Abstract
Background
A pharmacoinvasive strategy may alleviate the logistical and geographical barriers in timely reperfusion of ST-segment elevation myocardial infarction (STEMI), especially in a developing country like India.
Aim
To assess the safety and efficacy of pharmacoinvasive strategy versus primary PCI in STEMI patients at 2 years.
Methods
Patients enrolled in STEPP-AMI, an observational, multicenter, prospective study of 200 patients presenting with STEMI, were followed up for 2 years. Group ‘A’ comprised of patients with pharmacoinvasive strategy (n = 45), and patients who underwent primary PCI (n = 155) formed group ‘B’. Primary endpoint was composite of death, cardiogenic shock, reinfarction, repeat revascularization of the culprit artery, or congestive heart failure at 30 days, with follow-up till 2 years.
Results
The primary endpoint occurred in 11.1% and 17.8% in group A and in 3.9% and 13.6% in group B, at 30 days and 2 years, respectively (p = 0.07, RR = 2.87; 95% CI: 0.92–8.97 at 30 days and p = 0.47, RR = 1.31; 95% CI: 0.62–2.76). There was no difference in bleeding risk between groups, 2.2% in group A and 0.6% in group B (‘p’ = 0.4). The infarct-related artery patency varied at angiogram; it was 82.2% in arm A and 22.6% in arm B (‘p’ < 0.001). In group A, failed fibrinolysis occurred in 12.1%.
Conclusion
A pharmacoinvasive strategy resulted in outcomes that were comparable with primary PCI at 2 years, suggesting it might be a viable option in India. Larger studies are required to confirm these findings.
Keywords: ST elevation myocardial infarction, Timely reperfusion, Pharmacoinvasive strategy
1. Introduction
ST-segment elevation myocardial infarction (STEMI) is a life threatening manifestation of coronary artery disease (CAD) requiring timely reperfusion. The incidence of STEMI is higher in the Indian population when compared to developed countries and results in significant mortality.1 The current recommendations maintain primary percutaneous coronary intervention (PCI) as the treatment of choice in the management of STEMI, contingent upon rapid initiation of treatment at centers with a skilled PCI laboratory within suggested timelines.2 However, unavailability of primary PCI capable hospitals across India and delays in transport have restricted the access to this life-saving modality to less than 10% of patients with STEMI.3 Of those, patients who do reach the hospital early still have to deal with other issues, such as arranging for finances, as most Indian patients pay out-of pocket, even for the emergency services, such as primary PCI.4
On the other hand, introduction of fibrin-specific lytic agents like tenecteplase (TNK) has improved the infarct-related artery (IRA) patency rates significantly.5 Rapid fibrinolytic treatment after STEMI improved the outcomes in patients treated within an hour of symptom onset, with tapering benefits after 3 h.6 However, fibrinolysis is associated with high rates of reocclusion of IRA, hence a strategy of initial bolus lysis followed by early coronary angiogram within 3–24 h of fibrinolysis, with an appropriate PCI, now known as ‘pharmacoinvasive strategy,’7 has been considered as a good alternative in the treatment of STEMI, especially in a developing country such as India.8
2. Methods
This is prospective, observational, multicenter pilot study, which was conducted between August 2011 and May 2013. Study sites, which were capable of performing 24/7 primary PCI, were selected from Tamilnadu (3), Karnataka (1), and Kerala (1). All study centers were well equipped to handle cardiac emergencies. A total of 200 patients who fulfilled the inclusion/exclusion criteria with STEMI were enrolled in the study. Written informed consent was signed by all the patients and the study has been cleared by the ethics committees of the respective hospitals. As this is an observational study, the treatment options were chosen entirely by the patient and the attendants; hence, some patients who presented outside the recommended timelines for thrombolysis have received lytic therapy although all centers in the study were equipped with 24 × 7 primary PCI facilities. Thrombolysis was performed in the ICU of the hospital in all centers.
The aim of the study is to assess the safety, efficacy, and feasibility of a pharmacoinvasive strategy in comparison to primary PCI in patients with STEMI. The trial's inclusion and exclusion criteria and study protocol are described in the primary publication.9 Definitions used in the study are given in the appendix.
3. Endpoints
Our primary endpoint was set at 30 days and is a composite of death, cardiogenic shock, reinfarction, repeat revascularization, and congestive heart failure, and extended to 2 years. Safety endpoints are bleeding endpoints assessed using the TIMI classification at 30 days.
4. Statistical analysis
The detailed description of statistical analysis is published previously.9 As this was a pilot study, primarily conducted to assess feasibility of a pharmacoinvasive strategy in STEMI patients, a sample size of 200 patients was deemed sufficient for the study. Statistical analyses were performed using SAS software, version 9.2. Chi-square or Mantel-Haenszel test or Fischer's exact test were used for observed differences between groups. Relative risk estimates with 95% confidence intervals and Kaplan–Meier curves were used to compare differences in outcomes. A p-value of 0.05 was considered significant for all the statistical evaluations.
5. Results
The results of this trial, up to 1-year follow-up, have been published previously.9 Out of the 200 total patients enrolled, the pharmacoinvasive arm (arm ‘A’) had 45 patients and PPCI arm (arm ‘B’) had 155 patients. Baseline characteristics were no different between both groups, except more patients in arm B were in killip's class I.9 The salient points of procedural characteristics of patients are that 6.7% (n = 3) patients in arm A had insignificant disease; hence no intervention was performed for them, whereas 100% of patients in arm B required angioplasty and stent implantation. Patients in arm A also had better TIMI flow at CAG (TIMI 3 flow in 27.9%), higher radial procedures (76.7%), more IRA patency (82.2%), and less thrombus burden.9 In arm ‘A’, 12.1% was the incidence of failed thrombolysis.
The timelines for the study are given in Table 1; median total ischemic times are similar for both groups (245 min vs. 260 min); average door-to-balloon time is 80 min and the door-to-needle time is 47 min.9 Antiplatelets and other medication usage was published earlier9 and the safety endpoints are given in Table 29; there is no difference in bleeding outcomes between both groups (2.2% vs. 2.6%, ‘p’ not significant). The efficacy endpoints are studied at 30 days, 3 months, 6 months, 1 year, and 2 years; there is no difference between both groups in efficacy endpoints at any time period although there is trend of benefit for arm B in the initial few months (Table 3). The efficacy endpoints were adjusted for age, sex, and killips's class at presentation and were found to be no different between both groups (Table 4). The Kaplan–Meier curves for the primary endpoints are shown in Fig. 1. At the end of 2 years, 2 patients were lost to follow-up in arm ‘A’.
Table 1.
Important timelines for the study.
| Parameter | ‘A’ | ‘B’ | ‘p’ value |
|---|---|---|---|
| Total ischemic time (minutes) | 0.69 | ||
| Median | 245 | 260 | |
| Interquartile range | 185–395 | 185–390 | |
| Door-to-balloon time (minutes) | NA | ||
| Median | 0 | 80 | |
| Interquartile range | 0 | 60–120 | |
| Door-to-needle time (minutes) | NA | ||
| Median | 47 | 0 | |
| Interquartile range | 35–75 | 0 |
Reproduced with permission from “Open Heart-BMJ”
Table 2.
Safety endpoints.
| A | B | ‘p’ value | |
|---|---|---|---|
| Bleeding | |||
| Any bleeding – n (%) | 1 (2.2) | 4 (2.6) | 1.0 |
| Intracranial bleeding – n | 0 | 0 | NA |
| Bleeding at access site – n (%) | 1 (2.2) | 0 | 0.22 |
| TMI Bleeding | |||
| Major – n (%) | 0 | 1 (0.6) | 1.0 |
| Requiring medical attention – n (%) | 0 | 1 (0.6) | 1.0 |
| Minimal – n (%) | 1 (2.2) | 2 (1.3) | 0.54 |
NA – not applicable.
Reproduced with permission from “Open Heart-BMJ”
Table 3.
Efficacy endpoints.
| Endpoints | A (n = 45) n (%) |
B (n = 155) n (%) |
‘p’ value | Relative risk |
|
|---|---|---|---|---|---|
| Estimate | 95% CI | ||||
| Death, reinfarction, repeat revascularization of culprit artery, cardiogenic shock, CHF | |||||
| At 30 days | 5 (11.1) | 6 (3.9) | 0.07 | 2.87 | 0.92–8.97 |
| At 3 months | 6 (13.3) | 9 (5.8) | 0.10 | 2.30 | 0.86–6.11 |
| At 6 months | 6 (13.3) | 11 (7.1) | 0.19 | 1.88 | 0.74–4.80 |
| At 1 year | 6 (13.3) | 14 (9.0) | 0.40 | 1.48 | 0.60–3.62 |
| At 2 year | 8 (17.8) | 21 (13.6) | 0.47 | 1.31 | 0.62–2.76 |
| Efficacy endpoint – death | |||||
| At 30 days | 3 (6.7) | 2 (1.3) | 0.07 | 5.17 | 0.89–29.98 |
| At 3 months | 4 (8.9) | 4 (2.6) | 0.07 | 3.44 | 0.90–13.23 |
| At 6 months | 4 (8.9) | 5 (3.2) | 0.12 | 2.76 | 0.77– 9.83 |
| At 1 year | 4 (8.9) | 7 (4.5) | 0.26 | 1.97 | 0.60–6.42 |
| At 2 years | 5 (11.1) | 13 (8.4) | 0.57 | 1.32 | 0.50–3.52 |
| Efficacy endpoint – death/reinfarction | |||||
| At 30 days | 3 (6.7) | 5 (3.2) | 0.31 | 2.07 | 0.51–8.32 |
| At 3 months | 4 (8.9) | 7 (4.5) | 0.26 | 1.97 | 0.60–6.42 |
| At 6 months | 4 (8.9) | 8 (5.2) | 0.36 | 1.72 | 0.54–5.46 |
| At 1 year | 4 (8.9) | 10 (6.4) | 0.57 | 1.38 | 0.45–4.18 |
| At 2 years | 5 (11.1) | 16 (10.3) | 0.88 | 1.08 | 0.42–2.78 |
CHF – congestive heart failure.
Table 4.
Efficacy endpoints (after adjusting for age, sex, and killip's class as covariates).
| Endpoints | A (n = 45) n (%) |
B (n = 155) n (%) |
‘p’ value | Relative risk |
|
|---|---|---|---|---|---|
| Estimate | 95% CI | ||||
| Death, reinfarction, repeat revascularization, cardiogenic shock, CHF | |||||
| At 30 days | 5 (11.1) | 6 (3.9) | 0.12 | 2.22 | 0.81–6.13 |
| At 3 months | 6 (13.3) | 9 (5.8) | 0.23 | 1.70 | 0.72–4.05 |
| At 6 months | 6 (13.3) | 11 (7.1) | 0.34 | 1.50 | 0.65–3.43 |
| At 1 year | 6 (13.3) | 14 (9.0) | 0.64 | 1.21 | 0.54–2.71 |
| At 2 years | 8 (17.8) | 21 (13.6) | 0.69 | 1.15 | 0.57–2.33 |
CHF – congestive heart failure.
Fig. 1.
Kaplan–Meier curves for the primary endpoint. The primary endpoint was a composite of death, cardiogenic shock, reinfarction, repeat revascularization, and congestive heart failure at 2 years (p = 0.40). PCI, percutaneous coronary intervention.
6. Discussion
In this study, we have evaluated the strategy of pharmacoinvasive management of STEMI versus primary PCI. The primary endpoint was set at 30 days consisting of death, cardiogenic shock, reinfarction, repeat revascularization, and congestive heart failure, which was similar in both groups, although there was a trend toward benefit in the primary PCI group (11.1% vs. 3.9%, p = 0.07, RR = 2.87; 95% CI: 0.92–8.97).9 At the end of 2-year follow-up, the initial benefit from primary PCI seems to be narrowed as more events have occurred in the primary PCI group (A-17.8% vs. B-13.6%, p = 0.47, RR = 1.31; 95% CI: 0.62–2.76). The additions of events in the primary endpoint of primary PCI group are mainly due to death and repeat revascularization. This may be partly due to the fact that 6.7% of patients in the pharmacoinvasive group did not require a stent placement due to insignificant disease at the angiogram, which means they are at no risk of stent thrombosis or restenosis. The non-urgent basis on which the angioplasty was performed in the pharmacoinvasive group may also have influenced the primary endpoint over a period of time, but this fact needs further large studies to provide comprehensive evidence.
The STREAM trial is one of the pivotal trials, which compared the pharmacoinvasive strategy with primary PCI in STEMI patients.10 The combined primary endpoint of death, shock, congestive heart failure, or re-infarction was similar between the groups at 30 days and at 1 year11 as in our study. The FAST-MI Registry evaluated the “real world” management of 1492 patients with STEMI in France, who sought medical treatment within 12 h of symptom onset.12
Ninety-six percent of the patients treated with fibrinolysis underwent coronary angiography within 3–24 h and 84% underwent subsequent PCI. Survival at 5 years was 88% in the fibrinolysis group and 84% for those in PPCI group. (HR = 0.73; CI: 0.50–1.06; p = 0.1). However, pre-hospital fibrinolysis resulted in lower 5-year mortality (HR = 0.57; CI: 0.36–0.88), whereas in-hospital fibrinolysis was associated with a tendency toward increased 5-year mortality (HR = 1.19; CI: 0.72–1.96) when compared to primary PCI.
Gershlick et al. performed a pre-specified analysis of STREAM cohort according to PCI-related delay.13 Data from hospitals that enrolled more than 10 randomized patients were used in the analysis and PCI-related delay was categorized as ≤55, >55–97, and >97 min. While there was no worsening outcomes of death/congestive heart failure/cardiogenic shock/myocardial infarction for pharmacoinvasive patients across the PCI-related delay, as this delay increased to >55 min, patients in pharmacoinvasive strategy had better outcomes than primary PCI strategy, suggesting an event-free advantage with pharmacoinvasive strategy (p(interaction) = 0.094). Further analysis of PCI-related delay demonstrated that for every 10 min increase of this delay, there was a rising trend of benefit among pharmacoinvasive strategy patients (p(interaction) = 0.073).
Because of the small and uneven sample size between the groups of the study, our findings may not provide an exact estimate of outcomes and larger randomized trials are required to confirm these findings. Further discussion of the trial results and limitations of the study are detailed in the primary publication.9
7. Conclusion
Current guidelines sustain primary PCI to be the reperfusion strategy of choice in patients with STEMI contingent upon treatment at centers with a skilled PCI laboratory and rapid initiation. However, increasingly more data support a pharmacoinvasive strategy as an efficient therapeutic option in patients with STEMI. Our study showed that fibrinolysis followed by an early coronary angiogram within 3–24 h with PCI, if appropriate, resulted in similar outcomes when compared to primary PCI in patients with STEMI at 2-year follow-up. These findings lend further support to the adoption of a pharmacoinvasive strategy where patient and system-related delays are inherent.
Funding
Tenecteplase has been provided free of cost for patients participating in this trial by Boehringer Ingelheim.
Conflicts of interest
The authors have none to declare.
Footnotes
The study was conducted by Madras Medical Mission, Chennai, India.
Trial is registered with Clinical trial registry of India, CTRI number: REF/2011/07/002556.
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ihj.2015.08.027.
Appendix A. Supplementary data
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