Effectiveness and safety of intravenous unfractionated before fbrinolytic therapy in patients with STEMI: A retrospective observational study

Jinshan Fan (  [email protected] ) Yangtze University Medical School https://orcid.org/0000-0003-4493-0990 Xulong Mao Yangtze University Medical School Guoqiang He Wuhan University Renmin Hospital Jiachong Shi Wuhan University Renmin Hospital Qiang Gu Wuhan University Renmin Hospital Jiang Lan Wuhan University Renmin Hospital

Research article

Keywords: unfractionated heparin, ST-elevation ,

Posted Date: April 30th, 2020

DOI: https://doi.org/10.21203/rs.3.rs-21390/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

Page 1/16 Abstract

Background: The benefts and risks of administering intravenous unfractionated heparin (UFH) before fbrinolytic therapy in the treatment of patients with acute ST-segment elevation myocardial infarction (STEMI) remain unclear. This study investigated the effectiveness and safety of intravenous UFH before fbrinolytic therapy in STEMI patients.

Methods: A total of 260 STEMI patients were divided into a no-heparin group (n=130) and UFH group (n=130) according to whether they received intravenous UFH before fbrinolytic therapy. The infarction related artery (IRA) patency rate was determined by echocardiography. The primary end point was the clinical patency rate within 120 min after thrombolysis. The safety end point was the occurrence of a severe bleeding event such as gastrointestinal bleeding or . Covariates were balanced by propensity score matching, and the effectiveness of the treatment strategies was compared using a Cox proportional hazard model and subgroup analysis. The safety of intravenous UFH treatment was evaluated using a Cox proportional hazard model.

Results: The IRA patency rate was higher in the UFH group than in the no-heparin group. Additionally, UFH as pre-thrombolytic therapy was associated with a signifcantly lower risk of composite effectiveness outcomes but not a signifcantly lower risk of composite safety outcomes compared with the no-heparin therapy. Moreover, the 7- and 12-day survival rates were higher in the UFH group than in the no-heparin group. No signifcant difference in bleeding risk was observed between the two groups.

Conclusion: Intravenous UFH administered before fbrinolytic therapy improved the IRA patency rate in STEMI patients with appreciable safety.

Background

Acute ST-segment elevation myocardial infarction (STEMI) usually occurs when coronary fow decreases abruptly due to a thrombotic occlusion of a coronary artery. Most resulting from STEMI are caused by ventricular fbrillation and occur within the frst hour of its onset[1]. Hence, immediate rescuscitative intervention plays an important role in reducing the mortality of STEMI patients during the early phase of disease onset. In addition to antiplatelet therapy, an , which can restore and maintain the patency of the infarct-related artery (IRA) in STEMI patients, should be administered to STEMI patients before pharmacological fbrinolysis [2]. The overarching goal is to minimize the time from the frst medical contact to the initiation of reperfusion therapy. Reperfusion therapies applied for the IRA within 12 h include pharmacological fbrinolysis and percutaneous coronary intervention (PCI). However, not all STEMI patients can receive one of these treatments and not all hospitals have the capacity to offer PCI. Thus, administration of a pharmacological fbrinolysis agent should be initiated within 12 h. Anticoagulant therapy before fbrinolytic therapy can maintain the patency IRA in STEMI patients, but a major concern regarding anticoagulant therapy is bleeding complications, with being the most serious complication[3].

Page 2/16 Unfractionated heparin (UFH) is a mixture of polysaccharide chains of different lengths that prevents coagulation by blocking the activity of thrombin factor IIa and factor X [4,5]. UFH can also bind to circulating plasma proteins, endothelial cells, and acute-phase reactants to achieve anticoagulant activity. Due to its short half-life, UFH must be administered intravenously to maintain a stable blood level of anticoagulation in STEMI patients; however, few studies have been performed on the effectiveness and safety of UFH in STEMI patients in China. In the present study, we investigated the effectiveness and safety of intravenous UFH before fbrinolytic therapy in STEMI patients with the primary end point of patency rate and safety end point of severe bleeding.

Methods Study design and patient selection

This retrospective cohort study enrolled a total of 372 STEMI patients between 2008 and 2018. STEMI patients were diagnosed according to the International Classifcation of diseases, Tenth Revision, and Clinical Modifcation (ICD-10-CM) code; i.e., the diagnosis of STEMI was determined by electrogram, blood myocardial enzyme test, and the clinical presentation of patients. Consecutive hospitalized STEMI patients (including cases of cardiac arrest and ) were recorded in The Electronics Medical Records (EMR) management system of our hospital. STEMI patients in our study received fbrinolytic therapy but did not receive PCI. STEMI patients were divided into two groups based on whether they were given UFH treatment: the no-heparin group, in which 192 received only fbrinolytic therapy, and the UFH group, in which 180 were given intravenous UFH treatment (4000U, IV) before fbrinolytic therapy. However, after one-to-one propensity score matching (see below), a fnal number of 180 patients per group was determined.

Evaluation of thrombolytic outcomes

Coronary artery clinical patency was considered to be achieved if any two of the following criteria were met[6]:(1) ST-segment drop amplitude index ≥50% on the two most obviously elevated leads in the initial electrocardiogram within 120 min after administration; (2) signifcant improvement or disappearance of chest pain within 120 min of starting thrombolytic therapy; (3) dynamic electrocardiograph-monitored arrhythmia, such as atrioventricular block, accelerated ventricular arrhythmia, or bundle branch blockade, abruptly manifested or disappeared within 120 min after receiving thrombolytic therapy, or transient atrial-ventricular block and sinus bradycardia; and (4) the peak serum creatine kinase-MB (CK-MB) enzyme level appeared 16 h to 14 h earlier after symptom onset.

End points and follow up

The primary end point was the clinical patency rate within 120 min after thrombolysis. The secondary outcome was the composite of post-infarction angina, reinfarction/reocclusion, and all-cause

Page 3/16 within 7 days after thrombolysis. The safety end point was defned as the occurrence of severe bleeding such as gastrointestinal or intracranial hemorrhage that required additional treatment(s).

Statistical analysis

One-to-one propensity score matching using a greedy matching algorithm was applied to balance the covariates between the no-heparin group and UFH group. Data for baseline characteristics are presented as mean ± standard deviation (SD) or percentage and number when applicable. Effectiveness and safety end points were analyzed by calculating the event rates for each study group and comparing them using relative risks with two-sided 95% confdence intervals (CIs). For the primary end point, we also performed prespecifed subgroup analyses according to age, sex, Killip class, time to randomization, place of randomization, infarct location, systolic blood pressure, weight, history of diabetes or hypertension, and randomization before or after adoption of the protocol amendment. For the primary end point, we also compared Kaplan–Meier curves using a log-rank test. An imputation model was established based on baseline characteristics together with all single efcacy and safety end points. All analyses were performed on an intention-to-treat basis using either STATA12.0 software or Medcalc software.

Results Baseline characteristics of patient groups

A total of 372 STEMI patients were enrolled in the present study. After one-to-one propensity score matching, the fnal study cohort included a total of 130 matched pairs, of which 130 (34.9%) were in the UFH group and 130 (34.9%) were in the no-heparin group. The demographic and baseline characteristics of participants in these two study groups were all balanced based on propensity score matching (Table 1).

Page 4/16 Table 1 Baseline characteristics of patients with acute decompensated failure(n=376)According to serLymphocyte Proportion Categories Lymphocyte proportion distribution (%)

Characteristics Q1 (n=76) Q2 (n=91) Q3 (n=152) Q4 (n=57) P value

≤10.0% 10.1%-15.0% 15.1%-25.0% >25.0%

Age (years), mean±SD 72±9 73±9 69±14 71±9 0.06

Male, n (%) 46 (61%) 68 (75%) 83 (55%) 25 (44%) 0.001

History of Fibrillation,n (%) 48 (63%) 35 (38%) 73 (48%) 27 (47%) 0.20

CHD,n (%) 28 (63%) 39 (63%) 62 (63%) 24 (63%) 0.8

History of chronic bronchitis, n 8 (1%) 9 (10%) 35 (23%) 4 (7%) 0.3 (%)

History of Hypertension, n (%) 21 (27.6%) 50 (54.9%) 80 31 < (52.6%) (54.3%) 0.0001

History of diabetis, n (%) 4 11 17 0 0.5

Beats, Noumber /min 102.5±34 84±15 88.0±24 87±17 < 0.05

TBI(g/l) 24.3±19.8 24.5±17.9 20.9±12.0 16.6±7.0 < 0.05

Creatinine (mmol/l) 142.4±19.8 126.7±79.5 91.9±21.7 91.0±26.8 < 0.001

WCC (10*9/L) 7.0±2.7 5.8±2.0 7.5±7.8 5.8±1.4 0.053

LV,mm 59.0±9.7 58.5±5.8 56.4±7.3 50.7±7.7 < 0.05

Medications

Oral digxin, n (%) 33 22 27 4 < 0.0001

ACEI/ARB, n (%) 38 28 68 10 0.0003

β-Blocker, n (%) 9 15 22 10 0.5

EF,% 37.6±11.8 39.0±8.8 45.2±9.8 53.5±9.1 <0.0001

Diuretic,n (%) 68 (89.5%) 90 (93.8%) 87 3 (5.3%) <0.0001 (57.2%)

NYHA,n (%) <0.0001

Class I 0 0 0 8 (14.0%)

ClassII 8 (10.5%) 0 33 24 (21.7%) (42.1%)

Page 5/16 Class III 11 (14.5%) 47 (51.6%) 5 14 7(37.5%) (24.6%)

Class IV 57 (75%) 44 (48.4%) 62 11 (40.8%) (19.3%)

Number of rehospitalization

Case numbers of 60 (78.9%) 70 (76.9%) 95 19 (33.3) <0.0001 rehospitalization, n(%) (62.5%)

Time form discharge to 2.2±1.2 4.3±2.4 11.1±6.3 26.7±6.1 <0.001 rehospitalization

Abbreviations: CHD, coronary heart disease; TBI, Total bilirubin; WCC, white cell counts; LV, left ventricular; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; EF, ejection fraction; NYHA, New York heart function classifcation.P value for genereal association(ANOVA or chi-square).

Subgroup analyses of composite of effectiveness and safety outcomes

The IRA patency rate differed signifcantly between the prespecifed subgroups across multiple subgroups (P<0.05). The clinical patency rates for the no-heparin and UFH groups stratifed by initial features are shown in Figure 1. There was a lower risk of the primary end points in the UFH group. Also, UFH as pre-thrombolytic therapy was associated with a signifcantly lower risk of composite effectiveness outcomes (HR: 0.81; 95% CI: 0.66-0.90, P=0.01) than the no-heparin treatment approach. However, UFH as pre-thrombolytic therapy was not associated with a signifcantly lower risk of composite safety outcomes (HR: 0.98; 95% CI: 0.47–0.50, P=0.06; Table 2).

Table 2 Number of Events and HRs for the Risk of All-Cause Readmmission with Lymphocyte proportion Level

Muitivariable model was adjusted for sex; Age, History of Fibrillation,CHD, History of chronic bronchitis,History of Hypertensio, History of Tiabetis, Beats, TBI, Creatinine, WCC, LV, Oral digxin, ACEI/ARB, Β-Blocker, EF, Diuretic, NYHA. Lymphocyte No.of Events/ Crude HR Sex-Adjusted Multivariable HR proportion(%) Total of (95%CI) HR(95%CI) (95%CI) Patients

≤10.0% 25/76 44.88 (24.42- 44.85 (24.42- 73.99 (33.05- 82.46) 82.36) 165.68)

10.1%-15.0% 79/91 15.53 15.55 (9.37- 20.97 (10.36- 25.80) 42.42)

15.1%-25.0% 45/152 4.82 4.50 (2.94-6.89) 3.84 (2.17-6.81)

>25.0% 36/57 REF REF REF

Page 6/16 Comparison of clinical outcomes between the UFH and no- heparin groups

The IRA clinical patency rates at 0.5, 1.0, 1.5, and 2.0 h were 6.9%, 23.5%, 21.5%, and 14.6%, respectively, in the UFH group and 3.1%, 12.3%, 14.6%, and 22.3%, respectively, in the no-heparin group (P<0.05). The total IRA clinical patency rate was 84.6% (110 cases) at 2 h in the UFH group, which was higher than that of 52.3% (68 cases) in the no-heparin group (P<0.05; Fig. 2a).

All patients were followed-up after hospital discharge with a median follow-up period of 12.0 days. The heparin group had a higher 95% CI for the survival mean than the no-heparin group (10.903–12.190 vs. 8.361–9.903, P<0.0001). The 12.0-day survival rate in the UFH group was 95.3%, which was signifcantly higher than that in the no-heparin group (86.0%; P<0.0001). Also, the 7-day survival rate in the UFH group was 95.3%, which was signifcantly higher than that in the no-heparin group (88.3%; P<0.0001). No patient died of a serious bleeding complication, such as stroke or gastrointestinal bleeding, in either group. Discussion

Intravenous thrombolysis is known as a safe and effective treatment strategy for STEMI, especially when UFH is administered as quickly as possible after the onset of symptoms and then followed by timely fbrinolytic therapy. Intravenous thrombolysis can restore coronary fow in the IRA and salvage jeopardized myocardium. Urokinase is one of the main drugs used clinically for fbrinolytic therapy catalyzes the cleavage of plasminogen to plasmin and degrades fbrin clots by thrombolysis[7,8]. Also, urokinase, with its half-life of approximately 16 minutes, improves vascular adenosine diphosphate (ADP) activity, prevents ADP-induced platelet aggregation, and prevents thrombosis-related complications[9,10]. However, a study on intravenous UFH use in STEMI patients before fbrinolytic therapy has not been reported in China. Previous studies considered the most serious complication of bleeding in UFH-treated STEMI patients before thrombolytic therapy in a hospital unable to perform PCI[15,17], and such studies were likely limited by the small number of available patients. In other studies, a UFH- combination signifcantly reduced mortality among STEMI patients who did not undergo PCI without signifcantly increasing the risk of major bleeding[18,19]. A meta-analysis showed that fve fewer deaths and three fewer recurrent infarctions occurred in every 1000 patients treated with heparin versus alone, although three more major bleeding episodes occurred[20]. Our study was a small-scale clinical trial with the aim of exploring the effectiveness and safety of intravenous UFH given before fbrinolytic therapy in 260 STEMI patients. In the present study, we found that the UFH group had a signifcantly higher IRA patency rate than the no-heparin group; however, the IRA patency rate did not different among subgroups within each group. We also found that no patient died of a serious bleeding complication, such as stroke and gastrointestinal bleeding, in either group.

In the present study, we used the resolution of ST segment elevation as an indicator of treatment effectiveness, because it is a well-known indicator of improvement in myocardial reperfusion and is strongly associated with a decrease in mortality[12,15]. We found that UFH treatment signifcantly

Page 7/16 reduced the number of leads with ST segment elevation and also the amplitude of the ST segment compared with the no-heparin therapy.

UFH is the standard anticoagulant agent used in clinical practice. The available data suggest that addition of UFH to a regimen of aspirin and a non-fbrin-specifc thrombolytic agent can reduce mortality[21]. However, in the present study, we found that the UFH group had a signifcantly higher mortality rate than the no-heparin group within 14 days after thrombolysis. We noted that the patients in the UFH group tended to have increased bleeding compared with those in the no-heparin group, although no statistically signifcant different was observed. This may be due to the fact that the administration of UFH in our study was less rigorously controlled than in the previous randomized controlled trials with standardized anticoagulation protocols [22,23]. Alternative strategies include administration of UFH before thrombolytic therapy, or even pre-hospitalization or after the onset of symptoms, which may beneft the IRA patency after treatment with fbrinolytic therapy.

Some limitations of this study should be noted. For example, selection bias and residual confounding are two important inherent limitations. Although the groups were fairly well balanced after propensity score matching, unknown confounders may still have introduced bias in the results. Also, the information regarding the exact timing and dosage of UFH was limited. In addition, our study had a limited sample size. Thus, a large-scale randomized trial is needed to confrm the potential beneft of early administration of UFH in the treatment of STEMI patients.

Conclusions

In the present study, we found that early intravenous administration of UFH improved the IRA patency of STEMI patients without causing severe bleeding. Thus, intravenous UFH before fbrinolytic therapy is likely an efcient and safe approach for treating STEMI patients.

Abbreviations

IRA: infarction related artery; STEMI: ST-segment elevation myocardial infarction; UFH: unfractionated heparin; CI: confdence interval.

Declaration

Ethics approval and consent to participate This study was approved by the Ethics Committee of Qianjiang Central Hospital (No: QPH-HEC 2018-A-18), and all participants signed a document of informed consent. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication An informed consent form was signed by each participant before entering the study.

Page 8/16 Availability of data and materials Not applicable.

Competing interests The authors declare that they have no competing interests.

Funding No funding was received for this study.

Author contributions X-LM acquired data. X-LM, J-SF and G-QH drafted the manuscript. JL and J-CS contributed substantially to its revision. QG, and L-G take responsibility for the paper as a whole. All authors read and approved the fnal manuscript.

Acknowledgements None.

References

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Figures

Page 11/16 Figure 1

Distribution of baseline lymphocyte proportion levels in real-world patients with Heart failure, from January 2011 to December 2016.

Page 12/16 Figure 2

Crude effect of lymphocyte proportion on 36-month survival readmission rate. The curves were estimated in cox proportional hazards models using restricted cubic splines with four degrees of freedom(df) : 95%Cl in dotted area.Rug density of lymphocyte proportion distribution at the bottom. p for nonlinearity, p-vlue adjusted : <0.0071. (B) Adjusted effect of lymphocyte proportion on 36-month readmission rate. The curves were estimated in cox proportional hazards models using restricted cubic splines with four degrees of freedom(df) : 95%Cl in dotted area.Rug density of lymphocyte proportion distribution at the

Page 13/16 bottom. Adjusted for age, Hypertension, Beats, TBI, Creatinine, LV, EF, NYHA at heart failure diagnosis Is : p for nonlinearity , p- value adjusted : < 0.05.

Figure 3

The Kaplan-Meier survival curves show signifcant differences in heart failure readmissions between the groups. The uppest curve, of the 57 patients with serum lymphocyte proportion> 25.0%, 3 were readmitted within the study period. The Lowest curve, of the 76 patients with serum lymphocyte proportion < 10.0%, 68 were readmitted during the study period.

Page 14/16 Figure 4

ROC curves based on a univariate model examining the power of BNP and lymphocyte proportion to predict readmission rate.

Page 15/16 Figure 5

Plot showing correlation between BNP and Lymphocyte proportion for the whole cohort.

Page 16/16