a b s t r a c t

Background: The effectiveness and safety of administration of ticagrelor simultaneously with fibrinolytic agents in STEMI patients remain unclear.

Objective: This study aimed to investigate the effectiveness and safety of tenecteplase against alteplase in patients with STEMI receiving a loading dose of ticagrelor.

Methods: We conducted a cross-sectional study in patients with STEMI who were reperfused with fibrinolytic. The study included 150 patients (ages 18 to 75 years) administered tenecteplase or alteplase and concomitantly given ticagrelor [180 mg loading dose, 90 mg bid (bis in die)]. Patients who had active major bleeding, died, and who were decided to have a CABG surgery as a result of coronary angiography were excluded. Patients who un- derwent facilitated-PCI with fibrinolysis continued to receive ticagrelor without switching to clopidogrel. The MACE (in-hospital death, TIMI flow grade, major bleeding) rates of the two groups were compared.

Results: The study consisted of 150 patients, comprising 99 (66%) men and 51 women (34%) with a mean age of 60,33 +- 13,83 years. Patients were divided into two groups according to the thrombolytic therapy: alteplase (n = 60) and tenecteplase (n = 90). The Major adverse cardiac events (45% vs 22.2%), bleeding (11.7% vs 2.2%), hypertension (51.7% vs 30%), atrial fibrillation (26.7% vs 12.2%), left ventricular hypertrophy (26.7% vs 10%), CRP (p < 0.001) were significantly higher and the recanalization (66.7% vs 85.4%), hematocrit (p = 0.03) were significantly lower in the alteplase group compared to the tenecteplase group. No significant dif- ferences were found between the two groups about in-hospital mortality (p = 0.151). Kaplan Meier analysis was performed in terms of MACE (TIMI flow grade 1, major bleeding, in-hospital mortality) rates during the follow- up period (Log-rank test, p = 0.032). Patients who received tenecteplase treatment had a lower MACE, according to a Kaplan-Meier analysis.

Conclusions: The administration of tenecteplase in STEMI patients who received a loading dose with ticagrelor re- sulted in a significant reduction in MACE compared to alteplase. Larger multi-center studies are warranted to in- vestigate the effect of tenecteplase treatment on clinical results.

(C) 2022

1. Introduction

In patients with STEMI, a pharmacoinvasive treatment approach is recommended when Primary percutaneous coronary intervention is not possible within the target time interval (120 min) from the time of admission to the emergency department [1]. The pharmacoinvasive treatment approach also includes the transfer of pa- tients to centers with specialized coronary angiography laboratories for catheterization and PCI within 24 h after fibrinolytic administration. Paradoxically, high platelet reactivity is observed after fibrinolytic [2].

* Corresponding author at: Department of Cardiology, Dagkapi State Hospital, Dr. Seref Inaloz Street, 21100, Yenisehir, Diyarbakir, Turkey.

E-mail address: [email protected] (S. Gunlu).

Therefore, Dual antiplatelet therapy (aspirin+clopidogrel) is simulta- neously recommended with fibrinolysis [1,9]. Platelet inhibition is not successful in every patient. Ticagrelor has been shown to have both a pleiotropic effect and a faster and stronger platelet inhibition effect than clopidogrel [3,4]. Although most studies have revealed that tica- grelor further reduces platelet reactivity units (PRU) in patients with STEMI given short- and long-term fibrinolytic, its use with fibrinolytic has been avoided due to the thought of the potential for major bleeding [5]. In the TREAT and MIRTOS studies, it was demonstrated that the use of ticagrelor with fibrinolytic has a similar major bleeding effect com- pared to clopidogrel. In most studies, patients were given tenecteplase as the fibrinolytic agent, and some were given other agents. It is not known exactly whether the selected fibrinolytic agent affects the clini- cal results.

https://doi.org/10.1016/j.ajem.2022.05.021

0735-6757/(C) 2022

In our study, we investigated the effectiveness and safety of the si- multaneous receive of tenecteplase with ticagrelor against alteplase in patients with STEMI treated with a pharmacoinvasive approach.

1. Materials and methods
   1. Study design and subjects

The study population was formed by the retrospective evaluation of patients who were planned for emergency reperfusion with Fibrinolytic therapy due to STEMI. The study was conducted from 2017 to 2021 with patients transferred to the PCI-capable centers. Patients between the ages of 18 and 75 who were given fibrinolytic within the indication were included in the study. Fibrinolytic therapy was not given to pa- tients who have absolute and relative contraindications. In addition, pa- tients who died during transfer, coronary angiography could not be performed due to bleeding, and whose CABG surgery was decided as a result of coronary angiography were excluded from the study. Data were collected with coronary angiography images from the centers where the patients were transferred for coronary angiography. Patients whose records could not be reached were excluded. The study protocol was authorized by the local ethics committee (No: 2022-23 Date: 11/ 02/2022), and it followed the Declaration of Helsinki’s ethics rules for human experimentation (2013).

• 1. Thrombolytic protocol

Alteplase or tenecteplase were given as fibrinolytic agents to pa- tients who could not reach the center where PCI was performed within 120 min from the moment of admission to the emergency department. Before fibrinolytic therapy, patients were given a loading dose of 300 mg aspirin, 0.3 cc i.v. enoxaparin and 180 mg loading dose of tica- grelor were given (TNK: 30-50-mg single bolus weight-adjusted, t-PA: 15-mg bolus, followed by a 0.75-mg/kg (up to 50-mg) infusion over 30 min, followed by 0.50-mg/kg (up to 35-mg) infusion over 60 min). Echocardiography was used to determine the left ventricular ejec- tion fraction (LVEF). After fibrinolytic therapy, patients were transferred to an advanced center for catheterization and PCI within 24 h. Fig. 1 shows the flow diagram of the patients in the study.

Fig. 1. Study flow diagram.

The syntax score was calculated from the diagnostic coronary angi- ography images of the patients. Successful reperfusion was defined as TIMI flow grade 2-3 in the infarct-related artery before and after lytic- facilitated PCI. Patients received a maintenance dose of 90 mg of ticagre- lor twice a day post stenting. Follow-up of the patients after PCI was car- ried out in the hospital where the first intervention was performed. MACE (TIMI flow grade 1, major bleeding, in-hospital mortality) was ac- cepted as the clinical endpoint.

• 1. Statistical analysis

SPSS for Windows version 25.0 (Armonk, NY: IBM Corp.) was used to analyze the data. The Kolmogorov-Smirnov test was used to analyze if continuous variables had a normal distribution. Continuous variables with a normal distribution were compared using the Student’s t-test and were represented as mean standard deviation (SD) or median (in- terquartile range). To compare categorical variables, the Chi-square test or Fisher exact test were utilized. Total survival curves were esti- mated by the Kaplan-Meier method. The difference in MACE-free sur- vival rates of both groups compared follow-up days by Log-Rank test. To find MACE predictors, the study employed both univariate and mul- tivariate analyses with logistic regression. Using Receiver operating characteristic curve analysis, the optimal age cut-off values for the prediction of MACE were identified. A p-value of <0.05 was judged significant.

1. Results

The study included 150 patients, comprising 99 (66%) men and 51 women (34%) with a mean age of 60,33 +- 13,83 years. Patients were di- vided into two groups according to the thrombolytic therapy: alteplase and tenecteplase. Clinical characteristics and laboratory parameters of both groups are shown in Tables 1 and 2 respectively. The MACE (Fig. 2), bleeding, hypertension, atrium fibrillation, left ventricular hy- pertrophy and CRP were significantly higher and the recanalization and hematocrit were significantly lower in the alteplase group com- pared to the tenecteplase group (Tables 1 and 2).

In terms of in-hospital mortality, no significant differences were de- tected between the two groups (Table 1). Comparisons were made in terms of MACE (TIMI flow grade 1, major bleeding, in-hospital mortal- ity) rates during the follow-up period (Log-rank test, p = 0,032, Fig. 3). More negative clinical results were obtained in terms of MACE rates in the alteplase group (Fig. 2).

The univariate logistic regression analysis revealed that the type of thrombolytic therapy was related to an increased risk of MACE for an unadjusted model [HR (95% CI), 2864 (1406-5831), p = 0.004, Table 3]. In multivariate logistic regression analysis, the type of thrombolytic therapy after adjustment for all confounders that contribute to MACE has also predicted the MACE [HR (95% CI), 3078 (1333-7110), p = 0.008, Table 3]. The age-predicted MACE has a sensitivity of 68% and a specificity of 56% at a cutoff value of 59.5 (ROC area under the curve

[AUC]: 0.657, 95% CI: 0.563-0.752; Fig. 4).

1. Discussion

This cross-sectional study was done to prove that type of thrombo- lytic treatment is independently associated with risks of developing in-hospital mortality, TIMI flow grade 1, and major bleeding among STEMI patients treated with a ticagrelor loading dose. The study pre- sented two main findings: (i) Alteplase treatment was found to be an in- dicator of MACE and (ii) tenecteplase is highly effective in terms of successful reperfusion (TIMI II or III flow grade) and low bleeding risk. Emergency reperfusion therapy is required in patients admitted to the hospital with STEMI. As a first choice, pPCI is recommended in the guidelines [6]. However, this is not possible in real life, especially for pa- tients living in rural areas. Primary percutaneous coronary intervention

Table 1

Clinical characteristics of patients.

	Total N = 150	tPA N= 60	Tenecteplase N = 90	P value
Age (Years)	60,33 +- 13,83	60,62 +- 17,03	60,14 +- 11,32	0,839
Male gender	99 (66%)	36 (60%)	63 (70%)	0,205
Inhospital mortality	18 (12%)	10 (16,7%)	8 (8,9%)	0,151
Recanalization	116 (77,9%)	40 (66,7%)	76 (85,4%)	0,007
Bleeding	9 (6%)	7 (11,7%)	2 (2,2%)	0,017
MACE	47 (31,3%)	27 (45%)	20 (22,2%)	0,003
Hypertension	58 (38,7%)	31 (51,7%)	27 (30%)	0,008
Diabetes mellitus	50 (33,3%)	22 (36,7%)	28 (31,1%)	0,480
DL	35 (23,3%)	18 (30%)	17 (18,9%)	0,115
Smoker	109 (72,7%)	40(66,7%)	69 (76,7%)	0,178
CAD	20 (13,3%)	9 (15%)	11 (12,2%)	0,624
Atrium fibrillation	27 (18%)	16 (26,7%)	11 (12,2%)	0,024
Stroke	9 (6%)	6 (10%)	3 (3,3%)	0,09
Heart failure	22 (14,7%)	13 (21,7%)	9 (10%)	0,048
LVH	25 (16,7%)	16 (26,7%)	9 (10%)	0,007
TRT (minute) [IQR] TIMI score		27 [11]	25 [10]	0,07
TIMI 1	24 (16%)	12 (20%)	12 (13,3%)
TIMI 2	37 (24,7%)	9 (15%)	28 (31,1%)
TIMI 3 Myocardial infarction	89 (59,3%)	39 (65%)	50 (53,4%)
Anterior	66 (44%)	29 (48,3%)	37 (41,1%)
Inferior	38 (25,3%)	10 (16,7%)	28 (31,1%)	0,057
Lateral	36 (24%)	19 (31,7%)	17 (18,9%)
Posterior	10 (6,7%)	2 (3,3%)	6 (8,9%)
Antiaggregant	150 (100%)	60 (100%)	90 (100%)	*
Syntax score [IQR] Target vessel LAD proximal PCI	12 (10) 29 (19,3%)	13 (7,8) 10 (16,7%)	12 (11) 19 (21,1%)	0,718
LAD mid or distal PCI	31 (20,7%)	16 (26,7%)	15 (16,7%)
CX proximal PCI	7 (4,7%)	4 (6,7%)	3 (3,3%)
CX mid or distal PCI	25 (16,7%)	14 (23,3%)	11 (12,2%)	0,037
RCA proximal PCI	10 (6,7%)	0 (0%)	10 (11,1%)
RCA mid or distal PCI	28 (18,7%)	8 (13,3%)	20 (22,2%)
CABGO PCI	5 (3,3%)	1 (1,7%)	4 (4,4%)
Exitus	15 (%10)	7 (11,7%)	8 (8,9%)

Data are expressed as mean +- SD, number (percentage) or median (interquartile range) as appropriate. *No statistics are computed because asa, tikagrelor is a constant. tPA: tissue plasminogen activator, TIMI: the thrombolysis in myocardial infarction, DL: Dyslipidemia, CAD: Coronary artery disease, LVH: left ventricular hypertrophy, TRT: thrombolytic replasment time, LAD: left anterior descending, CX: circumflex, RCA: right coronary artery, CABGO: coronary artery bypass greft operation, PCI: percutaneous coronary intervention.

Table 2

Hematological and Biochemical parameters of patients.

Total tPA Tenecteplase P value

	N = 150		N = 60		N = 90
White blood cell count (x 103 uL) [IQR]	11,83 [4,76]	12,89 [6]		11,8 [3,7]		0,26
Neutrophils (x 103 uL) [IQR]	6,56 [4]	6,74 [6]		6,26 [4]		0,681
Lymphocytes (x 103 uL) [IQR]	2,69 [3]	2,42 [4]		2,92 [3]		0,398
Hemoglobin (g/dl)	13,71 +- 1,68	13,33 +- 1,79		13,96 +- 1,56		0,026
Hematocrit (%)	41,27 +- 4,63	40,27 +- 4,76		41,94 +- 4,45		0,03
Sodium [IQR]	140 [5]	139 [5]		140 [5]		0,858
Glucose (mg/dl) [IQR]	134 [89]	132,5 [99]		135 [82]		0,368
Creatine (mg/dl) [IQR]	0,87 [0,3]	0,87 [0,4]		0,86 [0,26]		0,849
serum albumin (g/dl) [IQR]	3,4 [0,65]	3,28 [0,65]		3,5 [0,68]		0,104
Total cholesterol (mg/dl) [IQR]	166 [63,5]	163,5 [61,5]		171 [66]		0,553
Triglyserides (mg/dl)	134 +- 97	120 +- 56		143 +- 115		0,166
LDL (mg/dl) [IQR]	107 [41,8]	106,5 [38,65]		109,9		0,953
				[43,45]
HDL (mg/dl) [IQR]	40 [14]	42,3 [16,55]		39,6 [11,75]		0,371
eGFR	94,8 [35,5]	94,3 [46,6]		94,8 [29,6]		0,407
CRP (mg/dl) [IQR]	2,1 [3]	2,63 [5]		1,2 [2]		<0,001

Data are expressed as mean +- SD and median [interquartile range] as appropriate. LDL: low-density lipoprotein, HDL: high-density lipoprotein, eGFR: estimated glomerular filtra- tion rate, CRP: C reactive protein.

Fig. 2. Bar charts of groups according to their MACE (TIMI flow grade 1, major bleeding, in- hospital mortality) percentages.

is not possible within the appropriate time interval (first 120 min.) fibri- nolytic therapy is important as an effective Reperfusion strategy in pa- tients.

The effectiveness of the pharmacoinvasive treatment strategy was demonstrated in the STREAM study [7]. On the other hand, prothrom- botic states have occurred due to high platelet reactivity after fibrinoly- sis [8]. In the CLARITY and COMMIT studies, receiving dual antiplatelet therapy with aspirin and clopidogrel on average 12-24 h after the ad- ministration of fibrinolytic therapy resulted in a significant reduction in mortality rate [2]. In the 2017 ESC guideline, a loading dose of clopid- ogrel and aspirin are recommended along with fibrinolytic therapy, also anticoagulation is recommended in addition to antiplatelet therapy [9]. It is also recommended that patients undergo diagnostic coronary angi- ography within 24 h after transfer, followed by rescue PCI if necessary [10].

Ticagrelor acts quick-action and suppresses platelet activity more strongly than clopidogrel. Furthermore, it binds directly to the P2Y₁₂ receptor with reversibility [11]. Due to this superiority, ticagrelor is included in the guidelines as the primary treatment in patients with ACS [12]. In the PLATO study, ticagrelor was found to be more protective and superior to clopidogrel in terms of recurrent MI, vascular-induced stroke, and mortality in patients who underwent PCI [13]. Patients who had received fibrinolytic therapy during the previous 24 h were excluded from the study. On the other hand, in the TREAT study, patients who underwent fibrinolysis within 24 h in ages 18-75 were included and evaluated the Safety endpoints of administration of thrombolytic with ticagrelor. Clopidogrel was ini- tially given to 89.4% of patients. After a mean of 11.4 h, patients were randomized to ticagrelor and clopidogrel after fibrinolysis. The patients were on average 58 years old, and it was observed that ticagrelor did not increase the risk of major bleeding, and also reduced Ischemic events. [14]. In another study, it was shown that platelet reactivity was signifi- cantly reduced 24 h after the loading dose of ticagrelor in patients who administer fibrinolytic therapy. [15]. Song et al. showed that major bleeding was similar in patients given clopidogrel and ticagrelor after fi- brinolysis [16]. Major bleedings were included in our study, and minor bleedings that were not clinically significant were excluded from the study. Major bleeding was defined as a decrease in hemoglobin value of more than 3 units due to Life-threatening causes. Although major bleeding is similar in patients receiving ticagrelor and clopidogrel after fibrinolysis, our study shows that the thrombolytic agent administered has different clinical outcomes in terms of MACE in patients who receive a loading dose of ticagrelor.

Tenecteplase which is derived from alteplase with recombinant tis- sue technology has high fibrin specificity and is easy to apply [17]. This study is created from patients receiving tenecteplase and alteplase. Although it was not statistically significant, 7 out of 9 patients with

Fig. 3. Kaplan-Maier analysis of both groups according to their MACE free survival rates (log-rank test, p = 0,032).

bleeding occurred in patients who received alteplase, and mortality rates were similar. In the study of Guillermin et al., patients receiving te- necteplase had less major bleeding than patients receiving alteplase, and 30-day mortality was similar [18]. Different proportions of throm- bolytic agents were used in the TREAT study. Tenecteplase was given the most as a thrombolytic agent with a rate of 39.6%. In the MIRTOS study, administration of ticagrelor as initial therapy with thrombolytic agents resulted in a reduction in MACE rates, but alteplase, a fibrin- specific agent, was not co-administered with ticagrelor. [19]. We inves- tigated the effectiveness of using ticagrelor with alteplase in real life, but there was no randomized comparison with a combination of alteplase and clopidogrel. In our study, a significant decrease in the rate of MACE (TIMI flow grade 1, major bleeding, in-hospital mortality) in the tenecteplase arm was found to be both clinically and statistically signif- icant (p = 0.003). MACE rates were observed to be high in the patient group who received alteplase in long-term follow-ups. Hypertension, atrial fibrillation, left ventricular hypertrophy and CRP values were found to be high in patients receiving alteplase, while hematocrit values were found low. Low ejection fraction was reported to be an indepen- dent predictor of mortality in patients undergoing fibrinolytic therapy by Falcao et al. [20]. In our study, patients who have heart failure were

Table 3

Independent predictors for MACE by multivariate logistic regression analysis.

Parameter	Univariate analysis			Multivariate analysis
	OR (95% CI)	P value		OR (95% CI)	P value
Age	1043 (1014-1073)	0,003		1007 (0,969-1046)	0,722
Sex	1506 (0,735-3083)	0,263
Dyslipidemia	1945 (0,888-4,26)	0,096
Hypertension	3135 (1533-6411)	0,002		0,875 (0,318-2407)	0,796
Diabetes mellitus	2698 (1312-5548)	0,007		1576 (0,510-4866)	0,429
CVE	1102 (0,264-4610)	0,894
LVH	1942 (0,806-4681)	0,139
Smoker	0,463 (0,219-0,98)	0,044		0,563 (0,224-1420)	0,224
Heart failure	5038 (1939-13,088)	0,001		2734 (0,818-9134)	0,102
Glucose	1004 (1-1008)	0,03		1001 (0,996-1007)	0,665
Creatine	3265 (1398-7629)	0,006		1479(0,409-5356)	0,551
Hemoglobin	0,718 (0,577-0,894)	0,003		0,878 (0,676-1141)	0,332
eGFR	0,982 (0,969-0,995)	0,006		0,988 (0,966-1011)	0,313
Thrombolytic	2864 (1406-5831)	0,004		3078 (1333-7110)	0,008

MACE: Major advers cardiac events, OR: Odds ratio, CI: Confident interval, CVE: Cerebro- vascular event, eGFR: estimated glomerular filtratition rate.

more common in the alteplase arm and in-hospital mortality was ob- served only in the alteplase arm.

The majority of the infarcts defined according to ECG were anterior in both groups. The left anterior descending (LAD) coronary artery made up the bulk of infarct-related arteries in this study, and there was no significant difference between the two groups. In diagnostic cor- onary angiography images, TIMI flow grades 1 and 3 were more com- mon in the alteplase arm. TIMI flow grade 2 was higher in patients receiving tenecteplase. On the contrary, Liang et al. found TIMI flow grade 3 in the distal lesion at the 90th minute after fibrinolysis similar between the two groups [21]. TIMI flow grade 3 increased from 53.4% to 85.4% with facilitated PCI in the tenecteplase arm. Likewise, it in- creased from 52% to 89% in the CAPITAL-AMI study [22]. While there were 86 patients in the research, there were only 76 in our study, and the results were determined to be similar. The anatomical complexity of the coronary artery lesions has increased the use of ticagrelor by in- terventional cardiologists. Our patients who were received tenecteplase had a higher syntax score. And this suggests that the combination of

Fig. 4. Receiver-operating characteristic (ROC) curve indicating the ability of age to predict MACE. AUC: Area under the curve, Cl: Confident interval.

tenecteplase and ticagrelor in the Fibrinolytic treatment strategy may be a good option in complex anatomical lesions.

Aspirin and clopidogrel have become the standard treatment after lytic-facilitated PCI. If planning to switch to ticagrelor in patients given clopidogrel as initial therapy, it is recommended to switch to ticagrelor after 48 h [1]. In the study of Coner et al., there was no statistical differ- ence found between the clinical endpoints of patients who were switched from clopidogrel to ticagrelor due to the anatomical complex- ity of the lesion [23]. On the other hand, in a study by Welsh et al., a de- crease in recurrent ischemic events was observed in the first year in patients switched from clopidogrel to ticagrelor. [24]. Our study com- plements other studies with significant clinical results of continuing with ticagrelor without switching to clopidogrel in patients undergoing lytic-facilitated PCI as a result of simultaneous administration of tenec- teplase with ticagrelor.

• 1. Limitations

As with any study, certain design limitations are inherent in the present study. First, a single-center retrospective study with a limited patient cohort. Second, the study was not designed as a randomized controlled which raised the risk of bias. The vascular access route (radial or femoral) of intervention and diameter, length and kind of the inserted stent, was left to the discretion of the experienced invasive car- diologist. Complex lesions were more common in the tenecteplase group on diagnostic coronary angiography images. Another limitation of the study is the exclusion of minor bleeding-related adverse events in both groups.

1. Conclusion

In patients with STEMI, where pPCI was not possible within the tar- get time interval after admission to the hospital, simultaneous adminis- tration of tenecteplase and ticagrelor resulted in a substantial decrease in in-hospital mortality, major bleeding, and TIMI flow grade 1 rate compared to alteplase. Maintenance of taking ticagrelor after tenecte- plase facilitated-PCI increases long-term survival.

Financial disclosure

The authors stated that they did not receive any funding for this work.

CRediT authorship contribution statement Serhat Gunlu: Conceptualization, Data curation, Formal analysis, In-

vestigation, Methodology, Project administration, Resources, Software,

Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Muhammed Demir: Supervision, Validation, Writ- ing, Review @ editing, Methodology.

Declaration of Competing Interest

The authors claim that they have no conflict of interest to declare.

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