Author + information
- Received March 7, 2016
- Revision received June 20, 2016
- Accepted June 30, 2016
- Published online October 10, 2016.
- Mohammed K. Rashid, BHSca,b,
- Nita Guron, MDc,
- Jordan Bernick, MSca,
- George A. Wells, PhDb,
- Melissa Blondeau, BSca,
- Aun-Yeong Chong, MDa,
- Alexander Dick, MDa,
- Michael P.V. Froeschl, MDa,
- Chris A. Glover, MDa,
- Benjamin Hibbert, MDa,
- Marino Labinaz, MDa,
- Jean-François Marquis, MDa,
- Christina Osborne, BSca,
- Derek Y. So, MDa and
- Michel R. Le May, MDa,∗ ()
- aUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada
- bFaculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- cUniversity of Calgary, Alberta, Canada
- ↵∗Reprint requests and correspondence:
Dr. Michel R. Le May, Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada.
Objectives This study investigated the safety and efficacy of a pharmacoinvasive strategy compared with a primary percutaneous coronary intervention (PCI) strategy for ST-segment elevation myocardial infarction (STEMI) in the context of a real-world system.
Background Primary PCI continues to be the optimal reperfusion therapy; however, in areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed.
Methods The University of Ottawa Heart Institute regional STEMI system provides a primary PCI strategy for patients presenting within a 90-km radius from the PCI center, and a pharmacoinvasive strategy for patients outside this limit. We included all confirmed STEMI patients between April 2009 and May 2011. The primary efficacy outcome was a composite of mortality, reinfarction, or stroke and the primary safety outcome was major bleeding.
Results We identified 236 and 980 consecutive patients enrolled in pharmacoinvasive and primary PCI strategies, respectively. The median door-to-needle time was 31 min in the pharmacoinvasive group and the median door-to-balloon time was 95 min in the primary PCI group. In a multivariable model, there was no significant difference in the primary efficacy outcome (odds ratio: 1.54; p = 0.21); however, the propensity for more bleeding with a pharmacoinvasive strategy approached statistical significance (odds ratio: 2.02; p = 0.08).
Conclusions Within the context of a STEMI system, a pharmacoinvasive strategy was associated with similar rates of the composite of mortality, reinfarction, or stroke as compared with a primary PCI strategy; however, there was a propensity for more bleeding with a pharmacoinvasive strategy.
- pharmacoinvasive strategy
- primary PCI
- regional STEMI program
- ST-segment elevation myocardial infarction
ST-segment elevation myocardial infarction (STEMI) accounts for one-third of patients with acute coronary syndrome (1). Current management standards for STEMI patients are focused on immediate reperfusion of the obstructed regions (2). Repeatedly, primary percutaneous coronary intervention (PCI) has been found to be superior to fibrinolysis (3,4). Primary PCI is more effective at reducing the risk of reinfarction, stroke, and death (5); however, the effectiveness of primary PCI is limited by a narrow window of door-to-balloon time (6–9). Currently, guidelines recommend a door-to-balloon time of <90 min for field transfer and <120 min for interhospital transfer for primary PCI to be effective (3). When door-to-balloon time is >120 min, primary PCI has no advantage over fibrinolysis with respect to in-hospital mortality (10).
In areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed. This strategy comprises the use of fibrinolysis with subsequent transfer to a PCI-capable facility for angiography within 24 h of presentation (3). Several regions have developed local STEMI systems (11,12). The aim of this study was to assess the safety and efficacy of a pharmacoinvasive strategy compared with a primary PCI strategy in the context of a real-world regional system.
The University of Ottawa Heart Institute is a tertiary care cardiac center located in Ottawa, Ontario, Canada, that covers a population of about 1.2 million. Fully operational since 2009, this STEMI system has been developed to provide a primary PCI strategy for patients presenting to 9 hospitals within a 90-km radius from the PCI center (zone 1), and a pharmacoinvasive strategy for patients presenting to 7 hospitals outside this limit (zone 2). In this study, we identified all confirmed STEMI patients between April 2009 and May 2011 who had an onset of myocardial ischemic symptoms of <12 h and ST-segment elevation of ≥1 mm in 2 contiguous leads on a 12-lead electrocardiogram; however, we excluded STEMI patients who required therapeutic hypothermia. As per regional protocol, all patients received chewable aspirin (160 mg) and intravenous bolus of unfractionated heparin (60 U/kg; maximum dose, 4,000 U). Patients in the primary PCI strategy received oral clopidogrel (600 mg). Patients in the pharmacoinvasive strategy received oral clopidogrel (300 mg if ≤75 years old), intravenous infusion of unfractionated heparin (12 U/kg/h), and weight adjusted intravenous bolus of tenecteplase (TNK).
Data collection, outcomes, and definitions
The primary efficacy outcome was a composite of mortality, stroke, or reinfarction within index hospitalization. The primary safety outcome was major bleeding within index hospitalization.
Critical time intervals were measured using the ambulance call reports, emergency department triage sheets, and time stamps on the qualifying electrocardiograms, medical charts, and catheterization laboratory reports. Coronary flow at baseline and after the procedure was reported based on the classification of the TIMI (Thrombolysis In Myocardial Infarction) trial (13). A stroke was defined as the presence of new neurological deficits lasting for >24 h with evidence of ischemia or hemorrhage demonstrated by computed tomography or magnetic resonance imaging. A reinfarction was defined as the recurrence of cardiac ischemic symptoms occurring at rest and lasting for >30 min in combination with re-elevation of ST-segment on an electrocardiogram and of cardiac enzymes (twice the upper limit of normal) or angiographic evidence of reocclusion of the infarct-related artery. Major and minor bleeding were defined according to the TIMI classification (13).
Data were extracted by research assistants from electronic medical records using dedicated case report forms. The study was approved by the Institutional Review Board at the University of Ottawa Heart Institute.
Categorical variables are presented as proportions and compared via the use of the chi-square test or Fisher exact test. Normally distributed continuous variables are presented as mean ± SD and compared using the Student t test. Critical time intervals are presented as median and interquartile range (IQR) and compared using the Wilcoxon test. A multivariable logistic regression, which included baseline characteristics with p < 0.15, was performed to compare the primary outcomes in the 2 groups. A subgroup analysis was also performed to include only those patients who underwent coronary angiogram within 24 h of presentation. A 2-sided p value of <0.05 was considered significant. All statistical analyses were done using SAS version 9.3 (SAS Institute, Cary, North Carolina).
Characteristics of the patients
Between April 2009 and May 2011, we identified 1,216 consecutive patients who were referred to the cardiac care center for STEMI. Of those, there were 980 patients (81%) referred for primary PCI and 236 patients (19%) referred for pharmacoinvasive strategy. The baseline characteristics of the patients are presented in Table 1. The mean age was 61.2 ± 11.6 years for the pharmacoinvasive group and 62.7 ± 13.3 for the primary PCI group. Anterior myocardial infarction was observed in 33.9% of patients in the pharmacoinvasive group and 40.6% of the patients in the primary PCI group (p = 0.06). Killip class 1 was identified in 93.2% of patients in the pharmacoinvasive group and in 89.7% of the patients in the primary PCI group (p = 0.10). At baseline, both groups were comparable except for higher rates of smokers (p = 0.0005) and a lower mean heart rate (p = 0.05) in the pharmacoinvasive group.
Critical time intervals
Critical time intervals are presented in Table 2. The median time from onset of symptoms to arrival at first hospital was significantly shorter in the pharmacoinvasive group (92 min; IQR: 55 to 147 min) compared with the primary PCI group (97 min; IQR: 60 to 205 min; p = 0.03). The median door-to-balloon time was 305 min (IQR: 228 to 421 min) for the pharmacoinvasive group and 95 min for the primary PCI group (IQR: 71 to 124 min; p < 0.0001). The median door-to-needle time was 31 min (IQR: 18 to 60 min) for patients in the pharmacoinvasive group. Furthermore, once they received fibrinolytics, the median time to first balloon inflation was 260 min (IQR: 201 to 385 min).
Procedural and angiographic results
Procedural and angiographic results within 24 h of presentation are shown in Table 3. Coronary angiography was performed on 93.6% of patients in the pharmacoinvasive group and on 98.8% of patients in the primary PCI group (p < 0.0001); PCI was performed on 85.2% of patients in the pharmacoinvasive group and on 92.2% of patients in the primary PCI group (p = 0.0007). TIMI flow grade 3 at baseline was present in 57.7% of patients in the pharmacoinvasive group and 22.8% of patients in the primary PCI group. After the procedure, the proportion of TIMI flow grade 3 became 96.4% and 90.5%, respectively.
In-hospital clinical outcomes
The rate of the primary composite outcome (mortality, reinfarction, or stroke) was 6.4% for the pharmacoinvasive group and 7.0% for the primary PCI group (p = 0.71) (Table 4). TIMI major bleeding occurred among 4.7% of patients in the pharmacoinvasive group and 3.2% of patients in the primary PCI group (p = 0.26). Hemorrhagic stroke was 1.3% in the pharmacoinvasive group and 0% in the primary PCI group (p = 0.0004). Baseline variables included in the multivariate model are age, diabetes mellitus, dyslipidemia, smoking, anterior myocardial infarction, heart rate, Killip class 1, and admission hemoglobin. Using multivariate analysis, the pharmacoinvasive group had 1.54 times the odds of having mortality, reinfarction, or stroke compared with the primary PCI group (p = 0.21) (Table 5). The pharmacoinvasive group had 2.02 times the odds of having TIMI major bleed compared with the primary PCI group (p = 0.08) (Table 6).
In the pharmacoinvasive group, 15 patients did not receive coronary angiography within 24 h of presentation; 12 underwent angiography later during the index hospitalization and 3 were treated medically. Two patients died, both within 24 h of presentation, and 1 had a stroke.
In the primary PCI group, 12 patients did not undergo coronary angiography within 24 h of presentation; 5 died in the emergency department before reaching the catheterization laboratory, 4 declined the procedure and subsequently died, 2 underwent angiography later during the index hospitalization, and 1 was treated medically.
The results of the subgroup analysis including only patients who underwent coronary angiogram within 24 h of presentation were similar to those obtained in the primary analysis. Using a multivariate analysis, there was no difference in the primary efficacy outcome between the 2 groups (odds ratio: 1.69; p = 0.14); the pharmacoinvasive group had 2.15 times the odds of having TIMI major bleed compared with the primary PCI group (p = 0.06).
In this study, we report on the efficacy and safety of a pharmacoinvasive strategy compared with a primary PCI strategy within the context of a real-world regional STEMI system. We found that a pharmacoinvasive strategy was associated with similar clinical outcomes as compared with a primary PCI strategy by univariable analysis. However, intracranial bleeding was significantly lower with a primary PCI strategy. In a logistical model using multivariable analysis, we found no difference between the 2 strategies in the primary efficacy outcome of mortality, reinfarction, or stroke; however, there was a propensity for more bleeding with a pharmacoinvasive strategy.
Although primary PCI remains the optimal reperfusion therapy for STEMI patients, its application is limited by the scarcity of resources in rural regions. Although fibrinolysis can be administered in a timely fashion in these contexts, it is associated with higher rates of nonreperfusion and reinfarction (7,14,15). In a large meta-analysis of 7 trials and 2,961 patients, early PCI after fibrinolysis has been found to be associated with a reduced risk of the combined endpoint of death and reinfarction without a significant increase in the risk of major bleeding or stroke (16). Of note, however, the comparator in all of the studies in this meta-analysis was not primary PCI, but conservative management in which PCI was used as a rescue treatment (16). The STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial compared fibrinolysis followed by PCI within 6 to 24 h to primary PCI (17). The investigators found that there was no difference in the composite endpoint of death, shock, congestive heart failure, or reinfarction at 30 days between the 2 treatments (17). However, a fibrinolysis-based therapy was associated with slightly higher rates of intracranial hemorrhage, a trend that was not observed after protocol amendment to reduce TNK by 50% for patients ≥75 years of age (17). According to current guidelines, a pharmacoinvasive therapy is suitable for STEMI patients who have a low risk of bleeding, present to a non–PCI-capable facility within 2 to 3 h of onset of symptoms, and have no immediate access to PCI (3).
Within this regional STEMI system, ≥50% of the patients managed with a pharmacoinvasive strategy underwent PCI within 260 min (4 h and 20 min) from the time of receiving fibrinolytic therapy. In randomized controlled trials looking at a pharmacoinvasive strategy, the median time from fibrinolysis to PCI was 84 min in CAPITAL-AMI (Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction) (18), 125 min in CARESS-in-AMI (Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction) (19), 163 min in NORDISTEMI (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction) (20), 234 min in TRANSFER-AMI (Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) (21), and 295 min in WEST (Which Early ST-elevation myocardial infarction Therapy) (22). This very rapid approach to intervention may have impacted the results in this study. Nevertheless, these results are encouraging for centers that do not have rapid access to a PCI center. Furthermore, the door-to-needle time of 31 min is in keeping with the international standards of 30 min (3,4).
The results of this study are comparable to those obtained by the Minneapolis Heart Institute (MHI) regional STEMI program, which similarly employs 2 reperfusion therapies based on distance from the PCI center (23). In their study, Larson et al. (23) found that there were no differences between a pharmacoinvasive strategy and a primary PCI strategy with respect to mortality, reinfarction, stroke, or major bleeding. Transfer times for the pharmacoinvasive strategy were considerably shorter for the MHI program compared with ours (11). The reason is that the majority of patients who presented >60 miles away from the PCI center were transferred by helicopter (11). Another difference is that the MHI program uses half-dose TNK and our program uses full-dose. This could explain the difference in the rate of TIMI grade 3 at baseline between our program (57.2%) and theirs (46.5%). However, the rate of intracranial hemorrhage in our study was higher (1.3%) compared with the MHI’s study (0.3%). In TIMI10B study, TIMI flow grade 3 at 90 min was achieved at a rate of 62% to 63% with TNK at doses greater or equal to 0.5 mg/kg; compared with 51% to 54% with lower doses (14). However, recent evidence from STREAM suggests that the use of half-dose TNK in patients ≥75 years of age is recommended to reduce the risk of intracranial bleed (24). In our study, the average age of the 3 patients with intracranial hemorrhage was 71 years. Accordingly, we are considering the introduction of a half-dose TNK regimen for patients ≥75 years old. Further studies will need to be undertaken to determine whether decreasing dose of TNK in this age group will the reduce risk of intracranial bleed.
The major limitation of this study is that it is not a randomized controlled trial, but rather a retrospective analysis of a registry data where confounding variables could have impacted the results. We controlled for known confounding variables through the use of a multivariable logistical regression. Furthermore, our results are only applicable to regions with established STEMI programs.
Primary PCI remains the optimal reperfusion therapy when administered within a reasonable time. This study demonstrates that the use of a regional STEMI program that uses both reperfusion therapies, primary PCI and pharmacoinvasive, based on geographical proximity to the PCI center is safe and effective. The use of half-dose TNK in patients ≥75 years old might be warranted to reduce risk of intracranial bleed.
WHAT IS KNOWN? Primary PCI strategy continues to be the optimal reperfusion therapy; however, in areas where specialized centers are not readily available, a pharmacoinvasive strategy has been proposed.
WHAT IS NEW? Within the context of a STEMI system, a pharmacoinvasive strategy was associated with similar rates of the composite of mortality, reinfarction or stroke as compared with a primary PCI strategy, but the propensity for more bleeding with a pharmacoinvasive strategy approached statistical significance.
WHAT IS NEXT? Further studies are needed to determine the safety and efficacy of using half-dose TNK combined with novel antiplatelet therapy in patients ≥75 years old treated with a pharmacoinvasive strategy.
Supported by the Summer Studentship Program, Faculty of Medicine, University of Ottawa, and Mach-Gaensslen Foundation of Canada, and The University of Ottawa Heart Institute Regional STEMI Program.
Dr. Chong is co-chair of Advanced OCT Symposium organized by St. Jude Medical (without honorarium). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received March 7, 2016.
- Revision received June 20, 2016.
- Accepted June 30, 2016.
- American College of Cardiology Foundation
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