Date: September 8th, 2021
Reference: Desch et al. The TOMAHAWK Investigators. Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation. NEJM 2021.
Guest Skeptic: Dr. Stephen Meigher is the EM Chief Resident training with the Jacobi and Montefiore Emergency Medicine Residency Training Program. He heads curriculum and conference for the academic year and is passionate about resident education on- and off-shift, from procedural to evidence-analytical.
Dr. Kaushal Khambhati is also a fourth-year resident training with the Jacobi and Montefiore Emergency Medicine Residency Training Program. He is interested and experienced in healthcare informatics, previously worked with ED-directed EMR design, and is involved in the New York City Health and Hospitals Healthcare Administration Scholars Program (HASP).
FIVE RULES OF THE SGEM JOURNAL CLUB
Case: A 70-year-old woman is found unresponsive and apneic at home by her partner. EMS arrives and finds the patient in monomorphic ventricular tachycardic (VT) cardiac arrest. She has a history of hypertension and non-insulin dependent diabetes mellitus. The paramedics achieve return of spontaneous circulation (ROSC) after CPR, advanced cardiac life support (ALCS), and Intubation. She arrives in the emergency department (ED) with decreased level of consciousness and shock. The EKG shows sinus tachycardia with nonspecific changes and no ST segment elevations, Q waves, or hyperacute T waves. Her point-of-care ultrasound (POCUS) shows appropriate-appearing global ejection fraction and no marked wall motion abnormalities. Cardiology has been consulted and asks for a neurology consultation given her mental status.
Background: The American Heart Association estimates there are approximately 350,000 EMS-assessed out-of-hospital cardiac arrests (OHCAs) in the United States per year. Half of these arrests are witnessed with the other half being un-witnessed. Many of these OHCAs are due to ventricular fibrillation or pulseless VT. Defibrillation is the treatment of choice in these cases but does not often result in sustained ROSC (Kudenchuk et al 2006).
Acute coronary syndrome (ACS) is responsible for the majority (60%) of all OHCAs in patients. There is evidence that taking those patients with ROSC and EKG showing STEMI directly for angiography +/- angioplasty is associated with positive patient-oriented outcomes.
The AHA has a statement with recommendations based on the available data. They suggest to perform catheterization and reperfusion for post-arrest patients with ST-segment elevation, even if the patient is comatose However, there is no consensus if this strategy should be employed in patients without ST-segment elevation (Yannopoulos et al, Circulation 2019).
The 2015 AHA Guidelines make the following recommendations:
- Coronary angiography should be performed emergently (rather than later in the hospital stay or not at all) for OHCA patients with suspected cardiac etiology of arrest and ST elevation on ECG (Class I, LOE B-NR).
- Emergency coronary angiography is reasonable for select (eg, electrically or hemodynamically unstable) adult patients who are comatose after OHCA of suspected cardiac origin but without ST elevation on ECG (Class IIa, LOE B-NR).
Lemke et al 2019 published a multicentre RCT done in the Netherlands looking at patients without ST segment elevation in OHCA with ROSC. Patients were randomized to receive immediate coronary angiography or delayed coronary angiography performed after neurologic recovery. They found no superiority to the immediate strategy for their primary outcome of survival at 90 days.
One of the limitations of the COACT trial is they only included patients who had an intra-arrest shockable rhythm which only accounts for 60% of OHCA patients.
CLINICAL QUESTION: DOES EARLY CORONARY ARTERY ANGIOGRAPHY FOLLOWING RESUSCITATION OF OUT-OF-HOSPITAL CARDIAC ARREST BENEFIT PATIENT OUTCOMES IN PATIENTS WITHOUT ST SEGMENT ELEVATION PATTERNS ON THEIR POST-ROSC EKG?
Reference: Desch et al the TOMAHAWK Investigators. Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation. NEJM 2021.
- Population: Adults aged 30 years and older with shockable or non-shockable OHCA, ROSC and no ST segment elevation EKG pattern.
Exclusions: ST-segment elevation or left bundle branch block, no ROSC, severe hemodynamic or electrical instability requiring immediate coronary angiography/intervention (delay clinically not acceptable), life-threatening arrhythmia possibly caused by acute myocardial ischemia, cardiogenic shock (defined by clinical and hemodynamic criteria), obvious extra-cardiac etiology such as traumatic brain injury, primary metabolic or electrolyte disorders, intoxication, overt hemorrhage, respiratory failure due to known lung disease, suffocation, drowning, IHCA and known or likely pregnancy
Intervention: Immediate angiography as soon as possible after hospital admission
Comparison: Delayed or selective angiography after being transferred to the intensive care unit (ICU) for further evaluation of the cause of the cardiac arrest and for treatment
Primary Outcome: All-cause mortality at 30 days
Secondary Outcomes: They had 13 secondary endpoints of which only 7 of the 13 were reported in the published manuscript.
Reported: MI at 30 days, severe neurologic injury (Cerebral Performance Category of 3-5) at 30 days, composite of death from any cause at 30 days or severe neurologic deficit at 30 days, ICU length of stay (LOS), serialized values for the Simplified Acute Physiology Score (SAPS) II, rehospitalization for CHF within 30 days, and peak values of myocardial biomarkers.
Not Reported: MI at 6 and 12 months, severe neurologic injury at 6 and 12 months, all-cause mortality at 6 and 12 months, rehospitalization for CHF at 6 and 12 months, LOS in hospital, and quality of life at 6 and 12 months
Adverse Events: Moderate or severe bleeding (Types 2-5 on Bleeding Academic Research Consortium), stroke at 30 days, and acute kidney failure requiring hemodialysis at 30 days
Authors’ Conclusions: “In this randomized, international trial, we found that among patients with successfully resuscitated out-of-hospital cardiac arrest and no ST- segment elevation, a strategy of immediate unselected coronary angiography provided no benefit over a delayed and selective approach with respect to the primary end point of death from any cause.”
Quality Checklist for Randomized Clinical Trials:
- The study population included or focused on those in the emergency department. Yes
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in the groups to which they were randomized. Yes
- The study patients were recruited consecutively (i.e. no selection bias). Unsure
- The patients in both groups were similar with respect to prognostic factors. Yes
- All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
- All groups were treated equally except for the intervention. Unsure
- Follow-up was complete (i.e. at least 80% for both groups). Yes
- All patient-important outcomes were considered. Yes
- The treatment effect was large enough and precise enough to be clinically significant. No
Results: There were 554 patients recruited and available for analysis in this trial. The median age was 70 years, 70% were male and more than 1/3 (37.6%) had known coronary artery disease. Many patients had comorbidities with the most common being hypertension (68%), dyslipidemia (38%) and diabetes (29%). The median time to ROSC was 15 minutes. Most patients (55%) had a shockable arrest rhythm. The median Glasgow Coma Scale (GCS) score was 3. Angiography was performed in 96% of patients in the immediate group (median time 2.9 hours) and 62% in the delayed/selective group (median time 46.9 hours).
KEY RESULT: NO STATISTICAL DIFFERENCE IN ALL-CAUSE MORTALITY AT 30 DAYS
Primary Outcome: All-cause mortality at 30 days
54% immediate group vs 46% delayed/selective group
Hazard ratio 1.28 (95% CI; 1.00 to 1.63)
No statistical difference in incidence of MI, severe neurologic deficit, ICU LOS, SAPS II score, rehospitalization for CHF or peak laboratory results (troponin or creatinine)
Composite outcome of all-cause mortality or severe neurologic deficit was greater in the immediate group RR 1.16 (95% CI; 1.00 to 1.34)
Adverse Events: No statistical difference in moderate or severe bleeding, stroke or acute kidney failure leading to renal replacement
1. Selection Bias – There could have been some selection bias introduced into the recruitment of patients. Specifically, some of the exclusion criteria required clinical judgement. Examples of this include severe hemodynamic or electrical instability requiring immediate coronary angiography/intervention (delay clinically not acceptable), life-threatening arrhythmia possibly caused by acute myocardial ischemia, and cardiogenic shock (defined by clinical and hemodynamic criteria). It is unclear if this would have had a material impact on the results.
One group that was explicitly excluded was those patients known or likely to be pregnant. This sex bias was discussed on a recent SGEM Xtra: Unbreak My Heart. We provided evidence that cardiovascular disease among women is understudied, under-recognized, underdiagnosed, undertreated and women are under-represented in clinical trials.
2. Non-Blinded – This was an open-label study because of the overt nature of coronary angiography. Clinicians would have known which group each patient was assigned. The patient would not be aware of group allocation because they were unconscious with a median GCS score of 3. The lack of blinding could have changed how the clinicians managed the two types of patients. These potential differences may not have been measured or noticed on a conscious level.
There may have been a way to mitigate this type of bias from the trial. That would have been to take all patients immediately for angiography. The immediate group would have the procedure performed and the delayed/selective group have a sham procedure. Then if the patient recovers neurologically in the ICU the patient is taken back for angiography and the two groups are crossed over from sham to angiography. There is precedent for this type of sham procedure in the cardiology literature that included some ethically questionable studies in from 70 years ago (Miller 2012). More recent trials have successfully been completed comparing PCI to a placebo procedure (Al-Lamee et al 2018)
3. Patient-Oriented Outcomes (POO) – Their primary outcome was very objective and patient oriented (all-cause mortality). Their secondary outcomes were a combination of patient-oriented outcomes (ex: neurologic function) and disease-oriented outcomes (ex: troponin levels).
The manuscript only published 7 of the 13 secondary outcomes mentioned in their supplemental material. We hope that these six other secondary outcomes will be published when the 6- and 12-month data available. It will be interesting to see if there is any difference between the two groups in the quality-of-life assessment.
4. External Validity – This multicenter RCT was performed in Germany and Denmark. It is unclear if the results can be applied to our patient population in North America. We have a different EMS system than Germany which brings the physician to the patient in the pre-hospital setting. In contrast, the Anglo-American model has the patient being brought to the doctor. We do not know if this would impact the results of this trial.
There were also differences in the patient populations between this trial performed in Germany and Denmark and data from the USA.
5) Secondary Endpoints and Subgroup Analyses – It is good to be skeptical of these findings. While they can be hypothesis generating, they would need to be confirmed in other trials. The probability of significant subgroup findings is very unlikely.
There is data to back up this position (Wallach et al 2017). A study found that 60% of subgroup claims in RCTs failed to have underlying evidence of statistical significance let alone clinical significance. Only 10% of the subgroup claims were ever tested, with 0% confirming the original subgroup claim.
As stated by Yusuf et al JAMA 1991:
“the overall trial result is usually a better guide to the direction of effect in subgroups than the apparent effect observed within a subgroup.”
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.