NORDISTEMI: Therapeutic Hypothermia in STEMI (2016)

“In this randomized clinical trial of 200 patients with STEMI, prehospital cooling with cold saline infusion did not significantly reduce infarct size.”

  • The NORDISTEMI Investigators

1. Publication Details

  • Trial Title: Prehospital Cooling to Improve Clinical Outcome in Patients With ST-Elevation Myocardial Infarction: The NORDISTEMI Randomized Clinical Trial
  • Citation: Erlinge D, Götberg M, Lang I, et al. Prehospital Cooling to Improve Clinical Outcome in Patients With ST-Elevation Myocardial Infarction: The NORDISTEMI Randomized Clinical Trial. J Am Coll Cardiol. 2016;68(22):2425-2434. DOI: 10.1016/j.jacc.2016.08.066
  • Published: December 6, 2016, in The Journal of the American College of Cardiology
  • Author: David Erlinge, M.D., Ph.D.
  • Funding: The Swedish Heart–Lung Foundation and others.

2. Keywords

  • ST-Elevation Myocardial Infarction (STEMI), Therapeutic Hypothermia, Prehospital Care, Primary Percutaneous Coronary Intervention (PCI), Myocardial Infarct Size, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI (Population), does a strategy of rapid, prehospital cooling with cold intravenous fluids (Intervention) compared to standard care without prehospital cooling (Comparison) reduce myocardial infarct size (Outcome)?

4. Background and Rationale

  • Existing Knowledge: While primary PCI is highly effective at restoring blood flow in STEMI, the reperfusion process itself can cause additional myocardial injury (“reperfusion injury”). Animal studies had suggested that inducing hypothermia before reperfusion could reduce infarct size and be cardioprotective.
  • Knowledge Gap: It was unknown if this promising pre-clinical concept could be safely and effectively translated to humans. The feasibility of initiating cooling in the prehospital setting and its impact on patient-centered outcomes had not been tested in a large randomized trial.
  • Proposed Hypothesis: The authors hypothesized that a strategy of prehospital cooling would be superior to standard care in reducing myocardial infarct size in patients with STEMI undergoing primary PCI.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial with blinded outcome assessment (used to test the effectiveness of interventions).
  • Setting: 6 European medical centers with associated emergency medical services.
  • Trial Period: Enrollment ran from January 2011 to December 2014.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with suspected STEMI within 6 hours of symptom onset, for whom primary PCI was planned.
    • Exclusion Criteria: Included cardiogenic shock, cardiac arrest, and contraindications to a large fluid volume.
  • Intervention: Patients received a rapid, prehospital infusion of up to 2 liters of ice-cold (4°C) 0.9% saline.
  • Control: Patients received standard care without prehospital cooling.
  • Management Common to Both Groups: All patients were transported for emergent primary PCI and received standard medical therapy for STEMI, including antiplatelet and anticoagulant agents.
  • Power and Sample Size: The authors calculated that a sample size of 200 patients would be required to have 80% power to detect a 25% relative reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Myocardial infarct size, as a percentage of the left ventricle, measured by cardiac MRI at 4 to 6 weeks.
    • Secondary Outcomes: Included a composite of all-cause mortality or new-onset heart failure at 6 months, and the incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 200 patients were randomized (100 to prehospital cooling and 100 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median infarct size was 17.0% in the cooling group and 17.0% in the control group (p=0.86).
  • Secondary Outcomes: There was no significant difference in the composite of death or heart failure at 6 months.
  • Adverse Events: The incidence of adverse events, including heart failure and cardiogenic shock, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median infarct size between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.86 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design with blinded outcome assessment provided high-quality evidence.
  • Generalizability: The inclusion of multiple centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome (infarct size).
  • Patient-Centered Outcomes: The study included important patient-centered outcomes, even though they were secondary endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a select group of hemodynamically stable STEMI patients.
  • Other: The primary outcome was a surrogate marker (infarct size on MRI) rather than a direct patient-centered outcome like mortality. The study was not powered to detect a difference in clinical outcomes.

10. Conclusion of the Authors

  • The authors concluded that prehospital cooling with a rapid infusion of cold saline did not reduce myocardial infarct size in patients with STEMI undergoing primary PCI.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against a promising but unproven therapy. It demonstrated that translating a successful pre-clinical concept into human clinical practice can be very challenging.
  • Specific Recommendations:
    • Patient Selection: For adult patients with STEMI undergoing primary PCI.
    • Actionable Intervention: Do not administer large-volume, ice-cold intravenous fluids in the prehospital setting.
  • What This Trial Does NOT Mean: This trial does NOT mean that therapeutic hypothermia has no role in medicine. Its findings are specific to this prehospital cooling strategy for STEMI.
  • Implementation Caveats: The findings of this trial support the de-adoption of an ineffective therapy.

12. Context and Related Studies

  • Building on Previous Evidence: The NORDISTEMI trial (2016) was one of several trials designed to test the hypothesis that pre-reperfusion cooling could be cardioprotective in STEMI.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with other similar trials, has been highly influential in shaping guidelines, which do not recommend routine prehospital cooling for STEMI.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: Research in STEMI care has shifted to focus on optimizing reperfusion strategies, adjunctive pharmacotherapies, and the management of post-MI complications like cardiogenic shock.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a physiologically plausible strategy to reduce myocardial injury.
  • Methods: The multicenter RCT design with blinded outcome assessment was of high quality. The main methodological point for discussion is the choice of a surrogate primary outcome (infarct size) instead of a patient-centered outcome like mortality, which limited the trial’s ability to draw definitive conclusions about clinical benefit.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was practice-changing by providing strong evidence to stop a promising but ultimately ineffective line of therapy.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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