TPA, STROKE, & TELEMEDICINE Improving utilization and improving outcomes in a constantly evolving field
OVERVIEW tpa inclusion and exclusion evolution Challenges to tpa administration Target:Stroke Telemedicine as tool for acute stroke assessment Cases
NINDS PIVOTAL TRIAL (1995) AND FDA APPROVAL OF TPA (1996) NINDS tpa trial released in 1995 demonstrating as primary endpoint of reduced disability based on all outcome measures at 90 days after tpa administration compared to placebo
TPA BACKGROUND Original NINDS trial in 1996 approved use of tpa for patient's with acute ischemic stroke if they could be treated within 3 hours of last known normal Extremely restrictive time frame Pooled data from multiple trials showed clear evidence to benefit early treatment (NINDS, ECASS, ATLANTIS) 0-90 minutes - odds ratio (OR) of favorable outcome at 3 months 2.8 91-180 minutes - OR of favorable outcome at 3 months 1.6 181-270 minutes - OR 1.4 Initial goal was for any physician presented with stroke patient to be able to assess for and treat acute ischemic stroke (ED, Internist, Neurology) Over the first 10-12 years, utilization rates of tpa were fairly stagnant nationwide ranging from 2-4 % on average In successful programs, door to needle times were at or below 60 minutes ~27% Target Stroke developed by American Stroke Association/American Heart Association to address these shortcomings
ODDS RATIO FOR TPA SUCCESS
IMPROVEMENT V WORSENING AFTER TPA Pooling data from the 2 NINDS tpa trials Trend toward recovery seen in both groups tpa group recover 2/3 to normal Placebo group recovers 1/2 to normal Saver, et al. Stroke. 2012; 41:2381-90.
BETTER OUTCOMES WITH TPA NINDS trial 2 looked at 4 outcome scales NIHSS Barthel Index Modified Rankin Score Glasgow Outcome Scale Benefit across all 4 endpoints Trials for stroke smaller than cardiac trials due to greater absolute benefit of tpa
NUMBER NEEDED TO TREAT/HARM Absolute risk from original NINDS for acute intracranial hemorrhage ~6% Further analysis has suggested time changes those numbers Challenging in stroke given variable outcomes on mrs (0-6) Treatment Time Window 0-90 min 91-180 min 181-270 min NNT 3.9 4.0 6.5 17 NNH 71 37 33 13 OR for favorable outcome 2.8 1.6 1.4 1.2 271-360 min Lansberg, et al. Stroke. 2009; 40:2079-84.
ORIGINAL EXCLUSION CRITERIA FOR USE OF IV TPA IN ACUTE ISCHEMIC STROKE a. Current use of oral anticoagulants or a prothrombin time >15 seconds (INR > 1.7) b. Use of heparin in the previous 48 hours and a prolonged partial thromboplastin time c. A platelet count <100,000/mm3 d. Another stroke or any serious head injury in the previous 3 months e. Major surgery within the preceding 14 days f. Pre-treatment systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg g. Neurological signs that are improving rapidly h. Isolated mild neurological deficits, such as ataxia alone, sensory loss alone, dysarthria alone, or minimal weakness i. Prior intracranial hemorrhage j. A blood glucose <50 mg/dl or >400 mg/dl k. Seizure at the onset of stroke l. Gastrointestinal or urinary bleeding within the preceding 21 days m. Recent myocardial infarction
NEW TPA PACKAGE INSERT (2/15) Contraindications Current Intracranial Hemorrhage Subarachnoid Hemorrhage Active Internal Bleeding Recent (3 months) intracranial or intraspinal surgery or serious head trauma Presence of intracranial condition that may increase bleeding risk (some neoplasms, AVM, aneurysm) Bleeding diathesis (no lab cut offs) Current severe uncontrolled HTN (no threshold) Conditions where risk should be weighed against benefits recent surgeries or procedures cerebrovascular disease recent ICH recent GI or GU bleeding recent trauma SBP > 175, DBP> 110 High likelihood of left heart thrombus, acute pericarditis, SBE hemostatic defects, severe hepatic or renal disease septic thrombophlebitis Advanced age Currently receiving anticoagulants
RAPIDLY IMPROVING OR MILD SYMPTOMS AND TPA CHANGES TO WARNINGS AND PRECAUTIONS ON TPA PRESCRIBING INFORMATION: Minor neurological deficit or rapidly improving symptoms was removed Blood glucose level warnings were removed Severe stroke was removed from Warnings & Precautions but added to Adverse Reactions (Section 6.1) Major early infarct signs was removed
STROKE MIMICS AND TPA No data suggest that treatment of these patients results in clinically significant adverse events that differ from those experienced by patients within the approved indication Totality of published data suggest that IV rt-pa may be beneficial in patients with either minor neurological deficit or RISS Observational data suggest patients with minor neurological deficit or RISS may in fact derive benefit from rt-pa with a lower rate of sich than patients with moderate and severe ischemic stroke
SHOULD WE TREAT MILD STROKES Author NINDS, 1997 and 2010 Steffenha gen, 2009 Tanne, 2002 Huisa, 2012 Wendt, 2013 Mild Stroke Definition NIHSS < 6 < 3 hours Time N sich 42 2.4% NIHSS < 6 <3 hours 77 2.6% NIHSS<6 < 3 hours NIHSS<6 < 3 hours NIHSS<5 <4.5 hours Urra, 2013 NIHSS<6 <4.5 hours Romano, 2015 NIHSS<6 <4.5 hours 115 4.5% 59 5% 107 1% 119 0 5910 1.8% 1. Willey JZ et al. J Stroke Cerebrovasc Dis. 2013;22:318 322. 2. Khatri P et al. Stroke. 2010;41:2581 2586. 3. Steffenhagen N et al. Cerebrovasc Dis. 2009;28:201 202. 4. Tanne, et al. Circulation. 2002;105:1679 85. 5. Huisa BN et al. J Stroke Cerebrovasc Dis. 2012;21:732 736. 6. Wendt M et al. J Stroke Cerebrovasc Dis. 2013;22:550 553. 7. Urra X et al. PLoS One. 2013;8:e59420. 8. Romano, JG et al. JAMA Neurology. 2015; 72(4):423 31.
GUIDELINE EVOLUTION - BLEEDING DIATHESIS Classical Exclusion Criteria: PLT less than 100,000 PT > 15, INR > 1.7 Any heparinoid within past 48 hours Updated Guideline/Recommendation: Platelet count, PT, aptt, and INR should be considered in all patients. In most instances, IV rt-pa should not be delayed AHA Statement: "[F]ibrinolytic therapy should not be delayed while awaiting the results unless there is clinical suspicion of a bleeding abnormality or thrombocytopenia, the patient has received heparin or warfarin, or the patient has received other anticoagulants (direct thrombin inhibitors or direct factor Xa inhibitors) Our practice: we follow the notion that IV tpa is not to be delayed while we are waiting for the platelets and coagulation panel unless there is history consistent with coagulation disorders or underlying anticoagulants. Jauch EC et al. Stroke. 2013;44:870 947
AGE CONSIDERATIONS AND TPA Original NINDS trial excluded patients over the age of 80
TARGET: STROKE (2010) Delays in recognition and delays in assessment seemed to be limiting tpa utilization Not only do delays limit ability to treat, but those treated earlier with tpa have better outcomes Goal of Target Stroke is to administer tpa in a Door to Needle (DTN) time frame of 60 minutes or less in at least 50% of those patients receiving tpa Class I evidence supports the following: ED standard operating procedures and protocols to triage potential stroke patient expeditiously Similar standards and protocols should be established for benchmarking time to evaluate and time to treat stroke patients Target to treat stroke patients with tpa should be within 1 hour of the patient's arrival to ED
TARGET: STROKE INITIATIVES Response timeframes recommended for Initial assessment (10 minutes) Stroke team notification (15 minutes) Time to CT completion (25 minutes) Time to CT interpretation (45 minutes) This has typically expanded to include Time to lab completion Time to neurology at bedside (in person or via telemedicine)
TARGET STOKE INITIATIVE FINDINGS Published in JAMA in April 2014 (JAMA. 2014;311(16):1632-1640.) pooled data from nearly 2000 hospitals, over 1.5 million strokes nearly 100K patients treated with IV tpa analysis of over 70,000 patients treated per standard protocols at hospitals that had pre and post-intervention tracking (intervention = enrollment in Target Stroke initiatives) 2003-2010 (pre-intervention/prior to TARGET STROKE initiative) DTN < 60 minutes ranged from 20-30%, slow but steady increase 2010-2013 (post-intervention) DTN times < 60 minutes rapidly improved to > 50% by 3Q 2013
TARGET STROKE OUTCOMES
TARGET STROKE MESSAGES Initiatives like Target Stroke following standard guidelines set by AHA/ASA lead to Improved timeliness of tpa administration (better DTN times) lower in-hospital mortality lower symptomatic intracranial hemorrhage fewer overall tpa complications increase in percentage of patients that are discharged home
TARGET: STROKE PHASE II building on the success of Target :Stroke, AHA/ASA now implementing Target Stroke Phase II Goals of Phase II include DTN of 60 minutes or less in 75 % of patients (primary goal) DTN of 45 minutes or less in 50% of patients (secondary goal) DTN of 45 minutes or less in 50% of patients (secondary goal)
lab patient LEAN METHODOLOGY Pharmacy Triage radiology ER Doc Neurologist
LEAN METHODOLOGY Stroke assessment is a multi-modality process involving EMS ED/nursing triage ED physicians Neurology Laboratory Services Radiology Services Pharmacy Services Improve processes by involving members at all levels to give input about process or identify and eliminate efficiencies
LEAN METHODOLOGY In acute stroke treatment, goal of this process is to: Identify current state aspire toward ideal state organize tools and metrics to track change from current to ideal state (DTN < 60 min) Value Stream Mapping involves members of all parts of stroke team maps the patient flow process for acute stroke assessment and treatment identifies process, highlights efficiencies and inefficiencies open for discussion recognizes barriers to improved flow, and team can work together to remove or lessen burden of those barriers Use of LEAN Methodology now being promoted by AHA/ASA to improve stroke systems of care
TELESTROKE Rapidly evolving field Important considerations technology advances improved access proven reliability patient satisfaction
TELEMEDICINE AND TECHNOLOGY
TELEMEDICINE EMBRACED BY AHA/ASA STROKE 2009 Jul:40(7):2616-34
2009 AHA GUIDELINES FOR TELESTROKE Acknowledges that telestroke is a relatively young field (oldest system initiated in 2001) there is room for continued research in the field led to 9 general recommendations for the initiation of telemedicine within stroke systems of care
2009 GUIDELINES G1 - telestroke should supplement limited local resources when 24/7 coverage is unavailable G2 - contractual agreements should exist between parties involved in telemedicine G3 - medical advice given via telemedicine should be disseminated in similar fashion to on-site medical evaluation (documentation, orders, etc.) G4 - Technology providers should adhere to widely accepted industry standards G5 - Technology standards to provide adequate view of patient environment and patient view of physician with appropriate monitoring and back-ups G6 - New models and codes for reimbursement for tele stroke should be developed G7 - Rationale for uniform national US licensure process limited to telemedicine should be adopted by state medical boards G8 - Development of tele stroke networks in communities with no access to PSC or similar facilities G9 - Multidisciplinary approach to establish effective hub and spoke models of tele stroke Stroke 2009 Jul 40(7):2635-60
TELESTROKE GUIDELINES Stroke 2013 Mar 44(3):870-947
TELESTROKE GUIDELINES Recognition of regions without local stroke expertise Telestroke can help solve the shortage of neurologists Ability to provide 24/7 acute stroke expertise Benefits seem to include Optimize use of tpa in appropriate patients Decrease time to initiate tpa Provides treatment with similar safety to PSCs Reliable examination and NIHSS scores When the physical presence of a stroke team physician at the bedside is not possible, telestroke should be established so that additional hospitals can potentially meet the criteria to become ASRHs and PSCs Stroke 2013 Mar 44(3):870-947
TELESTROKE RELIABILITY Stroke 2003 Dec:34(12):2842-6
TELESTROKE RELIABILITY Premise that rapid expert assessment in stroke patient's is key Utilization of NIHSS provides that rapid assessment patients were assessed via two way telemedicine system, and also assessed in person by a neurologist 41 patients were evaluated via telemedicine average time of assessment/nihss telemedicine group 11.4 minutes bedside group 10.8 minutes Mean NIHSS telemedicine group - 4.9 bedside group - 4.8 Stroke 2003 Dec:34(12):2842-6
Stroke 2003 Dec:34(12):2842-6
CASE DISCUSSION #1 74 yo previously healthy woman presents to ER EMS transported patient, ER arrival at 1705, onset symptoms 30 minutes prior On-call neurology contacted immediately after arrival as patient is being transported to CT No telemedicine available Travel time to ER 30 minutes Bedside neurology evaluation with NIHSS 18 Gaze preference Visual Field Deficit Left Hemiplegia Neglect
CASE DISCUSSION #1 Evaluation over 10 minutes included NIHSS Review of pertinent history Review of available imaging and labs Discussion with family about risks and benefits of thrombolysis At 1800, tpa bolus given Admission to ICU for close observation Patient discharged home with no residual deficits DTN 55 minutes, but success stems from treatment time within 90 minutes of last known well
CASE DISCUSSION #2 82 yo with acute onset of left sided weakness and gaze preference/neglect EMS contacted, pre-arrival notification to ER, symptom onset about 1700 Patient arrival to ER at 1730, rapid triage and immediately to CT Telemedicine evaluation waiting for patient on return from CT NIHSS = 14 Gaze preference Visual field deficit Left hemiparesis Neglect
CASE DISCUSSION #2 Family available at bedside, data reviewed Labs all within normal limits (coags, PLT) BP within acceptable range CT head with hyperdense R MCA sign, no other acute changes Discussion about risks and benefits of tpa and family agrees to treatment tpa ordered, bolus given at 1752, DTN 22 minutes CTA/P ordered for possible intervention By the time the patient returned from CT, NIHSS on telemedicine reassessment was 2 No intervention, patient discharged home 2 days later
CONCLUSIONS Since its initial FDA approval, tpa has been a successful treatment for stroke Tools now exist to help promote better utilization of tpa, and therefore better outcomes TARGET: STROKE confirmed what previous studies demonstrated More rapid treatment of acute stroke with tpa leads to less disability fewer ICH and tpa related complications more stroke patients discharged to home after hospitalization TARGET: STROKE and LEAN compliment each other in helping hospitals and systems achieve better outcomes for their stroke patients Use of telemedicine guarantees rapid response of neurology, but that is only part of the story and part of what is required to have a successful stroke program