Abstract
Background
The relationships between Q waves that appear during the acute phase of ST‐elevation myocardial infarction (STEMI), clinical characteristics, ST‐segment resolution (STRes), and clopidogrel therapy in patients treated with fibrinolysis are not well described.
Hypothesis
We hypothesized that Q waves would be associated with less successful reperfusion and increased cardiovascular events.
Methods
In the CLARITY‐TIMI 28 trial, 3491 STEMI patients treated with fibrinolysis were randomized to clopidogrel or placebo. Electrocardiograms were evaluated for STRes post‐fibrinolysis and the presence of pathologic Q waves during the index hospitalization in 3322 patients.
Results
Q waves were identified in 2045 patients (61.6%) prior to discharge and were associated with increased odds of congestive heart failure (CHF) (adjusted odds ratio [ORadj]: 2.10, P = 0.002) or the composite of cardiovascular death/CHF at 30 days (ORadj: 2.08, P ≤ 0.001). Q waves were associated with lower odds of Thrombolysis in Myocardial Infarction [TIMI] flow grade 2 to 3 (ORadj: 0.78, P = 0.028), TIMI myocardial perfusion grade 3 (ORadj: 0.83, P = 0.029), and complete STRes at 90 minutes (ORadj: 0.80, P = 0.030). Patients with both a Q wave and incomplete STRes 90 minutes after fibrinolysis were at higher risk for cardiovascular death or CHF (11.1%) than patients with no Q wave and at least partial STRes (1.9%). Overall, clopidogrel tended to be equally or more effective in patients without Q waves compared to those with Q waves.
Conclusions
Among STEMI patients treated with fibrinolysis, evaluating for Q waves prior to discharge is a simple method of assessing for less successful reperfusion and an increased risk of adverse 30‐day cardiovascular outcomes. The combination of Q waves and 90‐minute STRes allows additional risk refinement.
Introduction
Pathologic Q waves on the electrocardiogram (ECG) have historically been thought to represent scarred and nonviable myocardium. More recent evidence, however, suggests that Q waves may be present in myocardium that retains viability,1 and that Q waves that appear early in the course of acute coronary syndrome may be transient manifestations of severe ischemia without infarction,2, 3, 4 which may even regress over time.5, 6 Q waves have been shown to be better than the subjective time from symptom onset to presentation or treatment in identifying patients at high risk for complications after ST‐segment elevation myocardial infarction (STEMI).7, 8, 9 The appearance of new Q waves on the presenting ECG has also been associated with increased infarct size and biomarker release,2, 8, 10, 11, 12, 13 increased rates of adverse cardiovascular (CV) outcomes,7, 8, 9, 11, 12, 13 reduced infarct‐related artery (IRA) flow,8, 12, 14 poor ST‐segment resolution (STRes),7, 8, 15 and the no‐reflow phenomenon.16 Despite this, there are limited data on whether Q waves are associated with a differential benefit of early pharmacologic reperfusion therapy in patients with STEMI.2, 12, 17
The CLARITY‐TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28) study evaluated the addition of clopidogrel to standard therapy with aspirin and fibrinolytics in 3491 patients presenting with STEMI. Compared to patients who received placebo, patients who received clopidogrel were significantly less likely to experience the composite of an occluded IRA or death, or recurrent myocardial infarction (MI) prior to angiography. Additionally, patients were significantly less likely to experience a composite of death from CV causes, recurrent MI, or recurrent ischemia leading to the need for urgent revascularization within 30 days without a significant increase in bleeding complications.18 In the present analysis of the CLARITY‐TIMI 28 trial, we identify patient characteristics that are associated with the development of Q waves during the index hospitalization and evaluate their prognostic implications.
Methods
Patient Selection and Procedures
Details of the study design of the CLARITY‐TIMI 28 trial have been published previously.18, 19 Briefly, the trial was double‐blind, placebo‐controlled, and included 3491 patients 18 to 75 years of age who presented with the onset of ischemic chest discomfort lasting >20 minutes and ST‐elevations on the initial ECG (defined as >0.1 mV in at least 2 contiguous limb leads, >0.2 mV in at least 2 contiguous precordial leads, or presumed new left bundle branch block) who were scheduled to be treated with aspirin and fibrinolysis. Patients were randomized at the time of fibrinolysis to receive either clopidogrel (300 mg loading dose and 75 mg daily thereafter) or placebo that was continued until coronary angiography was performed (between 48 and 192 hours, median 84 hours), or until discharge or hospital day 8 in patients in whom angiography was not planned. Prespecified outcomes were assessed at 30 days by telephone follow‐up and then verified with medical records. Overall, 3487 of 3491 patients (99.9%) had their vital status ascertained at 30 days.
ECG Assessment of Q Waves and ST‐Segment Resolution
As prespecified, ECGs were performed at the time of presentation prior to administration of fibrinolytic, at 90 and 180 minutes after administration of fibrinolytic, and prior to discharge. The presence or absence of Q waves in the infarct‐related leads prior to discharge was assessed locally and using standard clinical definitions20 without confirmation in a core laboratory. The magnitude and total number of leads with Q waves were not assessed. A total of 169 patients (4.8%) had ECGs that were not interpretable for technical reasons or had unknown Q wave status and were therefore excluded from this analysis. STRes was assessed by a core laboratory using previously described methods.21 Complete STRes was defined as >70% in accordance with previous definitions.22
Statistical Analyses
In the description of patient characteristics, continuous variables, reported as the median and interquartile range, were compared using a 2‐sample Wilcoxon rank sum test or Kruskall‐Wallis test. Categorical variables, reported as a percentage of the total, were compared using a Pearson χ2 test. To determine which patient characteristics were correlated with Q waves, unadjusted odds ratios (ORs) were calculated. A multivariate logistic regression model was then constructed including baseline characteristics (age, systolic blood pressure, heart rate, time from symptom onset to fibrinolytic administration, gender, race, history of hypertension, history of hyperlipidemia, current smoking status, history of diabetes, history of prior MI, history of prior percutaneous coronary intervention (PCI), history of aspirin use, history of statin use, and anterior MI) to determine which variables remained independently associated with Q wave development.
To determine the association between Q waves and electrocardiographic, angiographic, and 30‐day outcomes, a logistic regression model was constructed with the following variables: Q wave status, Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI,23 history of prior MI, predominant type of heparin used, type of fibrinolytic used, IRA, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and duration from symptom onset to fibrinolytic administration. Similarly, to determine the effect of clopidogrel on 30‐day outcomes in patients with and without Q waves, patients were stratified according to Q wave (yes vs no) and then analyzed in a logistic regression model containing the same variables except for the removal of Q wave status and the addition of treatment status (clopidogrel vs placebo). Interaction terms were added to assess differences in outcomes based on randomization to clopidogrel or placebo in patients with and without Q waves.
All analyses were performed independently by the TIMI Study Group using R version 2.12.1 (R Foundation for Statistical Computing, Vienna, Austria; http://www.r‐project.org/).
Results
Baseline Patient Characteristics and Correlates of Q Wave Development
There were 3491 patients enrolled into the CLARITY‐TIMI 28 trial, and 3322 (95%) had ECGs during their index hospitalization that were valid for inclusion in these analyses. ECGs were equally distributed among patients randomized to clopidogrel or placebo (1661 in each group). A total of 2045 patients (61.6%) had a Q wave identified. Table 1 shows the characteristics of patients stratified by Q wave. After adjustment for all baseline characteristics, time from symptom onset to fibrinolytic administration (adjusted OR [ORadj]: 1.06 per 10 minutes, 95% confidence interval [CI]: 1.02‐1.11, P = 0.006), and male gender (ORadj: 1.35, 95% CI: 1.09‐1.67, P = 0.006) were independently and positively correlated with the presence of a Q wave. Patients who were Caucasian (ORadj: 0.62, 95% CI: 0.46‐0.83, P = 0.002) had a history of prior MI (ORadj: 0.68, 95% CI: 0.48‐0.97, P = 0.033) and had been receiving a statin within the prior 2 weeks (ORadj: 0.74, 95% CI: 0.56‐0.98, P = 0.033) were less likely to have Q waves.
Table 1.
Baseline Characteristics of Patients Stratified by the Presence of Q Waves During the Index Hospitalization
| Baseline Characteristic | Q Wave [n = 2045] | No Q Wave [n = 1277] | P Value |
|---|---|---|---|
| Age, y | 58 (50–66) | 57 (50–66) | 0.507 |
| Male (%) | 1669 (81.6) | 1007 (78.9) | 0.051 |
| Caucasian (%) | 1805 (88.3) | 1173 (91.9) | 0.001 |
| Hypertension (%) | 893(44.1) | 544 (43.1) | 0.582 |
| Hyperlipidemia (%) | 659 (39.0) | 438 (39.0) | 0.994 |
| Current smokers (%) | 1033 (50.6) | 637 (50.0) | 0.725 |
| Diabetes mellitus (%) | 349 (17.3) | 203 (16.2) | 0.391 |
| Prior MI (%) | 149 (7.3) | 145 (11.4) | <0.001 |
| Prior PCI (%) | 78 (3.8) | 82 (6.5) | 0.001 |
| Prior aspirin use (%) | 287 (14.0) | 227 (17.8) | 0.004 |
| Prior statin use (%) | 224 (11.0) | 194 (15.2) | <0.001 |
| Anterior MI (%) | 821 (40.1) | 525 (41.1) | 0.581 |
| Time from symptom onset to fibrinolysis, h | 2.83 (1.83–4.33) | 2.50 (1.67–3.63) | <0.001 |
| Systolic blood pressure, mmHg | 135 (120–150) | 135 (120–150) | 0.685 |
| Heart rate, bpm | 75 (63–86) | 72 (60–85) | 0.014 |
Abbreviations: MI, myocardial infarction; PCI, percutaneous coronary intervention.
Data are presented as median (interquartile range) or number (% of total). Information on baseline characteristics was not available for all patients.
Electrocardiographic, Angiographic, and Biochemical Characteristics
Electrocardiographic, angiographic, and biochemical characteristics stratified by Q wave are shown in Table 2. Patients with Q waves were significantly more likely to have residual thrombus at the time of angiography (ORadj: 1.28, P = 0.007) and incomplete reperfusion after fibrinolysis as indicated by TIMI myocardial perfusion grade 3 (ORadj: 0.83, P = 0.029) and TIMI flow grade 2 to 3 (ORadj: 0.78, P = 0.028). Patients with Q waves also were significantly less likely to have complete (>70%) STRes at 90 minutes (ORadj: 0.80, P = 0.030) and had larger infarcts as estimated by a higher median peak creatine kinase‐myocardial band (CK‐MB) (12.9 × the upper limit of normal [ULN] vs 8.5 × ULN, P < 0.001). In patients with Q waves, the IRA was more commonly the right coronary (48.4% vs 39.7%), less commonly the left circumflex (10.9% vs 18.1%), and the rates of a left anterior descending IRA (37.4% vs 38.2%), left main IRA (0.8% vs 1.7%), and multivessel IRA (2.5% vs 2.4%) were similar (global P < 0.001).
Table 2.
Electrocardiographic, Angiographic, and Biochemical Outcomes According to the Presence of Q Waves During the Index Hospitalization
| Outcome | Q Wave (%) | No Q Wave (%) | Adjusted OR (95% CI) | Adjusted P Value |
|---|---|---|---|---|
| Complete STres (>70%) at 90 minutes | 518/1511 (34.3) | 365/863 (42.3) | 0.80 (0.66‐ 0.98) | 0.030 |
| Complete STres (>70%) at 180 minutes | 690/1341 (51.5) | 415/752 (55.2) | 0.91 (0.74‐1.13) | 0.401 |
| Thrombus on angiography | 541/1912 (28.3) | 285/1193 (23.9) | 1.28 (1.10‐1.54) | 0.007 |
| TIMI flow 2–3 (vs 0–1) | 1611/1927 (83.6) | 1051/1209 (86.9) | 0.78 (0.62‐0.97) | 0.028 |
| TMPG 3 (vs 0–2) | 965/1876 (51.4) | 669/1168 (57.3) | 0.83 (0.71‐0.98) | 0.029 |
| Time to angiography, h | 88 (54–129) | 81 (51–120) | — | 0.026a |
| Peak CK‐MB (× ULN) | 12.9 (5.7–31.3) | 8.5 (3.0–20.3) | — | <0.001a |
Abbreviations: CI, confidence interval; CK‐MB; creatine kinase‐myocardial band; OR, odds ratio; STres, ST‐segment resolution; TIMI, Thrombolysis in Myocardial Infarction; TMPG, TIMI myocardial perfusion grade; ULN, upper limit of normal.
Adjusted ORs corrected for TIMI risk score for ST‐elevation myocardial infarction, history of prior myocardial infarction, predominant type of heparin used, type of fibrinolytic used, infarct‐related artery, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and duration from symptom onset to administration of fibrinolytic.
Data are presented as number/total (%) or median (interquartile range).
Data on time to angiography and peak CK‐MB were not adjusted in the above multivariable model. P values for time to angiography and peak CK‐MB are unadjusted.
Clinical Outcomes at 30 Days
The associations between Q waves and CV outcomes at 30 days are shown in Table 3. After multivariable adjustment, a Q wave was independently associated with an increased risk of congestive heart failure (CHF) (ORadj: 2.1, P = 0.002) and the composite of CV death or CHF (ORadj: 2.1, P < 0.001). Figure 1 shows Kaplan‐Meier event estimates for the composite outcome of CHF or CV death throughout the first 30 days. A Q wave was not associated with an increase in the risks of recurrent MI, recurrent ischemia, or stroke.
Table 3.
Thirty‐Day Cardiovascular Events According to the Presence of Q Waves During the Index Hospitalization
| Outcome at 30 Days | Q Wave (%) | No Q Wave (%) | Unadjusted OR | Unadjusted | Adjusted OR | Adjusted |
|---|---|---|---|---|---|---|
| [n = 2045] | [n = 1277] | (95% CI) | P Value | (95% CI) | P Value | |
| CV death or CHF | 187 (9.1) | 61 (4.8) | 2.01 (1.50 ‐2.72) | <0.001 | 2.08 (1.41‐3.16) | <0.001 |
| CV death | 97 (4.7) | 37 (2.9) | 1.67 (1.15‐2.48) | 0.009 | 1.47 (0.79‐2.86) | 0.238 |
| CHF | 100 (4.9) | 30 (2.4) | 2.14 (1.43‐3.29) | <0.001 | 2.10 (1.32‐3.46) | 0.002 |
| Myocardial infarction | 103 (5.0) | 65 (5.1) | 0.99 (0.72‐1.37) | 0.946 | 1.10 (0.78‐1.56) | 0.609 |
| Recurrent ischemia | 88 (4.3) | 70 (5.5) | 0.78 (0.56‐1.07) | 0.121 | 0.85 (0.59‐1.22) | 0.362 |
| Stroke | 27 (1.3) | 16 (1.3) | 1.05 (0.57‐2.01) | 0.867 | 0.83 (0.33‐2.11) | 0.680 |
Abbreviations: CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; OR, odds ratio.
Adjusted ORs corrected for TIMI risk score, history of prior myocardial infarction, predominant type of heparin used, type of fibrinolytic used, infarct‐related artery, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and duration from symptom onset to administration of fibrinolytic.
Figure 1.
Kaplan‐Meier curve of the composite outcome of cardiovascular (CV) death or congestive heart failure (CHF) over 30 days stratified by Q wave. Abbreviations: ORadj, adjusted odds ratio.
Combined Risk Stratification with Q Wave Status and 90‐Minute STRes
Both Q wave status and 90‐minute STRes could be calculated in 2374 patients (71.5% of the cohort), and results are shown in Figure 2. Patients were categorized into 4 groups according to whether or not a Q wave was present and whether or not there was complete STRes (>70%) 90 minutes after fibrinolysis. The lowest risk of CV death or CHF (1.9%) occurred in patients without a Q wave and with complete STRes (n = 365). Patients with either a Q wave/complete STRes (n = 518) or no Q wave/incomplete STRes (n = 498) had an intermediate risk of CV death or CHF (4.4%; OR: 2.38, P = 0.048 vs no Q wave/complete STRes and 6.0%; OR: 3.28, P = 0.005 vs no Q wave/complete STRes, respectively), with no difference between these 2 groups (P = 0.26). Patients with a Q wave/incomplete STRes at 90 minutes (n = 993) were at highest risk, with an 11.1% risk of CV death or CHF (OR: 6.37, P < 0.001 vs no Q wave/complete STRes).
Figure 2.
Thirty‐day composite of cardiovascular (CV) death or congestive heart failure (CHF) in patients stratified by Q wave and complete 90‐minute ST‐segment resolution (STRes). Odds ratios are unadjusted. Abbreviations: OR, odds ratio.
Infarct Size as Estimated by Peak CK‐MB
Regardless of 90‐minute STRes, a Q wave was associated with a higher peak CK‐MB and thus a larger estimated infarct (12.2 × ULN vs 7.2 × ULN, P < 0.001 among patients with complete STRes, and 14.2 × ULN vs 10.0 × ULN, P < 0.001 among patients with incomplete STRes). Patients who were in the lowest risk group (no Q wave/complete 90‐minute STRes, n = 282) had a peak CK‐MB that was only half as large as patients in the highest risk group (Q‐wave/incomplete 90‐minute STRes, n = 841).
Effect of Clopidogrel on Outcomes Stratified by Initial Q Wave
Overall, clopidogrel tended to be equally or more effective in patients without Q waves, particularly for the outcomes of CV death (ORadj: 0.31, P = 0.053 with no Q wave vs ORadj: 0.75, P = 0.432 with a Q wave; P interaction = 0.38), CHF (ORadj: 0.43, P = 0.063 with no Q wave vs ORadj: 1.23, P = 0.371 with a Q wave, P interaction = 0.04), or the composite of CV death or CHF (ORadj: 0.50, P = 0.061 with no Q wave vs ORadj: 1.09, P = 0.672 with no Q wave; P interaction = 0.07). Regardless of Q wave status, clopidogrel was equally effective in reducing the risk of recurrent MI (ORadj: 0.66, P = 0.053 with a Q wave vs ORadj: 0.68, P = 0.162 with no Q wave; P interaction = 0.93).
Discussion
In this study of over 3300 patients with STEMI treated with fibrinolysis, we observed that patients who developed Q waves during their index hospitalization were less likely to have achieved successful reperfusion after fibrinolysis as estimated by both electrocardiographic and angiographic parameters, and experienced an approximately 2‐fold increase in the odds of CV death or CHF at 30 days. The risk of CV death or CHF associated with a Q wave was further refined by assessing the degree of STRes at 90 minutes after fibrinolysis.
Q waves were associated with lower rates of reperfusion as assessed by complete STRes, normal TIMI flow, and normal TIMI myocardial perfusion grade (TMPG) after fibrinolysis. Several studies have shown similar results. In a 362‐patient subgroup from the HERO‐1 (Hirulog Early Reperfusion/Occlusion) trial, Q waves on the presenting ECG were associated with lower rates of TIMI 3 flow (35% vs 55%, P < 0.001).14 Similarly, initial Q waves were associated with significantly reduced IRA flow in the GRACE (Global Registry of Acute Coronary Events) registry.11 Correlation between Q waves and reduced TIMI flow has also been observed in patients treated with facilitated12 and primary PCI.8, 12 Thus, the development of Q waves indicated more extensive obstruction to coronary blood flow, either from larger thrombus burden or tissue edema, which prevents successful reperfusion therapy.
Overall, because fibrinolysis appears to be less effective in patients who have or present with Q waves, it has been suggested in other studies that patients who have Q waves on their initial ECG might benefit from a more aggressive reperfusion strategy with primary PCI being preferential to fibrinolysis.9, 12 The current results would tend to support this hypothesis, although no prospective, randomized, controlled trial data yet exist for selecting a reperfusion strategy based on Q wave status, and further study of the interplay between Q waves and the optimal method of reperfusion is needed.
Q Waves and Clinical Outcomes
Q‐waves were associated with an approximately 2‐fold increase in the odds of 30‐day CHF and the composite of CHF or CV death, but were not associated with a difference in the odds of 30‐day MI, recurrent ischemia, or stroke. The combination of Q wave status and 90‐minute STRes provided additional information regarding subsequent CV risk, and these results suggest that the development of Q waves and the degree of STRes may offer complimentary insight into the degree of myocardial necrosis and consequence of poor tissue level reperfusion.
In these analyses, the 30‐day benefit of clopidogrel in patients without Q waves was equal to or greater than it was in patients with Q waves. Prior analyses of the CLARITY‐TIMI 28 trial suggested that clopidogrel was not effective at opening an occluded artery but was effective in maintaining IRA patency after successful fibrinolysis.21 The current results support a correlation between Q waves and less successful reperfusion after fibrinolysis, and this may explain why patients with Q waves tended to derive relatively less benefit from clopidogrel.
These results may also add information regarding the physiologic mechanism behind the appearance of Q waves in STEMI. If a Q wave was purely the result of irreversible myocardial necrosis, one would expect that the rate of recurrent MI would differ between patients with and without Q waves, as patients without Q waves would likely retain a larger area of myocardium at risk for future ischemic events. Additionally, one would expect to see a further reduction in recurrent MI among patients without Q waves who received clopidogrel, but this was also not observed. The lack of a difference in recurrent MI supports the concept that Q waves do not simply represent scar or completed infarction, and it is possible that Q waves that appear early in the course of STEMI may be electrocardiographically distinct from Q waves that appear or persist later as the infarct heals. Recent data have shown that Q waves which develop in some STEMI patients during the acute phase of infarction may actually disappear with time, and that Q wave regression is associated with greater recovery of left ventricular ejection fraction and wall thickening as assessed by cardiac magnetic resonance imaging.6 Further investigations into the interplay between early Q wave development, the subsequent use of antithrombotic agents, and cardiovascular outcomes are needed.
Limitations
The CLARITY‐TIMI 28 trial was not primarily designed to assess the clinical implications of Q waves, and this post hoc analysis is therefore underpowered to detect differences in some outcomes. Q waves were not evaluated in a core lab, and as a result we cannot account for misclassification due to local physician interpretation (eg, some patients may have had small Q waves that did not meet pathologic criteria but were nonetheless considered significant). Use of local interpretation, however, allows the results from this study to have greater real‐world applicability, as physicians were instructed to follow established guidelines, and in routine clinical practice the presence or absence of pathologic Q waves is not established by multiple observers using strict ECG definitions. As prior ECGs were not readily available for all patients, we are unable to determine if the observed Q waves were related to the current STEMI or if they were from a prior documented or silent MI. This potential confounding effect from prior MI, however, is likely small, as only 149 patients (4.5% of the cohort) had a Q wave and a history of MI. The current study also only assessed STEMI patients treated with fibrinolysis and only assessed outcomes throughout the first 30 days. The results may therefore not be generalizable to patients treated with primary PCI or to longer‐term outcomes.
Conclusion
In patients with STEMI, assessment of Q waves during the index hospitalization is a readily available, rapid, and inexpensive way of assessing short‐term CV risk. The appearance of Q waves is a poor prognostic sign, associated with less effective reperfusion after fibrinolysis, larger infarction, and a 2‐fold increase in the odds of CHF or CV death within the first 30 days. Combining the assessment of Q waves with an assessment of 90‐minute STRes can further improve risk stratification.
Disclosures
The TIMI Study Group has received significant research grant support from Amgen, Astra‐Zeneca, Athera, Beckman Coulter, BG Medicine, Bristol‐Myers Squibb, Buhlmann Laboratories, Daiichi Sankyo, Eli Lilly and Co., Esai, GlaxoSmithKline, Johnson & Johnson, Merck, Nanosphere, Novartis, Ortho‐Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, sanofi‐aventis, Singulex. The authors disclose the following funding, financial relationships, or conflicts of interest: J Waks, none. M. Sabatine has received research grants/support from Amgen, AstraZeneca, AstraZeneca/Bristol‐Myers Squibb Alliance, Bristol‐Myers Squibb/sanofi‐aventis Joint Venture, Daiichi‐Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, sanofi‐aventis, Takeda, Abbott Laboratories, Accumetrics, Critical Diagnostics, Nanosphere, and Roche Diagnostics. He is a consultant for Aegerion, Amgen, AstraZeneca/Bristol‐Myers Squibb Alliance, GlaxoSmithKline, Merck, Pfizer, sanofi‐aventis, Vertex, and Intarcia. C. Cannon has received research grants/support from Accumetrics, AstraZeneca, CSL Behring, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, Takeda. He serves on the advisory board of Alnylam, Bristol‐Myers Squibb, Lipimedix, and Pfizer but donates all funds to charity and is a clinical advisor with equity in Automedics Medical Systems. D. Morrow has received remuneration for consulting from BG Medicine, Critical Diagnostics, Eli Lilly, Genentech, Gilead, Instrumentation Laboratory, Johnson & Johnson, Konica/Minolta, Merck, Novartis, Roche Diagnostics, and Servier. C. Gibson has received research grants/support from Angel Medical Corporation, Atrium Medical Systems, Bayer Corporation, Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson, Lantheus Medical Imaging, Merck, Portola Pharmaceuticals, Roche Diagnostics, sanofi‐aventis, Stealth Peptides, St. Jude Medical, Volcano Corporation, and Walk Vascular. He is a consultant with moderate support to AstraZeneca, Atrium Medical Systems, Baxter Healthcare, Bristol‐Myers Squibb, Cardiovascular Research Foundation, Consensus Medical Communications, CSL Behring, Cytori Therapeutics, Daiichi Sankyo, Eli Lilly, Exeter Group, Genentech, Inc., GlaxoSmithKline, St. Jude Medical, The Medicines Company, and is a consultant with no financial support for Bayer Corporation, Janssen Pharmaceuticals, Johnson & Johnson, and Ortho McNeil. He has received previous research grants/support and speaking/consulting support from Abbott, Angel Medical Systems, Archemix Corporation, Astra Zeneca, Ascenta Therapeutics, Atrium Medical Systems, Baxter Healthcare, Biogen IDEC, Boston Scientific Corporation, Bristol‐Meyers Squibb, British Biotech, PLC, Ciba Geigy Corporation, Eli Lilly, FibroGen, Inc., FoldRx, Genentech, GlaxoSmithKline, Heartscape Technologies, Ischemix, Merck, National Institutes of Health, Novartis, Pfizer, Pocket Medicine, Point Biomedical Corporation, Portola Pharmaceuticals, Regado Biosciences, sanofi‐aventis, Schering Plough, Smith Kline Beecham, St. Jude Medical, The Medicines Company, and timi3 Systems. S. Wiviott has received research grants from AstraZeneca, Bristol‐Myers Squibb, Eisai, Arena, Merck, Eli Lilly/Daiichi Sankyo, and sanofi‐aventis. He has received consulting fees from AstraZeneca, Bristol‐Myers Squibb, Eisai, Arena, Aegerion, Angelmed, Janssen Pharmaceuticals, Xoma, ICON Clinical, Boston Clinical Research Institute, and Eli Lilly/Daiichi Sankyo. R. Giugliano has received research grants from Daiichi‐Sankyo and Merck. He has received honoraria for continuing medical education lectures and/or consulting from Daiichi‐Sankyo, Merck, and sanofi‐aventis. S. Sloan, none. B. Scirica has received research grants from AstraZeneca, Bristol‐Myers Squibb, Daichi‐Sankyo, GlaxoSmithKline, Johnson & Johnson, Bayer Healthcare, Gilead, Eisai, and Merck. He has received consulting fees from Gilead, Lexicon, Arena, Eisai, St. Jude Medical, Boston Clinical Research Institute, Decision Resources, University of Calgary, and Elsevier Practice Update Cardiology.
A complete list of all author disclosures can be found at the end of this article.
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