Atorvastatin; Trimetazidine; Percutaneous coronary intervention; NT-pro-BNP; Cardiac function

Transcription

1 68 Original Article The Clinical Short-term Outcome of Atorvastatin and Trimetazidine Combination Treatment in Patients with Non-ST Segment Elevation Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention Jiang-you Wang, Han Chen, Dan Song, Jian Peng and Xi Su Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan, PR China Corresponding author: Xi Su, Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan, PR China. Abstract Background To investigate the effects of atorvastatin (ATV) and trimetazidine (TMZ) combination treatment in patients with non-st segment elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention. Subjects and Methods A total of 92 patients with NSTE-ACS were randomly divided into the pretreatment with (80mg 12h before PCI, with a further 20mg every day to 30th days after PCI, n=44) or the pretreatment with ATV (as the ) and TMZ (60mg 30min before PCI, with a further 20mg tid to 30th days after PCI, n=48). Echocardiography was executed and plasma N-terminal pro brain natriuretic peptide (NT-pro-BNP) levels were measured just prior to the PCI and 30th days after PCI. The main end point was a 30-day incidence of major adverse cardiac events. Result Major adverse cardiac events occurred in 9.1% of patients in the and 4.2% of those in the group (P=0.189). NT-pro-BNP of the two groups were decreased 30th days after PCI, however, NT-pro-BNP in the group were significantly lower than those in the (P<0.05). Cardiac function in NSTE-ACS patients, as reflected by the increased LVEF, FS as well as decreased LVEDd (P<0.05) in all groups at 30 days after intervention, but cardiac function parameters were more obviously improved in the group administered with (p<0.05). Conclusion Short-term pretreatment with the combination of ATV and TMZ administration prior to PCI can prominently decrease NT-pro-BNP and improve cardiac function compared to a single administration of the ATV. Keywords: Citation: Atorvastatin; Trimetazidine; Percutaneous coronary intervention; NT-pro-BNP; Cardiac function Wang J, Chen H, Song D, Peng J, Su X. The Clinical Short-term Outcome of Atorvastatin and Trimetazidine Combination Treatment in Patients with Non-ST Segment Elevation Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention. International Cardiovascular Forum Journal 2016;8: Introduction In spite of rapid advances in the therapeutic field of coronary artery disease (CAD), acute coronary syndromes (ACSs) are still the leading major cause of morbidity and mortality worldwide. As the number of coronary care units, reperfusion techniques, and medical therapies increases, so has the clinical outcome in patients with CAD improved. However, despite intensive therapies with hemodynamically effective agents, many patients * Corresponding author. Yaxin_suxi@163.com. ISSN: Barcaray Publishing

2 Original Article 69 with ischemic disease do not recover fully 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) had been proposed to possess multiple cardiovascular benefits besides its cholesterol lowering effect. It can be administered in a loading dose prior to PCI. The Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) trials suggest that reloading with intensive-dose atorvastatin could improve clinical outcomes of patients undergoing PCI [1-3]. Trimetazidine (TMZ; 1-[2,3,4 - trimethoxybenzyl] piperazine) is a cellular anti-ischaemic agent that selectively inhibits the activity of the final enzyme of the fatty acid oxidation pathway, 3-ketoacylcoenzyme 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 ischaemia including acute myocardial infarction [4-5]. Demirelli et al. reported Trimetazidine treatment commencing prior to 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]. The aim of this study was to investigate the impact of treatment with ATV and TMZ combination treatment in patients with non-st segment elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention. Subjects and Methods 1. Study population and protocol This was a random, prospective, double-blind, placebocontrolled clinical trial. A total of 130 patients fulfilling the inclusion criteria from August 2014 to February 2015 were initially evaluated. Eighteen patients were excluded because of current or earlier treatment with statins or trimetazidine, six because of low ejection fraction, two for liver or muscle disease, and two for renal failure. A total of 102 patients fulfilling the inclusion criteria were included in the study. Eligible patients (n=102) were randomly divided into the pretreatment with (80mg 12h before PCI, with a further 20mg every day to 30th days after PCI) or the pretreatment with ATV (as the ) and TMZ (60mg 30min before PCI, with a further 20mg tid to 30th days after PCI) combination therapy. After coronary angiography, 10 patients were excluded from the study (four were treated medically and six with bypass surgery). Thus, 92 patients were enrolled and they were the study population. According to our standard protocol, all patients without contraindications were pretreated with aspirin (100mg/d) and with Ticagrelor (180mg) or Clopidogrel ( mg) at least 6h before the procedure. Inclusion criteria were the presence of a 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 3mg/dl, history of liver or muscle disease, earlier or current treatment with statins or trimetazidine, any increase in liver enzymes [alanine transferase (ALT)/aspartate transferase (AST)], left ventricular ejection fraction of less than 30%. 2. 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 (180mg) or clopidogrel (300 mg initial oral bolus) the day before the procedure, followed by Ticagrelor (90mg/bid) or clopidogrel (75mg/day) for 12 month, in addition to lifelong aspirin medication (100mg/day). Intravenous bolus of unfractionated heparin (100 IU/kg), with activated coagulation time adjusted ( 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. 3. 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 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. 4. 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 left ventricular ejection fraction (LVEF) were calculated using a cubic formula. All parameters were averaged from more than three consecutive cardiac cycles. 5. Blood sampling and analyzing All samples were collected by venipuncture into EDTA tubes. The samples were analyzed within ten minutes using the Fluorescence Immunoassay technique and Biosite (CA, USA) using a NTpro-BNP Triage Kit in the Biochemistry Lab, Emergency Unit. The CK, and ALT/AST were assayed by Kriptor ultrasensitive immunofluorescent assay (Brahms), CK of less than 174 u/l, and ALT/AST (0 40 u/l). 6. Statistical analysis Statistical analyses were performed with SPSS version 17.0 software. Data are expressed as mean ± SD or percentages for categorical variables. To compare parametric continuous variables, the independent Student t-test was used. For categorical variables, theχ2 test was used. P<0.05 was considered to be statistically significant. Results The studied population was composed of 44 patients in the and 48 patients in the group. Pretreatment with an intensive-dose atorvastatin and a loading dose of TMZ and were well tolerated and there were no instances of serious adverse events during the in hospital follow-up. A CONSORT

3 70 Original Article (Consolidated Standards of Reporting Trials) flow diagram is shown in Figure 1. Clinical and procedural variables in the ATV and groups are shown in Tables 1, 2 and 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 ofimplanted stentswere similar. Primary composite end point: 30 days incidence of major adverse cardiac events (MACE; death, myocardial infarction, or target vessel revascularization). The result shows MACE in 9.1% of patients (four of 44) in the ATV group and in 4.2 % (two of 48) of those in the group (P=0.189). LVEF ( group 51.24±5.63 % at baseline and 55.62±4.89 % at 30 days; 52.46±4.82% at baseline and 54.29±3.29% at 30 days, both p > 0.05) did not significantly change after 30 days of treatment. However, LVEDd ( group 52.62±4.53mm and 42.53±5.84mm; 53.27±3.86% and 47.46±4.28% at baseline and at 30 days, respectively; both p < 0.05) significantly changed after 30 days of treatment as did LVFS ( group 27.53±3.59% and 35.53±3.72mm; ATV group 28.31±3.48% and 31.42±3.26% at baseline and at 30 days, respectively, both p < 0.05). LVEDd was lower in the group administered treatment and LVFS was higher in the group administered treatment. NT-pro-BNP ( group ±89.53 pg/ml and ±72.82 pg/ml; ±82.94 pg/ml and ±68.26 pg/ml at the baseline and at 30 days, respectively; p < 0.05) significantly changed after 30 days of treatment. NT-pro-BNP levels significantly decreased in both groups during the 30-day follow-up period (229.34±59.25 and ±63.48, respectively). However, the decrease of NTpro-BNP levels was higher in the group administered than the other group (p<0.05). (Table 4) Adverse drug reactions occurred in eight cases in the two groups, respectively, in which case the drug was discontinued for 2 weeks, and ALT and CK returned to normal. There was no case of a CK increase in excess of fivefold not any case of rhabdomyolysis in either group (Table 5). Table 1. Clinical characteristics of the study population Variables ATV+TZM Mean age in years ±SD 63.21± ± Male, 28(64) 32(67) History, Earlier myocardial infarction 4(9) 6(13) Earlier PCI 6(14) 9(19) Earlier CABG 2(5) 3(6) Unstable angina 25(57) 23(48) NSTEMI 19(43) 25(52) Risk factors, Smoking (past or current) 26(59) 28(58) Hypercholesterolaemia 23(52) 25(52) Hypertension 28(64) 33(69) Diabetes mellitus 16(36) 19(43) Family history 8(18) 7(15) Mean BMI in kg/m2±sd 26.23± ± Medication, ACE inhibitors or ARB 35(80) 40(83) β Blockers 36(82) 41(85) Calcium antagonist 12(27) 11(23) Aspirin 44(100) 48(100) Clopidogrel 18(41) 22(46) Ticagrelor 26(59) 26(54) Insulin 6(14) 8(17) Nitrates 36(82) 38(80) ACEI: angiotensin-converting enzyme inhibitors; CABG: coronary artery bypass grafting; PCI: percentaneous coronary intervention; NSTEMI: non-st segment elevation myocardial infarction; BMI : body mass index. ATV: atorvastatin ; TMZ: trimetazidine Discussion The present study demonstrated that short-term (30-day) combination treatment in patients with NSTE-ACS undergoing PCI reduces plasma levels of NT-pro-BNP, reduces LVEDd, and increases LVFS. Major adverse cardiac events did not significantly change after 30 days of treatment. However, the decrease of major adverse cardiac events was higher in the group administered compared to ATV alone. Figure 1. A CONSORT (Consolidated Standards of Reporting Trials) flow diagram. Legend: NSTE-ACS: non-st segment elevation acute coronary syndromes; MACE, major adverse cardiac events; NT-pro-BNP: N-terminal pro brain natriuretic peptide 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-ketoacylcoenzyme 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 on mechanism while TMZ has

4 Original Article 71 Table 2. Angiographic characteristics of the study population Variable, Lesion class* A+B1 32(73) 36(75) B2+C 12(27) 12(25) Artery involved Left main artery Left anterior descending artery 33(75) 35(73) Left circumflex artery 24(55) 28(58) Right coronary artery 30(68) 30(63) Single-vessel disease 12(27) 15(31) Double-vessel disease 21(48) 21(44) Three-vessel disease 11(25) 12(25) ATV: atorvastatin; TMZ: trimetazidine; *According to the American Heart Association/American College of Cardiology classification Table 3. Procedural characteristics and complications of the study population Parameters Stent length (mm) 23.26± ± Stent diameter (mm) 2.82± ± Total inflation time (s) 38.42± ± Inflation maximal pressure (atm) TIMI flow grade 1, TIMI flow grade=2, TIMI flow grade = 3, ST change during inflation, Procedural complications, 14.36± ± (5) 1(2) (7) 2(4) (88) 45(94) (18) 11(23) Side-branch occlusion 4(9) 4(10) Coronary dissection 2(5) 2(4) Coronary spasm 5(11) 6(13) Coronary embolisation 1(2) 1(2) TIMI: Thrombolysis In Myocardial Infarction Trial; ATV: atorvastatin; TMZ: trimetazidine Table 4. LVEF, LVEDd, LVFS and NT-pro-BNP differences between baseline and the 30th day (n=48) ATV Variables Baseline 30 days NT-pro-BNP (pg/ml) ± ±72.82 ab LVEF (%) 51.24± ±4.89 LVEDd (mm) 52.62± ±5.84 ab LVFS (%) 27.53± ±3.72 ab NT-pro-BNP (pg/ml) ± ±68.26 a LVEF (%) 52.46± ±3.29 LVEDd (mm) 53.27± ±4.28 a LVFS (%) 28.31± ±3.26 a NT-pro-BNP, N-terminal pro brain natriuretic peptide; LVEDd, left ventricular end-diastolic dimension; FS, left ventricular fractional shortening; LVEF, left ventricular ejection fraction; ATV, atorvastatin; TMZ, trimetazidine. Comparison baselineꜝap<0.05; Comparison ꜝbp<0.05. Table 5. Observation of adverse drug reactions AST/ALT increased CK increased 1-3 >3 1-5 >5 fold fold fold fold total ATV ALT: alanine transferase; AST: aspartate transferase; CK: creatine kinase; ATV: atorvastatin; TMZ: trimetazidine. been shown to have no haemodynamic 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 ischemiareperfusion 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 result is consistent with a previous report by Demirelli et al who observed that Trimetazidine treatment commencing prior to 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 atorvastatin cardioprotection have been investigated in the ARMYDA-CAMs study, a planned sub-analysis demonstrating that procedural protection in the atorvastatin arm was paralleled by reduction of PCI-induced endothelial activation, as expressed by significant attenuation in the increase of intercellular cell adhesion molecule-1and E-selectin levels at 24 h after intervention [3]. Other explanations include an atorvastatin-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

5 72 Original Article reduction of infarct size when an acute statin load is given before ischemia or before reperfusion [15-16]. Our result is consistent with a previous report by DiSciascio et al2, 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) combination treatment in patients with NSTE- ACS undergoing PCI reduces plasma levels of NT-pro-BNP. In conclusion, the ATV and the TMZ could improve cardiac function and clinical outcome following PCI through different pathways and different effects. However, whether the combination of both ATV and TMZ could improve cardiac function and clinical outcome more then either alone remains unknown. To the best of our knowledge, this is the first description of ATV and TMZ combination therapy on cardiac protective effects following PCI. Previous studies could not explain the pharmacokinetic interaction of ATV and TMZ but the results 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 experiments 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. Funding Acknowledgement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Statement of ethical publishing The authors state that they abide by the statement of ethical publishing of the International Cardiovascular Forum Journal [19]. 4. Di Pasquale P, Lo verso P, Bucca V, et al.effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: shortterm and long term results.cardiovasc Drug Ther1999;13: Steg PG, Grollier G, Gallay P, et al.a randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction.int J Cardiol 2001;77: DOI: dx.doi.org/ /s (00) Demirelli S, Karakelleoglu S, Gundogdu F, et al. 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DOI: /icfj.v2i1.4 Conflict of interest The authors declare no conflict of interest. References 1. Patti G, Pasceri V, Colonna 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 CollCardiol 2007;49: DOI: /j. jacc Di Sciascio G, Patti G, Pasceri V, et al. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial. J Am CollCardiol 2009;54: DOI: /j.jacc Patti G, Chello M, Pasceri V, et al. Protection from procedural myocardial injury by atorvastatin is associated with lower levels of adhesion molecules after percutaneous coronary intervention: results from the ARMYDA-CAMs (Atorvastatin for Reduction of Myocardial Damage during Angioplasty- Cell Adhesion Molecules) substudy. J Am CollCardiol 2006;48: DOI: /j.jacc