CHEST PAIN PROTOCOLS PART I

INTRODUCTION

Why have protocols? Well, so we don’t miss anything. Right?! But how many Myocardial infarctions (Heart attacks or “MI’s”) ARE we missing from the ED. Well any medical student knows that answer… anyone, anyone, Bueller?! Umm yes 2% (see note C), correct! That being said if we “do miss 2%” what should be an appropriate miss rate? I mean a zero miss rate is obviously impossible and unreasonable. I think most people consider an arbitrary cut off of 1% or less miss rate. I think this is possibly reasonable but obviously that is a different more philosophical discussion that we can have another time.

MISSED MI

So where did all this worry about miss rate start anyway? Well, I’m glad I asked that question. It all started a long time ago in a galaxy far far away from the one we live in at least. Lets go back, waaaay back. The start year, was 1993, the publishing year was Y2K (aka 2000 – why does that year sound so familiar? Hint See Note A). It was a dark and stormy night when the NEJM Pope article came out entitled “Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department” (1). Wait did they say were are missing Cardiac Ischemia!!!! Holy crap thats bad! We can’t miss that stuff!! Omg how many are we missing (you may ask yourself)??? Well according to the Pope article we missed.. hmm let me see guess I’ll just read the abstract… 2.1% “were mistakenly discharged from the emergency department”!!! Dang 2% that isn’t good. But yes that is where the magical 2% miss of MI came from. Well I have a few more minutes before GOT so maybe I will just look at the rest of the article… So 11618 reviewed, 10,689 patients in final count after exclusion, 889 had acute MI, 19 were discharged, and everyone was brought back 24 to 72 hours after initial presentation for repeat evaluation and 99% follow up rate… 99! That is unheard of good follow up! Wow! But I digress, they used CKMB for evaluation (it was the year 1993 after all). OK here we go, of 10689 studied, 889 had “Acute MI” and 19 were mistakenly discharged home and, yup, 19/889 = 2.1%. But WAIT is that denominator right? Yes 889 had MI but 889 weren’t screened??? Really it was 19 of the 10689 screened for chest pain were sent home so then shouldn’t it be 19 out of 10689 were sent home? Isn’t that 0.1777 or ok 0.18% of patient with AMI (defined in 1993 terms) sent home with AMI! Wow 0.18% sounds way better then 2%. So is that what all this is about? Dividing by the wrong denominator???? Oh boy but wait there’s more. Table 3 says that for those patients with AMI the unadjusted 30 day mortality rates were… huh?! Nearly identical (10.5 and 9.7 %)… what the what?!!! No difference if they were hospitalized or not? But then they did a “risk adjusted ratio of observed to predicted mortality that showed the risk for non hospitalized patients vs hospitalized patients was 9.8% vs 5.5%. That is a difference of 4.3%. What was this risk adjusted mortality??? What was the p-value of that difference? Was that statistically significant ? That is a lot of questions without answers! The only thing I can tell you is that the confidence interval of the risk ratio of the predicted mortality of hospitalized vs non hospitalized patients crosses 1. Doesn’t that mean no difference??? Wow that IS a lot of questions. So maybe we aren’t missing as many as we thought! One really interesting factoid from this study is that 285/889 pts with ami had a normal ST segment. That is 32%???? Wait what the what, what??? Ok now how can that be??? Ohhh remember that the AMI definition back then is completely different than the one now…Fibrinolytic Therapy Trialists which showed STE was best for PCI wasn’t published until 1994 in Lancet. Now,l lets move on to the history and physical exam for AMI.

CHEST PAIN HISTORY AND PHYSICAL

How good is the history and physical for acute MI? The answer to this depends on how much you want to read. If you want to save yourself some time then go ahead and skip to the next paragraph because the answer is decent but not great. Otherwise hang with me because this will be interesting! Ok well maybe not interseting but I still took the time to write it so the least you kids can do is read it, ya ingrates! Back in my day we read everything given to us and we liked, dag nabbit …and keep off my lawn! Sorry I’m aging quick, back to the point… So what are some decent predictors? Well Radiation to the right or both arms has an LR of 4, exertion, left arm radiation, diaphoresis have an LR of 2. In contradistinction, pleuritic, positional, sharp or completely reproducible have an LR of 0.3. Remembering that a helpful +LR is >10 and a helpful negative LR is <0.1 (3). Interestingly ST segment depression >0.5 mm has an +LR of 6. How about clinician gestalt? When the physician felt there to be “probably not or definitely not ACS” there was a high sensitivity (95.1%) but low specificity (31.8%) giving an +LR of about 1.38 and -LR of about 0.16 so not bad at all. Adding a troponin and an ECG to clinician gestalt increased the sensitivity to 100%, but specificity decreased (28.0%) giving a +LR of 1.39 and -LR of 0.001 so yay us! (4).

PROVOCATIVE TESTING

Ok This is my 2nd favorite thing to discuss because we get to talk about stress tests and wait for it… Cardiac CCTA.. yay… kinda… kill me. But don’t worry we are getting to the protocols so just stay with me here. So how did we get here? In 2012 the guidelines state “1. In patients with suspected ACS in whom ischemic heart disease is present or suspected, if the follow-up 12-lead ECG and cardiac biomarkers measurements are nor- mal, a stress test (exercise or pharmacological) to pro- voke ischemia should be performed in the ED, in a chest pain unit, or on an outpatient basis in a timely fashion (within 72 h) as an alternative to inpatient admission. Low-risk patients with a negative diagnostic test can be managed as outpatients (7). Even the most recent 2014 (isn’t this 2018?? Whatevs) AHA guidelines state that “Risk Stratification Before Discharge for Patients With an Ischemia-Guided Strategy of NSTE-ACS: Recommendations [Class I]… Noninvasive stress testing is recommended in low- and intermediate-risk patients who have been free of ischemia at rest or with low-level activity for a minimum of 12 to 24 hours. (Level of Evidence: B)” (6). So we HAVE to do this??? Ugh… Why???? How good are stress tests, anyway? To that end what gold standard should we compare stress testing. That is a GOOD question. So is it angiograms? For now lets say… yes because what else do we have… How do stress tests compare to angiograms, you ask impatiently? In a 1998 Study by Froelicher 814 VA patients agreed (that’s right! AGREED) to undergo BOTH a stress test and an angiography. Sn and Sp for stress testing in this study was 45% and 85% respectively (8).The results of 58 studies examined in a meta-analysis showed exercise testing to have a mean sensitivity of 67% and a mean specificity of 72% (9). So lets do a little Bayesian analysis here. Lets say you are a 50 yo male with no HTN, or other badness. Well, your pretest probability of ACS is 4% (10). If we use the generous result from the above meta-analysis of 67% and 72% for Sn and Sp for ST then that we can convert that to a Likelihood Ratio (LR). This gives us an +LR of 2.39 and a -LR of 0.46. Remember, that LR’s give us a way of converting a pretest probability (incidence of disease) to a post test probability. In order to convert to a post-test probability we use a Fagan nomogram. Oh, look below! Its a Fagan Nomogram! Therefore, from the above Fagan nomogram (courtesy of http://araw.mede.uic.edu/cgi-bin/testcalc.pl) a positive stress test will give us a post test prob of 10% and a negative stress test will give us a negative post test prob of 2%. So now you have taken your low risk patient from a 4% risk down only to a 2% risk… well that doesn’t help at all!!! Lets switch things up and say that the angiogram ISN’T the gold standard. What if I told you now the new gold standard is Fractional Flow Reserve (FFR)? What you might ask is FFR? Another good question! Well briefly to review, an angiogram gives you an anatomic picture of a vessels at the level of stenosis as a dye passes through the coronary arteries. However, is a vessel that is narrow from plaque necessarily the cause of the chest pain? Does stenosis = symptoms ie is this a cause-effect relationship? FFR is a way to see not just anatomic pictures but dynamic pictures of coronary arteries. In other words it is the functional severity of a lesion in the concerned coronary artery. FFR represents the fraction of normal maximal myocardial flow that can be achieved despite any coronary stenosis. It is literally the maximal blood flow to the myocardium in the presence of a stenosis in the supplying coronary artery, divided by the theoretical normal maximal flow in the same distribution (11). It is considered the new standard for measuring stenosis and to see if there is a cause effect relationship with blood flow as opposed to just a narrowing. It is accomplished by passing a guide wire across an area of stenosis and then measuring the flow and pressure of blood, after a coronary artery dilating agent, such as adenosine. An FFR value less than 0.80 corresponds to inducible ischemia (aka bad). Now that we understand that, lets look at ST vs FFR. In a study by Bhat et al. they enrolled over a 5-year study period, 5420 consecutive coronary angiograms that were screened, 326 patients had FFR measurements. Of these, 96 patients with FFR measurements who had a preceding stress test (stress echocardiography [SE] or myocardial perfusion imaging [MPI]) within a year were included. Stress testing had low sensitivity (55%) and specificity (47%) compared to FFR. The concordance (kappa) between FFR and ST was low for both presence and location of ischemia, 0.3 and 0.5, respectively. The number of ischemic areas was correctly estimated in only 39% of the ST. SE was more likely to overestimate and MPI more likely to underestimate extent of ischemia (5) Now lets take our same patient from above and use these numbers. Now we would get an +LR of 1.04 and -LR of 0.96. Both of these are essentially 1 and wouldn’t change our post-test probabilities in any direction. So all we have done is exposed our patient to harm with no benefit. Well then now to say ST is useless sounds to me like an understatement. Do I even need to discuss stress testing in the under 40 age group? I’m sure by my tone you can guess the answer (B). So… are there any other “provocative tests” or tests for “Risk Stratification” we can use? Now we get to CCTA.

CARDIAC CT ANGIOGRAPHY

CCTA is usually made up of two phases. The first where a “calcium score” is performed and the second where imaging of the coronary arteries is done while the heart rate is slowed to <= 70 bpm depending on the number of detectors on the CT. An arbitrary level of 50% obstructive (stenotic) disease is usually what is determined. Already this is a point of contention for me because a coronary angiogram by PCI usually uses a cutoff point of 70% so now we have arbitrary changes without even looking at the literature that predict an increase in interventions just by change the cutoffs! SHEESH! Calcium Scoring Lets look at the first part briefly, the coronary calcium score (CAS). In this study by Young, 2088 consecutively enrolled patients had undergone CAS. A CAS of zero was detected in 1114 patients. Of these, >50% obstructive lesion was found in a total of 48 patients (4.3%). During the 1000 day follow-up period, early revascularization was done in 25 patients (2.2%) and major adverse cardiac events (MACE) was found in 14 (1.3%) among patients with a zero CAS. One problem with this study is the inability to tell if all patients were ED patients, however, given an inclusion criteria of chest pain syndrome, one would assume they were. Another problem is this was a retrospective look at patients using apparently calcium scoring in isolation? This study was done out of Seoul, Korea so this may contribute to those issues. Additionally there are other studies that reproduce this result (14). Still, using calcium scores still doesn’t get us to less than 1%.

CORONARY CT ANGIOGRAPHY

How about CCTA? The two “big studies” that came out for CCTA appeared in a NEJM in 2012, first in March and then July. Lets go through these a bit. The first one was by Litt et al and they enrolled 1370 patients with 908 in the CCTA group and 462 in the traditional care group and followed them up for 30 days. They reported that as compared with the traditional care, group, patients in the CCTA group had a higher rate of discharge from the emergency department (50% vs. 23%), a shorter length of stay (18 vs. 25 hours), and a higher rate of detection of coronary disease (9.0% vs. 3.5%). There was one serious adverse event in each group. While this all sounds awesome what they don’t say is really important. First, the primary outcome was safety by the rate of MACE. With the 1370 patients they had ZERO deaths and 15 MI’s (both groups combined) all of which were found seemingly on the index visit! That is a 1% “bad outcome” in this population. Hardly any way to determine safety with such low numbers. Another factor, 6% of CCTA’s had an “indeterminate” result what do yo do with that? Next important fact, is that 37 of the CCTA vs 18 of the traditional care had PCI (15). That, my half-awake friends, is double from the traditional care. All that for 15 MI’s???? That is a lot of extra invasiveness. One thing I wish they did is tell you what the second troponin was in these studies and compare that to not testing at all! The second such large study comparing CCTA to traditional care was by Hoffman. They randomized 1000 patients, 500 to each group with a primary outcome of length of the hospital stay. [As an aside while I understand how that can be important to some I thought all this was about not missing MI’s!!! It used to be about the music man!]. They found 43 “acute coronary syndromes”, ie Unstable angina or MI, in the CCTA group and 32 “acute coronary syndromes” in the traditional care group. They found 2 (CCTA) vs 6 (traditional care) patients with MACE. That is a about a 6-8% incidence of ACS but still a low risk of “badness”. They also found more downstream testing in the CCTA (23% vs 11%) and those patient received 2 or more diagnostic tests (ST and/or PCI)! They also found about 3x the radiation exposure for the CCTA group (16). Finally, lets try to figure out how good CCTA really is since both of the above studies just looked at safety of discharging these low risk patients after “provocative testing”. To this end we look to the NXT Trial study group. Remember that little discussion on FFR we had before? Well we are going to use those same principles to see how good CCTA is. This prospective multicenter trial included 254 patients scheduled to undergo clinically indicated PCI. They did CCTA, CCTA with FFR (computer algorithm), and compared it with PCI and PCI with FFR. Here they looked at obstructive lesion >50% for ALL modalities. Bingo, That should tell us something! This is a complicated study but they found some interesting results. They found an accuracy of a whopping 53%! They found the Sn and Sp of CCTA to be 94% and 34%, respectively (in 220 patients). This give a +LR of 1.42 and a -LR of 0.18 (19). In another study that reproduced these results that also looked at CCTA vs FFR-CT, they found an accuracy of 61% +LR of 1.25 and -LR of 0.22 (20). So a positive test is not very helpful but a negative test is getting closer to being helpful (remember we want a -LR of <= 0.1). The arguments for CCTA are that you get patients out and don’t need to do more to patients once you have “ seen” their coronaries. I’m sure by now you know where Im going with this. Lets see how that worked out. In a follow up study by Hollander et al 1285 patients were followed up after randomization to either CCTA or ST. Unfortunately the incidence of MACE in both groups was REALLY low, like 1 death and <0.6% MI, MACE etc. We should probably call this group NO RISK rather than LOW RISK. However, the CCTA group had 154/820 (18%) ST and/or caths in the following year which was the same as the traditional care group in the following year. Another example is the Promise Trial which randomized 4996 patients to CTA and 5007 to ST and followed both groups for 2 years. This cohort after 2 years had an endpoint of death, nonfatal myocardial infarction, or hospitalization for unstable angina in 162/4996 (3%) in the CCTA group and 148/5007 (3%) in the traditional care group. A cardiac catheterization was performed in 12.2% of patients in the CTA group and 8% of patients in the ST group. Of the group that received both CCTA AND a cardiac Cath, 28% of those cath’s were negative. Of the group that received ST and a cardiac Cath a whopping 50% of those had a negative cath (21)! CCTA (not to mention ST) causes more downstream testing with negative procedures and more radiation. An editorial in NEJM by Dr. Rita Redberg, accompanied the CCTA protocol and summed it up better than I ever could. “In short, the question is not which test leads to faster discharge of patients from the emergency department, but whether a test is needed at all… [Dr. Redberg] believe[sic] judicious clinical follow-up is safer and in the best interests of the majority of these patients (17). Did I mention that Dr. Redberg, is from the Division of Cardiology, UCSF? Allow me to overstate this: a cardiologist from UCSF in NEJM 2012 wrote that no provocative testing is necessary at all for low risk patients.

TO BE CONTINUED IN PART II…

ABBREVIATIONS

ADP = accelerated diagnostic protocols aka rapid rule out

CAS = coronary calcium score

CCTA = Coronary CT Angiogram

CDT = clinical decision tool

FFR = Fractional Flow Reserve

LR = Likelihood Ratio (Positive or Negative)

MACE = major cardiac adverse events usually including: cardiac death, non-fatal MI, dysrhythmias, unstable angina requiring hospitalization, and late revascularization

MI = AMI = myocardial infarction

MPI = myocardial perfusion scan

PCI = Percutaneous Coronary Intervention

SE = Stress echo

Sn = Sensitivity

Sp = Specificity

ST = Stress Testing

NOTES

A. In 2000, the definition of acute myocardial infarction changed to: ‘typical rise and gradual fall of cardiac troponin, or more rapid fall of CK-MB, with at least one of the following: ischemic symptoms; the development of pathological Q waves; ECG changes indicative of ischemia (ST-segment elevation or depression); coronary artery intervention (2)

B. If you are reading this note then either you like my sarcasm or haven’t gotten my feelings for ST. Obviously ST in age group less than 40 is about as useful as a rubber ladder on a hot day. So it kills me when I see this in the community. I think this article sums it up nicely: “Routine stress testing added little to the diagnostic evaluation of this patient group and was falsely positive in all patients who consented to diagnostic coronary angiography” (13).

C. For ease of reading (and writing) all numbers are expressed as integers rounded to the nears whole number unless written with a decimal point for shock and awe.

D. This risk stratification has some clinical face value but is clearly unique to Australasia and has unknown generalizability to the US.

E. Risk was defined in a very complicated manner as follows:

1. Intermediate Risk: 
 No high risk features, and any of:

* Chest pain or discomfort during rest within past 48 h, or pain that was repetitive or prolonged, but currently resolved

* Age > 65 years

* Coronary heart disease: prior myocardial infarction with LVEF ! 40% or known coronary lesion > 50% stenosed

* Two or more of: known hypertension, family history, active smoking, hyperlipidaemia

* Diabetes (with atypical symptoms of ACS)

* Chronic kidney disease, eGFR < 60 mL/min/1.73 m2 (with atypical symptoms of ACS)

* Prior aspirin use

2. Low Risk:

1. * No intermediate or high risk features, and any of:

* Onset of angina symptoms during the past month

*Worsening in severity or frequency of angina

*Lowering of angina threshold

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