SGEM#133: Just Beat It (Atrial Fibrillation) with Diltiazem or Metoprolol?

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Date: October 23rd, 2015

Guest Skeptic: Dr. Anand Swaninathan is an assistant program director at NYU/Bellevue Hospital in the Department of Emergency Medicine. He is also part of REBEL EM, The Teaching Course, Emergency Medical Abstracts and a new FOAM site – Core EM.

Case: A 53-year-old woman with no past medical history presents to the emergency department with palpitations for four days. She says she has felt fatigued and a bit short of breath. Vitals reveal a blood pressure of 153/72 and a heart rate of 137 beats per minute. On physical examination, you notice that her heart rate is irregularly irregular and a 12-lead EKG confirms that the patient is in atrial fibrillation with rapid ventricular response.

Background: Atrial fibrillation is a commonly encountered dysrhythmia in the Emergency Department. Atrial flutter is less common but its management is very similar to that of atrial fibrillation.

There is quite a bit of debate on the management of patients with recent onset atrial fibrillation as to whether it is optimal to cardiovert patients or to leave them in atrial fibrillation.

We did a podcast looking at the Ottawa Aggressive Atrial Fibrillation Protocol on SGEM#88. It is a very effective approach to new onset atrial fibrillation but would not apply to this patient who has had four days of symptoms.

In patients with chronic atrial fibrillation or unknown time of onset and a rapid ventricular response, rate control and consideration and initiation of anticoagulation therapy are the standard emergency department approach.

Both beta-blockers and calcium channel blockers are commonly used for rate control in the emergency department, but it is unclear whether one of these agents is superior to the other as there is scant high-quality data on the topic (Demircan 2005).

Clinical Question: In patients with atrial fibrillation and rapid ventricular response, what agent, beta blocker or calcium channel blocker, will obtain rate control the fastest?

Reference: Fromm C et al. Diltiazem vs. metoprolol in the management of atrial fibrillation or flutter with rapid ventricular rate in the emergency department. J Emerg Med 2015.

This paper was picked via the SGEM Hot or Not function. Each week we post five recent publications and ask SGEMers to rate each paper as Hot or Not. Have your voice heard and pick the articles for us to review.

Population: Adult patients > 18 years presenting with atrial fibrillation or atrial flutter.
- Exclusion: SBP<90 mmHg, ventricular rate greater than or equal to 220 beats per minute, QRS >0.100 seconds, 2nd or 3rd degree atrioventricular block, temperature >38.0 ˚C, acute ST elevation myocardial infarction, known history of NYHA Class IV heart failure or active wheezing with a history of bronchial asthma or COPD.
Intervention: Diltiazem 0.25 mg/kg (max dose of 30 mg) or metoprolol 0.15 mg/kg (max dose of 10 mg) IV
Comparison: As Above
Outcome:
- Primary: Heart Rate < 100 beats per minute (bpm) within 30 minutes of drug administration
- Safety: HR<60 and SBP<90mmHg

Authors’ Conclusions: “Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Yes. All recruitment was done in the emergency department.
The patients were adequately randomized. Yes. They used 1:1 computerized randomization.
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). No. This was a convenience sample and the authors do not tell us how many patients presented in AF with RVR that weren’t included and why they weren’t included.
The patients in both groups were similar with respect to prognostic factors. Yes. They noted no difference in baseline characteristics.
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes. Blinding was complete.
All groups were treated equally except for the intervention. Yes..
Follow-up was complete (i.e. at least 80% for both groups). Yes. Follow up was 100%.
All patient-important outcomes were considered. No. The primary outcome was rate control at 30 minutes. There were no longer-term outcomes.
The treatment effect was large enough and precise enough to be clinically significant. Yes.

Key Results: They had 52 patients enrolled in the study (28 in the metoprolol group, 24 in the diltiazem group). The mean age was 66 years and 53% were women.

The mean SBP was 132mmHg and DBP 89 mmHg. About 2/3 of the patients were new onset atrial fibrillation.

Primary Outcome: Heart Rate < 100 beats per minute at 30 minutes

96% Diltiazem vs. 46% Metoprolol (NNT=2)

At every 5-minute interval, the diltiazem group was more likely to be rate controlled to a HR<100bpm than the metoprolol group. No difference was noted between groups in terms of hypotension or bradycardia.

Using an informal poll of emergency physicians, diltiazem seems to be the preferred agent for rate control in atrial fibrillation with rapid ventricular response. Cardiologists, on the other hand, seem to prefer beta-blockers like metoprolol. This study appears to support the preference of emergency physicians. However, there are some issues with this paper that need to be discussed.

Convenient Sample – These were not consecutive patients presenting to the emergency department with rapid atrial fibrialltion but rather a convenience sample. This can introduce selection bias into the study. We aren’t given information on how many patients presented in atrial fibrillation with rapid ventricular response that would allow us to know how many were not approached for the study. This adds in the possibility that some patients were felt to not be good candidates and were thus not even considered for the study or there were patient characteristics that caused physicians to not approach them.
Stopped Trial Early – The authors performed a sample size calculation and determined that 200 patients would have to be recruited to have 80% power to detect non-inferiority. However, only 54 patients were recruited and only 52 included for analysis. They explain that a blinded, independent biostatistician recommended stopping the study because more patients in the diltiazem group were reaching the desired endpoint.
- The researchers observed a large effect size during an interim analysis. This probably over inflates the effect size and it would probably have regressed to the mean if the study had continued.
- There are differences between superiority, non-inferiority and equivalence trials. I have asked my friend and Pediatric Emergency Medicine EM Super Hero Anthony Crocco at SketchyEBM to create a video to explain these concepts in more detail.
  - Mulla et al. How to Use a Noninferiority Trial. JAMA 2012
  - Montori et al Randomized Trials Stopped Early for Benefit: A Systematic Review. JAMA 2005
  - Mueller et al. Ethical Issues in Stopping Randomized Trials Early Because of Apparent Benefit. Annals of Int Med 2007
Drug Dosing – A third critique is about the dosing of the different medications. The diltiazem was dosed at 0.25 mg/kg (with a max dose of 30 mg) and the metoprolol was given at 0.15 mg/kg (with a max dose of 10 mg). This may not be an equivalent comparison. I’ve talked with some of doctors I work with on this and they use a bit higher doses of metoprolol. However, the study authors did allow for additional doses to be given if rate control was not achieved at 15 minutes.
Patient Oriented Outcome – We question whether or not achieving a heart rate < 100 bpm in 30-minutes is an important patient oriented outcome. It’s definitely not a hard patient centered outcome like death but you’re not going to see much, if any, death when it comes to rate control. It would have been nice to have additional longer term outcomes aside from simply 30 minutes after drug administration. Did the patients stay rate controlled? Did either of the groups (once rate controlled) require additional medications to stay rate controlled and if so how much? I think these are important questions to answer.
External Validity – There were some other issues including external validity, as this was a single center study. This isn’t an issue for Swami because this study was done up the street from his hospital in the Bronx and they’ve got an inner-city population similar to his. In contrast, this may not apply to smaller community or rural hospitals.

Despite these limitations, this study represents some of the best evidence on this particular topic. There is limited research looking at the optimal agent for rate control. Bryan Hayes did an excellent review of all the literature on this topic for ALiEM some time ago and recently updated that post with this study.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: I agree with the authors’ conclusions. Despite the above limitations, they did demonstrate non-inferiority of diltiazem to metoprolol for rapid rate control in patients with AF with RVR and this goes along with my clinical experience.

SGEM Bottom Line: The best available evidence shows that diltiazem will achieve more rapid rate control in patients with atrial fibrillation than metoprolol.

Case Resolution: The patient was given 0.25 mg/kg of diltiazem as a slow push and 10 minutes after the push, her rate came down to 93 bpm. She was started on oral diltiazem to continue her rate control. The emergency physician performed a CHADS-VASC score on the patient and she was found to be very low risk for stroke. Therefore, she was started on aspirin alone and discharged home with follow-up with a cardiologist in two days.

Dr. Anand Swaminathan

Clinical Application: Although the evidence is sub-optimal and this study has some flaws, this set of data defends emergency physicians use of diltiazem for rate control in atrial fibrillation with rapid ventricular response.

What Do I Tell My Patient? It appears that the cause of your symptoms is that your heart is in an irregular rhythm called atrial fibrillation. Your heart rate is very high and so we need to give you medicine to reduce it. This will also make you feel more comfortable. We have two major medication choices but the best available evidence indicates that a medication called diltiazem will get you rate controlled the fastest.

Keener Kontest: Last weeks’ winner was Thomas Freeman, the Chief Resident from Georgia Regents University in Augusta, Georgia. He knew the smallest bone in the human body is the Stapes.

Listen to the podcast for this weeks’ question. If you know the answer, then be the first person to email TheSGEM@gmail.com with “keener” in the subject line to win a cool skeptical prize.