EM Lyceum

4. How reassuring is a recent (< 1 year) negative stress test in managing a patient with chest pain? How about a recent “normal” cath (i.e., < 30% blockage, no intervention)?

In a word (or two): not very.

The problem of what to do with a patient who has had a recent “negative” cardiac work-up and who now presents to the ED with the same complaint of chest pain is a frustrating one for all parties involved.   There is no clear cut answer to this conundrum and there is scant literature addressing the issue, though there has been at least one proposed, but not studied or validated, algorithmic approach to assessing such patients (Lewis, 2010).  Concerningly, some studies have suggested that cardiac morbidity and mortality after a negative ACS work-up may be as high as 14% for adverse cardiac events and 2% mortality at 6 months (Manini, 2002).

In approaching these situations, it is helpful to: 1) have an understanding of the pathophysiology of coronary artery disease and ACS; 2) be familiar with the type of test or study the patient had: What are its diagnostic and prognostic abilities? Its limitations?; and 3) understand the limitations of those statistics as they relate to an individual patient.

Pathophysiology-wise, the key point to remember is that plaques can rupture at any size including when they are considered non-obstructive (less than 50% occluded) (Hackett, 1988). While studies suggest that there is a direct relationship between size of a plaque and its vulnerability to rupture (Rao, 2005), other studies have also shown that lumen-preserving eccentric plaques may be even more vulnerable than those that partially obstruct the lumen (Varnava, 2002; Yamagishi, 2000). This means that what appears to be a patent vessel may in fact be a ticking time-bomb.

Stress tests come in many flavors. For the sake of this question, we’ll use the extreme ends of the spectrum of studies used to assess coronary artery disease burden. On the simplest end we have the electrocardiogram exercise stress test, and on the other end, we have the “gold standard” of cardiac catheterization. Between these two lie many other tests including stress echocardiography, myocardial perfusion imaging (SPECT, PET, etc.), cardiac magnetic resonance imaging, and multi-detector cardiac computed tomography, all with varied sensitivities, specificities, positive and negative predictive values.

Electrocardiogram exercise stress tests (ESTs) are the workhorse of risk stratification of patients with low-and-intermediate-risk chest pain who have normal resting ECGs and who are able to exercise. While they have reasonable sensitivities for detecting three-vessel disease they are relatively poor at identifying single vessel disease-with the exception of left main occlusion, for which they are also sensitive (Detrano, 1989), but of course incredibly high risk to perform. Despite high negative predictive values of 90-99%, which are even better when combined with the Duke Treadmill Score, (Mieres, 2005, Johnson, 2008, Manini, 2010), ESTs do not rule out coronary artery disease and a “negative” test should only be considered valid in ruling out ischemia as a cause of chest pain at the time of the test (Jones, 2010).

Cardiac catheterization, though considered the gold standard in diagnosing coronary artery disease, is also not fail-safe.  It is known to have limitations in identifying lesions, in part due to its two-dimensional nature (Topol, 1995). Even when luminal narrowing is appreciated, the nature and stability of the plaques is not known, and plaques that are eccentric are likely not recognized at all (Yamagishi, 2000). Small plaques may result in a “normal” angiogram, but may rupture the following day. (Of note, intravascular ultrasound has been used to help identify and characterize plaques, but is an additional procedure, not regularly performed with angiographies.) One study showed that 9% of NSTEMIs studied had non-obstructive disease (half of which had no disease seen at all); these patients nonetheless had a 2% death and/or MI rate  and a 12.1% primary end point rate (death, MI, UA, revascularization, stroke) at one year, indicating that lack of “significant” disease is not necessarily reassuring (Bugiardini, 2005).

Patients have been found to have ischemic events even in the absence of any coronary vessel disease. Myocardial infarction with clean coronaries is a frustrating entity to cardiologists. Some causes are believed to be myocardial bridging, coronary tortuosity and microvascular dysfunction (Gaibazzi, 2011).  Syndrome X (normal coronaries with chest pain and either ST changes or a positive stress test) afflicts women more often than men.  Though the prognosis for these patients is generally good, chest pain with non-obstructive disease has also not found to be entirely benign (Bugiardini, 2005).

In considering the weight of a stress test result in evaluating a chest pain patient, it is important to keep in mind that while exercise stress test results are generally considered “valid” for 1-2 years, many of the studies evaluating outcomes of patients, and hence ascribing prognostic value to these tests, only followed patients for 30 days to one year.  Perhaps even more important is to understand that prognostic data applies to a population, not to one individual’s risk of developing ACS at any given time after having a negative study. Hence, even if the likelihood of having ACS within 30 days of a negative test is exceedingly small, it doesn’t mean that the patient in front of you, who had a normal test five days ago, didn’t just rupture a plaque.

In summary then, while stress tests are excellent for prognosticating risk of ACS, and angiograms are strong at determining plaque burden, the ED clinician should be careful not to give too much import to the results of a prior test when facing a patient complaining of chest pain.  If concern for ischemic disease persists, the patient warrants further inpatient evaluation.  Indeed, this seems to be the practice pattern of most ED physicians. According to one prospective cohort study,  ED physicians admitted chest pain patients with and without prior negative stress tests at the same rate. Contributing even more to a brewing sense of nihilism:  both groups had the same cardiac event rate (Nerenberg, 2007).

3.  How do you risk stratify patients with chest pain?  Do you use any clinical decision rules?

It’s a daily ED conundrum: how concerning is this patient’s chest pain? This most common, yet challenging, clinical quandary is not an insignificant one as there is a high cost (in lives and dollars) associated with missed diagnoses and over-admission of patients found not to have ACS.  Despite the efforts of many, there is still no (validated) answer as to how to identify the patient who is safe to discharge or who is sure to have ischemic disease. Sadly, we will not be providing you with one here, either.  But, we’d like to leave you with some pearls to use when risk stratifying ED chest pain patients.

Clinical impression: Several studies have looked at how good a clinician’s gestalt is in risk stratifying patients.  Outcomes of these suggest that while our clinical estimation of a patient’s risk does have some prognostic value in that it correlates with adverse outcomes in patients, our intuition together with an ECG are not sufficient to identify patients safe for discharge (Chandra, 2009). Even when we think we have a “clear cut” non-cardiac explanation for chest pain, it turns out we may not be right: although these patients have a reduced risk of adverse events, they have been found nonetheless to have a 4% thirty day event rate (death, MI, revascularization) (Hollander, 2007). These findings are made all the more concerning by the results of a recent study that found the presence of “atypical” chest pain to be an independent predictor of in-hospital mortality (El-Menyar, 2011).

Bottom line: Your clinical impression is important, but not sufficient.

Risk factors: Ah, risk factors. We all find comfort in asking questions about hypertension, hyperlipidemia, smoking, diabetes, and family history. The problem is that these “risk factors” are risk factors for developing coronary artery disease–not for acute cardiac ischemia.  Established through the Framingham study, these risk factors have been found to be poor predictors of AMI or ACS, and are considered much less useful than symptoms, EKG, or cardiac biomarkers (AHA/ACC NSTEMI Guidelines 2007).  One study found that risk factors had no predictive value in women, and that the only risk factors that increased risk of acute ischemia in men (with a very low relative risk) were diabetes and family history (Jayes, 1992). Another, more recent study that analyzed over ten thousand patients using the Internet Tracking Registry of Acute Coronary Syndromes (i*trACS) registry, found that while the absence of risk factors in patients under 40 has a strong negative predictive value, the presence (or absence) of them in patients over 40 has limited clinical significance (Han, 2007).

Bottom line: Risk factors are for coronary artery disease, not for acute ischemia. They have limited utility in assessing the presence (or absence) of ACS.

History & Clinical features:  Among the gamut of questions we ask patients about the quality, location, severity, and alleviating/exacerbating factors of their pain, few have been shown to be independent positive or negative predictors of ACS.  Several studies and reviews have evaluated various symptoms and chest pain descriptors.  The one, common, positive predictor of ACS/AMI is radiation of pain to the shoulders, especially if it is to both shoulders (LRs ranging from 4.1-7.1) (Panju, 1988; Swap 2005; Goodacre 2002). Other potential predictors are not as clear.  Nausea, vomiting and diaphoresis has been found predictive by some (Panju, 1988), while others found exertional pain to be predictive (Goodacre, 2002). With respect to characteristics that may help rule out ACS, Panju, et al., found that pleuritic, positional, reproducible (with palpation) or sharp/stabbing chest pain has a negative predictive value.  However, Goodacre’s study found only a non-significant trend towards an unlikely ACS diagnosis for pleuritic pain, and found no association at all for the other characteristics.  Severity, location, character (e.g. pressure, ache, burning) were all found to be poor predictors.

Bottom line: Chest pain radiating to the shoulders is concerning for AMI/ACS.  Other findings are not independently reliable; however, they may be more useful in aggregate (See clinical decision rules below).

Response to treatment: While we might hope that response to nitroglycerin might suggest angina, or that improvement of symptoms with a GI cocktail might reassure us that the pain is indeed related to GERD, studies have suggested otherwise.  It seems that nitroglycerin can also relieve esophageal causes of chest pain and has been found to equally improve pain in patients with and without ACS (Henrikson,  2003). Similarly, studies and case reports suggest caution in using a GI cocktails to differentiate ischemia from gastrointestinal pain  (Wrenn, 1995, Servi, 1985).

Bottom line: Exercise caution in attributing diagnostic weight to the relief (or absence of relief) of symptoms by nitroglycerin or GI cocktails.

Clinical decision rules: Because of all the disheartening  studies that have failed to identify the single Golden Key to separating the sick hearts from the well ones, multiple clinical decision rules have tried to amalgamate predictive factors to increase the ability to do just that.  Two of the most commonly used and compared are the TIMI Risk Score (for UA/NSTEMI and STEMI) and the GRACE score. Both have been validated as risk stratification tools for patients presenting to the ED, and hence can help guide treatment, according to the ACC/AHA guidelines (Lyon, 2007). However, even these tools do not help determine whether a patient is safe to be discharged.  One clinical decision rule that may help with this is the Vancouver Chest Pain rule. This rule was found to have 98.8% sensitivity for AMI/ACS, and defined a group of patients who were safe for discharge after a few hours in the ED, but has not yet been validated (Christenson 2006). Unfortunately, this rule, plus seven others, were systematically reviewed by Hess et al., who found none of the rules yet acceptable for clinical practice (Hess, 2008).

Bottom line: Clinical prediction rules can be used to help risk stratify, but are not helpful in identifying patients safe for discharge.

Is there anyone I can discharge? The ACC/AHA guidelines allow for discharge of patients established to have non-cardiac causes of chest pain, but require at least a “rule-out” work-up (initial and repeat cardiac enzymes, ECGs and preferably an in-house stress test) for any patient for whom ischemic disease is considered a possibility, no matter how low the risk.  Of course, establishing whether a patient’s pain is ischemic or not in origin is the crux of the problem we face daily.  TIMI and GRACE scores may help. Others have used data from a few studies including that by Han (2007) and Marsan (2005) to support discharging patients under 40 years of age with a normal ECG, no established CAD, and none of the traditional Framingham risk factors, as they had only a 0.2% thirty-day rate of death or MI (Newman, 2011). But, again, this approach has not been validated.

In summary, establishing whether someone’s chest pain is ischemic in origin can be difficult, and one should be wary of placing too much emphasis on individual clinical findings in making that determination. Ultimately, if ischemia is at all a concern, the patient should be risk stratified (TIMI and GRACE scores together with history and clinical findings help with this) and treated according to the ACC/AHA guidelines based on that risk stratification, which at the very least may include admission to an observation or chest pain unit. There may be some patient groups who are safe for discharge, but rules defining such groups have yet to be validated.  Here’s to hoping for a validated rule soon.

2.  How do you identify and manage patients with unstable angina?

Patients with unstable angina (UA) are  on the same ACS spectrum as NSTEMIs and STEMIs.  Unstable angina is defined as either angina at rest, new onset (< 2 months) severe angina, or worsening angina. UA should not be considered benign, as its cause is plaque instability/rupture, just as in NSTEMIs and STEMIs. It is usually not that difficult to identify; however, there is often much hesitation or inertia in starting aggressive therapy for it, as there are no significant ECG findings and biomarkers are negative.  It is important to note, though, that UA and non-occlusive CAD are not benign and include a 2% risk of death or MI at 30 days follow-up (Bugiardini, 2005).

Accordingly, the ACC/AHA guidelines recommend that patients with UA be treated the same as patients with NSTEMIs: full anti-platelet and anti-coagulation (as described in question #1) as well as early invasive treatment (< 24-48 hrs) for high risk patients, (GRACE score > 140). These treatments are, of course, in addition to the oxygen, nitroglycerin, beta-blocker, ACE inhibitor/ARB, and statin recommended for all ACS patients.

Unfortunately, there has been a long-recognized lack of compliance with guidelines regarding treatment of UA and NSTEMIs (collectively referred to as NSTE ACS).  This problem led to the development of the CRUSADE (Can Rapid risk Stratification of Unstable angina patients suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines) quality improvement initiative (Hoekstra, 2002).  This initiative involved over 400 EDs nationwide and established a registry of high risk NSTE ACS patients, characterizing demographics, risk stratification results, and treatments given.  It also provided feedback to the hospitals, so that they could monitor and improve their performance.

Findings from the CRUSADE registry underscored the importance of adhering to guidelines.  One group found that guidelines were followed only 74% of the time, and that a hospital’s composite guideline adherence rate was significantly associated with in-hospital mortality. Indeed they found that for each 10% increase in the composite adherence to the ACC/AHA guidelines, there was a 10% decrease in the odds of in-hospital mortality (Peterson, 2006). Another study conducted in Spain yielded similar results where underuse of Class I recommendations was found to be an independent predictor of death in patients with NSTE ACS (Heras, 2006).

Perhaps one of the most intriguing patterns uncovered by researchers analyzing the CRUSADE data was that of paradoxical care. Those at highest risk (i.e. those who should have been receiving more aggressive intervention) were precisely those that received the least care. Some of these higher risk groups included the elderly and patients with chronic renal insufficiency, both of whom were often were undertreated with antithrombotics/antiplatelets (Tricoci, 2006).  This paradox extended to patients chosen for early invasive strategies. While angiography and PCI are intended for high-risk patients–for whom it is expected to have the most benefit–multiple studies have found instead an inverse relationship between cardiac risk level and invasive cardiac procedures, where younger and healthier patients (i.e. those with fewer co-morbidities or risk factors) were taken to the cath lab preferentially (Bhatt, 2004, Cohen 2009, Zia 2007). The significance of this is seen in Bhatt’s study, where in propensity-matched pairs analysis he found the frequency of in-house mortality to be significantly lower in those undergoing early invasive treatment (2.5% v 3.7%).

NB: For this topic, perhaps the most researched in all of modern medicine, we are going to break up the answers to avoid dyspepsia. Our apologies for the extra emails.

1.     What anti-coagulants and/or anti-platelet agents do you use in a patient with a STEMI?  In an NSTEMI?

While the use of some anti-thrombotic agents in ACS is exceedingly standard–e.g., aspirin–that of others is much more variable. This is in part because of the ever-expanding drug development and research surrounding the care of the ACS patient. The ACC/AHA most recently updated its STEMI guidelines in 2009 and its UA/NSTEMI guidelines in 2011. Below is a summary of the latest recommendations (as well as some more recent updates) for STEMIs (PCI only) and NSTEMIs.

STEMI

Dual-antiplatelet therapy is recommended in STEMIs, with PCI or fibrinolysis. Aspirin 162 or 325mg (Class I, LOE A) should be given as soon as possible, as should either clopidogrel (Class I, LOE C) or prasugrel (Class I, LOE B) (the latter two being thienopyridines).  If the thienopyridine is held until the coronary anatomy is elucidated via angiography in anticipation of possible need for CABG, it should be given as soon as PCI has been decided upon.  While the recommended loading dose for prasugrel is set at 60mg, that of clopidogrel (300 v 600mg) remained unresolved as of the 2009 update. However, at least two trials since then (HORIZONS-AMI, CURRENT-OASIS 7) have both suggested that the higher dose of 600mg may be superior in PCI, though the benefit is possibly offset by an increase in major bleeding.

As for which of these two thienopyridines to choose, the 2009 recommendations do not specifically endorse one over the other.  Notably, prasugrel achieves greater inhibition of platelet aggregation, has a more rapid onset, and is not susceptible to the variable response in patients that clopidogrel is.  In the pivotal prasugrel trial, TRITON-TIMI 38, prasugrel was associated with a significant absolute and relative reduction in composite rate of death due to cardiovascular causes, non-fatal MI. or non-fatal stroke relative to clopidogrel; however, the clopidogrel dose used was only 300mg (not 600mg). Prasugrel also had a greater risk of bleeding and was found to not have a net benefit in patients with a history of stroke or TIA, in patients over age 75, or those with a body weight less than 60kg.  Consequently, the current recommendations are to avoid use of prasugrel in these patients.  Of note, the 2009 recommendations do not discuss ticagrelor, a promising, reversible adensosine diphosphate receptor antagonist that was shown in the PLATO trial to have significantly reduced cardiac and all-cause mortality in patients, relative to clopidogrel, without an attendant increase in bleeding risk. This agent was FDA approved on July 20, 2011 and will likely be added to the recommended arsenal of ACS agents soon.

Glycoprotein IIb/IIIa receptor antagonists (GPIs, e.g., abciximab, tirofiban, and eptifibatide) are another group of anti-platelet agents that have been amply shown to reduce recurrent ischemia and MI in ACS patients who undergo PCI (Boersma, 2002).  However, there have not been many trials studying GPIs with current STEMI treatments, particularly in the era of dual anti-platelet therapy. The few that have looked at GPIs as adjuncts to oral antiplatelet therapy (BRAVE-3, On-TIME 2, HORIZONS-AMI) have found no difference in infarct size or thirty day mortality, and have found either no difference in bleeding or an increased risk of bleeding.  So, while the AHA still considers them to be a reasonable treatment at the time of PCI in selected patients (such as those with large thrombus burden or those not adequately loaded with thienopyridines),  these agents have fallen out of favor as a pre-PCI or “upstream” intervention  where they are associated with increased bleeding risk (FINESSE). This means that this class of drugs will primarily be administered in the cath lab and not in the ED for STEMIs being treated with primary PCI.

When it comes to anticoagulation, there are multiple possible agents including unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin.  Although UFH has long been a main-stay of anti-coagulation in fibrinolysis and PCI, and is still considered a Class I recommendation in the AHA STEMI guidelines, its utility is limited by its bleeding risks, unpredictable anticoagulant effect, and risk of heparin-induced thrombocytopenia (HIT).  Enoxaparin, however, has more predictable effect, does not require monitoring, and has been shown to be superior to UFH in multiple studies including the ExTRACT-TIMI 25, FINESSE and ATOLL trials.  It is generally considered safe with primary PCI, and is the anticoagulant of choice in patients undergoing PCI after fibrinolysis.  (Wong, 2011)

Bivalirudin, a direct thrombin inhibitor, was added to the 2009 guidelines as a useful supportive measure for primary PCI, with or without prior treatment with UFH, for patients who had also received aspirin and a thienopyridine.  It was also recommended for patients undergoing PCI who had a high risk of bleeding, as it was found to have a decreased bleeding risk associated with it. It is considered by some to be the preferred anticoagulant in primary PCI (Diez 2010, Wong 2011).

In summary, patients with STEMIs who are heading to the cath lab should receive aspirin, either clopidogrel 600mg or prasugrel 60mg, and an anticoagulant–preferably enoxaparin or bivalirudin–while in the emergency department. Consultation with the cardiologists at your hospital is always prudent in making these decisions, as local practice may vary.

NSTEMI

Much as for STEMIs, dual antiplatelet therapy with aspirin and a thienopyridine is recommended for NSTEMIs.  However, while the aspirin is to be administered immediately, the timing of the thienopyridine can be delayed until “as soon as possible after admission” for those patients being treated with medical management, according to the 2011 guidelines.  For those undergoing an early invasive strategy, it should be administered before (or at the latest, during) PCI.   Clopidogrel is the thienopyridine recommended in most circumstances, with the guideline updates allowing for prasugrel to be given only during (and not prior to) PCI for those NSTEMIs being treated with an invasive strategy. The reason for this was prasugrel’s high risk of bleeding, as discussed above. Ticagrelor will likely soon play a role in NSTEMI management as well, now that it has been FDA approved.

The 2011 guidelines brought about a change in recommendations regarding GP IIa/IIIb inhibitors in NSTEMIs.  Again, as with STEMIs, few trials exist examining GPIs in the setting of dual anti-platelet therapy.   Two trials that have examined GPIs in the setting of aspirin/clopidogrel compared early and delayed administration of  GPIs in UA/NSTEMI patients scheduled for PCI (EARLY ACS, ACUITY).  Neither found a significant difference in their primary end points (all-cause mortality, MI, recurrent ischemia), but both noted significantly greater risk of major hemorrhage in the early GPI patients than the later GPI patients.  These results were confirmed by a meta-analysis of studies evaluating early and delayed GPI use (De Luca, 2011). It is important to note, however, that these studies were done in moderate and high-risk patients scheduled for early invasive therapy, and hence their results may not apply to those UA/NSTEMI patients being treated with medical management.  Nonetheless, the ACC/AHA guidelines recommend that the use of a GPI as part of triple anti-platelet therapy should only be undertaken when the risk-benefit ratio suggest a potential benefit for the ACS patient who is undergoing PCI. The guidelines do not recommend GPIs  for patients being treated with medical management.

Anticoagulation regimens for NSTEMI vary, depending on whether a medical management or early invasive strategy is being taken, and on the patient’s bleeding risk.  If the patient is being treated with medical management, or the decision has not yet been made to pursue invasive interventions, then either enoxaparin or fondaparinux is recommended over UFH, in part for the reasons given above for STEMI. In addition, a Cochrane review of UFH versus placebo in ACS found no difference in mortality.  While it did find a lower incidence in non-fatal MI in the first week after the initial ACS event, the benefit was no longer seen at thirty days, three, and six months (Magee, 2008).   Enoxaparin has been found to be non-inferior, and likely superior, to UFH in preventing in-hospital death or MI  (ACUTE II,  A to Z trial).

For patients undergoing early invasive therapy, UFH, enoxaparin or bivalirudin are acceptable agents.  Of note, unlike in medical management of NSTEMI,  at least one study (SYNERGY) has shown that in patients undergoing PCI, enoxaparin has a higher rate of bleeding than UFH, with similar rate of death or MI.  Bivalirudin was found to be non-inferior to heparin/LMWH combined with a GPI, (especially when clopidogrel was given early versus after PCI), and had a significantly lower bleeding rate. Hence, it is considered a good option in NSTEMI patients undergoing PCI at high risk for bleeding complications (ACUITY).

Below is a flow chart summarizing the 2011 ACC/AHA guidelines for management of UA/NSTEMI: