Abstract
Aims
To assess both epicardiac macrovascular as well as microvascular and tissue reperfusion following different intravenous preadmission antithrombotic strategies prior primary PCI in STEMI patients.
Methods and results
Consecutive STEMI patients (n = 488) undergoing pPCI received prehospitally either bivalirudin (n = 179), bivalirudin and periprocedural GPIIb/IIIa inhibitors (GPI) (n = 109), heparin (n = 99) or heparin and periprocedural GPI (n = 101). Epicardial perfusion and microvascular perfusion were assessed by angiography (TIMI flow rate and corrected TIMI frame count [cTFC]) and by ECG (ST resolution [STR]).
TIMI 3 flow was restored at the end of the procedure in 85.2% of the cases; cTFC of ≤23 was obtained in 37.2% of cases and STR >70% in 42.5% of the cases. The rates of STR >70% and cTFC ≤23 were not different between the three groups. Multivariate analysis did not identify a predictive antithrombotic treatment to obtain either post-procedural TIMI 3 flow rate or a STR rate >70%.
TIMI 3 flow before procedure and delay first symptoms-balloon <6 h represented a positive predictive value of STR rate >70% and the LAD as infarct related artery a negative predictive value of STR rate of >70%.
Conclusion
The process of myocardial reperfusion by pPCI continues to be improved with earlier reperfusion but an optimal tissular reperfusion was present in only half of the cases.
Highlights
- •
The major goal of reperfusion strategies in STEMI is to limit infarct size and improve outcomes
- •
The prompt restoration of coronary flow in STEMI is necessary but not sufficient to achieve effective myocardial reperfusion
- •
An optimal corrected TIMI Frame Count was obtained in only one patient out of three
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Microvascular reperfusion attested by complete ST resolution remained modest and found in 44% of cases
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No differences in myocardial reperfusion were found according to the different antithrombotic strategies used
1
Introduction
The major goal of reperfusion strategies in acute ST-segment elevation myocardial infarction (STEMI) is to limit infarct size and improve outcomes [ ]. The prompt restoration of antegrade coronary blood flow in acute STEMI is necessary [ , ] but not sufficient to achieve effective myocardial reperfusion [ ]. Indeed, myocardial recovery is often impaired by loss of microvascular integrity, diffuse myocardial oedema, or distal embolization into the microcirculation.
Last decade, antithrombotic treatments and manual thrombectomy were developed to reduce distal embolization during primary percutaneous coronary intervention (pPCI) to limit their adverse consequences. Several randomized clinical trials successively introduced GPIIbIIIa inhibitors (GPI) [ ] and bivalirudin [ , ] as either an upstream or periprocedural treatment which proved efficient and safe for early administration in patients undergoing PCI. However, a number of changes have occurred in clinical practice since GPI and bivalirudin trials were conducted: (1) PCI via radial-artery access, which may reduce the risk of bleeding and vascular complications, has expanded (2) the use of manual thrombectomy and (3) new ADP receptor antagonists have been increasingly adopted.
The aim of our monocentric study was to assess the effect of different intravenous preadmission antithrombotic strategies on epicardial as well as myocardial reperfusion after primary PCI in a series of consecutive patients with STEMI in a contemporary, real world setting.
2
Methods
2.1
Patient selection
All consecutive patients admitted for STEMI and primary PCI in the cardiology department of the CHRU of Nancy, France between January 1st 2012 and March 31st 2015 were included in this retrospective observational cohort study.
Inclusion criteria were continuous chest pain for at least 20 min, ECG changes defined as: (1) ST-segment elevation ≥1 mm (0.1 mV) in ≥2 contiguous leads on the 12‑lead electrocardiogram (ECG); (2) persistent ST-segment depression in precordial leads V1 to V4, with or without ST segment elevation in inferior or lateral leads; or (3) new-onset left bundle branch block as well as treatment within 12 h of pain onset.
2.2
Percutaneous intervention and antithrombotic treatment
Primary PCI was performed using standard technique by radial (preferential access route) or femoral approach according to physician choice. The infarct-related artery (IRA) was the only target of the emergency procedure and either bare-metal or drug-eluting stents could be used at the discretion of the operators.
Before the procedure all patients received salicylic acid 250 to 500 mg intravenously, thereafter orally 100 to 325 mg/day. Either prehospital bivalirudin dispensed by the mobile care unit (0.75 mg/kg IV bolus followed by 1.75 mg/kg/h infusion until the end of PCI procedure) or heparin (70 U/kg IV bolus) were administered. A GPI was added in the catheterization laboratory according to the physician.
P2Y 12 inhibitors were given as soon as possible during the prehospital period with an oral loading dose of 60 mg (prasugrel), 180 mg (ticagrelor) or 600 mg (clopidogrel) continued at a dose of 10 mg once daily, 90 mg bi daily or 75 mg once daily, respectively.
2.3
Angiographic analysis
During PCI procedure, coronary angiograms were repeated in the same working-projection to assess TIMI flow grade and corrected TIMI frame count (cTFC). cTFC was determined by the number of cine frames required for the dye to reach the distal coronary landmark. The duration of the last cine filming was at least three cardiac cycles. Visual analysis was performed by two independent operators.
2.4
Electrocardiographic analysis
Electrocardiograms (ECGs) were done during the prehospital period (baseline ECG), at arrival in the catheterization laboratory (pre-procedural ECG) and 1 h after pPCI/angiography (post-procedural ECG).
The preprocedural ST-segment deviation (pre-procedural ECG) and residual ST-segment deviation (post-procedural ECG) were used for the assessment of the ST deviation.
In addition, the degree of resolution of ST-segment deviation (STR) from paired ECGs was calculated by dividing the extent of ST-segment deviation on the post-procedure ECG by the extent of ST-segment deviation on the pre-procedural ECG and expressed in percentage [ ].
2.5
Definition of clinical events
The clinical outcome included death from all causes, myocardial re-infarction and stent thrombosis at 30 days as defined by the Academic Research Consortium [ ]. Patients did not undergo systematic control angiography during the follow-up period.
Follow-up was performed through comprehensive questionnaires and by telephone with the patient’s personal physician. If death occurred, the patient’s physician or appropriate hospital record department were interviewed to document the cause.
2.6
Statistical analysis
To describe patients’ characteristics overall and by preadmission antithrombotic strategies, continuous variables are presented as means ± standard deviations or median and interquartile range and categorical variables as percentages.
To identify potential indication bias, patient characteristics in the different preadmission antithrombotic strategies were compared, using analysis of variance (ANOVA) or Kruskal-Wallis test, according to conditions of application, for continuous variables, and χ 2 or Fischer exact test, according to conditions of application, for categorical variables.
To assess the effect of preadmission antithrombotic strategies on ST resolution, TIMI flow, and cTFC after PCI, logistic regression models were used, using ST resolution ≥70%, TIMI flow ≥3, and cTFC ≤23 as the dependent variables. To account for potential confounding, the models were then adjusted for variables with p-values ≤0.3 in crude logistic regression models assessing their association with the dependent variables. Results are presented as odds ratios (OR) and 95% confidence intervals (CI).
All the tests performed were two-sided, and the significance level was set at 0.05.
All statistical analysis were performed using SAS© 9.3 software (Cary, NC).
3
Results
The mean age of patients was 59.9 ± 13 years and 20.7% of patients were female. The median delay from first symptoms to balloon was 5.2 [3–6.1] hours.
Radial access was used in 79% of the patients and ad hoc PCI using stents was the principal management strategy in 83.7% of the patients. Among patients who didn’t undergo stent implantation during the index procedure, a delayed stenting was performed in 34 patients (6.9%), and angioplasty with balloon alone in 23 patients (4.7%). A prehospital loading dose of salicylic acid was used in all patients and a prehospital loading dose of P2Y 12 inhibitors in 92% of the patients with maintenance after PCI for up to one year: prasugrel, ticagrelor or clopidogrel use was 71.3%, 18.4% and 10.5% respectively. Upstream prehospital bivalirudin was used in 288 patients and heparin in 200 patients. No patient received a prolonged infusion of bivalirudin after PCI procedure. GPI was used in 210 patients (68%) pretreated with bivalirudin or heparin in a bail out setting or at the discretion of the operator. Aspiration thrombectomy was performed in 53.5% of cases.
Patients’ characteristics, angiographic findings, and procedure characteristics according to preadmission antithrombotic strategies are summarized in Table 1 .
| n | Heparin (n = 99) | n | Heparin + GPI (n = 101) | n | Bivalirudin (n = 179) | n | Bivalirudin + GPI (n = 109) | p value | |
|---|---|---|---|---|---|---|---|---|---|
| %/Med (Q1–Q3) | %/Med (Q1–Q3) | %/Med (Q1–Q3) | %/Med (Q1–Q3) | ||||||
| Age, years median (IQR Q1 Q3) | 99 | 65 (48–77) | 101 | 57 (48–63) | 179 | 60 (52–68) | 109 | 58 (48–63) | 0.009 |
| Sex, female | 26 | 26.3% | 22 | 21.8% | 37 | 20.7% | 16 | 14.7% | 0.226 |
| Body mass index (kg/m 2 ) | 72/99 | 25.7 (23–28.4) | 75/101 | 27.4 (24.1–31.1) | 161/179 | 25.9 (24.0–28.4) | 95/109 | 27.2 (24.2–29.4) | 0.008 |
| Cardiovascular risk factors | |||||||||
| Diabetes | 21 | 21.6% | 18 | 17.8% | 25 | 14% | 15 | 13.9% | 0.331 |
| Hypertension | 38 | 38.4% | 33 | 32.7% | 63 | 35.2% | 37 | 33.9% | 0.801 |
| Hyperlipidemia | 29 | 29.9% | 34 | 33.6% | 67 | 37.4% | 34 | 31.5% | 0.578 |
| Smoker (current or past) | 46 | 47.4% | 58 | 57.4% | 83 | 46.4% | 60 | 55.6% | 0.180 |
| Previous myocardial infarction | 4 | 4.1% | 6 | 5.9% | 12 | 6.7% | 5 | 4.6% | 0.791 |
| Previous PCI | 8 | 8.2% | 7 | 6.9% | 13 | 7.3% | 4 | 3.7% | 0.562 |
| Delay first symptoms–balloon (h) | 84/99 | 86/101 | 164/179 | 94/109 | 0.559 | ||||
| <3 | 16 | 19.0% | 19 | 22.1% | 29 | 17.7% | 12 | 12.8% | |
| 3–6 | 47 | 56.0% | 46 | 53.1% | 90 | 54.9% | 62 | 66.0% | |
| >6 s | 21 | 25.0% | 21 | 24.4% | 45 | 27.4% | 20 | 21.3% | |
| Acute heart failure | 12 | 12.6% | 10 | 9.9% | 19 | 10.6% | 14 | 12.8% | 0.872 |
| Prehospital cardiogenic shock | 7 | 7.4% | 6 | 5.9% | 4 | 2.2% | 6 | 5.5% | 0.171 |
| Delay first symptoms ≥6 h | 23 | 27.4% | 23 | 26.7% | 48 | 29.3% | 21 | 22.3% | 0.688 |
| Angiography | |||||||||
| Culprit lesion location: | 0.001 | ||||||||
| Left anterior descending artery | 58 | 61.1% | 50 | 49.5% | 77 | 43% | 49 | 67.9% | |
| Left circumflex artery | 25 | 26.3% | 24 | 23.8% | 75 | 41.9% | 49 | 22.9% | |
| Right coronary artery | 12 | 12.6% | 27 | 13.9% | 27 | 15.1% | 11 | 9.2% | |
| Multivessel coronary disease | 49 | 50.5% | 37 | 36.7% | 71 | 39.7% | 35 | 32.1% | 0.052 |
| Pre-PCI flow grade | <0.0001 | ||||||||
| TIMI 0/1 | 76 | 76.8% | 76 | 75.3% | 117 | 65.3% | 87 | 79.8% | |
| TIMI 2 | 0 | 0.0% | 10 | 9.9% | 19 | 10.7% | 8 | 7.3% | |
| TIMI 3 | 23 | 22.2% | 15 | 14.8% | 43 | 24.0% | 14 | 12.9% | |
| Oral antithrombotic treatment: | |||||||||
| Prasugrel | 58 | 58.6% | 71 | 70.3% | 135 | 76.3% | 82 | 75.9% | 0.231 |
| Ticagrelor | 27 | 27.3% | 17 | 16.8% | 23 | 13.0% | 21 | 19.5% | 0.124 |
| Clopidogrel | 14 | 14.1% | 13 | 12.9% | 19 | 10.7% | 5 | 4.6% | 0.095 |
| Stent implantation | 82 | 84.5% | 92 | 91.1% | 143 | 79.9% | 90 | 82.6% | 0.106 |
| Manual thrombectomy | 59 | 59.6% | 49 | 48.5% | 81 | 45.3% | 72 | 66.1% | 0.002 |
| Delayed angioplasty | 4 | 4.0% | 3 | 2.9% | 14 | 7.8% | 7 | 6.4% | 0.270 |
3.1
Clinical outcomes
The follow-up at day 30 was obtained in 97% of cases.
The overall 30 day mortality rate for the study population was 3.9%.
Patients with worse outcomes presented at admission with cardiogenic shock and/or cardiac arrest in two third of the cases. Mean LVEF at hospital discharge was 46.8 ± 9.6% and LVEF was <45% in 22% of the cases. Stent thrombosis occurred in 11 patients (2.2%), mainly in first two days. The comparison between the different parenteral antithrombotic and antiplatelet therapies showed no significant difference concerning these major clinical events. Bleeding occurred in 23 patients, 7 of them needed transfusions. Only one patient presented with a TIMI bleeding score of 2. Concerning haemorrhagic events, no differences were observed among the different groups.
Angiographic and electrocardiographic results according to antithrombotic strategy are presented in Table 2 and independent predictors of TIMI flow grade 3 and post PCI ST resolution ≥70% are presented in Tables 3 and 4 .
| Heparin (n = 99) | Heparin + GPI (n = 101) | Bivalirudin (n = 179) | Bivalirudin + GPI (n = 109) | p value | |||||
|---|---|---|---|---|---|---|---|---|---|
| n (%) | n (%) | n (%) | n (%) | ||||||
| ST resolution (%, IQR: Q1 Q3) | 91 | 60.0% (50–80) | 78/101 | 66.7% (50 100) | 154/179 | 66.7% (50 100) | 88/109 | 66.7% (40–100) | 0.626 |
| ST resolution (%) | 0.230 | ||||||||
| <30% | 9 | 9.9% | 15 | 19.2% | 26 | 16.9% | 14 | 15.9% | |
| 30–70% | 45 | 49.5% | 33 | 42.3% | 52 | 33.8% | 35 | 39.8% | |
| >70% | 37 | 40.7% | 30 | 38.5% | 76 | 49.4% | 39 | 44.3% | |
| ST resolution >70% | 30 | 38.5% | 30 | 38.5% | 76 | 49.4% | 39 | 44.3% | 0.367 |
| TIMI flow after reperfusion | 101/101 | 177/179 | 109/109 | 0.001 | |||||
| 0/1 | 10 | 10.1% | 2 | 1.9% | 3 | 1.7% | 2 | 1.8% | |
| 2 | 7 | 7.1% | 15 | 14.9% | 13 | 7.3% | 18 | 16.5% | |
| 3 | 82 | 82.8% | 84 | 83.2% | 161 | 91.0% | 89 | 81.7% | |
| TIMI 3 after reperfusion | 82 | 82.8% | 84 | 83.2% | 161 | 91.0% | 89 | 81.7% | 0.085 |
| cTFC after reperfusion | 99 | 28 | 101 | 26.0 | 172/179 | 28 | 104/109 | 28 | 0.750 |
| cTFC ≤23 | 38 | 38.4% | 41 | 40.6% | 63 | 36.6% | 35 | 33.7% | 0.767 |
| Myocardial blush | 0.557 | ||||||||
| 0–1 | 25 | 24.8% | 54 | 31.0% | 35 | 33.3% | 27 | 28.4% | |
| 2–3 | 76 | 75.2% | 120 | 69.0% | 70 | 66.7% | 68 | 71.6% | |
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