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Journal Club – IV TNK compared with tPA for Acute Ischemic Stroke in Canada

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Presenter: Dr. Rhiannan Pinnell (FRCPC-EM R1)

Host: Dr. Paul Atkinson

Article:

Research Question/PICO

  • Research Question
    • “The aim of the Alteplase compared to Tenecteplase (AcT) trial was to determine whether intravenous tenecteplase, at a dose of 0·25 mg/kg, is non-inferior to alteplase in all patients presenting early after acute ischaemic stroke who meet standard of care criteria for intravenous thrombolysis.”
  • Population:
    • Patients >18year presenting to stroke center within 4.5h of symptom onset with disabling acute ischemic stroke
  • Intervention
    • TNK at a dose of 0.25mg/kg
  • Comparison
    • Standard dose alteplase
  • Outcome:
    • “Excellent neurological outcome” as measured by the proportion of patients with a mRS of 0-1 at 90-120 days

Background

  • There are 2 mainstays of treatment for ischemic stroke – thrombolysis and endovascular therapy (EVT).
    • Thrombolytics are “clot buster” medications, whereas EVT is an interventional radiology procedure which physically removes the clot
  • The major thrombolytic used since the 90s has been alteplase or tPa.
  • Current guidelines indicate that within 6 hrs since onset of disabling stroke, consider thrombolysis (disabling) and/or EVT. Strongly recommended for <4.5h as long as there are no standard lytic contraindications.
    • Per Canadian stroke best practices, median door to needle time <30 min, 90% should be less than 60 min.
  • There are 2 issues with tPA
    • First, there is a fair bit of debate surrounding both the quality of evidence and the efficacy of this treatment. Throughout the numerous trials, some have been neutral and others have been stopped early due to increased harm/bleeding compared to placebo. The current practice is based mostly on ECASS-3 (2008) and NINDS 2 (1995) and there are some concerns around the fragility indices and baseline imbalance in stroke severity.
    • Also, tPA must be given as an infusion as the half life is only 5-10 mins.
  • What is new?
    • Tenecteplase has a higher fibrin specificity and longer half life so it can be given as a single dose.
    • Currently preferred for MI, given as 5 tier weight-based system which works out to around 0.5-0.55mg/kg.
  • Prior phase 2 studies of TNK for ischemic stroke have found that 0.25mg/kg probably best dose. Phase 3 studies have found that TNK at 0.4mg/kg is not superior to standard alteplase.
  • To date, there have been no phase 3 comparisons between 0.25 and standard alteplase.

Methods

  • Design:
    • Prospective multicentre RCT at 22 Canadian stroke centers (both regional and EVT capable).
    • Open label for treatment, outcome mRS was taken over the phone by a blinded evaluator.
    • Non-inferiority, with subsequent superiority calculations.
    • Used “minimal sufficient balance” algorithm to balance allocation by site.
  • Funding: Funded by Canadian Institutes of Health Research & Alberta Strategy for Patient Oriented Research Support Unit.
  • Population:
    • Inclusion
      • 18+ w/ ischemic stroke, presenting within 4.5h. Could be eligible for EVT but did not have to be.
    • Exclusion
      • Standard contraindications for IV thrombolysis (ICH, etc.)
    • Intervention/procedures:
      • Alteplase – 0.9mg/kg IV to max of 90, w 10% bolus in 1 min, rest over 1 hr
      • TNK – bolus of 0.25mg/kg
    • Outcomes
      • Primary
        • mRS 0-1 at 90-120 days
      • Secondary
        • mRS 0-2 at 90-120
        • EQ-VAS and EQ-5D-5L 90-120
        • Door to needle
        • Proportion given EVT
        • Recanalization at angiogram
        • Baseline CT to arterial puncture time
        • Cognition assessment
        • Length of stay in hospital
        • Discharge destination
        • Safety: sICH, orolingual angio-edema, extracranial bleeding requiring transfusion (within 24h of thrombolysis). 90 day all cause mortalit
    •  Statistics
      • Non-inferiority was established if the lower 95% CI of in TNK group was more than -5%
      • Sample size 1600 for 90% power assuming 35% in tPA and 38% in TNK group have mRS 0-1
      • Intention to treat analysis

Results

  • Sample
    • Size: 1577. 0.6% lost to follow up.
    • Baseline characteristics (No statistical calculations reported for baseline differences)
      • Median age 74y, 48% female.
      • Baseline NIHSS 10 in alteplase group, 9 in TNK group
      • 93-94% at comprehensive stroke centre
      • 32% got EVT
      • Times (min in TNK vs alteplase group)
        • Symptom onset to hospital arrival: 82 vs 83
        • Symptom onset to randomization:121 vs 123
        • Door to CT 15 vs 16
        • Symptom onset to needle 128 vs131
        • Door to needle 36 vs 37
        • CT to arterial puncture 60 vs 58,
        • Puncture to reperfusion 31 vs 27
      • Median follow up at 97 days
    • Results
      • Primary:
        • 90-120 day mRS 0-1 36.9% of patients who received TNK, 34.8% of those who received alteplase.
        • Unadjusted risk difference ****** Lower bound 95% CI of difference of rate of primary outcomes (-2.6-6.9) >-5%, so non-inferior.
        • No difference based on subgroup – e.g. age, sex, NIHSS, large vessel occlusion (defined as internal carotid artery, M1 segment middle cerebral artery (MCA) occlusion, or functional M1 MCA, occlusion (ie, all ipsilateral M2-MCA segments)), etc.
      • Secondary:
        • No significant difference in any secondary outcomes or in safety outcomes in either intention to treat or per protocol analysis.

Authors conclusions

  • “The AcT trial provides robust empirical evidence that tenecteplase is comparable to alteplase in patients presenting with acute ischaemic stroke, with similar function, quality of life, and safety outcomes. Given the ease of administration of tenecteplase compared with alteplase, these results provide a compelling rationale to support switching the standard-of-care intravenous thrombolytic agent for acute ischaemic stroke from alteplase to tenecteplase at a dose of 0·25 mg/kg.”

Discussion at Journal Club

Strengths

  • ED focus
  • Large size, multi center. Involved a range of types of hospitals, from community to academic.
  • RCT with what appears to be good randomization (although no statistics were reported regarding the success of randomization).
  • Excellent per protocol analysis (800/806, 762/771) and very low loss to follow up.

Weakness

  • Conception: Is there an issue surrounding the fundamental comparison to alteplase, since this is so debated? We had some debates about this, and whether there should have been a control group who did not receive a lytic, but concluded that this would probably have been impossible from an ethics board perspective.
  • Baseline values: Numerically slightly more patients with baseline NIHSS <8 (40.5%) in TNK group vs alteplase (38.4%)
  • Methods:
    • This was an open label study. Although the authors did blind the outcome assessors, they did not blind the patients. This still has a risk of exaggerating results, as the Rankin scale has inter-rater variability.
    • There are many secondary outcomes used, which is sometimes seen as scavenging for statistical significance. In this non-inferiority trial, however, it may be a benefit as they are looking for any possible dangers.
    • There may be some issues with using the Rankin score as dichotomous – e.g. there a large difference between “requires some assistance” and “bedridden”
    • There was no subgroup analysis looking at the impact of EVT.

Bottom line

  • This is a well performed study and has good internal validity. It opens up another alternative for stroke treatment – but, based on a non-inferiority trial, TNK wouldn’t be considered a mandatory alternative yet. What it does provide is the opportunity to conduct future studies that could show it to be superior.
  • TNK might also improve treatment timelines (e.g. giving a dose right before going to EVT), as well as permit patients to be lysed and immediately transported with EMS (as currently there are barriers surrounding running the infusion during transport).

 

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Journal Club – Diagnostic Accuracy of ECG for Acute Coronary Occlusion resulting in MI

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Presenter: Dr. Nick Byers (iFMEM R2)

Host: Dr. Colin Rouse

Article:

Research question/PICOD

  • Question:
    • Does shifting from a STEMI/NSTEMI paradigm to a new approach (ACO-MI/ non-ACO-MI) result in better identification of the patients who need acute reperfusion therapy?
  • Population:
    • Adult ED patients with ACS Symptoms
  • Intervention/Comparison:
    • STEMI/NSTEMI vs ACOMI/NACOMI
  • Outcome:
    • Composite ACO defined as one of:
      • A) Total occlusion or presence of culprit lesion on angiography with a peak troponin I level equal to or greater than 1.0 ng/mL plus an at least 20% rise within 24 h
      • B) A highly elevated peak troponin (greater than 5.0 ng/mL), which was shown to be correlated with ACO
      • C) Cardiac arrest before any troponin rise has been documented with supporting clinical evidence of possible ACO
    • All cause in hospital mortality
    • All cause long term mortality
  • Secondary Outcomes: 
    • Time from ECG to coronary angioplasty or CABG
    • The sensitivity and specificity of current criteria in diagnosing ACO
    • The sensitivity and specificity of ECG without ST-segment elevation to diagnose ACO (accuracy of ECG interpretation of acute coronary occlusion without STEMI criteria)
    • The specificity of ECG with STEMI criteria (correct ECG interpretation of false positive STEMI criteria)
    • The sensitivity of ECG with STEMI criteria (correct ECG interpretation of false negative STEMI criteria)
    • The outcome according to ECG subclassifications (outcomes of the patients who are labeled as STEMI and the patients who are labeled as having NSTEMI but have acute coronary occlusion)
  • Design:
    • Single center, retrospective case-control study in Turkey

Results

Authors conclusions

“We believe that it is time for a new paradigm shift from the STEMI/non-STEMI to the ACOMI/non-ACOMI in the acute management of MI”

 

Discussion at Journal Club

Strengths

  • 3000 patients included, 1000 per arm
  • Reviewers were blinded, disagreements were resolved by a 3rd independent reviewer
  • EKGs were reviewed again 3 months later to decrease inter-observer variability
  • Consecutive patients with an initial diagnosis of MI (i.e. not a convenience sample)
  • All patients received guideline-recommended medical treatment
  • There were documented criteria of ECG findings to classify the ECGs

Weakness

  • This was a retrospective study and at a single centre.
  • When troponins were taken was not controlled for/accounted for in any way
  • Control group age, medical comorbidities, and cardiac risk factors were much less
  • Their results suggest 17% of patients in N-ACOMI (N-STEMI Subgroup B) with angiographic ACO were missed (slide 16 results)
  • Study wasn’t powered enough to indicate modest benefit of early intervention over late
  • Extrapolating results to the real world may be difficult because ecg interpretation

 

Bottom line/suggested change to practice/actions

  • This single center retrospective chart review suggests that considering coronary occlusion vs. just ST elevation on ekg decreases long-term mortality, and has a better sensitivity, specificity, PPV, and NPV.
  • This could be a great way of getting patients better access to PCI for occlusive lesions, though inter-operator variability and time constraints are likely to be difficult to implement

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Handover from EMS to Trauma Team: an analysis

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SJRHEM Journal Club March 29, 2021

Dr. Luke Edgar PGY1 FMEM, Dr. Dan Hines

Dalhousie University Department of Emergency Medicine

Javidan AP, Nathens AB, Tien H, da Luz LT. Clinical handover from emergency medical services to the trauma team: A gap analysis. CJEM. 2020 Sep;22(S2):S21-S29. doi: 10.1017/cem.2019.438. PMID: 33084560.

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PoCUS for Diverticulitis

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Dal PoCUS Fellowship – Journal Club – Feb 2021

Dr. Mandy Peach  CCFP-EM

PoCUS Fellow

Dalhousie University Department of Emergency Medicine

 

A Prospective Evaluation of Point-of-Care Ultrasonographic Diagnosis of Diverticulitis in the Emergency Department Allison Cohen, MD*; Timmy Li, PhD; Brendon Stankard, RPA-C; Mathew Nelson

 

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SJRHEM Journal Club Report Oct 2017

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SJRHEM Journal Club Report Oct 2017

Allyson Cornelis, R1 iFMEM

Hosted by Dr Andrew Lohoar

Abstract:

Idarucizumab for Dabigatran Reversal — Full Cohort Analysis

Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., Joanne van Ryn, Ph.D., John W. Eikelboom, M.B., B.S., Stephan Glund, Ph.D., Richard A. Bernstein, M.D., Ph.D., Robert Dubiel, Pharm.D., Menno V. Huisman, M.D., Ph.D., Elaine M. Hylek, M.D., Chak-Wah Kam, M.D., Pieter W. Kamphuisen, M.D., Ph.D., Jörg Kreuzer, M.D., Jerrold H. Levy, M.D., Gordon Royle, M.D., Frank W. Sellke, M.D., Joachim Stangier, Ph.D., Thorsten Steiner, M.D., Peter Verhamme, M.D., Bushi Wang, Ph.D., Laura Young, M.D., and Jeffrey I. Weitz, M.D.

N Engl J Med 2017; 377:431-441August 3, 2017DOI: 10.1056/NEJMoa1707278

 

BACKGROUND
Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran.

METHODS
We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures.

RESULTS
A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.

CONCLUSIONS
In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.)

 

http://www.nejm.org/doi/full/10.1056/NEJMoa1707278

 

SJRHEM Journal Club Report

 

Download (PDF, 89KB)

 

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Apneic Oxygenation – Report from SJRHEM Journal Club

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This week Dr James French hosted a journal club on the following paper:

 

Am J Respir Crit Care Med. 2016 Feb 1;193(3):273-80. doi: 10.1164/rccm.201507-1294OC.

Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill.

Semler MW1, Janz DR2, Lentz RJ1, Matthews DT1, Norman BC1, Assad TR1, Keriwala RD1, Ferrell BA1, Noto MJ1, McKown AC1, Kocurek EG1, Warren MA1,Huerta LE1, Rice TW1; FELLOW Investigators and the Pragmatic Critical Care Research Group.

 

 

The Four Part Question was:

Patients: Adult patients in an American Medical ICU requiring Rapid Sequence Induction of Anesthesia

Intervention: Usual Care (that includes bagging, biped) with the addition of Hi Flo Nasal Cannula during the preoxygenation and intubation.

Comparison: Usual Care (that includes bagging, BiPap).

Outcome: Lowest Oxygen Saturation.

 

A Randomized open table intention to treat pragmatic trial in 146 patients.

The session was great fun and was greatly enriched by the telepresence of Dr George Kovacs of AIME fame. Many thanks to Dr Mark Tutc

Please find below a summary of the appraisal and subsequent discussions. The appraisal structure is from cebm.net

 

 

 

Bottom Line. High flow Nasal cannula is still likely to be of benefit in preventing desaturation during Rapid Sequence Induction of Anesthesia. 

Further Commentary By Dr George Kovacs – Here is an excerpt from our Oxygen delivery chapter:

There has been some controversy regarding the value of HFNO for apneic oxygenation with data from critical care patients demonstrating mixed results in the use of HFNO during the apneic period of an RSI. (Miguel-Montanes et al, 2014)(Vourc’h et al, 2015)(Patel & Nouraei, 2015)(Semler et al, 2016)(De Jong & Jaber, 2016) The findings that HFNO provided no added benefit in two of these studies seemed inconsistent with physiologic principles of preoxygenation and apneic oxygenation. Methodologically, there were inconsistencies in airway maintenance maneuvers between groups with the control group receiving PPV with an open airway as opposed to HFNO who had no airway opening documented. Vourc’h et al, 2015) Patients were reasonably well preoxygenated and commonly had PPV (NIV or BVM support) until laryngoscopy with relatively rapid intubation times (particularly in HFNO group) which would make the benefit of HFNO less apparent. (Semler et al, 2016) Collectively these studies do help us appreciate pearls and pitfalls of preoxygenation and apneic oxygenation using HFNO:

 

  1. For normal patients with normal lungs, preoxygenation is relatively easily achieved but is likely best performed with passive closed system BVM at 15 l/min for at least four minutes. For patients with increased minute ventilation needs, the addition of standard HFNO under a BVM with PEEP allows additional flow for preoxygenation and provides CPAP conditions.
  2. The use of dedicated HFNO (flows up to 60 l/) alone for preoxygenation may be an option for some patients. Standard HFNO (flows up to 15 l/min) should not be used alone for preoxygenation.
  3. During the induction period until full neuromuscular blockade is achieved and laryngoscopy begins, preoxygenation techniques, including HFNO delivery, require an actively opened airway (jaw thrust +/-OPA).  If not providing assisted ventilation during this phase, a closed system using BVM/PEEP with HFNO will likely provide the best ongoing preoxygenation conditions as the patient transitions to apnea.
  4. The addition of standard HFNO when performing assisted ventilations under a BVM/PEEP manual resuscitator or a mask delivering NIV is of questionable additional value. Benefit may come from distending (stenting) the upper airway, improving the nasopharyngeal oxygen reservoir and providing additional PEEP.
  5. Clinicians should be aware of the potential for leak from the use of HFNO under a mask. However, with a properly applied, tightly-fitted mask, leakage is likely negligible and insignificant.
  6. True apneic oxygenation provided by HFNO occurring during laryngoscopy will extend the apnea time. If preoxygenation was near complete and laryngoscopy is completed as it should be in under one minute, the value of ongoing HFNO may not be realized.
  7. The value and safety of HFNO is most recognized when difficulty is anticipated or encountered and allows more timethan would otherwise be available. This provides the clinician a less hurried, less stressed approach to the airway.
  8. HFNO should never be an excuse to “stay and play.” Time-based endpoints of  30-90 seconds, depending on preoxygenation status of the patient, should be predetermined as an end point and trigger active reoxygenation and “stop and think” time.
  9. HFNO is not a substitute for active reoxygenation between laryngoscopy attempts.

Further Commentary by Dr James French

Thats great, looking forward to getting the book!

With regards point 1 above 1.     “For normal patients with normal lungs, preoxygenation is relatively easily achieved but is likely best performed with passive closed system BVM at 15 l/min for at least four minutes. For patients with increased minute ventilation needs, the addition of standard HFNO under a BVM with PEEP allows additional flow for preoxygenation and provides CPAP conditions.”

I understand the excerpt is a physiological discussion so this may be covered in later chapters….

Even in the patient with no appreciated increased risks for hypoxia or assessed as having normal lungs, it may be logical to preoxygenate with a BVM, hi-flo nasal cannulas and a peep valve as routine for a number of system and human factors reasons, namely:

  1. The team have a checked and working “maximally aggressive” setup, the components of which are less vulnerable to errors of omission in the less adrenal pre-induction phase.
  2. The clinical sensitivity for identifying the “low risk for hypoxia patient” is likely to be poor. We know clinicians are have limited accuracy when assessing minute volume. The test characteristics of the pulmonary clinical exam are also variable. We also don’t have an accurate past medical history on many of our seriously ill patients. Or what happens in the adrenal state and as a fallible human we get the assessment wrong? We may therefore easily fail to identify the patient with sick lungs.
  3. If there is unexpected need to ventilate a patient with sudden onset shunt or deadspace secondary to an in procedure emergency e.g. laryngospasm, bronchospasm, aspiration, anaphylaxis, AMI, mucous plugging, unknown pulmonary tumour causing collapse and so on. In this situation being able to provide immediate peep, maximal FiO2, Ipap and rate could be lifesaving.
  4. The moments using the BVM as a tight mask in the pre-induction phase serve as a tactile substrate for visualization and near future planning of BVM practice.

Should all BVMs have a peep valve to ensure it is a closed circuit?!

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