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Table of Contents
RESEARCH ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 41-46

Effect of atorvastatin and trimetazidine combination treatment in patients with NSTE-ACS undergoing PCI


Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan, China

Date of Web Publication16-Jul-2018

Correspondence Address:
Hua Yan
Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_11_18

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  Abstract 


Background: Our study sought to assess the effect of atorvastatin (ATV) and trimetazidine (TMZ) combination treatment in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). Materials and Methods: Two hundred and fifty patients with NSTE-ACS who were undergoing PCI were enrolled in this study. Standard secondary prevention of coronary heart disease drug treatment was administered to both the groups (the ATV + TMZ group and the ATV group). In the ATV + TMZ group, patients were given 80mg of the combination medical orally 12h before PCI, 60mg 30min before PCI, and a further 20mg every day for 30t days after PCI, and. In the ATV group, patients were given only 80mg orally 12h before PCI, with a further 20mg every day for 30t days after PCI. Echocardiography was executed and plasma N-terminal pro brain natriuretic peptide (NT-pro-BNP) levels were measured just prior to the PCI and at 30 days after PCI. The major cardiovascular events (MACE) were also evaluated in both groups 30 days after PCI. Results: MACE occurred in 14.17% of patients in the ATV group and 6.50% of those in the ATV + TMZ group (P = 0.047). NT-pro-BNP levels were decreased 30 days after PCI for both groups; however, NT-pro-BNP levels in the ATV + TMZ group were significantly lower than those in the ATV group (P < .05). Cardiac function in NSTE-ACS patients, as reflected by the increased left ventricular ejection fraction, fractional shortening as well as decreased left ventricular end-diastolic dimension (P < .05) increased in all groups at 30 days after intervention, but cardiac function parameters were more significantly improved in the group administered with ATV + TMZ (P < .05). Conclusions: Our study suggests that short-term pretreatment with the combination of ATV and TMZ administration before PCI could reduce the incidence of MACE, further decrease NT-pro-BNP levels and improve cardiac function compared to a single administration of the ATV.

Keywords: Atorvastatin, cardiac function, N-terminal pro-brain natriuretic peptide, percutaneous coronary intervention, trimetazidine


How to cite this article:
Wang JY, Chen H, Yan H, Su X. Effect of atorvastatin and trimetazidine combination treatment in patients with NSTE-ACS undergoing PCI. Cardiol Plus 2018;3:41-6

How to cite this URL:
Wang JY, Chen H, Yan H, Su X. Effect of atorvastatin and trimetazidine combination treatment in patients with NSTE-ACS undergoing PCI. Cardiol Plus [serial online] 2018 [cited 2018 Oct 19];3:41-6. Available from: http://www.cardiologyplus.org/text.asp?2018/3/2/41/236816




  Introduction Top


In spite of rapid advancements in the therapeutic field of coronary artery disease, acute coronary syndromes (ACSs) are still the leading major cause of morbidity and mortality worldwide. The numbers of coronary care units, reperfusion techniques, and medical therapies increases has significantly improved the clinical outcome in patients with coronary artery disease. However, despite intensive therapies with hemodynamically effective agents, many patients with with ischemia do not fully recover and remain at high risk for undesired further events. Hence, it is imperative to attempt to develop novel therapies.

Atorvastatin (ATV, hydroxymethylglutaryl-coenzyme A reductase inhibitors) has been proposed to have multiple cardiovascular benefits besides its cholesterol-lowering effect and can be administered in a loading dose before percutaneous coronary intervention (PCI). The ATV for Reduction of Myocardial Damage during Angioplasty (ARMYDA) trials suggest that reloading with intensive-dose ATV could improve in the clinical outcome of patients undergoing PCI.[1],[2],[3]

Trimetazidine (TMZ; 1- [2, 3, 4-trimethoxybenzyl] piperazine) is a cellular anti-ischemic agent that selectively inhibits the activity of the final enzyme of the fatty acid oxidation pathway: 3-ketoacyl-coenzyme A thiolase. Administration of this drug leads to a switch in preference of the energy substrate, resulting in partial inhibition of fatty acid oxidation and increased glucose oxidation. Clinical studies have shown that TMZ has cardioprotective effects in the setting of myocardial ischemia, including acute myocardial infarction.[4],[5] Demirelli et al. reported that in patients with NSTEMI, Trimetazidine treatment prior to, and continued after, PCI provided improvements in the myocardial performance index, left ventricular end-diastolic volume, and resulted in a decrease in brain natriuretic peptide levels.[6] Therefore, our study sought to evaluate the clinical effect of ATV and TMZ combination treatment in patients with non-ST elevation (NSTE) ACS undergoing PCI.


  Materials and Methods Top


Patients

This was a double-arm, randomized clinical trial. A total of 312 patients fulfilling the inclusion criteria from August 2016 to November 2017 were initially evaluated. Twenty-eight patients were excluded because of concurrent or prior treatment with statins or TMZ, ten because of low ejection fraction, eight for liver or muscle disease, and six for renal failure. A total of 260 patients fulfilling the inclusion criteria were included in the study.

Inclusion criteria were the presence of an NSTE-ACS (unstable angina or NSTE acute myocardial infarction) sent for early coronary angiography (<4 days).

Exclusion criteria were as follows – ST-segment elevation acute myocardial infarction, NSTE-ACS with high-risk features needing emergency coronary angiography, renal failure with creatinine of more than 3 mg/dl, history of liver or muscle disease, earlier or current treatment with statins or TMZ, any increase in liver enzymes (alanine transferase [ALT]/aspartate transferase [AST]), left ventricular ejection fraction (LVEF) of <30%.

Study protocol

Our research was approved by the Ethics Committee of Wuhan Asia Heart Hospital, and all patients provided written informed consent. All patients were fully informed about the study protocol and signed informed consent forms before the study. A consolidated standards of reporting trials (CONSORT) flow diagram is shown in [Figure 1].
Figure 1: A consolidated standards of reporting trials flow diagram. NSTE-ACS: non-ST-segment elevation acute coronary syndromes, MACE: Major adverse cardiac events, NT-pro-BNP: N-terminal pro-brain natriuretic peptide

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Eligible patients (n = 260) were randomly divided into the pretreatment with ATV group (80 mg 12 h before PCI, with a further 20 mg everyday for 30 days after PCI) or the pretreatment with ATV (as the ATV group) and TMZ (60 mg 30 min before PCI, with a further 20 mg for 30 days after PCI) combination therapy. After coronary angiography, ten patients were excluded from the study (four were treated medically and six with bypass surgery). Thus, 250 patients were enrolled and they were the study population, the ATV + TMZ group was 123 patients and the ATV group was 127 patients. According to our standard protocol, all patients without contraindications were pretreated with aspirin (100 mg/d) and with ticagrelor (180 mg) or clopidogrel (300–600 mg) at least 6 h before the procedure.

Interventional procedure

PCI was performed using a standard technique, through the radial artery route. Routine care was taken before and after the procedure for all patients, including pretreatment with a loading dose of ticagrelor (180 mg) or clopidogrel (300 mg initial oral bolus) the day before the procedure, followed by ticagrelor (90 mg/bid) or clopidogrel (75 mg/day) for 12 month, in addition to lifelong aspirin medication (100 mg/day). An intravenous bolus of unfractionated heparin (100 IU/kg), with activated coagulation time adjusted (200–300 s with Hemochron devices), was administered at the beginning of the procedure. The radial artery sheath was removed immediately after the end of the procedure.

Angiographic analysis

Classification of coronary artery morphology based on the report of the American Heart Association/American College of Cardiology Task Force was used.[7] Coronary angiograms were reviewed by independent observers blinded to the results of biochemical assays. Intimal major or minor dissection, thrombus, abrupt closures in a previously patent vessel, no-reflow, spasm, and side-branch occlusion were assessed. The degree of perfusion was evaluated according to the TIMI criteria.[8] No-reflow phenomenon was defined as TIMI flow Grade 0, 1, or 2 without a mechanical obstruction on angiograms after PCI. Left ventricular function was assessed by angiography in all patients.

Echocardiography

One experienced investigator who was blinded to the study protocol captured the transthoracic echocardiogram using a GE VIVID 7 system and a 3.5 MHz transducer. Briefly, the 3.5 MHz transducer was placed on the left anterior chest wall to obtain the left ventricular end-diastolic dimension (LVEDd), left ventricular fractional shortening (FS), and LVEF were calculated using a cubic formula. All parameters were averaged from at least three consecutive cardiac cycles.

Blood sampling and analyzing

All samples were collected by venipuncture into ethylenediaminetetraacetic acid tubes. The samples were analyzed within 10 min using the Fluorescence Immunoassay technique and Biosite (CA, USA) using an N-terminal pro-brain natriuretic peptide (NT-pro-BNP) Triage Kit in the Biochemistry Lab, Emergency Unit. The creatine kinase (CK) and ALT/AST were assayed by Kriptor ultrasensitive immunofluorescent assay (Brahms), CK of <174 u/l, and ALT/AST (0–40 u/l).

Statistical analysis

Statistical analyses were performed with SPSS software (IBM Corporation, Armonk, NY, USA) version 17.0. Data are expressed as mean ± standard deviation or percentages for categorical variables. To compare parametric continuous variables, the independent samples Student's t-test was used. For categorical variables, the X2 test was used. P <.05 was considered to be statistically significant.


  Results Top


Baseline clinical characteristics

Clinical, angiographic, and procedural descriptions for the ATV and ATV + TMZ groups are shown in [Table 1], [Table 2], [Table 3], respectively. The two groups were similar with regard to age, sex, cardiovascular risk factors, mean time to angiography, and medical therapy at the time of intervention. Coronary anatomy, lesion type, procedural characteristics, use of drug-eluting stents, diameter, and length of implanted stents were also similar.
Table 1: Clinical characteristics of the study population

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Table 2: Angiographic characteristics of the study population

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Table 3: Procedural characteristics and complications of the study population

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Cardiac function changes after treatment

Baseline cardiac function was similar between the ATV+TMZ group (50.12±8.59 %) and ATV group (51.25±8.54%), p >.05). LVEF was significantly elevated 30 days after treatment in both the ATV+TMZ group (56.23±7.59%) and the ATV group (52.68±7.65%), P<.05. LVEDd decreased from baseline in both the ATV+TMZ group (52.89±5.86mm to 42.86±7.59mm) and the ATV group (53.58±4.98mm to 48.35±5.68mm) 30 days after treatment, P<.05. LVFS increased from baseline in both the ATV+TMZ group (28.86±4.89% to 36.85±5.68%), and a; ATV group (29.68±5.89% and 31.54±5.94%) 30 days after treatment, P<.05. When comparing between groups, the ATV+TMZ group had lower LVEDd and higher LVFS [Table 4].
Table 4: Left ventricular ejection fraction, left ventricular end-diastolic dimension, left ventricular fractional shortening, and N-terminal pro-brain natriuretic peptide differences between the baseline and the 30th day

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N-terminal pro-brain natriuretic peptide after treatment

The two groups had similar NT-pro-BNP levels at baseline (ATV+TMZ: 489.65±112.35 pg/ml, ATV: 478.96±123.53 pg/ml, P >.05). NT-pro-BNP levels significantly decreased in both groups during the 30-day follow-up period in both the ATV+TMZ and ATV groups (235.89±89.82 pg/ml and 325.59±85.39 pg/ml, respectively, P<.05). However, NT-pro-BNP levels were significantly lower in the group administered ATV+TMZ than the ATV group, P<.05 [Table 4].

The incidence of major adverse cardiac events

Primary composite end-point – 30 days incidence of major adverse cardiac events (MACE; cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and heart failure). Overall, MACE occurred in 10.40% of all patients (26/250). The prevalence of MACE was lower in the ATV+TMZ group (6.50%, 8/123: zero cardiovascular deaths, two nonfatal myocardial infarctions, three target vessel revascularizations, and three heart failures) than the ATV group (14.17%, 18/127: one cardiovascular death, five nonfatal myocardial infarctions, six target vessel revascularizations, and six heart failures), P<.05.

Adverse drug reactions

Adverse drug reactions occurred in both the ATV+TMZ group (21 cases) and the ATV group (23 cases), in which no case the drug was discontinued for one month, and ALT and CK returned to normal. CK increased to more than fivefold and rhabdomyolysis did not occur, and there is no significant difference between groups, P >.05 [Table 5].
Table 5: Observation of adverse drug reactions

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  Discussion Top


In our study we found that short-term (30-day) ATV+TMZ combination treatment in patients with NSTE-ACS undergoing PCI reduced plasma levels of NT-pro-BNP, reduced LVEDd, and increased LVEF and LVFS. Meanwhile, the incidence of MACE was significantly decreased with ATV+TMZ combination treatment. Therefore, our study indicates ATV+TMZ combination treatment can improve cardiac function, reduce NT-pro-BNP and prevent MACE in NSTE-ACS patients who are undergoing PCI compared with using ATV alone.

TMZ (TMZ; 1- [2, 3, 4-trimethoxybenzyl] piperazine) is a cellular anti-ischemic agent that selectively inhibits the activity of the final enzyme of the fatty acid oxidation pathway, 3-ketoacyl-coenzyme A thiolase. Clinical studies have shown that TMZ has cardioprotective effects in the setting of myocardial ischemia including acute myocardial infarction.[9],[10] The effect of TMZ on myocardial necrosis could be explained by its metabolic and biological effects in mechanism, while TMZ has been shown to have no any hemodynamic effects.[11] It acts by improving cardiac energy metabolism through switching ATP production from lipid to glucose oxidation, thus enhancing intramitochondrial coupling and favoring a more efficient mode of ATP production per mole of oxygen.[10] Moreover, TMZ reduces intracellular acidosis and protects against oxygen free radical-induced toxicity. The drug therefore directly protects myocyte structure and function and increases cell resistance to hypoxic stress.[12],[13] TMZ is also beneficial in preventing ischemia-reperfusion injury. In fact, an animal experiment demonstrated that TMZ could limit lethal ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening, which represents a crucial event in cardiomyocyte death following myocardial ischemia reperfusion.[9] Our study indicated that ATV + TMZ combination treatment can improve cardiac function, reduce NT-pro-BNP, and prevent MACE in NSTE-ACS patients who are undergoing PCI compared with using ATV alone. Our results are consistent with a previous report by Demirelli et al. who observed that TMZ treatment commencing before PCI and continued after PCI in patients with NSTEMI provides improvements in the myocardial performance index and left ventricular end-diastolic volume and a decrease in brain natriuretic peptide levels.[6]

Possible mechanisms of ATV cardioprotection have been investigated in the ARMYDA-Cell Adhesion Molecules study, a planned subanalysis demonstrating that procedural protection in the ATV arm was paralleled by reduction of PCI-induced endothelial activation, as expressed by significant attenuation in the increase of intercellular cell adhesion molecule-1 and E-selectin levels at 24 h after intervention.[3] Other explanations include ATV-induced early increase of endothelial progenitor's cells differentiation and subsequent augmentation of circulating endothelial progenitor's cells with attendant cardioprotective effects.[14] Those acute effects of short-term treatment may support a lipid-lowering independent mechanism of action; this is in accordance also with animal studies that have shown a reduction of infarct size when an acute statin load is given before ischemia or before reperfusion.[15],[16] Our results are consistent with a previous report by Di Sciascio et al.,[2] who suggested that reloading with high-dose ATV could improve cardiac function and then impact clinical outcome.

NT-pro-BNP is released in response to ventricular myocardial contraction, indicating myocardial wall stress.[17] It has been established in several clinical studies that increased NT-pro-BNP is related to ischemia, rather than myocardial necrosis in ACS. NT-pro-BNP is considered an important prognostic indicator for ACS.[18] The present study demonstrated that short-term (30-day) ATV + TMZ combination treatment in patients with NSTE-ACS undergoing PCI reduces plasma levels of NT-pro-BNP compared with using ATV alone.

The ATV and the TMZ could improve cardiac function and clinical outcome following PCI through different pathways and various effects. However, whether the combination of both ATV and TMZ could remarkably improve cardiac function and clinical outcome to the greater magnitude is still unknown. To the best of our knowledge, this is the first description of the ATV and the TMZ combination therapy on cardiac protective effects following the PCI. Previous studies could not explain the pharmacokinetic interaction of ATV and TMZ, but the result of our study indirectly demonstrate that there was a synergistic effect when both ATV and TMZ were orally taken. The synergistic effect needs further drug experiment to explore.

Study limitations

This study was based on a limited number of observations made in a small population of patients and a brief follow-up period, potentially diminishing the validity of the drawn statistical inference. The present study results should be applied only with caution to clinical situations, in which NSTE-ACS is potentially involved, and further investigation is required. Future studies are required for these findings to be applied to clinical practice.


  Conclusions Top


Despite several significant limitations, our study suggests that the ATV and the TMZ could improve cardiac function and clinical outcome following PCI through different pathways and various effects.

Acknowledgment

This study was supported by a grant from the Wuhan Health and Family Planning Commission Research Foundation funded (Grant No. WX17Q36) and Hubei Province health and family planning scientific research project (Grant No. WJ2018H0108). China youth clinical research fund-VG fund.

Financial support and sponsorship

This study was supported by a grant from Wuhan Health and Family Planning Commission Research Foundation funded (Grant No.WX17Q36) and Hubei Province health and family planning scientific research project (Grant No. WJ2018H0108).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: Results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007;49:1272-8.  Back to cited text no. 1
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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