In this second EMC Journal Club (where we take the “boring” out of journal clubs and deliver clear, concise, practical critical appraisal knowledge based on an Emergency Medicine journal article that may have flown by your radar – not too detailed and not too brief), Dr. Rohit Mohindra, an Emergency Physician at North York General in Toronto and SREMI researcher works his critical appraisal magic on the article “Dosing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response” by Posen et al. Plus, for the EBM keeners, we have Dr. Shelley McLeod, clinical epidemiologist at SREMI give us a research methodology hot take on the limitations of retrospective observational studies, and possible ways to account for confounders.
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Dosing strategy effectiveness of diltiazem in atrial fibrillation with rapid ventricular response
Case
You are called to the resuscitation room in your ED for a 76-year-old female who presents with tachycardia. She has a history of atrial fibrillation, hypertension, dyslipidemia, and type 2 diabetes. Her medications include apixaban, ramipril, atorvastatin and metformin. Initial vital signs include a heart of 140 bpm and a BP of 100/60 mmHg. ECG shows atrial fibrillation with rapid ventricular response.
You have seen your colleagues use varying doses for the initial order of diltiazem. You recall that a weight-based dose is typically recommended (0.25mg/kg), but you know of other clinicians who advocate for lower or even higher doses. You wonder if any evidence supports the use of these other dosing regimens. A colleague tells you that a retrospective chart review comparing low dose (≤ 0.2 mg/kg), standard dose (> 0.2 and ≤ 0.3 mg/kg), and high dose (> 0.3 mg/kg) diltiazem from 2011 suggested that there was no difference in therapeutic response but less hypotension in the low dose arm, and you wonder whether it might be safer to use low dose diltiazem. However, they heard that a new study challenges this…
Summary
Patients: adults who received IV diltiazem for atrial fibrillation with a HR > 100 bpm
Intervention: low dose (<0.1875 mg/kg – 13mg in a 70kg adult) or high dose (>0.3125 mg/kg – 22mg in a 70kg adult) of diltiazem
Comparison: standard dose (0.25mg/kg – 17.5mg in a 70kg adult)
Outcomes: Primary outcome was heart rate <100 bpm after 30 minutes of receiving the medication. Secondary outcomes included SBP decreasing by more than 20% or <90, need for 2nd dose of rate control medication, disposition, length of stay, return visits and mortality.
Results: Data were collected over 5 years at a single center, and 252 patients were enrolled. 139 received a low dose, 107 received a weight-based dose, and only 6 patients received a high dose of diltiazem. Therefore, the high-dose group was only included in a portion of the analysis.
There were some important differences between the low-dose and standard dosing groups. Specifically, the low-dose group had patients with higher BMI and more chronic kidney disease.
For the primary outcome of rate control <100 bpm at 30 minutes, there was a significant improvement for the patients in the standard dosing, with 29% more patients achieving this goal (95% CI: 17% to 40%). There was also a small improvement in the need for rescue therapy. Interestingly, the low-dose group had a higher number of patients who died (9 vs 1).
Study author’s conclusions: Standard dosing diltiazem (0.25 mg/kg) was associated with greater rate control without increased adverse effects.
Critical appraisal
The finding that patients who received the weight-based dosing had good rate control at 30 minutes is helpful clinically. Still, it’s important to note that there was no difference in length of stay, the need for admission, or proportion with return visits (which are more patient-oriented outcomes).
This study is a good example of why it is difficult to use results from a retrospective chart review to inform clinical care. It seems quite apparent that the sicker, heavier patients received lower doses, as clinicians likely treated these patients with more caution. There are likely unreported biases that also informed the clinicians’ decision to use a certain dose.
Take home message on dosing of diltiazem for atrial fibrillation with rapid ventricular response
Unfortunately, this study does not provide any useful information, so you decide to stick with the weight-based dosing, which is supported by guidelines with low to moderate quality evidence.
Research Methodology Hot Take – controlling for confounders and why retrospective observational studies are weak evidence
The primary goal of clinical research, whether observational or interventional, is to obtain valid measures of the treatment effects or potential risk factors on patient outcomes. In this study, the investigators were trying to assess the treatment effect of low dose and weight-based diltiazem for the outcome of rate control. However, as Dr. Rohindra mentioned, these types of retrospective observational studies are generally more difficult to interpret than randomized controlled trials, often because confounding by other factors frequently exists and is not accounted for.
In this retrospective observational study, the treatment assignment was not randomized, and was instead determined by clinical indications. A particularly important type of confounding in clinical research is “confounding by indication,” which occurs when the clinical indication for selecting a particular treatment (eg, severity of the illness) also affects the outcome. For example, patients with more severe illness are likely to receive more intensive treatments and, when comparing the interventions, the more intensive intervention will appear to result in poorer outcomes.
To control for potential confounding in the analyses, researchers typically use statistical procedures like stratified analyses, regression modelling, or propensity scoring. Failing to adjust for confounding in the statistical analysis may result in inaccurate estimates of the relationship between the treatment and the outcome. In this study, neither propensity score matching, nor other means of adjustment were used to account for baseline imbalances between the low dose and weight-based groups. As Dr. Mohindra correctly pointed out, there were significant baseline differences in body weight more than 100kg, and past medical history including chronic kidney disease. It is unknown how these differences may have influenced both the dosing strategy and the outcomes of interest.
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Drs. Mohindra, McLeod and Helman are supported by the Schwartz-Reisman Emergency Medicine Institute.
References
- Lee J, Kim K, Lee CC, Nam YW, Lee JH, Rhee JE, Singer AJ, Kim KS, Ro Y. Low-dose diltiazem in atrial fibrillation with rapid ventricular response. Am J Emerg Med. 2011 Oct;29(8):849-54.
- Posen A, Bursua A, Petzel R. Dosing strategy effectiveness of diltiazem in atrial fibrillation with rapid ventricular response. Ann Emerg Med. 2022 Nov 16;S0196-0644(22)01085-X.
- Long B, Keim SM, Gottlieb M, Stiell IG. What is the Best Agent for Rate Control of Atrial Fibrillation With Rapid Ventricular Response? J Emerg Med. 2022 Sep;63(3):467-476.
I had a very similar case in a rural setting. IV diltiazem titration kept dropping her BP dramatically.
After consulting a cardiologist I switched to titration with digoxin. That worked brilliantly and her BP remained stable.