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Reference: Wilkinson-Stokes M, Betson J, Sawyer S. Adverse events from nitrate administration during right ventricular myocardial infarction: a systematic review and meta-analysis. Emerg Med J. February 2023

Date: January 24, 2024

Guest Skeptic: Dr. Rupinder Sahsi is a fellow EBM enthusiast with academic appointments at McMaster University and Wright State University who works as an emergency physician in Kitchener-Waterloo, Ontario, Canada. He is also an assistant medical director for EMS at the Centre for Paramedic Education and Research in Hamilton, Ontario, Canada.

Case: You are an advanced care paramedic dispatched to the scene of a 53-year-old female with chest pain. She developed retrosternal chest discomfort shortly after she came in from using her snowblower. You provide her with two tablets of ASA to chew while your partner acquires an ECG, which ultimately shows clear ST elevation in the inferior leads and some ST changes in V1-V2 that make you wonder if your patient is having an acute myocardial infarction (MI) with right-sided ventricular involvement (RVI). Your patient rates their pain as an 8/10 and looks visibly uncomfortable. Do you give nitroglycerin?

Background: You have likely heard the caution to avoid nitrates in acute myocardial infarctions that have right ventricular involvement. What is that based upon? As is often the case, when you go back to the primary literature, you discover we are standing on pillars of salt and sand. The evidence for this recommendation is a single observational study of 40 patients published in 1989 [1].

Yet, the findings in those 40 patients went on to be the evidence commonly cited by the American Heart Association (AHA) [2] and the European Society of Cardiology (ESC) [3] in their recommendation against the use of nitrates in acute MIs if there is right ventricular involvement.

The pathophysiologic rationale was that nitrates would cause vasodilation and thus reduce RV preload, decreasing left end diastolic volume, and ultimately resulting in clinically important hypotension. Many times, pathophysiology has been used to explain something in medicine only to be discovered later that the body is much more complicated than we thought.

That 40-patient study by Ferguson et al did show a statistically significant increased likelihood of hypotension in RVMI patients who received nitrates, but to me, the study design was just plain weird.

  • This was a retrospective trial that looked at 40 patients with inferior MIs. Twenty of them had hypotension after nitrates and 20 of them were not hypotensive. They looked back and saw that a higher proportion of patients with inferior MI and hypotension had ECG evidence of RV involvement. Sounds okay, but by having equal numbers of hypotensive and non-hypotensive patients, they’ve exaggerated the incidence of hypotension. It’s not 50-50. In all comers with MI, the rate is probably closer to <3%. On top of that, there was no standardization of the nitrate dose or route of administration, so it’s hard to know how to extrapolate the findings to our standard nitrate admin protocols.

I was not surprised by this information. Fanaroff et al looked at the ACC/AHA guidelines from 2008-2018 [4]. They found 26 guidelines with 2,930 recommendations. Only 9% were Level A while 50% were Level B and 41% were Level C.

Compare that previously mentioned 40-patient study to the 2016 Canadian study by Robichaud et al which was 22 times larger (n=1,004) than the Ferguson study [5]. It looked at the administration of a standardized amount of nitroglycerin in MI patients with various vascular territories involved. It shows no statistical difference in adverse events between patients with and without RVMI – a relative risk of 1.02 (95% CI: 0.49 to 2.15) p-value = 0.95.

Clinical Question: Is nitrate administration to patients with right ventricular myocardial infarction (RVMI) associated with increased adverse events compared with nitrate administration to patients with myocardial infarctions only in other regions?

Reference: Wilkinson-Stokes M, Betson J, Sawyer S. Adverse events from nitrate administration during right ventricular myocardial infarction: a systematic review and meta-analysis. Emerg Med J. February 2023.

  • Population: Adult patients diagnosed with acute MI
    • Exclusions: Patients with coronary vasospasm were specifically excluded. Nitrates are an effective primary treatment for coronary vasospasm, and the inclusion of these patients may skew results toward a finding of increased nitrate safety.
  • Exposure: Receiving nitrates in any dose and by any route.
  • Comparison: Patients with acute right-sided myocardial infarctions to patients with acute MI involving any other anatomic distribution
  • Outcome:
    • Primary Outcome: All forms of adverse outcomes reported in the identified literature.
    • The primary meta-analysis excluded studies of low quality, but a secondary analysis was also performed including identified studies that were deemed of lower methodologic quality.
  • Type of Study: Systematic review and meta-analysis following the PRISMA guidelines

Authors’ Conclusions: “This review suggests that the [American Heart Association] and [European Society of Cardiology] contraindications [stating that nitrates are contraindicated in RV MI] are not supported by evidence. Key limitations include all studies having concomitant inferior and RVMI, no evaluation of beneficial effects in any of the studies, and very low certainty of evidence. As adverse events such as hypotension are transient and easily managed, nitrates are a reasonable treatment modality to consider during RVMI on current evidence.”

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable.  Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. No
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Unsure
  6. There was low statistical heterogeneity for the primary outcomes. Yes
  7. The treatment effect was large enough and precise enough to be clinically significant. No
  8. Funding for this study: “MW-S received a faculty funding grant from Australian Catholic University to support this research. Funding was determined independently of the review process and no individuals in either group were involved with or report to each other.'”

Results: Their search produced five studies that met the inclusion criteria. Only two of the studies used nitroglycerin 400 μg sublingual as their treatment and could be meta-analyzed. One was a small study of 46 patients done in the UK with 19 RVMI [6]. The other was a larger Canadian study of 1,004 patients yet it only contained 86 patients with RVMI in the cohort [5].

Key Results: No statistical difference in adverse events with administration of nitrates based upon the region of cardiac infarction.

  • Primary Outcome: The meta-analysis of the two studies did not find a statistically significant difference in adverse event rates to combined inferior and RVMI
    • Relative risk 1.31 (95% CI 0.81 to 2.12, p=0.27)
    • Adverse events reported were categorized as minor and transient.

1. Pathophysiology: When we get our medical education, we’re expected to consolidate large amounts of information in a very short amount of time. Naturally, that deprives us of the opportunity to critically examine every single assumption we’re given. Such is the case for this dogmatic admonition against nitrate administration in patients who might be experiencing a right ventricular MI. I remember getting that drilled into my head in residency. There’s this fear that nitrates will decrease their preload to an already impaired right ventricle, which goes on to reduce the patient’s LV end-diastolic volume, which itself leads to hypotension and malperfusion.

Sometimes this warning gets extended to patients who show signs of inferior ischemia on a 12-lead ECG because that /might/ involve the RV (which is where posterior leads would be nice). So, paramedics and emergency physicians see inferior ST ischemia on an ECG and get unnecessarily freaked out about giving nitrates.

Just because something makes pathophysiologic sense does not mean it always turns out to be true when tested.

2. Pillars of Salt and Sand: The SRMA authors point out that the “don’t give nitrates in RVMI patients” recommendation seems to stem from a study of 40 patients by Ferguson et al in 1989 [1]. It took a retrospective look at 20 patients with inferior MI and hypotension after getting nitrates, and 20 patients with inferior MI who weren’t hypotensive after receiving nitrate therapy. 15/20 patients in the first (hypotension) group had electrocardiographic evidence of RV involvement. Only 2/20 patients in the non-hypotension group had electrocardiographic evidence of RV involvement. As is often the case, when you go back to the primary literature that informs guideline recommendations you discover it’s not high-level evidence.

3. Best Paper: Of the papers included in the systematic review, arguably the most compelling is the larger one from Robichaud et al (n=1,004) [5]. It looked specifically at the administration of 400ug of sublingual nitroglycerin in MI patients who were categorized as inferior MI, inferior + RVMI, inferior + other, and MI’s involving only non-inferior/RVMI territories. What it showed was that there was no increased risk to any of those subgroups when given nitrates. Oddly enough, nitrate administration appeared to be safest in patients experiencing an isolated inferior MI.

When the Robichaud et al data was analyzed to look specifically at RVMI vs non-RVMI, the relative risk was 1.02 (not statistically different). Furthermore, the discussion in the SRMA points out that the definition of hypotension – a systolic BP of < 90 – doesn’t consider that the hypotension is often transient and easily managed, and as such unlikely to be clinically meaningful in the first place.

4. The Other Paper: McConnell et al 2017 is the other study meta-analyzed in this systematic review [6]. When I went to look it up, I discovered it was an abstract presented at a conference. The SRMA authors were able to contact the study team, get the original study data, and incorporate that into their meta-analysis.

I’m not entirely sure why the McConnell paper weighed so heavily in the final analysis when it had such a small sample size (n=46). It’s a function of weighted relative risk calculation in a random effects model. I give more psychological weight to the Robichaud paper, but McConnell’s findings are congruent.

5. Benefits: None of the studies included in the SRMA looked at the benefits of nitrate administration (analgesia and reduced sympathetic activation) balanced against the risks of transient hypotension. That is only looking at one side of the coin. We know that any intervention will have potential benefits and potential harms. It’s difficult to know the clinical impact when only considering one aspect of a treatment. We do know that nitrate administration doesn’t appreciably affect morbidity/mortality in acute MI, but its provision still has some potential benefits worth considering.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Don’t be afraid to give nitrates to patients with right ventricular MI. However, be prepared to manage transient hypotension in any patient to whom nitrates are administered.

Case Resolution: The patient is clearly in discomfort, and nitroglycerin may help to ease their symptoms. Though you recognize the historical call for caution when administering nitrates to a patient with suspected RVMI, the best evidence says that doing so is no more dangerous than giving it to any other MI patient. Hypotension is a possibility regardless of the cardiac territory involved, though usually transient and easily managed, so you make sure to start an IV line before giving that first dose.

Dr. Rupinder Sahsi

Clinical Application: The overall level of evidence as assessed by GRADE criteria is very low. The authors recommend that the AHA and European guidelines be revised from contraindicating nitrates in RVMI to permitting them with a more appropriate degree of caution. We echo that position as a reasonable step in the right direction.

What Do I Tell My Patient? This nitroglycerin spray might help to ease some of your chest discomfort, but there’s always the risk that it could drop your blood pressure too. We’ll watch your vital signs on the monitor, and we have this IV set up in case your blood pressure drops too low.

I would also tell my EMS partner if their BP pressure drops do what Bobby McFerrin says, “it will soon pass, whatever it is. Don’t worry…be happy” 

Keener Kontest: Last week’s winner was….no winner. The question was, who first described using a mechanical device to provide artificial ventilation to a human? The answer from Dr. Chris Root was Alexander Monro of Scotland who recommended fitting a wooden pipe to the nostril of the patient and blowing into it with a pair of bellows.

Listen to the SGEM podcast to hear this week’s keener question. The first correct answer will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Ferguson JJ, Diver DJ, Boldt M, et al. Significance of nitroglycerin-induced hypotension with inferior wall acute myocardial infarction. Am J Cardiol 1989;64:311–4.
  2. Neumar RW, Shuster M, Callaway CW, et al. Part 1: Executive summary. Circulation 2015;132:S315–67.
  3. Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2018;39:119–77.
  4. Fanaroff AC, Califf RM, Windecker S, Smith SC Jr, Lopes RD. Levels of Evidence Supporting American College of Cardiology/American Heart Association and European Society of Cardiology Guidelines, 2008-2018. JAMA. 2019 Mar 19;321(11):1069-1080. doi: 10.1001/jama.2019.1122. PMID: 30874755; PMCID: PMC6439920.
  5. Robichaud L, Ross D, Proulx M-H, et al. Prehospital nitroglycerin safety in inferior ST-elevation myocardial infarction. Prehosp Emerg Care 2016;20:76–81.
  6. McConnell AH, Davis M, Van Aarsen K, et al. LO33: prehospital adverse events associated with nitroglycerin use in STEMI patients with right ventricle infarction. CJEM 2017;19:S39.