71 year old male: Chest Discomfort

 

This very interesting case comes from Bryan F, a Paramedic from Long Island.

A 71 year old male is cooking breakfast when he experiences sudden onset of 10/10 chest discomfort. He waits 20 minutes or so for it to subside, but it does not and he calls 911.

EMS arrives to find him lying in bed, stating the chest “pressure” has subsided somewhat (6/10), but he now feels some discomfort in his left shoulder. He has never experienced this before.

He denies any shortness of breath, diaphoresis, n/v, or numbness/tingling.

His Vitals:

  • HR: 74, slight sinus arrhythmia
  • BP: 178/96
  • RR: 20, regular, lungs clear,  SpO2 97% on RA
  • Skin: Pale and dry

He has taken 324 ASA prior to EMS arrival, and SL NTG and 50 mcg of Fentanyl are additionally given.

Here are two of the 12 lead ECGs:

 

 

In the time between ECG #1 and #5 shown above, approximately 30 minutes, there were no obvious changes or evolution. You are about 25 minutes from the hospital.

Would you call a STEMI alert?

Why or why not?

 



 


 

In Defense of Morphine (Part 2)

Yesterday, I introduced some of the history preceding the recent Thrombosis and Haemostasis study looking at morphine in patients experiencing ST-elevation myocardial infarctions (STEMIs). [For the curious, we’ll talk about that new article in Part 3. I have to work today, so I can’t guarantee that it’ll be up tomorrow, but soon!]

We started with a retrospective, observational study from 2005—one of the first to associate morphine with significant harms [1]. In that dredge of the CRUSADE data, patients experiencing acute coronary syndrome (ACS) who received morphine did significantly worse than those who didn’t. The numbers are alarming at first glance, showing that morphine administration conferred an increased risk of mortality, with an odd ratio of around 1.50 across most of the calculations.

One must never conflate correlation with causation.

There is a high risk of confounding with this sort of study, and the CRUSADE data missed an important variable: refractory ischemia. The registry gathered no information on which patients experienced recurrent or refractory chest pain (presumably due to ischemia). As a result, we cannot determine if the patients in the morphine group both received the medication, and did worse, in association with this third, outside factor.

I think it’s likely.

I’m reviewing these points because I believe they render the entire CRUSADE study useless. With such a large unmeasured confounder in play, we cannot trust any of the results. I wish there was something we could do to work around that, but there isn’t. Such are the pitfalls of retrospective registry studies. In an ideal world, this article would simply be forgotten and drift into obscurity as the non-evidence it is.

As you may have guess, we don’t live in an ideal world, and instead this study is continually cited in reference to morphine’s safety in ACS. A lot (let me know if that link doesn’t work, but the results are below anyway).

But what’s done is done, and many people now worry that morphine may harm patients with ACS. There are plenty of theories why it may be harmful, and some of them are interesting, but so far none of them fit with the effect-size measured in the CRUSADE article. The most popular at the moment is that morphine impairs absorption of P2Y12 inhibitors like clopidogrel. This effect is very real and is consistently demonstrable. There’s currently a rush to examine the mechanism; it’s almost certainly why this week’s article in Haemostasis and Thrombosis was performed. But there is a small issue…

It’s illogical.

I don’t mean that the mechanism is unproven, or the data is fuzzy. Rather, the whole explanation makes no sense when you look at the magnitude-of-effect it’s supposed to account for. It’s preposterous.

Thankfully, Dr. Rory Spiegel over at EMCrit/EMNerd has done a far better job examining this issue than I ever could [2] [3] [4]. If you want to have an intelligent discussion about this topic, you absolutely need to read at least reference #4: The Case of the Inconsequential Truth. I’ll summarize his major points here:

  • Opioids impair absorption of P2Y12 inhibitors, probably by decreasing intestinal motility and delaying gastric emptying.
    • Of note, it doesn’t turn the medications into an inert placebo—it makes them reach a slightly lower and significantly later peak concentration. They still function.
  • Investigators theorize that this reduced efficacy of a second antiplatelet agent (on top of aspirin) could explain the increased mortality seen in ACS patients who receive morphine.
  • HOWEVER, when you look at the trials that studied “upstream” P2Y12 inhibitors given before PCI, their beneficial effects were extremely small—some argue, negligible.
  • Those benefits were almost entirely measured as reductions in peri-procedural MIs (type 4 MIs), without significant reductions in mortality or morbidity.
  • If morphine is really impairing the function of these medications, doing so would only cut into that small benefit in periprocedural MIs.
    • If P2Y12 inhibitors do not decrease mortality, reducing their efficacy with morphine cannot, in turn, increase mortality. It’s like trying to multiply or divide by zero.

Based the science available to us, it is impossible for morphine’s effects on P2Y12 inhibitors to explain the increased mortality seen in the CRUSADE study. Either there is another mechanism at play, or morphine isn’t causing harms and we’re just seeing a spurious association due to confounding. As I argued in Part 1, the latter seems more likely to me.

 

Make sure you check out Part 3 in a day or two, when I’ll finally examine the recent study that inspired this entire line of posts.

 

Addendum

What about fentanyl? I’ve seen many people who claim they are moving to fentanyl because it doesn’t have the same harms associated with it that morphine does. You might as well move to ketamine if you want a pain medicine with absolutely no outcome evidence against it in ACS.

Histamine release caused by parenteral morphine.

While I agree that fentanyl has a cleaner pharmacodynamic profile with less histamine release, vasodilation, or hemodynamic effects, it’s dishonest to cite morphine’s association with worse outcomes or effects on P2Y12 inhibitors as evidence for switching. The only reason fentanyl doesn’t carry the same baggage as morphine is that it has not been used as much in ACS. You can’t find any CRUSADE-style studies that show fentanyl causing harm because no one has done them. Likewise, until recently, morphine seemed unique in how it impaired P2Y12 inhibitor function, but that was only because it was the only opioid studied (although there was every reason to believe it was an opioid-class effect based on the proposed mechanism).

Enter: the recent PACIFY randomized clinical trial [5]. This study examined the effects of pre-PCI fentanyl on plasma concentrations of ticagrelor (another P2Y12 inhibitor) and platelet function. Guess what: it showed the same effect we’ve seen in morphine. Fentanyl delayed platelet inhibition with a lower area under the curve for the ticagrelor concentrations, but these differences narrowed after 4 hours.

I prefer fentanyl and I think you should too. There are a lot of things to like about it, but please, don’t make unsubstantiated claims that morphine is hurting patients; it’s a lazy, myopic misuse of the evidence.

 

References

  1.  Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, Ohman EM, Peacock WF, Pollack CV Jr, Gibler WB, Peterson ED; CRUSADE Investigators. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J. 2005 Jun;149(6):1043-9. doi: 10.1016/j.ahj.2005.02.010. PMID: 15976786.
  2. Spiegel, R. A Case of Identity. https://emcrit.org/emnerd/a-case-of-identity/
  3. Spiegel, R. A Case of Identity Part Two. https://emcrit.org/emnerd/case-identity-part-two/
  4. Spiegel, R. The Case of the Inconsequential Truth. https://emcrit.org/emnerd/em-nerd-case-inconsequential-truth/
  5. McEvoy JW, Ibrahim K, Kickler TS, Clarke WA, Hasan RK, Czarny MJ, Keramati AR, Goli RR, Gratton TP, Brinker JA, Chacko M, Hwang CW, Johnston PV, Miller JM, Trost JC, Herzog WR, Blumenthal RS, Thiemann DR, Resar JR, Schulman SP. Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial. Circulation. 2018 Jan 16;137(3):307-309. Epub 2017 Oct 18. doi: 10.1161/CIRCULATIONAHA.117.031678. PMID: 29046319.

In Defense of Morphine (Part 1)

Every time I hope this debate is going to die out, or that science will swing back toward rationality, another study gets published and throws a wrench in things. I’ll type this very carefully:

There is no convincing evidence that morphine causes harm to patients experiencing ST-elevation myocardial infarctions (STEMIs).

As long as there isn’t a contraindication (e.g. hypotension or an allergy), it is fine to give morphine to your patient with a STEMI. MONA is not dead*, FAN is not the solution**, and I see no reason to give our patients with acute cardiac ischemia ketamine***.  I think fentanyl is a better choice in most situations,  but it’s not because morphine is a “bad drug” or “causes harm”; I just prefer fentanyl’s pharmacodynamic profile. Please, give morphine if the situation dictates or it’s what you prefer.

 

Why am I worked up?

The journal Thrombosis and Haemostasis published a study earlier this week [1]:

Just reading the title pushes me into a prothrombotic state… Though its authors express some appropriate reservations in the Discussion, we all know why they performed this study, what they expected it to show, and how it will be cited for years to come. It demonstrates an association between morphine and worse outcomes in patients with ST-elevation acute myocardial infarction (STEMI).

I don’t know why everyone has been ganging up on poor old morphine for acute coronary syndrome (ACS)—maybe because it’s been beloved by so many for so long—but while I may not be able to empathize with the hardships of being popular, I sympathize with the hate it’s been receiving and hope to offer some exculpation.

 

How did we get here?

Let’s start with a little back-story. For decades, morphine has been a staple for treating ACS. It was initially thought to reduce myocardial oxygen demand, dilate coronary arteries, and even exert direct myocardial protective effects through μ-opioid receptor agonism—all of which theoretically benefit the ischemic heart. I’ll walk through all the data on this someday (I’ve got three different articles that have been stalled in the “draft” phase for a couple of years), but it suffices to say those benefits, if present, are difficult to detect and almost certainly won’t prevent death or severe morbidity. As a result, we don’t need to administer morphine to every patient with ACS. Heck, I’ve seen it given to asymptomatic patients just because the provider thought they had to as part of the MONA package; that’s overkill.

But if we’re not giving morphine to protect the heart, why are we pushing it?

We administer morphine to relieve pain.

Even ignoring the argument that reducing pain theoretically reduces catecholamines and stress on the heart, the simple reason to give morphine to our patient with a STEMI is to make them feel better. Many of our patients experiencing acute myocardial infarctions are in moderate to severe pain—some even state they feel like they are going to die. We give morphine to relieve that pain and anxiety because it is the humane thing to do.

 

A bump in the road

Morphine had a good run for the better part of a century. Even after all that time, its cardio-protective properties were still unproven and under investigation, but it didn’t seem to hurt ACS patients either. Until…

I loathe this study. More accurately, I can’t stand how often it is misinterpreted. I get furious when I tally up all the time I’ve wasted explaining why this data does not show morphine causing harm. Diving in…

The CRUSADE registry was active from July 2001 to December 2006 as a way of following the in- and post-hospital treatment and outcomes of patients with non-ST-elevation myocardial infarctions (NSTEMIs), and later, STEMIs. Its goals were to examine current practices and outcomes across a huge swath of patients and improve adherence to ACC/AHA guidelines. Unsurprisingly, it was funded by multiple pharmaceutical companies who, I suspect, wanted data to push providers into prescribing more of their medications. At least they didn’t name it something overtly inflammatory like Get With The Guidelines

Anyway, over fifty publications have used the data from the CRUSADE registry, but the above study keeps popping up on my Facebook and Twitter feeds. It retrospectively examined observational data from 17,003 patients who presented with, “ischemic symptoms at rest within 24 hours prior to presentation and high-risk features including ST-segment depression 0.5 mm, transient ST-segment elevation 0.5-1.0 mm (lasting for <10 min), and/or positive cardiac markers (elevated troponin I or T and/or creatine-kinase [CK]-MB > upper limit of normal [ULN] for the local laboratory assay).” In simpler terms, they looked at patients with moderate-to-high-risk unstable angina (UA) or NSTEMI.

The outcomes examined were, “inhospital death, recurrent myocardial infarction, congestive heart failure, and cardiogenic shock”—the typical grab-bag of “major adverse cardiac events” (MACE) common to cardiology studies. They looked at both individual outcomes and a composite endpoint. I don’t see where they picked a primary endpoint.

On their first pass, the investigators looked at the outcomes of patients treated with morphine compared to those who had no morphine administration recorded. Then they adjusted for just about every variable in the registry:

It’s an admirable list of co-variates, but it misses the point. The Achilles’ heel of this study is that patients who received morphine represent a higher-risk group than those who didn’t, for reasons directly affecting why they were administered morphine. None of the variables listed above account for refractory angina, and except for that physician I mentioned who liked to give everyone with a positive troponin 2 mg, it’s not like morphine is randomly administered.

So, not only is this study unable to prove causality since it is retrospective, any associations it identifies linking morphine to poor outcomes are inevitably, and irreparably, biased because sicker patients were more likely to receive the medication.

Look at it this way: It’s unlikely that numeric pain values correspond well to the amount of at-risk myocardium in the patient with ACS [2]. Most of us have seen patients with 10/10 pain from mild unstable angina or, alternately, 1/10 epigastric discomfort experiencing a giant anterior/septal/lateral/apical STEMI. But what does portend a worse outcome in the patient with proven ACS is ongoing pain that’s refractory to medical therapy. It doesn’t much matter if a patient’s ischemic pain is a 1/10 or a 10/10—if it doesn’t resolve with medical therapy, the artery is not open and myocardium is still ischemic or infarcting. It’s why refractory chest pain in a patient with UA/NSTEMI is a Class I, LOE A indication for immediate revascularization according to the AHA/ACC [3].

NSTEMI/UA patients rarely receive this recommended management, however. Here’s how it often plays out:

A patient comes in with chest pain and new ST-depression, T-waves inversions, or non-specific ECG changes (even intermittent ST-elevation). He or she gets diagnosed with UA or NSTEMI (depending on the troponin) and admitted on nitro paste and anti-platelet/antithrombotic therapy. On the floor the pain recurs, or was never totally abolished to begin with, so the patient receives morphine PRN to control the symptoms. The next day, their troponin is through the roof, an echo shows a large area of akinesis, and/or their ECG shows large Q-waves—all because they infarcted through the night and morphine was used to mask the symptoms. The patient eventually goes for angiography and, depending on the findings, revascularization. The infarction is irreversible, but since it’s UA/NSTEMI and not a missed STEMI, no one really cares about the delay (except for the patient, but he or she doesn’t know any better).

I could probably put together a case series of those sorts of encounters, but I doubt I’d get permission to publish a bunch of avoidable bad outcomes… This management is common, and I’m confident it was even more prevalent when this data was gathered in the early 2000s.

That is why I almost never recommend giving opioids to the patient with UA/NSTEMI. It masks the problem without fixing anything. This isn’t an issue for recognized STEMIs because they typically receive revascularization regardless of their symptoms, but pain really is the “5th vital sign” for UA/NSTEMI patients because it can affect critical, time-dependent treatment decisions.

Getting back to the article… In this sort of retrospective study, refractory ischemia is intimately entwined with morphine administration. The two cannot be separated and all you can see is a signal for harm associating morphine with worse outcomes. The morphine did not cause those worse outcomes, and even if it did contribute, you cannot measure the effect through the bias.

The authors from the CRUSADE article were well aware of this issue and attempted to account for it:

Unfortunately, I don’t see how that fixes things. I cannot explain why a patient would receive morphine but not IV nitro, or vice versa (though patients receiving neither are lower risk). The reasons are probably too numerous, scattered, or patient-specific to account for here.

Looking at the variables measured in the registry, we run into the same issues we’ve encountered before. I don’t see how they can be used to create useful propensity scores. It doesn’t matter if you balance out the groups based on age, chronic health problems, vital signs, or the dozen other factors listed earlier—the real factor that determines who gets IV nitro or morphine was not measured and cannot be included.

No matter how much you try, you cannot make the patients in the morphine group equivalent to the patients in the no-morphine group using retrospective, observational data.

In spite of that, the article soldiers on. As described in the Discussion:

But that’s the point! Patients whose pain was controlled with nitro didn’t need morphine because their ischemia responded to medical therapy—of course they’ll to do better. If they needed morphine on top of nitro, or morphine was used to mask the pain in lieu of nitro, they did worse.

That issue invalidates the whole study, but the authors gloss over it and dedicate one sentence in their entire paper to the problem.

Still, I cannot fault their final statement.

A prospective, randomized, clinical trial is exactly what we need to determine whether morphine causes harm in ACS.

Unfortunately, that is not what we received this week…

 

To be continued… in Part 2!!!

I’ll gladly discuss the CRUSADE study further in the comments or on our Facebook page, but please hold your thoughts about the recent Thrombosis and Haemostasis study or any others I haven’t yet addressed until I get to them tomorrow.

 

* [Morphine, Oxygen, Nitro, Aspirin] Well there are a lot of stipulations about giving oxygen only if hypoxemic, nitro not really changing outcomes, and morphine maybe not being the preferred agent, but you get my drift.
** [Fentanyl, Aspirin, Nitro] It isn’t a solution only because there isn’t a problem. FAN is a fine alternative for most patients, just not a necessary replacement.
*** Just… why? It’s fine to discuss, and I’d be interested in seeing it studied, but I hope no one is doing this because they believe it’s safer than fentanyl or morphine right now.

References

  1. Farag M, Spinthakis N, Srinivasan M, Sullivan K, Wellsted D, Gorog DA. Thromb Haemost. Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion and Greater Infarct Size. Thromb Haemost. 2018 Feb 14 [Epub ahead of print]. doi: 10.1055/s-0038-1629896. PMID: 29444530

  2.  Leach A, Fisher M. Myocardial ischaemia and cardiac pain – a mysterious relationship. Br J Pain. 2013 Feb; 7(1): 23–30. doi: 10.1177/2049463712474648. PMID: 26516494. [Free Full Text at PMC]
  3. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes.