age: At age 69 and younger, stents were slightly better, for patients older than 70, surgical results were superior to stent.
New medication for stroke prevention in certain patients with atrial fibrillation:
18113 patients randomly assigned to 110 mg or 150 mg dabigatran (Pradaxa) twice daily or to warfarin dose adjusted to international normalised ratio 2·0 to 3·0. Patients and investigators were aware of whether patients received warfarin or dabigatran, but not of dabigatran dose. Within the subgroup of patients with previous stroke or transient ischemic attack, 1195 patients were from the 110 mg dabigatran group, 1233 from the 150 mg dabigatran group, and 1195 from the warfarin group. Stroke or systemic embolism occurred in 65 patients (2·78% per year) on warfarin compared with 55 (2·32% per year) on 110 mg dabigatran and 51 (2·07% per year) on 150 mg dabigatran. The rate of major bleeding was significantly lower in patients on 110 mg dabigatran (RR 0·66, 95% CI 0·48-0·90) and similar in those on 150 mg dabigatran (RR 1·01; 95% CI 0·77-1·34) compared with those on warfarin. The effects of both doses of dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischaemic attack and those without for any of the outcomes from RE-LY apart from vascular death (110 mg group compared with warfarin group, interaction p=0·038). The effects of 110 mg dabigatran and 150 mg dabigatran twice daily in patients with previous stroke or transient ischaemic attack are consistent with those of other patients in RE-LY, for whom, compared with warfarin, 150 mg dabigatran reduced stroke or systemic embolism and 110 mg dabligatran was non-inferior. Of note Pradaxa dose must be adjusted in renal patients. (Lancet Neurology 2010 Dec;9(12), 1157-63 Therapeutic Hypothermia: Many clinical trials showed a significant improvement of neurological outcome after restoration of circulation in some forms of cardiac arrests such as V-fib. Still TH is underused in most hospitals and in not a routine protocol in emergency rooms. There are ongoing researches in regard to TH in patients with acute ischemic stroke as well. References: Levine, Steven R.; Adamowicz, David; Johnston, Karen C.PRIMARY STROKE CENTER CERTIFICATION.,CONTINUUM: Lifelong Learning in Neurology. 14(6) Acute Ischemic Stroke:98-116, December 2008. Khatri, Pooja; Levine, Joshua; Jovin, Tudor. INTRAVENOUS THROMBOLYTIC THERAPY FOR ACUTE ISCHEMIC STROKE.CONTINUUM: Lifelong Learning in Neurology. 14(6) Acute Ischemic Stroke:46-60, December 2008., Spence D, et al . Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis, Arch Neurol. 2010;67(2):180-186 Hopkins LN, et al, The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase , J Stroke Cerebrovasc Dis. 2010 Mar;19(2):153-62. Therapeutic Hypothermia after cardiac arrest. Scirica BM, et al. Circulation 2013
Many clinical trials showed a significant improvement of neurological outcome after restoration of circulation in some forms of cardiac arrests such as V-fib. Still TH is underused in most hospitals and in not a routine protocol in emergency rooms. There are ongoing researches in regard to TH in patients with acute ischemic stroke as well.
References: Levine, Steven R.; Adamowicz, David; Johnston, Karen C.PRIMARY STROKE CENTER CERTIFICATION.,CONTINUUM: Lifelong Learning in Neurology. 14(6) Acute Ischemic Stroke:98-116, December 2008. Khatri, Pooja; Levine, Joshua; Jovin, Tudor. INTRAVENOUS THROMBOLYTIC THERAPY FOR ACUTE ISCHEMIC STROKE.CONTINUUM: Lifelong Learning in Neurology. 14(6) Acute Ischemic Stroke:46-60, December 2008., Spence D, et al . Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis, Arch Neurol. 2010;67(2):180-186 Hopkins LN, et al, The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase , J Stroke Cerebrovasc Dis. 2010 Mar;19(2):153-62. Therapeutic Hypothermia after cardiac arrest. Scirica BM, et al. Circulation 2013