TTM2

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Dankiewicz J, et al. "Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest". The New England Journal of Medicine. 2021. 384(24):2283-2294.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

In adult patients with coma following out-of-hospital cardiac arrest, does targeted hypothermia improve survival and performance outcomes compared to normothermia?

Bottom Line

In adult patients with coma following out-of-hospital cardia arrest, targeted hypothermia was not associated with improved survival, functional outcomes, or quality of life measures compared to normothermia; arrhythmias were more common in the hypothermia group.

Major Points

Animal studies and early clinical trials in humans suggested a benefit to hypothermia over normothermia after cardiac arrest. For example, the HACA trial (2002) found that targeted hypothermia to 33°C was associated with improved survival and neurologic outcomes in patients with cardiac arrest and a shockable rhythm (eg, either VF or pulseless VT). The more recent HYPERION study (2019) compared 33°C to 37°C in patients with non-shockable rhythms, finding favorable outcomes in the hypothermia group. A 2012 Cochrane review suggested that mild hypothermia likely improves survival and neurologic outcome after cardiac arrest.[1] In contrast, the TTM trial (2013) enrolled patients with cardiac arrest and either a shockable or non-shockable rhythm, finding no differences in survival or neurologic outcomes between hypothermia (33°C) and normothermia (36°C) groups.

The TTM2 trial, published 2021, randomized about 1,900 patients with coma after out-of-hospital cardiac arrest to targeted hypothermia (33°C) or normothermia (≤37.5°C). Overall there was no difference in the primary outcome mortality at 6 months in the hypothermia group (50%) compared to the normothermia group (48%). Additionally, secondary outcomes showed no difference between groups for functional outcomes at 6 months.

Investigators postulate that the observed results differed from those of prior studies largely on the basis of improved supportive care in the intervening years, as well as the possibility that TTM2's larger sample size minimized the likelihood of observing a difference due to random chance. Overall, this study provides high-quality evidence that targeted hypothermia for out-of-hospital cardiac arrest does not meaningfully improved outcomes. It's worth noting that hypothermia therapy isn’t without its complications. Lowering the body temperature requires sedation and paralysis, and can lead to electrolyte and glucose derangements, decreased cardiac output, and infection. In this trial, hypothermia was associated with a higher exposure to sedation and arrhythmias.

Guidelines

As of August 2021, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, blinded assessment, randomized, superiority, controlled trial
  • N=1,861 patients with out-of-hospital cardiac arrest
    • Hypothermia (33°C) (n=930)
    • Normothermia (≤37.5°C) (n=931)
  • Setting: 61 centers in 14 countries
  • Enrollment: 2017-2020
  • Analysis: Intention-to-treat
  • Primary Outcome: All-cause mortality

Population

Inclusion Criteria

  • Age ≥18 years
  • Admission to hospital after out-of-hospital cardiac arrest of a presumed cardiac/unknown cause, regardless of initial cardiac rhythm
  • Unconsciousness, defined as a sore of <4 on the Full Outline of Unresponsiveness (FOUR) scale
  • >20 consecutive minutes of spontaneous circulation after resuscitation

Exclusion Criteria

  • ROSC to screening time of >180 minutes
  • Unwitnessed cardiac arrest with asystole as the initial rhythm
  • Limitations in care

Baseline Characteristics

From the hypothermia group.

  • Demographics: Age 64 years, female 20%
  • Comorbidities: 37% hypertension, 19% diabetes, 15% myocardial infarction, 14% PCI, 8% CABG, 10% Heart Failure
  • Location of Arrest: 52% at home, 36% in public, 11% other, 91% bystander witnessed, 82% bystander-performed CPR
  • First monitored rhythm: 72% shockable, 28% unshockable rhythm
  • Median time from arrest to ROSC 25 min, median time to randomization 136 min

Interventions

  • Hypothermia: 40 hour intervention—cooled to a surface or intravascular temperature of 33°C, maintained for 28 hours then rewarmed by hourly increments of 1/3 of a degree to 37°C, then maintaining normothermia out to 72 hours total
  • Normothermia: goal to maintain ≤37.5°C. If conservative management or pharmacologic therapy could not maintain temperature below 37.8°C, cool was initiated

Outcomes

Comparisons are hypothermia vs. normothermia

Primary Outcomes

All-cause mortality at 6 months
50% vs. 48% (RR 1.04, 95% CI 0.94-1.14; P=0.37)

Secondary Outcomes

Modified Rankin score 4-6 at 6 months
55% vs. 55% (RR 1.00, 95% CI 0.92-1.09)
Poor functional outcome at 6 months
54% vs. 54% (RR 1.00; 95% CI 0.91-1.08)
Health-related quality life (EQ-5D-5L)
Difference between groups −0.8 points (95% CI, −3.6-2.0)

Subgroup Analysis

No statistical difference seen between groups in all pre-defined subgroups (sex, age, time to ROSC, initial rhythm, shock at admission).

Adverse Events

Arrhythmia resulting in hemodynamic compromise
24% vs. 16% (RR 1.45, CI 1.21–1.75; P<0.001)
Bleeding
5% vs. 5% (RR 0.95, CI 0.63–1.42; P=0.81)
Skin complication related to device used for targeted temperature management
1 vs. <1 (RR 1.99, CI 0.71–6.37; P=0.21)
Pneumonia
36% vs. 35% (RR 1.02, CI 0.90–1.15; P=0.75)
Sepsis
11% vs. 9% (RR 1.19, CI 0.90–1.57; P=0.23)

Criticisms

  • Follow-up functional assessment were hampered by COVID-19 restrictions so some were completed via telephone in consultation with family/caregivers
  • Unblinded study design may have led to changes in treatment choices by clinical staffs
  • This trial lacked a control group
  • Concomitant care was not protocolized
  • 1/5 of patients were co-enrolled in the Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial

Funding

  • the Swedish Research Council [Vetenskapsrådet], Swedish Heart–Lung Foundation, Stig and Ragna Gorthon Foundation, Knutsson Foundation, Laerdal Foundtion, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, and Regional Research Support in Region Skåne
  • Governmental funding of clinical research within the Swedish National Health Service

Further Reading

  1. Arrich J et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2012. :CD004128.