Thursday, August 28, 2014

9 Hours of Chest Pain and Deep Q-waves: Is it too late for Thrombolytics? (Time Window for Reperfusion; Acuteness on the ECG)

A 50 year old hypertensive presented with 9 hours of central crushing chest pain.  BP was 250/120, and after placement on an IV nitroglycerine drip, BP declined to 170/90.  Here is the presenting ECG:
There is diagnostic ST elevation with large T-waves.  However, there are deep QS-waves.  
1. How do we know these QS-waves do not represent LV aneurysm?
2. Do these Q-waves imply that the STEMI is too far progressed for benefit from tPA?

Let's answer question 1: The T-waves are too tall for LV aneurysm!  You can use this LV Aneurysm Rule to Determine whether there is acute STEMI or ST elevation due to LV aneurysm.
Question 2 is answered extensively below.

Time window for thrombolytics: The GISSI and the LATE trial both established that late thrombolysis, up to 12 hours after onset of chest pain, is beneficial for STEMI.  The FTT collaborative group meta-analysis confirmed this, and the benefit at various time points after pain onset is best described in the paper by Boersma (see Table below).  There are many STEMI, however, which will benefit beyond 12 hours of chest pain: the time onset of chest pain is not necessarily the time of onset of irreversible ischemia.  Many MIs have dynamic occlusion and reperfusion of the infarct-related artery and the pain can go on for days without any significnat necrosis.

The best indicator of MI "Acuteness" is the ECG, with these as indicators of high acuteness:
1. Absence of Q-waves
2. High ST segments
3. Large size of T-waves
4. Absence of T-wave inversion all indicators of high acuity.
At the bottom, I have reprinted a section that I wrote on "Acuteness" that comes from a chapter on reperfusion thereapy that I wrote with Bill Brady.

In this case, the ST segments are high, the T-waves are large, and there is no T-wave inversion.  The Q-waves are the only indicator of prolonged ischemia.  Moreover, the chest pain is less than 12 hours.  Unless there are important contraindications to reperfusion (i.e., high bleeding risk), then either tPA or PCI are indicated.

Case Progression
The physician could not get the interventionalist to take the patient for PCI (I am not sure why).  

The emergency physician sent this case to me real time, wondering if the QS-waves (absence of any R-wave) were a contraindication to tPA.  Before I could answer that, "no" they are not a contraindication, he gave tPA.

Shortly after tPA, this ECG was recorded:
There is significantly lower ST elevation, T-waves are no longer acute (tall) and have begun to invert.  These are signs of reperfusion.

In addition, and importantly, the pain completely resolved with thrombolytics.

An echocardiogram showed akinesis of the mid-apical portion of the anterior septum and mid-apical portion of the inferior septum.  There was no thinning to suggest old MI (not LV aneurysm). This was consistent with acute anterior STEMI.

Subsequently, the interventionalist agreed to take the patient for rescue PCI (even though the thrombolytics had clearly lysed the thrombus).  Angiogram revealed a severely stenotic mid-LAD lesion with no more thrombus present and TIMI-3 flow (excellent).  Thus, the artery had opened.  It was stented.

How long after onset of chest pain are thrombolytics effective (how long is the time window)?

Table 33-1 (from my book: The ECG in Acute MI): Time to thrombolysis and mortality reduction.  From: Boersma et al., Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet October 21, 1996, 348:771-775.  (This applies to all MI: anterior, inferior, lateral)
Time Window
Lives saved per 1000 patients treated (confidence intervals)
0-1 hour
65 (38-93)
1-2 hours
37 (20-55)
2-3 hours
26 (14-37)
3-6 hours
29 (19-40)
6-12 hours
18 (7-29)
12-24 hours
9 (-5-22) (not statistically significant)

What is the significance of pathologic Q-waves on the inital ECG?

Q-waves are often seen in the first hour after pain onset.  Raitt et al. found in a subgroup of 432 first MI patients whose ECG was recorded within the first hour after onset of chest pain that pathologic Q-waves were already present, and this was particularly true for anterior MI patients.  These patients had larger final infarct size, but equal benefit from thrombolytic therapy. 

More recently, Armstrong et al. showed that Q-waves on the baseline ECG are an independent marker of worse clinical outcome and, importantly, "after multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF."  Thus, another study shows that the ECG is a better marker of "acuteness" of the ECG than is time of symptom onset.

Lastly, when is it too late for emergent PCI?  Never, if there is persistent chest pain.

How about if the chest pain is resolved, but there is still ST elevation?  That was assessed in this study by Schomig et al. (this is linked to full text; reference and abstract below). They randomized patients who had at least one chest pain episode of at least 20 minutes that occurred between 12 and 48 hours before presentation, and had no persistent symptoms (!), but had unequivocal ischemic ST elevation on the ECG.  Randomized to immediate angiogram with PCI vs. later unplanned invasive evaluation and treatment if they developed recurrent severe angina, hemodynamic and electrical instability, severe congestive heart failure and/or pulmonary edema, mechanical complications, new relevant electrocardiographic changes (new or reelevation of ST-segments of 0.2 mV in 2 contiguous precordial leads or 0.1 mV in 2 adjacent limb electrocardiographic leads), reelevation of creatine kinase or creatine kinase-MB by at least 50% above the trough level after documentation that the level was decreasing prior to this re-elevation, or signs of induced ischemia during exercise testing.

It is taken as a given that if there are persistent symptoms, emergent PCI is indicated!!

Mechanical Reperfusion in Patients With Acute Myocardial Infarction Presenting More Than 12 Hours From Symptom Onset: A Randomized Controlled Trial.  Schomig et al. 
JAMA. 2005;293:2865-2872


Context: No specifically designed studies have addressed the role of primary percutaneous 
coronary intervention in patients with acute ST-segment elevation myocardial infarction (STEMI) presenting more than 12 hours after symptom onset. Current guidelines do not recommend reperfusion treatment in these patients.
Objective: To assess whether an immediate invasive treatment strategy is associated with a reduction of infarct size in patients with acute STEMI, presenting between 12 and 48 hours after symptom onset, vs a conventional conservative strategy. Design, Setting, and Patients International, multicenter, open-label, randomized controlled trial conducted from May 23, 2001, to December 15, 2004, of 365 patients aged 18 to 80 years without persistent symptoms admitted with the diagnosis of acute STEMI between 12 and 48 hours after symptom onset.
Interventions: Random assignment to either an invasive strategy (n=182) based predominantly
on coronary stenting with abciximab or a conventional conservative treatment
strategy (n=183).
Main Outcome Measures: The primary end point was final left ventricular infarct size according to single-photon emission computed tomography study with technetium Tc 99m sestamibi performed between 5 and 10 days after randomization in 347 patients (95.1%). Secondary end points included composite of death, recurrent MI, or stroke at 30 days.
Results: The final left ventricular infarct size was significantly smaller in patients assigned to the invasive group (median, 8.0%; interquartile range [IQR], 2.0%-15.8%) vs those assigned to the conservative group (median, 13.0%; IQR, 3.0%-27.0%; P .001). The mean difference in final left ventricular infarct size between the invasive and conservative groups was −6.8% (95% confidence interval [CI], −10.2% to −3.5%). The secondary end points of death, recurrent MI, or stroke at 30 days occurred in 8 patients in the invasive group (4.4%) and 12 patients in the conservative group (6.6%) (relative risk, 0.67; 95% CI, 0.27-1.62; P=.37).
Conclusion: An invasive strategy based on coronary stenting with adjunctive use of
abciximab reduces infarct size in patients with acute STEMI without persistent symptoms
presenting 12 to 48 hours after symptom onset.

This is a section on "Acuteness" that I wrote in a Chapter on Reperfusion therapy that I wrote with Bill Brady in Critical Decisions in Emergency and Acute Care Electrocardiography.  I have updated it here.

Here are a couple posts that demonstrate the issue of acuteness.

Acuteness—when is it too late for reperfusion?  
In deciding on reperfusion, particularly on fibrinolytic therapy, it is important to assess the amount of viable injured myocardium at risk of infarction.  This is traditionally done by assessing time since pain onset, and randomized trials of fibrinolytics found no significant advantage if pain duration was greater than 12 hours.[12, 32, 49]  However, time since pain onset is a crude way of assessing amount of infarcted (irreversible), vs. ischemic (viable, salvageable), myocardium.  Often, occlusion is incomplete, or collateral circulation maintains the viability of ischemic myocardium, or there is ischemic preconditioning, and myocardium that is fully salvageable may have pain duration of days.  Fortunately, the ECG is a better indicator of salvageable myocardium than pain duration. 
            High ECG “acuteness” is associated with significant salvageable myocardium.   An ECG has a high acuteness score if it has tall T-waves, and lower acuteness if there are Q-waves or T-wave inversion is present.[50]  In 395 patients, this score was shown to add the most value in situations of data disagreement: 1) in acute anterior MI when the history indicates symptom onset of greater than 2 hours but the acuteness score is high, or 2) in acute inferior MI, if history indicates a time since symptom onset less than 2 hours but the acuteness score is low.[51]  More recently, a high acuteness score was found on SPECT scanning and Cardiac MRI to be associated with more salvageable myocardium, and to be superior to time since pain onset for determining myocardium at risk (but not yet infarcted).[52]  This corresponds to other data showing that tall T-waves are an independent marker of benefit from fibrinolytics.[53] and that, among those with positive T waves, mortality after thrombolytics is the same for those who have greater than 2 hours vs. less than 2 hours of symptoms.[54]  It is also important to know that QR-waves are present in 50% of anterior MI within the first hour, and represent ischemia of the conducting system, not infarction.[55]      
            There are no randomized fibrinolytic trials based on EKG characteristics of acuteness.  However, PCI is proven beneficial in a randomized trial of patients with persistent ST elevation at greater than 12 hours after onset, even though they were pain free.[56] 
            Finally, ischemic discomfort is far less predictive of on ongoing ischemia than is persistent STE and tall T-waves.  ECG acuteness should not be ignored because of resolution of symptoms.[57]
            In summary, tall T-waves indicate a large amount of viable, salvagable, myocardium.  Q-waves indicate lower acuteness, but may be present early in anterior MI; thus, in anterior MI, T-waves are more important.   Inverted T-waves signify either low acuteness or an open artery (see chapter 11 on reperfusion).

12.       LATE Study Group, Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet, 1993. 342: p. 759-766.
32.       Fibrinolytic Therapy Trialists' (FTT) Collaborative Group, Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet, 1994. 343: p. 311-322.
49.       EMERAS (Estudio Multicentro Estreptoquinsa Republicas de America del Sur), Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet, 1993. 342(8874): p. 767-772.
50.       Wilkins, M.L., et al., An electrocardiographic acuteness score for quantifying the timing of a myocardial infarction to guide decisions regarding reperfusion therapy. Am J Cardiol, 1995. 75(8): p. 617-620.
51.       Corey, K.E., et al., Combined historical and electrocardiographic timing of acute anterior and inferior myocardial infarcts for prediction of reperfusion achievable size limitation. Am J Cardiol, 1999. 83(6): p. 826-831.
52.       Engblom, H., et al.  The evaluation of an electrocardiographic myocardial ischemia acuteness score to predict the amount of myocardial salvage achieved by early percutaneous coronary intervention : Clinical validation with myocardial perfusion single photon emission computed tomography and cardiac magnetic resonance.  Journal of Electrocardiology 44(5):525-532; Sept-Oct 2011.
53.       Hochrein, J., et al., Higher T-wave amplitude associated with better prognosis in patients receiving thrombolytic therapy for acute myocardial infarction (a GUSTO-1 substudy).  Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded Coronary Arteries. Am J Cardiol, 1998. 81(9): p. 1078-1084.
54.       Herz, I., et al., The prognostic implications of negative T-waves in the leads with ST segment elevation on admission in acute myocardial infarction. Cardiology, 1999. 92(2): p. 121-127.
55.       Raitt, M.H., et al., Appearance of abnormal Q waves early in the course of acute myocardial infarction: implications for efficacy of thrombolytic therapy. J Am Coll Cardiol, 1995. 25(5): p. 1084-1088.
56.       Schomig, A., et al., Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial. Jama, 2005. 293(23): p. 2865-72.
57.       2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. J Am Coll Cardiol, 2008. 51(2).

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