|Year : 2022 | Volume
| Issue : 3 | Page : 152-159
Clinical outcomes with the use of ticagrelor or clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction – A prospective observational study
Bibek Agarwal, Sudarshan Kumar Vijay, Amresh Kumar Singh, Ashish Jha, Bhuwan Chandra Tiwari, Naveen Jamwal
Department of Cardiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||07-Nov-2022|
|Date of Decision||19-Nov-2022|
|Date of Acceptance||21-Nov-2022|
|Date of Web Publication||14-Dec-2022|
Sudarshan Kumar Vijay
Department of Cardiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow - 226 010, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Thrombolytic therapy in the appropriate window period remains the most commonly used therapy in ST-elevation myocardial infarction patients, despite the advantage of primary percutaneous coronary intervention (PCI) over it. Use of newer more potent antiplatelets agents early after thrombolysis carries the chance of increasing bleeding complications, thus we planned to have a study to assess the safety and efficacy of ticagrelor as compared to clopidogrel in thrombolysed patients.
Materials and Methods: This was a prospective observational study in Indian patients. A total of 142 patients were enrolled in the study with 76 in the ticagrelor group and 66 in the clopidogrel group. All patients received thrombolysis as the primary reperfusion strategy. Patients receiving either clopidogrel or ticagrelor after thrombolysis irrespective of the subsequent PCI status were followed up for any bleeding events (primary endpoints) as per thrombolysis in myocardial infarction (TIMI) definition and Bleeding Academic Research Consortium (BARC) definition. Major adverse cardiac events (MACE) including death from cardiovascular causes, myocardial infarction (MI), and stroke were also assessed as markers of efficacy and secondary endpoints.
Results: Mean time from thrombolysis to study drug use was 18.9 ± 2.1 h in the ticagrelor group as compared to 14.8 ± 3.3 h in the clopidogrel group (P > 0.05). For major bleeding events (TIMI major), no statistically significant difference was observed between groups (2.6% in ticagrelor vs. 1.5% in clopidogrel) (P = 0.6). BARC 3–5 bleeding at 1-month follow-up was significantly higher in the ticagrelor group compared to the clopidogrel group (P = 0.04). At 1-month follow-up, BARC 1–2 or 3–5 bleeding events in the subjects who underwent PCI were higher in the ticagrelor group than the clopidogrel group (P = 0.03). Patients in the clopidogrel group have more major adverse cardiac events than the ticagrelor group especially driven by more fatal and nonfatal MI in the clopidogrel group (P = 0.04).
Conclusions: Ticagrelor can be safely administered in postthrombolytic patients similar to clopidogrel albeit at the cost of slightly increased minor bleeding events in short-term follow-up.
Keywords: Clopidogrel, fibrinolysis, ticagrelor
|How to cite this article:|
Agarwal B, Vijay SK, Singh AK, Jha A, Tiwari BC, Jamwal N. Clinical outcomes with the use of ticagrelor or clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction – A prospective observational study. Heart India 2022;10:152-9
|How to cite this URL:|
Agarwal B, Vijay SK, Singh AK, Jha A, Tiwari BC, Jamwal N. Clinical outcomes with the use of ticagrelor or clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction – A prospective observational study. Heart India [serial online] 2022 [cited 2023 Feb 3];10:152-9. Available from: https://www.heartindia.net/text.asp?2022/10/3/152/363546
| Introduction|| |
Primary percutaneous coronary intervention (PCI) has been shown as the preferred reperfusion strategy over thrombolysis in patients with ST-elevation myocardial infarction (STEMI) when performed within appropriate door-to-balloon time. However, it is often not feasible for STEMI patients to be treated at hospitals with PCI capabilities in a timely manner as shown by registry data from several parts of the globe. There are many factors which cause a delay in STEMI patients reaching a PCI-capable hospital. Because of this delay, many patients receive fibrinolytic therapy as the initial reperfusion strategy with very few patients receiving primary PCI especially in the developing parts of the world.
Fibrinolysis is itself associated with a procoagulant state with high platelet reactivity (HPR) due to enhanced platelet activation, and current clinical practice guidelines recommend the use of dual antiplatelet (aspirin and clopidogrel) co-therapy with fibrinolysis (Class IA). Many trials have shown the superiority of ticagrelor, a reversible, and direct-acting inhibitor of adenosine diphosphate receptor P2Y12, than clopidogrel in patients with acute coronary syndrome (ACS). Despite better efficacy outcomes with ticagrelor, its safety postfibrinolytic therapy remains uncertain with the scarcity of data in this clinical setting. Some of the prior studies have revealed better short-and long-term pharmacodynamic effects of ticagrelor when administered in postfibrinolysis STEMI patients.,
The major concern regarding the use of ticagrelor or clopidogrel after fibrinolysis is the occurrence of major bleeding, particularly intracranial hemorrhage or other fatal bleeding. These patients who experience bleeding complications have a higher rate of major adverse cardiovascular events (MACEs) eventually culminating in increased morbidity and mortality. A major trial was performed in the Caucasian population to evaluate the safety of ticagrelor in this clinical setting. With the paucity of data in this context in the Indian population, we piloted research to study the clinical safety and efficacy outcomes with the use of ticagrelor or clopidogrel after the fibrinolytic therapy in patients with STEMI.
| Materials and Methods|| |
Patients aged more than 18 years who had STEMI and received fibrinolytic therapy (either with nonfibrin-specific or fibrin-specific agent) within 12 h of the onset of pain were allowed to participate in the study. Patients were excluded if they had any contraindication to thrombolysis and if they had any contraindication to the use of ticagrelor or clopidogrel.
A single-center pilot study was conducted in 142 STEMI patients admitted in the Department of Cardiology at Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, during the study period of March 2020 to September 2021. The patients were followed up at 1 month. Patients of both sex after obtaining informed consent were included in the study.
Patients found eligible for enrolment if they present within 12 h after the onset of symptoms, and had evidence of acute STEMI on their qualifying electrocardiogram (ECG) (≥1 mV in ST elevation ≥2 continuous leads), and, due to anticipated delay to primary PCI, received thrombolysis as the primary mode of reperfusion. All patients received aspirin, statins, and other agents as adjunctive therapy at the time of fibrinolysis as recommended by guidelines. Postfibrinolysis, further treatment, and subsequent revascularization were done as per the discretion of the treating physician. Patients receiving either clopidogrel or ticagrelor after thrombolysis irrespective of the subsequent PCI status were followed up for any bleeding events (primary endpoints) as per thrombolysis in myocardial infarction (TIMI) definition and for adverse events including death from vascular causes, myocardial infarction (MI), and stroke (secondary endpoints). Patients were followed-up till hospital discharge and at 1 month.
The study protocol was reviewed and approved by the Institutional Ethics Committee of the hospital. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in accordance with the International Conference on Harmonization's Good Clinical Practice Guidelines, applicable regulatory requirements, and in compliance with the protocol.
A detailed history, physical examination, and all routine investigations including complete blood count, renal function test, liver function test, lipid profile, 12 channel ECG, and echocardiography were done for all the patients at admission. Data pertaining to the demography, comorbidities, and clinical features were also obtained at admission. Thrombolysed STEMI patients who were either on clopidogrel or ticagrelor as per the discretion of the treating physician were followed up for safety outcomes during the hospital stay and at 1-month follow-up. The primary endpoint was TIMI major bleeding. TIMI major bleeding was defined as any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI), or, clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hb) of >5 g/dL, or, fatal bleeding (bleeding that directly results in death within 7 d).
The data analysis was done using Statistical Package for Social Sciences (SPSS Inc., Chicago, Ilinois, USA). Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean ± standard deviation and median. Quantitative variables were compared using Student t-test between the two groups. Qualitative variables were compared using the Chi-square test/Fisher's exact test. P < 0.05 was considered statistically significant.
| Results|| |
A total of 142 patients were enrolled, of which 76 were enrolled in the ticagrelor group and the rest 66 were in the clopidogrel group. The mean age was 56.5 ± 10.1 and 54.3 ± 11.3 years for the ticagrelor and clopidogrel groups, respectively, and males were in majority in both the groups and all the demographic parameters were equally matched in between the groups (P > 0.05), as shown in [Table 1]. The major risk factor associated with STEMI in both groups was tobacco chewing, followed by hypertension, diabetes mellitus, and alcohol consumption. There was no significant difference in both groups in terms of the prevalence of risk factors (P > 0.05). Anterior wall MI constituted the major STEMI group, followed by inferior wall MI. Aspirin, statin, and proton-pump inhibitor were the major medication given to almost all the studied patients in both groups. Unfractionated heparin was given to more number of patients in the clopidogrel group as these patients had more patients with acute renal dysfunction. The major thrombolytic agent used in the study was streptokinase because of its low cost followed by other fibrin-specific agents. The mean time from thrombolysis to study drug use was 18.9 ± 2.1 h in the ticagrelor group as compared to 14.8 ± 3.3 h in the clopidogrel group [Figure 1]. Left ventricular ejection fraction (LVEF) was compared in both groups, and it was found that LVEF ranging between 36% and 50% was found in the majority of the patients in both groups (P > 0.05). The angiography done was significantly higher in the ticagrelor group (P = 0.01), and on the basis of angiography, PCI was also significantly higher in the ticagrelor group (P < 0.05) [Figure 2]. The reason for this discrepancy was that ticagrelor is used in the majority of patients who underwent PCI at our center and very few patients with simple PCI were on clopidogrel.
|Figure 2: Comparison of PCI between two groups. PCL: percutaneous coronary intervention|
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All bleeding events were recorded and classified according to TIMI and Bleeding Academic Research Consortium (BARC) during the 1-month study period. For major bleeding events (TIMI major), no statistically significant difference was observed between groups (2.6% in ticagrelor vs. 1.5% in clopidogrel, P = 0.6) [Table 2]. In contrast, the rates of minor, minimal, and total bleeding events were numerically higher with ticagrelor than with clopidogrel [Table 3], but this finding did not reach statistical significance. Different types of bleeding in the two groups are presented in [Figure 3]. In the ticagrelor group, two patients had TIMI major bleeding and both had underwent PCI. One among them had TIMI major bleeding at index hospitalization. He had grade III perforation during PCI and developed cardiac tamponade and eventually died of refractory VT. This was a procedural complication and may be not related to the drug per se. The other patient in the ticagrelor group who had TIMI major bleeding had developed a hemorrhagic stroke at home 24 days after hospital discharge (this may be ascribed to the study drug) [Figure 3]. In the clopidogrel group, one patient had TIMI major bleeding at index hospitalization. The patient developed gastrointestinal (GI) bleeding after PCI and there was a drop in Hb by 5.5 g/dl. The patient was given 3 units of packed red cell transfusion and lower GI endoscopy was done which showed rectal ulcers (infective etiology) and the same was managed. This patient was also given tirofiban post-PCI. Hence, bleeding could also be related to tirofiban administration. The GP IIb/IIIa inhibitor use was similar in the two groups with bleeding events and study drug use. In the present study, the fibrinolytic therapy was used on all patients with three different thrombolytic drugs which were streptokinase, reteplase, and tenecteplase, and the correlation of these drugs with BARC-type bleeding among both groups was assessed. The association was found to be nonsignificant among groups (P > 0.05) for all three thrombolytic agents. BARC 3–5 bleeding at 1-month follow-up was significantly higher in the ticagrelor group compared to the clopidogrel group [Table 3].
|Table 2: Comparison of thrombolysis in myocardial infraction major bleeding between two groups|
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|Table 3: Comparison of any bleeding events (as per bleeding academic research consortium definition) among study groups|
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Out of 69 post-PCI patients in the ticagrelor group, a total of 7 bleeding events occurred including 3 major (BARC 3–5) and 4 minor (BARC 1–2) [Table 4]. The 3 major bleeding events were one patient had cardiac tamponade following grade III coronary artery perforation during PCI which was a procedural complication. Second patient had upper gastrointestinal (UGI) bleed post-PCI where tirofiban was also used so, it could be related to the use of tirofiban. The third patient developed hemorrhagic stroke at 24 days post-MI and at 30 days follow-up, this patient was alive with left hemiparesis on supportive care. There were four minor bleeding events in this subgroup of patients, out of which, three patients developed bleeding after hospital discharge. Hence, overall it seems that at 1-month follow-up, ticagrelor-related bleeding in post-PCI patients was 1 major (excluding the patients with cardiac tamponade and UGI bleed) and 3 minor if we take confounding factors into consideration.
|Table 4: Comparison of bleeding events (as per bleeding academic research consortium definition) among patients who underwent percutaneous coronary intervention versus who did not underwent percutaneous coronary intervention|
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Out of 16 post-PCI patients in the clopidogrel group, only 1 patient had major bleed (BARC 3–5) [Table 4]. This patient developed lower GI bleeding and lower GI endoscopy showed rectal ulcers, and there was a history of tirofiban use in this patient. In this patient, bleeding may be associated with preexisting ulcers and additional use of drugs.
The rates of MACE events were statistically similar in both groups of patients [Table 5]. Although the association was found statistically insignificant for the total number of MACE events (2 vs. 4 events in the ticagrelor and clopidogrel group, respectively, the fatal/nonfatal MI was significantly higher in the clopidogrel group compared to ticagrelor group (P < 0.05). A total of five mortalities were reported in the study. One patient died with cardiac tamponade in the ticagrelor group. In the clopidogrel group, a total of four deaths were reported, in these deaths, during 1-month follow-up, two patients had probable stent thrombosis, one patient had ischemic stroke, and one patient died at hospital with fatal MI during stabilization.
| Discussion|| |
Fibrinolytic therapy is the most commonly administered reperfusion therapy worldwide in STEMI patients with concomitant use of antiplatelet agents. Dual antiplatelet therapy is recommended in STEMI patients after fibrinolytic therapy use. For the new-generation P2Y12 inhibitors, the PLATO and TRITON TIMI-38 trials showed that ticagrelor or prasugrel had even lower MACE rates in patients with ACS when compared with clopidogrel. This advantage of newer antiplatelet agents was explained by the increased potency of these drugs, their rapid onset of action, and less inter-individual variation of the drug effect due to associated gene polymorphisms, but the data of safety with fibrinolysis were not available from these trials. Ticagrelor has been found to mitigate high platelet reactivity (HPR) postfibrinolysis when compared with clopidogrel, but the safety of ticagrelor has always been a matter of concern when combined with thrombolysis. In one study in the western population, ticagrelor was not associated with increased major bleeding events (≥BARC 3) than clopidogrel, which were identical in the two study groups. The total number of bleeding events was greater in the ticagrelor group, due to increased minor bleedings, especially BARC 1 (7 of the 8 minor bleeding events in the ticagrelor group). A trial by Dehghani et al. compared ticagrelor with clopidogrel in 144 patients undergoing early PCI postreperfusion with tenecteplase. All patients received clopidogrel prerandomization, and the median time of thrombolytic administration to randomization (and initiation of ticagrelor vs. clopidogrel) was about 6 h. The BARC types 3–5 bleeding rates at 30 days were 1.3% in both the ticagrelor and clopidogrel groups at 30 days. Çoner and Müderrisoğ. reported that complications related to mild bleeding were commonly reported with ticagrelor more than with clopidogrel in STEMI patients in their clinical follow-up. On the other hand, Song et al. reported that major bleeding complications defined as BARC 2, 3, or 5 were similar between ticagrelor and clopidogrel patients. A study by Çoner and Müderrisoğ did not find any differences in neither minor nor major bleeding complications defined by BARC classification (P = 0.539 and 0.443, respectively).
In the present study of Indian patients with STEMI treated with fibrinolytic therapy as their initial reperfusion strategy, the administration of ticagrelor postfibrinolysis was similar to clopidogrel administration with regard to short-term safety. In contrast, the rates of minor, minimal, and total bleeding events were numerically higher with ticagrelor than with clopidogrel, but this finding did not reach statistical significance [Table 3]. Since there was a considerable difference in the number of patients undergoing PCI in the two groups, a further subanalysis was done among patients who underwent PCI and who did not underwent PCI with respect to BARC bleeding. This also showed that bleeding events were not statistically different among the groups [Table 4]. In the two major bleedings among the ticagrelor group, one was cardiac bleeding due to PCI complication and the other was a GI bleed probably related to tirofiban use. Third major bleed in the ticagrelor group occurred at 1 month and was a hemorrhagic stroke and probably this was due to drug per se and not due to the interaction of ticagrelor with thrombolysis. In the clopidogrel group, one major bleed occurred in the PCI subset with per rectal bleed probably related to tirofiban use.
Our findings were consistent with previous other ethnic studies comparing ticagrelor and clopidogrel in patients with STEMI treated with fibrinolytics. In the TREAT trial, ticagrelor was administered postthrombolysis in 1800 patients and proved to be a safe alternative to clopidogrel in terms of bleeding events, while no difference in ischemic events was observed. Similarly, in the MIRTOS trial, ticagrelor was not associated with increased major bleeding events (≥BARC 3), which were identical in the two study groups. The total number of bleeding events was greater in the ticagrelor group, due to increased minor bleedings, especially BARC 1 (7 of the 8 minor bleeding events in the ticagrelor group). The results of Schmucker et al. underline the safety of the ticagrelor in elderly patients with relatively low bleeding rates and a significant benefit for Major adverse cardiac and cerebrovascular events (MACCEs).
MACE events in our trial occurred more in the clopidogrel group than in the ticagrelor group. Although the association was found statistically insignificant, the events were numerically more in patients who received clopidogrel compared to ticagrelor. Patients on clopidogrel had more MACE events than those on ticagrelor irrespective of the PCI status. Two patients who were on clopidogrel post-PCI had probable stent thrombosis suggesting lower efficacy of clopidogrel than ticagrelor for its antiplatelet activity. A study by Zhu et al. demonstrated more efficacy of ticagrelor as compared to clopidogrel in Chinese subjects. A study by Winter et al., however, demonstrated no major difference in myocardial blush grade and disclosed no difference in the ST-segment changes, cTFC, or TIMI flow rate between groups. The possible explanation for the lack of a significant difference between drugs could be the two antiplatelet agents have very tiny role in the immediate resolution of the thrombosis post-MI and play a more influential role in the subsequent thrombus formation. Wang et al. showed better efficacy and similar safety of ticagrelor as compared to clopidogrel in Taiwanese subjects. A study in another east Asian population, however, showed contradictory results with more events in ticagrelor as was reported in the North American arm of the PLATO trial.
Kheiri et al. did a meta-analysis of randomized controlled trials of ticagrelor versus clopidogrel after the fibrinolytic therapy in STEMI patients and reported similar short-term clinical outcomes between the ticagrelor and the clopidogrel regarding rates of BARC type ≥2 bleeding (P = 0.83), major adverse cardiovascular events (P = 0.62), mortality (P = 0.77), MI (P = 0.36), and stroke (P = 0.82), and similar findings were reported from another meta-analysis.
Mortalities reported in our study in the ticagrelor arm were related to PCI complication and at 1 month due to hemorrhagic stroke and these cannot be ascribed to the interaction of ticagrelor with thrombolysis.
The major limitation of the present study is the small number of patients that could be enrolled. This study was done in a tertiary care level hospital during the peak of COVID which showed a decline in the number of patients reaching health-care facility timely. Hence, the results cannot be applied broadly to the general population. More effectively powered trials and longer follow-up of the patients who received ticagrelor and clopidogrel postfibrinolysis would give us a more accurate picture of the risks and benefits of the ticagrelor in this setting.
Another important limitation was that the choice of study drug to be given to a patient was on the discretion of the treating physician and was not blinded. This may introduce bias.
Patients with other comorbidities such as acute kidney injury and patients with more severe disease were kept in the clopidogrel group, which may be responsible for more MACE events in this group. Similarly, in the ticagrelor group, more patients underwent PCI, so more likelihood of better outcomes in terms of efficacy.
There were additional drugs used besides the study drugs, which could add to the bleeding events such as the use of tirofiban post-PCI. More number of the patients in the ticagrelor group underwent PCI and hence more patients were given tirofiban. This tirofiban might be responsible for some of the bleeding events in such patients.
| Conclusions and Implications|| |
Our results in Indian patients supported the previous other ethnic studies that the STEMI patients treated with the postfibrinolysis ticagrelor experience similar short-term rates of TIMI major bleeding and less ischemic events as those who continued clopidogrel therapy. Treatment with ticagrelor, than clopidogrel, reduced the death rate from vascular causes, MI, or stroke, without an increase in the rate of the overall major bleeding, but with an increase in the rate of the nonprocedure-related minor bleeding. Thus, ticagrelor can be safely used with thrombolysis in the first 24 h after administration of a fibrinolytic agent.
More effectively powered trials and longer follow-ups of the patients who received ticagrelor and clopidogrel postfibrinolysis would give us a more accurate picture of the risks and benefits of the ticagrelor in this setting. Further examination must also seek to explore the potential of the ticagrelor and clopidogrel when simultaneously used with the fibrinolytics as opposed to postfibrinolysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Study was approved from institutional ethics committee.
Bibek Agarwal (BA) and Sudarshan Kumar Vijay (SKV) planned, conducted and analysed the study, Amresh Kumar Singh (AKS), Ashish Jha (AJ), Bhuwan Chandra Tiwari (BCT), and Naveen Jamwal (NJ) helped in cosupervision, data collection and patient enrollment.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]