ED Muskoka Physicians - Living the Dream

Paxlovid Pharmacies

It looks like the following pharmacies should have Paxlovid as well. I haven’t called any others to confirm, but based on the Covid 19 website, they should have it. Great news for access. Just wanted to share in case you weren’t aware.

https://covid-19.ontario.ca/covid-19-antiviral-treatment
https://files.ontario.ca/moh-paxlovid-pharmacy-master-list-en-utf8-2022-04-12.csv

Bracebridge Drug Store Pharmacy 270 Wellington Street
Bracebridge Rexall 3-36 Macdonald Street
Bracebridge Rexall 55 Highway 118 West
Bracebridge Shoppers Drug Mart 1-248 Manitoba Street

Gravenhurst Drug Store Pharmacy 290 First Street North
Gravenhurst Gravenhurst Ida Pharmacy 180 Brock Street
Gravenhurst Shoppers Drug Mart 511 Muskoka Road South

Huntsville Huntsville’s Hometown Ida Drug 10 Main Street East
Huntsville Loblaw Pharmacy 131 Howland Drive
Huntsville Shoppers Drug Mart 51 King William Street

Parry Sound Shoppers Drug Mart 90 Bowes Street

Thanks!
Heather

November Journal Club – TTM2

TTM2: Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384:2283-2294. https://www.nejm.org/doi/10.1056/NEJMoa2100591

TL;DR

  • Cooling comatose patients to 33°C after out of hospital cardiac arrest (OHCA) did NOT improve survival at 6 month compared to simply maintaining normothermia (<37.8°C)
  • There was also NO difference in survival with severe neurological disability, quality of life, but there was a higher risk of arrhythmias in the hypothermia treated patients.
  • The TTM2 trial is a well-designed trial that is the highest level of evidence to date. Current guidelines are based on previous studies with significant limitations.
  • With no benefit of survival and risks, (ie. more paralytics and arrhythmias) cooling may not be as helpful as originally thought.
  • Actively avoiding fevers using a temperature regulating device is still advisable.
  • Focus on delivering excellent comprehensive post-arrest care.

Background:

  • Animal studies and early clinical trials in humans suggested a benefit to hypothermia over normothermia after cardiac arrest. (Minimize reperfusion injury, makes sense to me)
  • The HACA trial (2002) found targeted hypothermia of 33°C was associated with improved survival and neurological outcomes in patients with cardiac arrest and a shockable rhythm. (14% ARR in mortality! Sign me up! Don’t mind the limitations, we have got to be on to something!)
  • A 2012 Cochrane review suggested that mild hypothermia likely improves survival and neurologic outcome after cardiac arrest. (Look at us, we are doing good things!)
  • The TTM trial (2013) enrolled patients with both shockable and non-shockable rhythms found no differences in survival or neurologic outcomes between hypothermia (33°C) and normothermia (36°C) groups. (Cool, cool, cool. Aim for cool but not frozen – easier for us, better for them!)
  • The HYPERION study (2019) compared 33°C to 37°C in patients with non-shockable rhythms finding favourable outcomes in the hypothermia group. (Hmmm, but how convincing? Let’s keep calm and cool-on)
  • Initiating therapeutic hypothermia in the ED for post arrest patients is resource heavy and time intensive, and hypothermia itself poses some clinical risks for the patient.

Clinical Question:

  • In adult patients with coma following out-of-hospital cardiac arrest, is targeted hypothermia at 33 °C followed by controlled rewarming associated with a lower mortality rate than targeted normothermia with early fever treatment?


Design: Prospective, randomized superiority trial. International, multicenter trial.


Patients: 1900 patients who were admitted after OHCA due to a primary cardiac or unknown cause, 1861 included in intention to treat analysis

Inclusion:

  • Adults >18
  • OHCA presumed cardiac or unknown cause
  • Unconscious, not able to obey verbal commands, no verbal response to pain
  • Sustained (20min) ROSC
  • Eligible for ICU without restrictions or limitations
  • Inclusion within 180min of ROSC

Exclusion:

  • Unwitnessed cardiac arrest with an initial rhythm of asystole
  • Temp of <30’C upon admission
  • Requiring ECMO prior to ROSC
  • Obvious or suspected pregnancy
  • Intracranial bleeding
  • Severe COPD requiring long-term home oxygen therapy

Intervention:

  • Patients were randomized in a 1:1 ratio into one of two groups for an intervention period of 40 hours.
  • 1) Hypothermia/intervention group: 925 patients, rapid target hypothermia via cold fluids and surface/intravascular cooling devices (cooling to 33°C x 28hr), followed by controlled rewarming to 37°C by changing 0.33°C per hour x 12 hours, then normothermia out to 72hr
  • 2) Normothermia/control group:
    925 patients, targeted normothermia with early fever treatment for patients in whom fever reached a threshold of 37.8°C (surface or intrasvascular cooling devices to aggressively maintain temperature of 37.5°C). This was maintained for 72hours in patients who remained sedated or comatose.

Outcome:

1) Primary: death from any cause at 6 months.

2) Secondary: poor functional outcome (score 4-6 on modified Rankin scale) at 6 months, hospital-free survival, health-related quality of life, survival in a time-to-death analysis, any of the following adverse events (arrhythmia, bleeding, skin complications, pneumonia, sepsis).

  • Clinicians were non-blinded due to challenges blinding body temperature, however the assessors of clinical prognosis, participants, outcome assessors, statisticians and data managers were all blinded.
  • Outcomes were assessed at 30 days, 180 days, and (ongoing) 24 months.

Results:

  • There was no statistically significant different in the primary outcome: death from any cause at 6-months (hypothermia: 465/925, normothermia 446/925, RR 1.04, p=0.37)
  • The only secondary outcome to be statistically significant at <0.001 was arrhythmia causing hemodynamic compromise. (hypothermia 24%, normothermia 17%, RR 1.45, 95% CI 1.21-1.75)
  • The hypothermia group required more paralytics and longer duration of mechanical ventilation than the normothermia group

Limitations:

  • Unclear if it can be applied to in hospital cardiac arrest
  • Predominance of males in both groups (only ~20% females)
  • There was no third group to answer the question as to whether temperature management is better than no temperature management.
  • External validity is questionable is that 75% of patients had a shockable rhythm, 90% had bystander CPR, a cohort of patients we do not often see.
    

Strengths:

  • Very thoughtful methodology, well organized
  • Clear separation in temperatures between the two groups
  • Large sample size (larger than combined enrolment of earlier trials) leading to less chance of random error in outcomes
  • Large sample size and international, multi-centered trial helps external validity
  • Low risk of bias in nature of primary outcome and assessors were blinded
  • Physician performing neurological assessment at 96 hours for those patients who stayed in ICU was blinded
  • Nearly complete follow-up with 94% retention at 6 months

Thoughts:

  • Unique group captured: witnessed arrest, 90% had bystander CPR, and roughly half survived at 6 months.
  • Perhaps with such quick bystander CPR and a shockable rhythm, the overall ischemic neurological burden was less.
  • The care delivered to these patients is the pinnacle of ICU comprehensive post arrest care, independent of the temperature selected.
  • At the minimum this trial highlights the importance of bystander CPR, efficient pre-hospital care, rigorous post-arrest critical care, as well as the importance of minimizing premature withdrawal of life-sustaining therapy.
  • Half of the normothermic patients required a cooling device to avoid fever, so practically will still need early and close monitoring.
  • Perhaps the initial mortality benefit to TTM/hypothermia was secondary to the intense monitoring and care delivered, and not specifically the temperature reached.
  • This is by far the largest, best designed trial to date, however there is always momentum to maintain the status quo, so it will be interesting to see how this impacts clinical practice and guidelines moving forward.

Take Home:

  • It looks like it may be time to cool it (pun intended) with aggressive therapeutic hypothermia. Target normothermia and avoid fever as there is evidence of fever being associated with unfavourable neurological outcomes and no evidence to date of its benefit.
  • I think we should be cautious to not interpret this is “do less” for our OHCA patients, but rather to focus on delivering excellent post arrest care with a new temperature target.
  • I will still place a temperature probe, but likely hold off on actively cooling normothermic patients in the ED, and discuss with accepting MRP.
  • Stay tuned for further studies and to see how guidelines may change to reflect this best level of evidence. The the AAC did just released a statement suggesting pursuing TTM37.8., but AHA ROSC guidelines last came out in 2020, ERC released their guidelines in March 2021 just prior to this study.
  • What do you think? Will this change your practice?

References:

  1. Arrich J et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2012. :CD004128.
  2. Bro-Jeppesen J., Hassager C., Wanscher M.et al. Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest.
    Resuscitation. 2013; 84: 1734-1740
  3. Dankiewicz J, et al. “Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest”. The New England Journal of Medicine. 2021. 384(24):2283-2294. https://www.nejm.org/doi/10.1056/NEJMoa2100591
  4. Holzer M, et al. “Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”. The New England Journal of Medicine. 2002. 346(8):549-556.
  5. Lascarrou J-B. “Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm”. N Engl J Med. 2019. Epub ahead of print:
  6. Nielsen N, et al. “Target Temperature Management 33°C vs. 36°C after Out-of Hospital Cardiac Arrest”. The New England Journal of Medicine. 2013. 369(23):2197-2206.
  7. https://www.acc.org/Latest-in-Cardiology/Articles/2021/11/09/13/16/A-Contemporary-Update-on-Targeted-Temperature-Management
    https://canadiem.org/targeted-temperature-management-2/
    https://emcrit.org/pulmcrit/ttm2/
    https://rebelem.com/ttm2-hypothermia-vs-normothermia-for-ohca/

HALT IT – TXA for GI Bleeds

For this month’s physically distanced Journal Club – a review of the HALT IT trial looking at TXA for GI Bleeds.

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet. 2020; 395(10241):1927-1936.  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30848-5/fulltext

TL;DR:

  • Tranexemic acid (TXA) did NOT reduce 5-day mortality in upper and lower GI bleed patients.
  • It did show small increase risk of VTE.
  • Well designed, large trial. Best evidence to date for TXA in GI bleed.

Background:

  • GI bleeds have a high mortality rate (10%)
  • TXA is an antifibrinolytic agent that has been shown to be effective at preventing bleeding complications in a variety of settings (surgery, trauma, epistaxis)
    • We love it for its low cost, minimal SE profile, and numerous indications in the ER
  • A 2012 Cochrane Review for UGIB showed a reduction in all-cause mortality with TXA for GI bleeds
    • However, individual trials were small and prone to biases making it difficult to draw definitive conclusions… but was the best evidence we had until now

Clinical Question:

  • Does IV tranexamic acid reduce 5-day death due to bleeding?

Methods:

  • International, multi-centre, randomized, double-blind, placebo controlled trial (15 countries, 164 hospitals)
  • Intervention:
    • 1g TXA IV over 10 min the 125mg/hr x 24 hours (3g) vs. Placebo

Patients:

  • Adults (>16/18 yo depending on country)
  • With “significant” acute GI bleeding
    • Risk of bleeding to death:  
      • Hypotension
      • Tachycardia
      • Signs of shock
      • Likely to need transfusion, urgent endoscopy or surgery
  • Treating clinician had to be “substantially uncertain” about whether to use TXA

Outcome:

  • Primary outcome: death due to bleeding at 5 days
  • Secondary outcomes:
    • Death due to bleeding at 24 h and 28 d randomization
    • All cause and cause specific mortality at 28d
    • Rebleed (24h, 5d, 28d)
    • Blood product transfusion
    • MI/CVA
    • VTE (DVT/PE)
    • Seizures
    • Days in the ICU
    • Functional status in-hospital or at 28d
    • Other (cardiac events, sepsis, pneumonia, resp failure, renal failure, liver failure)

Results:

  • Patients:
    • 12 009 patients enrolled
    • 65% male, mean age 58
    • the mean time from bleeding onset to randomization was 22 hours
      • only 16% of patients presented within 3 hours
    • 89% had upper GI bleeding
    • 45% suspected to have variceal bleeds
    • 60% showed NO signs of shock at enrolment
  • NO BENEFIT
  • Primary outcome:
    • Death due to bleeding at 5 days = 3.7% (n=222) of TXA group and 3.8% (n=226) of placebo group (RR 0.99, 95% CI 0.82-1.18)
  • Secondary outcomes:
    • All cause mortality at 28 days (9.5% of TXA group and 9.2% of placebo group, RR 1.03, 95% CI 0.92-1.16)
    • No difference in rebleeding, surgery, endoscopy, need for transfusion, or total blood products transfused
    • RISKS – doubling of venous thromboembolic events (0.4% placebo and 0.8% TXA (RR 1.85, 95% CI 1.15-2.98)
    • NNH = 250

Limitations:

  • The authors changed the primary outcome from “all-cause mortality” to “death due to bleeding at 5d”
    • Not entirely sure why, as “all cause mortality” is clinically more relevant to us, “death” vs “death from bleeding” are one and the same when talking to family members
    • However, the change of this primary outcome forced the authors to increase their sample size by 4000, and still powered the study to detect a difference in the original outcome
  • The majority of patients in the trial had variceal bleeding due to liver disease and accounted for 75% of deaths, but also increased risk of VTE was more pronounced in patients with liver disease
  • Only 9% of patients were on anticoagulants, so unsure of applicability of data to that group

Thoughts:

  • Overall really well done study, very few protocol violations, excellent follow up
  • Time to randomization was high (mean ~ 22hrs)
    • Looking back at CRASH-2 showed mortality benefit (>20 000 pts, 4.9% vs 5.7% (p = 0.0077)) when 1g TXA given <3 hrs, but not after that.
    • Perhaps we would have been benefit it TXA was administered earlier in GI bleed patients
    • However, if these patients don’t present to us within that time frame, there is no point seeing if TXA works for GI bleeds if given in <3hrs
  • Since CRASH2 there has been lots of interest in TXA, but multiple studies since this positive publication have failed to show similar benefit from TXA
    • TICH -2 – no difference in mortality or neurological outcomes with TXA and ICH (Sprigg 2018)
    • WOMAN no difference in mortality or hysterectomy in PPH (WOMAN 2017) (*revised primary outcome, “death due to PPH” showed small benefit, NNT 267, but fragility index 0…, so overall not a resounding “positive study” in my opinion)
    • CRASH3 – no difference in mortality or neurologic outcomes in TBI (CRASH 2019)
    • Important to have these negative studies published given the well known publication bias of only positive studies
  • Not entirely clear why they had the inclusion criteria of “clinician substantially uncertain whether to use TXA”
    • How do we know if our gestalt is correct if we eliminated those patients from the trial?
    • Perhaps this is mostly to include obvious criteria such as allergy, or for ethical reasons for clinicians to be able to treat patients to the best of their ability, but it is hard to know how many patients were not included and if that would have had any effect on the outcome

Take Home Thoughts:

  • Despite some of the study weaknesses, this is a very well-designed, large trial, and a “negative” trial of this magnitude is clinically important.
  • Based on the current evidence, I will not be using TXA in the management of the GI bleed patients
  • What are you thoughts? Does this change your clinical practice?

References:

  1. Crash-2 Collaborators. (2011). The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. The Lancet377(9771), 1096-1101.
  2. Dewan, Y., Komolafe, E. O., Mejía-Mantilla, J. H., Perel, P., Roberts, I., & Shakur, H. (2012). CRASH-3-tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials13(1), 1-14.
  3. Gluud, L. L., Klingenberg, S. L., & Langholz, E. (2012). Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews, (1).
  4. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet. 2020; 395(10241):1927-1936. 
  5. Justin Morgenstern, “TXA for GI bleeds”, First10EM blog, March 9, 2020. Available at: https://first10em.com/txa-for-gi-bleeds/.
  6. Roberts, I., Shakur-Still, H., Afolabi, A., Akere, A., Arribas, M., Brenner, A., … & Jairath, V. (2020). Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet395(10241), 1927-1936.
  7. Salim Rezaie, “REBEL Cast Ep85: The HALT-IT Trial – TXA in Acute GI Bleeds”, REBEL EM blog, June 27, 2020. Available at: https://rebelem.com/rebel-cast-ep85-the-halt-it-trial-txa-in-acute-gi-bleeds/.
  8. Shakur, H., Elbourne, D., Gülmezoglu, M., Alfirevic, Z., Ronsmans, C., Allen, E., & Roberts, I. (2010). The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials11(1), 40.
  9. Sprigg, N., Flaherty, K., Appleton, J. P., Salman, R. A. S., Bereczki, D., Beridze, M., … & Dineen, R. A. (2018). Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. The Lancet, 391(10135), 2107-2115.