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Abstract
Background We evaluated the prespecified endpoint, aborted myocardial infarction (AbMI), according to the use of a pharmacoinvasive (PI) strategy versus primary percutaneous coronary intervention (PCI) in 1754 patients randomised within 3 h of symptom onset in the STrategic Reperfusion Early After Myocardial infarction (STREAM) trial.
Methods Based on sequential ECG's and biomarkers, AbMI was defined as ST-elevation resolution ≥50% (90 min posttenecteplase (TNK) in the PI arm or 30 min postprimary PCI) with minimal biomarker rise.
Results In the PI arm 11.1% (n=99) had AbMI versus 6.9% (n=59) in primary PCI arm (p<0.01). In a multivariable model, AbMI patients overall had less baseline ΣST-deviation, fewer baseline Q-waves and shorter total ischaemic times. PI AbMI patients had faster time to TNK (90 vs 100 min, p=0.015): total ischaemic time was 100 min longer in primary PCI AbMI patients and no difference in ischaemic time existed between AbMI and non-AbMI patients within this group. Although no significant interaction between treatment and AbMI on the composite endpoint of death/shock/congestive heart failure/recurrent MI occurred (p=0.292), PI AbMI patients had a lower incidence in this endpoint than non-AbMI patients (5.1 vs 12%, p=0.038); this was not evident in primary PCI patients. Forty-five patients (ie, 2.5%) had masquerading MI with minimal biomarker elevation and no evolution in baseline ST-elevation.
Conclusions A PI strategy of early fibrinolysis more frequently aborts MI than primary PCI. Such PI patients had more favourable outcomes as compared with non-AbMIs. Diligent review of ECG evolution in STEMI distinguishes AbMI from infarct masquerade.
Clinical Trials.gov ID NCT00623623.
- CARDIAC FUNCTION
- INTERVENTIONAL CARDIOLOGY
- MYOCARDIAL ISCHAEMIA AND INFARCTION (IHD)
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Introduction
Aborted myocardial infarction (AbMI) during acute ST-elevation myocardial infarction (STEMI) has been defined by ≥50% resolution in ST-segment elevation coupled with no or minimal subsequent rise in cardiac biomarkers and deemed to be an indicator of successful reperfusion therapy.1 ,2 This entity was originally identified in the context of prehospital fibrinolysis and is known to be time sensitive.3 ,4 Subsequently, AbMI has been shown to be associated with smaller infarct sizes, better ventricular function and improved outcomes than those without AbMI, thereby leading to the call for prospective validation of its prognostic relevance and the suggestion that it might constitute a novel and useful efficacy endpoint when assessing treatment interventions in STEMI.4–7
While prior studies in patients with myocardial infarction (MI) have examined the frequency of AbMI both after fibrinolysis1–4 and primary percutaneous coronary intervention (PCI),5 ,6 no direct prospective comparison of the incidence of AbMI between these two reperfusion strategies has ever been performed. Accordingly, we provide the first report from a prespecified comparison within the STrategic Reperfusion Early After Myocardial Infarction (STREAM) study of AbMI in patients with STEMI who were randomised to either a pharmacoinvasive (PI) strategy of fibrinolysis followed by rescue/scheduled catheterisation or primary PCI.8 This endpoint was specifically identified of interest in STREAM because of the trial's unique focus on prehospital enrolment and requirement for a symptom onset to randomisation time of less than 3 h. Our objectives were to (i) compare the incidence of AbMI in the two treatment groups of the STREAM trial, (ii) examine the relationship between AbMI and the clinical outcomes according to assigned study treatment and (iii) evaluate the relationship between AbMI and clinical outcomes, irrespective of study treatment assignment.
Methods
STREAM was a randomised multicentre trial to compare a PI strategy versus primary PCI in STEMI. The specific entry criteria and treatment strategies of STREAM trial have been published previously.9 Briefly, STEMI patients >18 years, presenting within 3 h from symptom onset were randomised to either (i) a strategy of fibrinolysis with tenecteplase (TNK) followed by scheduled or rescue PCI, based on achievement or failure to achieve at least 50% ST resolution in the single worst lead at baseline (PI) or (ii) primary PCI administered according to local standards (Primary PCI). STEMI was defined by ≥2 mV ST-elevation in two contiguous leads of the baseline ECG. Creatinine kinase (CK), creatinine kinase MB isoenzyme (CK-MB) and troponin levels were collected as multiples exceeding the upper limit of normal (ULN) at baseline, 8–12 h and 24 h after randomisation.
Baseline ECGs were collected at each site on admission; additional ECGs were acquired for the PI group at 90 min post-TNK and postcatheterisation/PCI; and for primary PCI, prior to catheterisation/PCI and 30 min after PCI. A core ECG laboratory (Canadian VIGOUR Centre, Edmonton, Canada) analysed these ECGs according to methods previously documented.10
AbMI was defined by assessing whether there was ≥50% ST-elevation resolution in the ECG lead exhibiting the maximal baseline ST-elevation at either 90 min post-TNK or 30 min post-PCI in PI and primary PCI patients, respectively. In addition, biomarker analysis, using either CK-MB ≤2 times the ULN (n=74) or if CK-MB was not available, then total CK ≤2 times the ULN (n=77) on at least two measurements within the first 24 h. If neither CK-MB nor CK was available (n=7) then cardiac troponin I/T (cTn) levels ≤5 times the ULN was required.11 Serial ECGs of the patients who met the cardiac biomarker criteria were analysed and patients who developed significant new Q-waves in their post-treatment or discharge ECGs were excluded from the AbMI category. Patients with minimal or no rise in biomarker data simulating the AbMI patients but who did not exhibit evolutionary ECG changes between their qualifying and discharge ECGs were classified separately as infarct masquerade.4
Statistical analysis
Patient and procedural characteristics were presented according to AbMI and non-AbMI, and then further according to randomised treatment strategy (ie, PI or primary PCI). Categorical variables were reported as percentages, and differences between groups were tested by the χ2 test; Fisher's exact test was applied when the cell count was less than five patients. Continuous variables were summarised as medians with 25th and 75th centiles, and differences between groups were tested via Wilcoxon rank-sum test.
Multivariable logistic regression analysis was applied to identify the factors significantly associated with AbMI. Baseline patient characteristics in table 1 were first tested using univariable logistic regression and then variables with p ≤ 0.20 were included in the full multivariable model and then stepwise selection (p≤0.20 as ‘in’ criteria and p≤0.05 as ‘out’ criteria) was used to identify the final model. Variables considered in the full model were age >75 years, Killip class, previous MI, previous PCI, previous coronary artery bypass graft surgery, baseline Q-wave, ∑ST-deviation on the baseline ECG and time from symptom onset to first medical contact.
Selected patient characteristics according to aborted myocardial infarction and assigned study treatment
The association between AbMI and the primary clinical outcomes (ie, the composite of all-cause death, cardiogenic shock, congestive heart failure (CHF), recurrent MI and the individual components) within 30 days was examined using Poisson regression model with robust error variance. Relative risks (RR) with 95% CI were reported. Given the small number of events in the AbMI group, the Thrombolysis In Myocardial Infarction (TIMI) risk score12 was used as an aggregate measure of risk to account for imbalances in baseline patient characteristics. The interaction between AbMI and randomised study treatment was tested to examine whether the treatment assignment modulated the association between AbMI and 30-day clinical outcomes. The Kaplan–Meier estimates for 1-year all-cause mortality are reported, and the log-rank test was applied to test the difference according to AbMI. A sensitivity analysis was performed to examine the outcomes according to whether AbMI was observed pre-PCI or post-PCI in the primary PCI arm. All statistical tests were two-sided, with p<0.05 was considered as statistically significant. Statistical analyses were performed using SAS, V.9.3 (Cary, North Carolina, USA).
Results
The derivation of the study cohort is shown in figure 1. Of the 1892 patients randomised in the STREAM trial, 138 were excluded due to lack of sequential CK/CK-MB and cTn levels or inadequate ECG data, leaving a cohort of 1754 of whom 893 patients were in the PI group and 861 patients in the primary PCI arm. After applying the biomarker criteria and evaluating the sequential ECGs, the total number of patients with AbMI was 158 (9.0%). Hence, as it relates to our first objective, the incidence of AbMI was significantly greater in the PI arm than in those assigned to primary PCI, that is, 99/893 (11.1%) vs 59/861 (6.9%, p<0.001) patients, respectively.
Study cohort derivation. AbMI, aborted myocardial infarction; CK, creatine kinase; CKMB, creatinine kinase MB isoenzyme; cTn, cardiac troponin I/T; PCI, percutaneous coronary intervention; PI, pharmacoinvasive.
In table 1, the baseline patient characteristics, according to the presence of AbMI overall and within the two study groups, are shown. In the total STREAM population, AbMI patients tended to be younger, more often had prior MI and PCI, and appeared more likely to be in Killip class I and more frequently had anterior infarction at presentation. They had less extensive baseline ∑ST-deviation and were less likely to have a Q-wave in their acute infarct territory. In general, these differential characteristics were similarly aligned within the two treatment groups. Three factors were found to be significantly associated with AbMI in a multivariable model; namely, lesser frequency of a baseline Q-wave in the infarct territory, less ∑ST-deviation on the baseline ECG, and shorter time from symptom onset to first medical contact (table 2). Clopidogrel was administered at the time of randomisation that occurred about 11 min earlier in AbMI patients overall. Interestingly concomitant use of clopidogrel was more common in PI patients with ABMI than in non-AbMI patients (97.0 vs 90.7% p=0.036).⇓
Factors associated with aborted myocardial infarction
Procedural characteristics according to randomised study treatment and aborted myocardial infarction
In both groups, the times from symptom onset to randomisation were comparable (table 3); notably however, these times were shorter in AbMI as compared with non-AbMI patients. As expected given the STREAM trial design, the time from symptom onset to TNK therapy in the PI group was substantially shorter than the time to primary PCI (sheath insertion). For PI patients, the median time to therapy was 10 min shorter in AbMI compared with non-AbMI patients (90 vs 100 min, p=0.015) but this was not the case for primary PCI patients. Notably the total ischaemic time for AbMI PI patients was substantially shorter than for primary PCI (90 min to TNK vs 190 min to sheath insertion). Since all patients were intended to undergo angiography in STREAM, the longer times to PCI in PI patients versus primary PCI reflect investigator discretion on the timing of angiography as permitted by protocol (ie, between 6 and 24 h, except when rescue PCI was required). Patients with AbMI more frequently had TIMI 3 flow both precoronary and postcoronary intervention in each treatment group: furthermore, PCI was less frequently performed among AbMI patients (PI: 73.7% vs 81.6%, p=0.060; primary PCI: 81.4% vs 92.2%, p=0.004).
As expected, the early postreperfusion ST-resolution data also indicate better resolution of both the baseline ST-elevation and ST-deviation and a greater proportion of patients with <1 mm worst lead residual ST-elevation, especially in the PI AbMI patients. When the ST-segment data were evaluated following PCI in those patients who received the procedure, the lesser residual ST-elevation among AbMI patients was again evident and the preponderance of <1 mm residual ST-elevation in PI patients was even more striking.
Association with clinical outcomes
Among PI patients, the incidence of primary composite of death/cardiogenic shock/CHF/recurrent MI was lower among AbMI patients treated with PI strategy (5.1 vs 12.0% p=0.038). This difference was attenuated after adjustment (p=0.092). In total, 69 of the 99 AbMI patients occurred within 120 min of symptom onset, whereas 50 of the 59 AbMI patients in the primary PCI group were ≥ 120 min. AbMI afforded no significant advantage over non-AbMI on the composite outcomes in primary PCI patients (10.2 vs 12.9% p=0.545). When the components of the composite were examined separately, less cardiogenic shock and CHF occurred in AbMI compared with non-AbMI patients in PI patients (shock: 0.0 vs 4.4%, p=0.026; CHF: 1.0 vs 6.6%, p=0.023), but this was not evident in the primary PCI group (shock: 3.4 vs 4.6%, p=1.000; CHF: 3.4 vs 7.3%, p=0.423). The interaction between treatment group and AbMI on the composite endpoint was not statistically significant (p=0.292), Within 1 year, all-cause mortality was nominally but not significantly lower among AbMI patients in the PI arm (3.1 vs 5.6%, p (log-rank)=0.295); and no significant difference was observed among those in the primary PCI arm (5.2 vs 4.5%, p (log-rank)=0.818).
Evaluation of the 30-day outcomes across the AbMI and non-AbMI groups irrespective of the treatment is presented in figure 2. AbMI was associated with improved overall outcomes and the rate of the composite of death/cardiogenic shock/CHF/recurrent MI was lower among AbMI than non-AbMI patients (7.0 vs 12.5%, p=0.042). This difference in composite outcomes was mainly driven by lower rates of cardiogenic shock and CHF in AbMI. The relative risk was 0.56 (95% CI 0.31to 1.00), p=0.051), which was attenuated after adjusting for baseline TIMI risk score (RR: 0.58; 95% CI 0.32 to 1.06, p=0.075). One-year mortality for the AbMI patients was 3.9% and 5.1% for non-AbMI patients (p (log-rank)=0.509), and there was no significant risk reduction after adjustment for the TIMI risk score (adjusted RR: 0.84; 95% CI 0.26 to 2.69, p=0.767).
Relative risk plot of the primary composite outcome and its components. AbMI vs non-AbMI. AbMI, aborted myocardial infarction; CHF, congestive heart failure; reMI, recurrent myocardial infarction; * Adjusted for Thrombolysis In Myocardial Infarction (TIMI) risk score.
Of note within the 59 AbMI patients in the primary PCI group, 36 met the criteria of AbMI before a coronary intervention was performed. The rate of the composite endpoint in this cohort was nominally, but not significantly, higher in this subset of patients when compared with those who AbMI after PCI (13.9 vs 4.4%, p=0.274).
Forty-five patients initially presenting to the STREAM study, that is, 2.5% (evenly distributed by treatment group) had infarct masquerade as defined by no or minimal biomarker elevation (fitting the AbMI definition) yet has persistent ST-elevation without evolution between their qualifying and discharge ECGs related to ST-elevation in the context of prior Q-wave MI (n=14) left ventricular hypertrophy (n=7), left bundle branch block (n=4), pericarditis (n=6) and early repolarisation (n=14). Within the masquerade population, the preangiography TIMI 3 flow in the PI group (n=22) was 95.5%, and in the primary PCI group (n=21), it was 66.7%. PCI was conducted in four PI patients and three primary PCI patients. The 30-day composite outcome for patients with infarct masquerade was 6.7% and similar in both treatment groups: one major non-intracranial haemorrhage bleed also occurred in each group.
Discussion
Our study of 1754 STEMI patients in the STREAM trial contains key novel findings. We found that our prespecified comparison of the incidence of AbMI in STREAM revealed a significantly higher rate in the PI arm as compared with those undergoing primary PCI (11.1 vs 6.9%, p<0.01). The overall incidence of 9.0% AbMI (n=158) in our study is consistent with prior work.1 ,2 ,4–6 It is noteworthy that while we found a 25% incidence of AbMI in patients treated within the first hour in our previous report from ASSENT 3, we precluded randomisation of such early treated patients in STREAM if they could undergo primary PCI within 1 h of first medical contact.4 ,9 As compared with patients without AbMI, those with AbMI tended to be younger, with a history of more prior coronary disease and were randomised earlier. Based on careful observations from a core ECG laboratory, we observed less extensive territory at risk as defined by the extent of baseline ST-deviation as well as less advanced MI evolution as suggested by the lower frequency of Q-waves in the presenting infarct zone of AbMI patients.13 Taken together in a multivariable analysis, the three key factors associated with AbMI, that is, lesser frequency of baseline Q-waves, shorter time to first medical contact from symptom onset and less extensive territory at risk, provide a new coherent portrait of these patients.
Our study also indicates that patients with AbMI receiving PI therapy had significantly improved overall 30-day composite outcomes primarily related to a lesser incidence of shock and heart failure. These findings are well aligned with the CAPTIM study that demonstrated significantly less shock and a trend towards lower mortality among patients receiving PI therapy within 2 h of symptom onset versus those undergoing primary PCI.14 This difference was likely related to the substantially shorter total ischaemic time, that is, 100 min for PI strategy versus 190 min primary PCI AbMI patients and is further supported by better ST-segment resolution and greater proportion of patients with <1 mm ST-elevation. However, the clinical outcome differences were somewhat attenuated after adjustment for TIMI risk score and no interaction existed between treatment assignment and clinical outcomes associated with AbMI. Nonetheless, our findings are supportive of AbMI contributing to the overall favourable outcomes of the PI arm of STREAM.8 Of additional note, the AbMI patients within the PI group had more frequent early use of clopidogrel than the non-AbMI patients. Interestingly, we identified a subset of 36 of 59 AbMI patients receiving primary PCI who had spontaneous ST-elevation resolution before undergoing catheterisation and PCI. This finding likely relates to spontaneous fibrinolysis and may have been potentiated by early use of antithrombotic therapy and clopidogrel.15 Recognition of this phenomenon should be a continuing consideration in reporting ECG and angiographic reperfusion rates irrespective of the choice of reperfusion therapy.
Finally, we identified 2.5% of our study cohort, balanced across treatment arms, who did not have STEMI but rather infarct masquerade. The 30-day composite event rate was similar in both treatment groups at 6.7%, and PCI was undertaken infrequently. We suggest that unless sequential ECG documentation of STEMI is established by careful review of both admission and discharge ECGs with commensurate documentation of no ST-segment or other ECG changes, this entity may be incorrectly attributed to AbMI. Despite prior identification of this phenomenon and the likely associated entities that characterise it, this remains a challenge to clinical trials especially as it relates to the balance between risk and benefit.4 ,5 Importantly, it also represents a reason for unneeded activation of a PCI laboratory.
Our study has both strengths and limitations. The prospective validation of the clinical and ECG characteristics and outcomes of AbMI in a well-characterised clinical trial population indicates that AbMI is a useful endpoint in clinical trials,7 This entity likely sits at one end of the overall spectrum of myocardial necrosis but appears to be clinically relevant. Although the outcome of AbMI patients was improved within the PI group, our sample size and the relatively modest number of adverse events is insufficient to confirm a true study treatment interaction with clinical outcomes. It could be argued that our choice of a ≤5-fold rise in troponin is arbitrary for the definition of AbMI given that a ≤2-fold increase in CK/CK-MB has been traditionally employed. However, this threshold for troponin is in accordance with the type 4A MI as defined in the 2012 universal classification of MI11; moreover, only seven AbMI patients fit this criterion and our results remain unchanged if they are excluded. We do not have access to prior medications use that might have better informed our results.
In conclusion, we have demonstrated that AbMI is a useful endpoint in studies of STEMI especially after PI reperfusion therapy. It carries a readily identifiable clinical signature and this prespecified metric was more common in patients receiving PI therapy in STREAM and was associated with an improved 30-day outcome.
Key messages
What is already known on this subject?
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Aborted myocardial infarction (MI) is known to occur when reperfusion therapy in ST elevation MI is begun early. It is also associated with improved clinical outcomes in observational cohorts.
What might this study add?
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This is the first prospective randomised trial to study the frequency and outcomes of aborted MI with pharmacoinvasive versus primary percutaneous coronary intervention (PCI) treatment early after symptom onset. It shows that there are significantly more aborted MIs with the pharmacoinvasive approach.
How might this impact on clinical practice?
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This study emphasises the advantage of a pharmacoinvasive approach in ST-elevation myocardial infarction patients who cannot undergo primary PCI within 1 h of symptom onset.
Acknowledgments
It is a pleasure to acknowledge the contributions of Pushpa Jagasia, MD, from the Canadian VIGOUR Centre Core ECG Laboratory.
References
Footnotes
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Contributors ND-M: analysis and interpretation of data; drafting and revising manuscript; final approval. FVdW: concept, design, analysis and interpretation of data; revising manuscript; final approval. PG, JA, YL, , VS , FR-O and AHG: concept, design, revising manuscript and final approval. YZ: analysis and interpretation of data; revising manuscript; final approval. CMW: analysis and interpretation of data; drafting and revising manuscript; final approval. PWA: concept, design, analysis and interpretation of data; drafting and revising manuscript; final approval.
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Funding This work was supported by Boehringer Ingelheim through sponsorship of the STREAM clinical trial.
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Competing interests FVdW discloses research grant and other support from Boehringer Ingelheim. PG discloses Speakers Bureau support from AstraZeneca and Bayer; honoraria from Sanofi Aventis, Boehringer Ingelheim, Eli Lilly and The Medicines Company. YL and FRO disclose other support from Boehringer Ingelheim. VS discloses honoraria from Bayer, Sanofi Aventis, AstraZeneca, Boehringer Ingelheim, Abbott and Nicomed-Takeda. PWA discloses grant support from Boehringer Ingelheim and honoraria from Boehringer Ingelheim. PWS's financial activities outside the submitted work are posted and routinely updated through http://www.vigour.ualberta.ca/en/About/ConflictofInterest.aspx. AHG reported Advisory Board: Boston Scientific, Abbott, Medtronic Corp; Speaker fees: Eli Lilly, Boehringer Ingelheim; Travel Sponsorship: all companies he listed above plus Orbus Niche. NDM, JAA, CMW and YZ have no conflicts to declare.
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Ethics approval IRB’s at participating sites.
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Provenance and peer review Not commissioned; externally peer reviewed.
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Data sharing statement Data from a presentation at the American Heart Association 2013 are available in abstract form and PDF of powerpoint slides on the impact of Rescue PCI in fibrinolytic-treated patients in the STREAM study.