Chief Corner: Nitrates and Chest Pain

This week during Intern Boot Camp, we went over a few bread-and-butter cases of chest pain and their initial management. While we were discussing ACS, an interesting question came up that I have never really looked into - In someone with an Inferior STEMI, is it safe to give nitrates?

We learn the dogma in medical school that you can never give nitrates to right ventricular infarcts, but medicine is rarely so black-and-white. So let’s review why we give nitrates, what the evidence is, and what we should think about in these cases.

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Our concern is that we will decrease preload in a right ventricular MI (RVMI) causing hypotension and shock, but there is chest pain (i.e. active ischemia) ongoing, so what do we do?

That leads a few questions…

  • How concerned for RVMI should we be with in people with inferior infarcts?

  • Why do we give nitrates?

About 40-50% of inferior MIs are RVMI - a decent amount, so should probably be concerned enough to think about why we're giving it before we do.

So why do we give sublingual nitro?

Mechanism of Action: There are a number of mechanisms, but they are thought to decrease ischemia via large coronary artery vasodilation, decreasing preload and heart strain, and decreasing afterload - all ways to decrease oxygen demand and increase supply.

But what’s the data…

A Lancet Review from 1988 reviewed RCTs which used IV nitroprusside and IV nitroglycerin in acute MI. Primary outcome was mortality, secondary outcomes were Early (<1wk) vs Late (several months) mortality. The author’s conclusion was as follows (2):

“Both nitroglycerin and nitroprusside reduced mortality, the reduction being non-significantly greater with nitroglycerin than with nitroprusside. The greatest reduction in mortality occurred during the first week or so of follow-up, with a non-significant further reduction after this early period. This suggests that the early benefit is not rapidly lost.”

But how do we apply this to the acute-PCI era

A 2009 Cochrane Review looked at RCTs comparing anti-hypertensive drugs with placebo or no treatment within 24 hrs of onset of an acute cardiovascular event. Most of these studies were also done in the 80s and 90s. The largest of the two studies, and the only ones to show a significant mortality benefit were ISIS-4 and GISSI-3. (3)

  • ISIS-4 (1995): 80% of these patients had STEMIs because this was the pre-troponin era! 58,050 patients presenting within 24 hours of an MI who were randomized to Oral Captopril vs Oral Nitrate for 1 month. “Mononitrate, there was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry).”

  • GISSI-3 (1993): 19,394 patients presenting within 24 hours of an MI, randomized to PO Lisinopril vs Transdermal Nitroglycerin and evaluated mortality at 6-weeks. “In the same trial the systematic administration of transdermal GTN did not show any independent effect on the same outcome measures (0.94 [0.84-1.05] and 0.94 [0.87-1.02]).”

Taken together, these two trials had a modest mortality benefit from nitrates at 2 days with the Cochrane Review concluding that “isolating the 2 trials above the mortality benefit for nitrates at day two were the same for both both trials (RR 0.82; 95% CI 0.73 – 0.92 and RR 0.82; 95% CI 0.68 – 0.99 respectively)”. Take note that the confidence intervals get pretty close to 1.

A study from 2016, looked at about 700 patients with STEMIs who received nitrates. “Over a 29-month period, we identified 1,466 STEMI cases. Of those, 821 (56.0%) received NTG. We excluded 16 cases because of missing data. Hypotension occurred post NTG in 38/466 inferior STEMIs and 30/339 non-inferior STEMIs, 8.2% vs. 8.9%, p = 0.73. A drop in systolic blood pressure ≥ 30 mmHg post NTG occurred in 23.4% of inferior STEMIs and 23.9% of non-inferior STEMIs, p = 0.87.”(4)

Physiologically, nitrates make sense in acute MIs even though there is no robust data supporting their use (not to mention that they are a class I recommendation) but we need to use them cautiously when they can cause significant harm (Right Ventricular infarcts) and think about how their use fits into the overall treatment. Discussing with a cardiology fellow and attending, this is a decision they make in a case by case. For instance, if the blood pressure is significantly elevated in an inferior STEMI, it is probably relatively safe to try SLN. If the blood pressure is borderline, probably not as safe. When is patient going to receive definitive therapy with PCI or tPA? Can the patient get fluids if their preload drops a little too much? There are a lot of factors that go into this decision.

I leave you with a really cool review of RV Physiology

Structurally, RV cardiomyocytes are 15% smaller than LV myocytes and hence the RV has more collagen. However, gene expression and protein composition are similar. Yet, metabolism differs, making the RV more resistant to ischemia. Contributing factors include more oxidative metabolism than anaerobic glycolysis and higher oxygen extraction compared to the LV. Furthermore, coronary flow to the RV occurs in both systole and diastole.

(1) Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: A Report of the American college of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am coll Cardiol 2014. PMID: 25260718
(2) Yusuf S et al. Effect of Intravenous Nitrates on Mortality in Aute Myocardial Infarction: An Overview of the Randomised Trials. Lancet 1988. PMID: 2896919
(3) Perez MI et al. Effect of Early Treatment with Anti-Hypertensive Drugs on Short and Long-Term Mortality in Patients with an Acute Cardiovascular Event (Review). Cochrane Database Syst Rev 2009. PMID: 19821384
(4) Prehospital Nitroglycerin Safety in Inferior ST Elevation Myocardial Infarction: Prehosp Emerg Care. 2016;20(1):76-81. doi: 10.3109/10903127.2015.1037480. Epub 2015 May 29.