low dose v standard dose altephase in acute ischemic stroke

Journal Stroke

 

Korean authors

Abstract

Background and Purpose—The low-dose (0.6 mg/kg) alteplase strategy to treat acute ischemic stroke patients became widespread in East Asian countries, without rigorous testing against standard-dose (0.9 mg/kg) alteplase treatment. Our aim was to investigate the comparative effectiveness and safety of the low-dose versus standard-dose intravenous alteplase strategy.

Methods—A total of 1526 acute ischemic stroke patients who qualified for intravenous alteplase and treated within 4.5 hours were identified from a prospective, multicenter, and nationwide stroke registry database. Primary outcomes were a modified Rankin scale score of 0 to 1 at 3 months after stroke and occurrence of symptomatic hemorrhagic transformation. Inverse probability of low-dose alteplase weighting by propensity scores was used to remove baseline imbalances between the 2 groups, and variation among centers were also accounted using generalized linear mixed models with a random intercept.

Results—Low-dose intravenous alteplase was given to 450 patients (29.5%) and standard-dose intravenous alteplase to 1076 patients (70.5%). Low-dose alteplase treatment was comparable to standard-dose therapy according to the following adjusted outcomes and odds ratios (95% confidence intervals): modified Rankin scale score 0 to 1 at 3 months and 0.95 (0.68–1.32); modified Rankin scale 0 to 2 at 3 months and 0.84 (0.62–1.15); symptomatic hemorrhagic transformation and 1.05 (0.65–1.70); and 3-month mortality and 0.54 (0.35–0.83). The associations were unchanged when the analysis was limited to those without endovascular recanalization.

Conclusions—The low-dose alteplase strategy was comparable to the standard-dose treatment in terms of the effectiveness and safety.

New guidelines for endovascular therapy with emphasis on Class I level a

New Class I level A recommendations for endovascular therapy

 

(1) pre-stroke modified Rankin Score (mRS 0-1)
(2) acute ischemic stroke receiving IV rtPA within 4.5 hours of onset according to guidelines from professional medical societies,
(3) causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1),
(4) age 18 years and over,
(5) National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater,
(6) Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of6 or greater, and
(7) treatment can be initiated (groin puncture) within 6 hours of symptom onset

 

"If endovascular therapy is contemplated, a noninvasive intracranial vascular study is strongly recommended during the initial imaging evaluation of the acute stroke patient but should not delay IV rtPA if indicated. For patients who qualify for IV rtPA according to guidelines from professional medical societies, initiating IV rtPA before non-invasive vascular imaging is recommended for patients who have not had non-invasive vascular imaging as part of their initial imaging assessment for stroke. Non-invasive intracranial vascular imaging should then be obtained as quickly as possible"  (Class I, Level A recommendation)

 

"Regional systems of stroke care should be developed. These should consist of consisting of:
Health care facilities that provide initial emergency care including administration of IV rtPA, including PSCs, CSCs and other facilities
Centers capable of performing endovascular stroke treatment with comprehensive peri-procedural care, including CSC and other health care facilities, to which rapid transport can be arranged when appropriate"

Class 1 Level A evidence

 

When treatment is initiated beyond 6 hours from symptom onset, the benefits of endovascular therapy are uncertain for patients with acute ischemic stroke who have causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1).Additional randomized trial data are needed

 

"It might be reasonable to favor conscious sedation over general anesthesia during endovascular therapy for acute ischemic stroke. However, the ultimate selection of anesthetic technique during endovascular therapy for acute ischemic stroke should be individualized based on patient risk factors, tolerance of the procedure, and other clinical characteristics. Randomized trial data are needed.  (RATES ONLY LEVEL 2B, CLASS C RECOMMENDATION)" (Dr. Tsappidi previously outlined case for anesthesia and our policy is that the interventionist can decide whether to use).

REVASCAT

206 patients with acute ischemic stroke
•
PROBE design
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NIHSS ≥ 6
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Intracranial ICA or M1 occlusion by CTA, MRA or DSA.
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Patients who had received IV rtPA were eligible if there was no significant neurological improvement (criteria specified in the protocol) at 30 minutes post initiation of the infusion and vascular imaging at this time confirmed an eligible occlusion.
•
Groin puncture had to be possible within 8 hours of stroke onset.
•
There were exclusion criteria for coagulopathies. The main exclusion criteria on imaging were ASPECTS <7 on NECT or <6 on DWI-MRI. After the enrollment of 160 patients, the inclusion criteria were modified to include patients up to the age of 85 years (initially 80 years was maximum allowed) with an ASPECTS >8.
•
Only 95% confidence intervals were reported.

 

Results:
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The primary outcome analysis showed a common odds ratio of improvement in the distribution of the modified Rankin scale score (shift analysis) favoring endovascular treatment (adjusted odds ratio 1.7, 95% CI 1.05 to 2.8).
•
The proportion of patients with a mRS of 0-2 at 90 days was 43.7% in the intervention group and 28.2% in the control group (adjusted odds ratio 2.1, 95% CI 1.1 to 4.0).
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There were no significant differences in death or sICH.
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Ninety-five per cent of those in the endovascular group underwent thrombectomy.
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TICI 2b/3 recanalization was observed in 66% of the endovascular group.
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Across the pre-specified subgroups, there were no significant interactions according to NIHSS score, vessel-occlusion site, baseline ASPECTS score, administration of IV rtPA, age or time of randomization, although for the latter dichotomized at 4.5 hours, the p-value for interaction was 0.9 with the later group doing worse. No data are given for those who underwent groin puncture after 6 hours

 

COMMENT-- ALLOWED GROIN PUNCTURE UP TO 8 HOURS BUT DID NOT ANALYZE THAT GROUP, REQUIRED ASPECTS > 7, AGE UP TO 85 

EXTEND 1A

•
Seventy participants who were eligible using "standard criteria" to receive IV rtPA within 4.5 hours of stroke onset were randomized in a PROBE design to receive either IV rtPA only or IV rtPA plus endovascular therapy with a stent retriever.
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Groin puncture had to be within 6 hours and endovascular treatment had to be completed within 8 hours after stroke onset.
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CT or MRI had to be performed before commencing IV rtPA. Occlusion of the ICA or of M1 or M2 on CT angiography was required. In addition, CT or MRI perfusion imaging had to show (a) mismatch ratio of greater than 1.2, and (b) absolute mismatch volume of greater than 10 mL, and (c) infarct core lesion volume of less than 70mL based on specialized software
•
Exclusion criteria for coagulopathies as in SWIFT-PRIME
•
The co-primary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the NIHSS or a score of 0 or 1 at day 3). The mRS at 90 days was a secondary outcome.

 

Results Interim Analysis:
•
Trial halted showed that stopping criteria had been met.
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Occlusion sites: ICA 31%, MCA 54%
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Percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular group than in the IV rtPA group.
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Outcomes: Endovascular therapy, initiated at a median of 210 (IQR 166-251, IQR) minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, p=0.002).
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More patients achieved functional independence in the endovascular group (mRS 0-2, 71% vs. 40%; p=0.01).
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There were no significant differences in rates of death or sICH.
•
Recanalization to TICI2b/3 was achieved in 86% of patients in the endovascular group at a median of 248 (IQR 204-277) minutes after stroke onset.

 

COMMENT---ENDOVASCULAR THERAPY 'WAS INITIATED' AT 3.5 HOURS

 

SWIFT PRIME

•
Purpose:
–
To determine if patients experiencing an acute ischemic stroke due to large vessel occlusion, treated with combined IV tPA and Solitaire FR within 6 hours of symptom onset, have less stroke-related disability than those patients treated with IV tPA alone.
•
Methods:
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Global, multicenter, prospective, randomized, open, blinded endpoint (PROBE) IDE Study

Intervention: IV rtPA with Solitaire FR Device

Control: IV rtPA alone
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39 enrolling centers

 

Inclusion Criteria
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Acute ischemic stroke
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Age 18-80
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Pre-stroke mRS<1
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ASPECTS <6
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Baseline NIHSS 8-29 at time of randomization
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Initiation of IV rtPA within 4.5 hours of onset of stroke
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CTA or MRA confirmation of large vessel occlusion in ICA, M1 segment of MCA or carotid terminus
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Endovascular treatment can be initiated within 6 hours of onset of stroke symptoms and within 90 minutes from CTA/MRA to groin puncture

 

If CTA or MRA was part of local standard of care, it was performed at initial evaluation prior to commencing IV rtPA; if not, it was performed after review of the initial imaging and signing of informed consent.
•
Initially, CT perfusion or multimodal MRI was required and enrollment was restricted to patients with the target mismatch profile (as assessed by specialized software) and defined as: the ischemic core lesion measured 50 mL or less, the volume of tissue with a time to maximum delay of more than 10 seconds was 100 mL or less, and the mismatch volume was at least 15 mL and the mismatch ratio was more than 1.8.
•
Midway through the trial, the inclusion criteria were modified to accommodate sites with limited perfusion imaging capability. Sites with perfusion imaging were encouraged to continue to use the target mismatch criteria. Sites without perfusion imaging used ASPECTS scores (ASPECTS > 6 was required)

 

Results:
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196 patients were randomized after IV rtPA up to 6 hours from onset to groin puncture to Solitaire IA therapy or control.
•
Two primary outcomes (shift analysis): mRS at 90 days (p < 0.001) and increased proportion with mRS 0-2 at 90 days -60% in the endovascular group and 35% in the rtPA alone group (risk ration 1.70, 95% CI, 1.23-2.33)
•
No differences in death or symptomatic ICH (sICH)
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TICI 2b/3 recanalization: = 88% in the endovascular group.

escape TRIAL

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PROBE two-arm superiority trial of 316 patients with acute ischemic disabling stroke, NIHSS > 5, capable of being randomized up to 12 hours after onset.
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CT/CTA, NECT and CTA (multiphase): door to imaging <25 minutes
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Small infarct core (ASPECTS = 6-10 or CTP)
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Occluded proximal artery in anterior circulation, MCA -M1 or 2 or more M2, moderate to good collaterals(filling of 50% of the pial MCA on CTA)
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1:1 randomization of 58 patients who received IV rtPA within 4.5 hours
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Receive guideline-based care alone or guideline-based care plus endovascular treatment with the use of available thrombectomy devices. The use of retrievable stents and suction through a balloon guide catheter during thrombus retrieval was also recommended.
•
The primary outcome was the odds ratio that the intervention would lead to lower scores on the mRS at 90 days (shift analysis).

 

Results:
•
Interim analysis after the O'Brien Fleming stopping boundary was crossed.
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Primary Outcome: The adjusted odds ratio (indicating the odds of improvement of 1 point on the mRS) was 3.1 (95% CI, 2.0 to 4.7) favoring endovascular intervention.
•
The difference in proportion of patients with a mRS of 0-2 at 90 days was 53% in favor of the intervention group versus 23.7% in the control group (p<0.001).
•
Retrievable stents were used in 86.1% who underwent an endovascular procedure.
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TICI 2b/3 recanalization was observed in 72.4% in the endovascular group.
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The number randomized after 6 hours was too small to reach any conclusions regarding intervention beyond 6 hours.

 

COMMENT

used cta AND ct-p AND ASPECTS SCORE

MR Clean results

•
A PROBE, two-arm, superiority trial that studied 500 patients with acute ischemic stroke caused by an proximal intracranial occlusion in the anterior circulation [distal intracranial carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery (A1 or A2)] established by computed tomographic angiography (CTA), magnetic resonance angiography (MRA), or digital-subtraction angiography (DSA), and a score of 2 or higher on the NIHSS
•
Initiation of endovascular treatment within 6 hours of stroke onset had to be possible.
•
Patients who were eligible in agreement with national guidelines received IV rtPA. Those with a non-favorable response were eligible for inclusion.

 

Results:
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Randomized 1:1 (usual care, IA treatment plus usual care)
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Occlusion site: M1 (64%), ICA + M1 (27%)
•
Onset to groin puncture: 260 (210-313 IQR) minutes
•
Stent retriever used in: 81.5%
•
TICI 2b/3 revascularization in 59%; Stroke to reperfusion time: 322 (279-394 IQR) minutes
•
The treatment effect was estimated as an odds ratio, adjusted for pre-specified prognostic factors, that IA treatment would lead to lower mRS at 90 days, as compared with usual care alone (shift analysis)
•
Outcome:Absolute difference of 13.5% (95% CI, 1.21 to 2.30) in achieving mRS 0-2 in favor of the intervention group
•
This difference became non-significant if reperfusion was delayed > 6.2 hours

 

COMMENT- MAY SUPPORT NOT INTERVENING AFTER SIX HOURS

 

ONSET TO GROIN PUNCTURE 4.3 HOURS

ONSET TO REPERFUSION 5.3 HOURS

The earlier tpa is given, the better GWTG evidence

Saver JL, Fonarow GC, Smith EE. et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke.  JAMA 2013; 309; 2480-2488. 

Authors used real world data based on GWTG registry, covering 54,353 patients treated between 2003-2012 at 1395 institutions, and analysed in fifteen minute increments for treatment effects.  Across the ninety minute increments (0-90, 91-180, 181-270 minutes) there was no difference in hospital characteristics such as treatment time or volume, treatment rates, or designation as a stroke center.  Patients treated in first ninety minutes had higher NIHSS scores (mean 12) than those treated in the 181-270 time frame  (mean 9.0).  Nonetheless, faster treatment . 

Findings based on fifteen minute increments showed less mortality  for each 15 minute increment (0.96 OR), and increased odds of independent ambulation at discharge (or 1.03 per 15 minute increment). 

IST 3 -- benefits of tpa in elderly at greater than three hours

Sandercock P, Wardlaw JM, Lindley RI, et al.  The benefits and harms of  intravenous thrombolysis with recombinant tissue plasminogen activator within six hours of acute ischaemic stroke(the third international stroke trial IST 3); a randomized control trial.  Lancet 2012; 379: 2352-2363.

 

Study looked at tpa among patients without clear indication or contraindication to tpa, in a European study.  Due to approval initially in Europe for age < 79  and use within 3 hours of onset, this study was in effect for those >79, and those outside 3 hours, in Europe.  Study looked at tpa + usual care v. usual care. 156 sites enrolled 2025 patients.   53 % were > 79, 72 % were treated after 3 hours after stroke onset but thin six hours.  There was no significant difference in the dichotomized outcome, the initial primary measure, but by shift analsysi of the Oxford Handicap scores, TPA improved the odds of a one level improvement in the outcome.  sICH occurred in 7 % v. 1 % of the control group. 

 

In the subset treated within 3 hours, the primary dichotomized outcome occurred more with tpa than with the control group (OR 1.64) 

Wardlaw JM, Murray V, Berge E. et al.  Recombinant tissue plasminogen activator  for acute ischaemic stroke: an updfated systematic review and metanalysis.  Lancet 2012; 309: 2480-2488.

An updated metaanalysis of tpa trials that included IST 3 showed that ivv tpa given within 3 hours of stroke improved the odds of a good functional outcome (OR 1.53)

Large percent of posterior circulation strokes missed by acute MRI; however tpa does not usually resolve diffusion deficits on MRI

Hotter B, Kufner A, Malzahn U. et al.  Validity of negative high resolution diffusion weighted imaging in transient cerebrovascular events.  Stroke 2013; 44:2598-2600

 

151 patients with suspected stroke and negative DWI in first twenty four hours , 63 underwent followup MRI showing stroke in seven (11%).  5/7 had at least one point on NIHSS. 

 

Oppenheim C, Stanescu R, Dormont D, et al.  False negative diffusion weighted MR findings in acute ischemic stroke.  AJNR 2000; 21: 1434-1440

 

older study showing miss rate of about 20 %

 

Schellinger PD, Bryan RN, Caplan LR et al.  Evidence -based guideline: the role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology; 2010; 75:177-185.

 

guideline from AAN cautioning that sensitivity of MRI to diagnose stroke is imperfect.

 

Albach FN, Brunecker P, Usnich T, et al.  Complete early reversal of diffusion weighted imaging hyperintensities after ischemic stroke is mainly limited to small embolic lesions.  Stroke 2013; 44:1043-1048

Authors studied 153 patients with an average NIHSS of 4 who received tpa; and underwent MRI on admission and in subsequent week.  97/611 (16%) of MRI diffusion hyperintensities resolved, but only 2 % of patients had ALL of their diffusion abnormalities resolve after receiving tpa.

 

 

renal function and tpa

IV thrombolysis and renal function.

Gensicke H1, Zinkstok SM, Roos YB, Seiffge DJ, Ringleb P, Artto V, Putaala J, Haapaniemi E, Leys D, Bordet R, Michel P, Odier C, Berrouschot J, Arnold M, Heldner MR, Zini A, Bigliardi G, Padjen V, Peters N, Pezzini A, Schindler C, Sarikaya H, Bonati LH, Tatlisumak T, Lyrer PA, Nederkoorn PJ, Engelter ST.

 

Abstract
OBJECTIVE: To investigate the association of renal impairment on functional outcome and complications in stroke patients treated with IV thrombolysis (IVT).

METHODS: In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3-6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group.

RESULTS: Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m(2)). A GFR decrease by 10 mL/min/1.73 m(2) increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17-1.24]; ORadjusted 1.05 [1.01-1.09]), death (ORunadjusted 1.33 [1.28-1.38]; ORadjusted 1.18 [1.11-1.249]), and sICH (ORunadjusted 1.15 [1.01-1.22]; ORadjusted 1.11 [1.04-1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10-1.58]), death (ORadjusted 1.73 [1.39-2.14]), and sICH (ORadjusted 1.64 [1.21-2.23]) compared with normal GFR (60-120 mL/min/1.73 m(2)). Low GFR (ORadjusted 1.64 [1.21-2.23]) and stroke severity (ORadjusted 1.05 [1.03-1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41-2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63-0.94]).

CONCLUSION: Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m(2) seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.

ESCAPE, SWIFT PRIME and EXTEND -1A tirals

ESCAPE trial  (" Endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times")

 

120 patients with proximal anterior circulation occlusion were randomized to alteplase v. alteplase + embolectomy.  Study was stopped early due to positive results.  Outcome measure was mrs at 90 days.  The study used CT and CT-A and multiphase CT angiogram. mrs of 0-2 was achieved in 53 % v. 29.2 % (p<0.001).

 

SWIFT PRIME ("Solitaire with the intention for thrombectomy as primary endocascular treatment"). 98 patienrs were randomized in each arm within 4.5 hours to tpa and 6 hours of symptom onset to Solitaire.  Outcome was mrs 0-2 at 90 days 60.2 % with endovascular treatment v. 35.5 % without (p= 0.0002)

 

For every 100 patients treated, 39 would have a better outcome with endovascular than with just tpa, and an additional 25 % would reach functional independence. Study was led by Dr. Saver.  He notes that whether to perform the procedure after six hours is not answered.

 

For MRS of 0, 17 % of patients achieved who got alteplase + procedure v. 8.6 % of alteplase only

For MRS of 1, 25.5 % v. 10.8 % 

For MRS of 2, numbers wwere 17.3 % v. 17.2 %

 

Overall good outcome occurred in 60.1 % of patients with embolectomy v. 35.5 % of patients with T-pa alone.

 

EXTEND 1A: ("Extending the time for thrombolysis in emergency neurological deficits-intraarterial").  35 patients were randomized to tpa alone, 33 to embolectomy but only 27 underwent embolectomy.  37 % of tpa patients achieved early reperfusion v. 100 % of embolectomy patients (p<0.0001).  37 % of patients on tpa achieved early neurological recovery v. 80 % of patients receiving embolectomy (p=0.0002).  They used the Solitaire stent and a 4.5 hour tpa window.  Endovascular was initiated within 210 minutes after onset of stroke.  Study was led by Dr. Bruce Campbell in Austrailia. 

 

 

 

 

Safety of IV tpa with aneurysms

Stroke. 2012; 43: 412-416

The Safety of Intravenous Thrombolysis for Ischemic Stroke in Patients With Pre-Existing Cerebral Aneurysms

A Case Series and Review of the Literature

1. Nancy J. Edwards, MD;
2. Hooman Kamel, MD;
3. S. Andrew Josephson, MD

+ Author Affiliations

1. From the Department of Neurology (N.J.E., S.A.J.), University of California San Francisco, San Francisco, CA; and the Department of Neurology and Neuroscience (H.K.), Weill Cornell Medical College, New York, NY.

1. Correspondence to Nancy J. Edwards, MD, University of California San Francisco, Neurovascular Service, 505 Parnassus Avenue, Box 0114, San Francisco, CA 94143-0114. E-mail nancy.edwards@ucsfmedctr.org

Abstract

Background and Purpose—Unruptured cerebral aneurysms are currently considered a contraindication to intravenous tissue-type plasminogen activator for acute ischemic stroke. This is due to a theoretical increase in the risk of hemorrhage from aneurysm rupture, although it is unknown whether this risk is a significant one. We sought to determine the safety of intravenous tissue-type plasminogen activator administration in a cohort of patients with pre-existing aneurysms.

Methods—We reviewed the medical records of patients treated for acute ischemic stroke with intravenous tissue-type plasminogen activator during an 11-year period at 2 academic medical centers. We identified a subset of patients with unruptured cerebral aneurysms present on prethrombolysis vascular imaging. Our outcomes of interest were any intracranial hemorrhage, symptomatic intracranial hemorrhage, and subarachnoid hemorrhage. Fisher exact test was used to compare the rates of hemorrhage among patients with and without aneurysms.

Results—We identified 236 eligible patients, of whom 22 had unruptured cerebral aneurysms. The rate of intracranial hemorrhage among patients with aneurysms (14%; 95% CI, 3%–35%) did not significantly differ from the rate among patients without aneurysms (19%; 95% CI, 14%–25%). None of the patients with aneurysms developed symptomatic intracranial hemorrhage (0%; 95% CI, 0%–15%) compared with 10 of 214 patients without aneurysms (5%; 95% CI, 2%–8%). Similar proportions of patients developed subarachnoid hemorrhage (5%; 95% CI, 0%–23% versus 6%; 95% CI, 3%–10%).

Conclusions—Our findings suggest that intravenous tissue-type plasminogen activator for acute ischemic stroke is safe to administer in patients with pre-existing cerebral aneurysms because the risk of aneurysm rupture and symptomatic intracranial hemorrhage is low.

Disclaimer--
Please note these are people who were incidentally found to have aneurysms on screening.  There is no guideline to say that managing patients with tpa is safe or valid.

Effects of Golden Hour Thrombolysis

Ebinger M, Kunz Am Wendt M et al  Effects of golden hour thrombolysis: a prehospital acute neurological treatment and optimizatyion of medical care in stroke (Phantom S ) Study.  JAMA Neurol 2015; 72: 25-30 with accompaning editorial

German study with stroke emergency mobile units, ie ambulances with CT scanner, POC lab, and telemedicine connection.  It also is staffed with a neurologist.

Rates of thrombolysis in golden hour 22 v. 32 % with deployment of STEMO, rate of golden hour thrombolysis is higher and were more likely to be discharged home with no increased risks to patient. The future?

Comment-- watch what happens in Germany and try to apply it to the United States

Our ambulances have cited short drive times to OH