a b s t r a c t

Purpose: Trimetazidine (TMZ) improves clinical outcomes in patients with chronic heart failure and stable coronary artery disease. No study has yet evaluated the efficacy of TMZ in type 2 diabetes patients with acute myocardial in- farction (AMI) undergoing Percutaneous Coronary Intervention (PCI). We performed this study to evaluate the ef- ficacy TMZ in DM patients with AMI undergoing PCI, such as the effect on reductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function.

Methods: For this randomized study, we enrolled 173 AMI patients with type 2 diabetes undergoing PCI between January 1, 2014, and January 1, 2016. All patients received aspirin and ticagrelor upon admission and throughout their hospitalization. Patients in the experimental group were treated with a loading dose of 60 mg TMZ at ad- mission, and 20 mg TMZ three times a day thereafter. 89 patients were included in experimental group, and 84 patients were included in control group. All patients received PCI treatments. The endpoints evaluated were serum creatine kinase and its isoenzyme (CK and CK-MB), Cardiac troponin I , serum creatinine (Cr), serum urea, blood glucose, serum glutamic pyruvic transaminase (ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimension (LA), left ventricular ejection fraction (LVEF), left ventricu- lar end-diastolic dimension (LVEDD), and cardiac output (CO).

Findings: Compared with the control group, TMZ treatment significantly reduced CK and CK-MB on the second day in hospital ([797 +- 582] vs. [1092 +- 1114]; [80 +- 60] vs. [105 +- 100]; p = 0.029, p = 0.041, respectively), and cTNI after one and six days in hospital ([13.5 +- 12.7] vs. [19.8 +- 19.2]; [3.3 +- 3.2] vs. [4.8 +- 4.7]; two-tailed p = 0.012). In addition, TMZ significantly lowered Liver enzymes (ALT, AST) at 6 days ([29.0 +- 11.6] vs. [42.4 +- 24.5]; [39.8 +- 17.3] vs. [69.2 +- 70.0]; two-tailed p = 0.000), lowered glucose after 6 days ([6.80 +- 2.12] vs. [7.59 +- 2.24]; p = 0.019), and increased LVEF after ten to fourteen days ([58.4 +- 8.6] vs. [54.9 +- 8.4]; p = 0.008). There were no significant effect on Cr and serum urea (p = 0.988, p = 0.569, respectively), nor on LA, LVEDD, and CO ([36.3 +- 4.5] vs. [37.0 +- 4.1], p = 0.264; [52.0 +- 4.9] vs. [53.1 +- 4.6], p = 0.128; [5.4 +- 0.9] vs. [5.4 +- 0.9], p = 0.929, respectively).

Implications: Among Type 2 Diabetic patients with AMI undergoing PCI, TMZ significantly reduces serum myocardial enzyme, improves liver function, adjusts blood glucose and improves cardiac function.

(C) 2017

Introduction

Acute myocardial infarction (AMI) is a primary cause of morbidity and mortality and remains a therapeutic challenge [1,2]. type 2 diabetes mellitus is a coronary artery disease (CAD) risk factor. AMI patients with type 2 diabetes mellitus tend to have more extensive vessel

* Corresponding author at: Department of Critical Care Medicine, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan Road, Urumqi, Xinjiang 830054, China.

E-mail address: [email protected] (X. Yu).

¹ Runjun Li and Xiuying Tang have contributed equally and share first authorship.

disease [3-5] and more clinical compromise [6-7] than those who do not have diabetes, despite advancements in pharmacotherapy [8] and non-pharmacologic treatments [9,10] in recent decades.

Modulation of myocardial free fatty acid metabolism is a therapeutic strategy for patients with AMI in the setting of DM. Trimetazidine (2,3,4- trimethoxybenzyl-piperazine dihydrochloride; TMZ) is a metabolic agent with anti-ischemic effects that result from shifting cardiac energy metab- olism from b-oxidation of free fatty acid (FFA) to the more efficient glucose oxidation. As a result, TMZ therapy during AMI preserves ATP levels in cardiomyocytes, and reduces intracellular acidosis resulting from

http://dx.doi.org/10.1016/j.ajem.2017.05.024 0735-6757/(C) 2017

ischemia. TMZ additionally may protect the cell against harmful effects of oxygen free radicals (OFRs). TMZ could by these means ameliorate the del- eterious glucoMetabolic effects of DM in AMI, improve myocardial cellular homeostasis, normalize metabolic disturbances induced by ischemia and reperfusion damage, and reduce cell damage [11-16]. This theory explains that TMZ may be more effective for the patients with type 2 diabetes mellitus who have higher levels of glucose and b-oxidation of free fatty acid (FFA) than in other patients without type 2 diabetes mellitus.

Previous studies support that TMZ could increase left ventricular ejec- tion fraction and total exercise time, improve clinical symptoms and cardiac function, reduce the area of myocardial infarction, and decrease hospitaliza- tion, all-cause mortality, and Major adverse cardiac events (MACEs) over 12 months [15-18]. TMZ has been recommended for treatment of stable coronary artery disease [19]. We performed this study to evaluate the effi- cacy TMZ in DM patients with AMI undergoing PCI, such as the effect on re- ductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function.

Methods

Patient population

We enrolled Chinese patients diagnosed with AMI at the Zhujiang Hospital of Southern Medical University and the First Hospital of

Qinhuangdao, China, between January 1, 2014, and January 1, 2016. The current study is part of a larger parent trial.

The inclusion criteria were as follows: 1) age N 18 years; 2) chest dis- comfort N 20 min not responding to nitroglycerin; 3) myocardial injury markers in accordance with the guidelines for the management of acute myocardial infarction, or ST-segment elevation N 1 mm in two or more limb leads or N 2 mm in two or more contiguous precordial leads; 4) el- igible and willing to undergo PCI; 5) Killip class <= 3; 6) the provision of informed consent; 7) documented diagnosis of type 2 DM.

The exclusion criteria were as follows: 1) cardiogenic shock, defined as systolic blood pressure b 90/60 mmHg not responding to fluids;

2) malignant or life-threatening diseases; 3) contraindications to TMZ (because of the presence in TMZ of the sunset yellow FCF S(E110) and cochineal red A(E124), risk of Allergic reactions); 4) severe hepatic and renal dysfunction; 5) pernicious anemia 6) inability to provide in- formed consent; 7) absence of type 2 DM and 8) suspected mechanical complications of AMI including dysfunction of papillary muscle, Cardiac rupture and acute ventricular aneurysm; 9) patients with Parkinson’s syndrome.

AMI was defined according to the guidelines of the European Society of Cardiology [20,21]. All patients were hospitalized in the cardiac inten- sive care unit. The study was approved by the local ethics committee and patients provided written informed consent prior to study enrollment.

Fig. 1. Flowchart of patient enrollment. AMI, acute myocardial infarction; TMZ, trimetazidine.

Drug strategy

All patients received 300 mg of aspirin and 180 mg ticagrelor upon admission, followed by 100 mg of aspirin once a day and 90 mg of

Table 1

Baseline clinical characteristics.

Indices TMZ group (n =

89)

Control group(n = 84)

P

value

ticagrelor twice a day. Patients were randomized into control or exper- imental groups using an envelope method. Patients in the experimental group were provided a loading dose of 60 mg TMZ at admission, follow- ed by 20 mg TMZ three times a day. All patients received PCI treatments. All researchers involved in this study were physicians.

Age (years) 62.8 +- 12.6 64.0 +- 11.6 0.543

Male sex (%) 62 (70) 58 (69) 0.930

Hypertension (%) 46 (52) 53 (63) 0.130

Dyslipidemia (%) 39 (44) 33 (39) 0.545

HbA1c (%) 7.7 +- 1.5 8.1 +- 1.7 0.327

Smoker (%) 44 (49) 43 (51) 0.818

All included patients without any contraindication also received	Prior MI (%)	9 (10)	8 (10)	0.897
conventional drugs such as ?-blockers, ACEIs/ARBs, and statins in accor-	Angina pectoris (%)	20 (22)	22 (26)	0.569

dance with the guidelines for the management of acute myocardial in- farction [20,21].

Peripheral arterial disease (%)	7(8)	9 (11)	0.518
Atrial fibrillation/flutter	5 (6)	8(10)	0.330
Prior stroke/TIA (%)	15 (17)	18 (21)	0.444
Killip (%) 1	43 (48)	40 (47)	0.927
2	38 (43)	35 (42)	0.891
3	8 (9)	9 (11)	0.703
Culprit lesion (%) LAD	48 (54)	50 (60)	0.458

Study endpoints

We evaluated the following endpoints: serum creatine kinase and its isoenzyme (CK and CK-MB), cardiac troponin I (cTNI), serum creatinine

(Cr), serum urea, glucose (Glu), serum glutamic pyruvic transaminase	LCX	22 (25)	18 (21)	0.608
(ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimen-	RCA	19 (21)	16 (19)	0.707

sion (LA), left ventricular ejection fraction (LVEF), left ventricular end- diastolic dimension (LVEDD), and cardiac output (CO).

Follow-up

All data except for echocardiographic indices were measured at ad- mission. CK, CK-MB, and cTNI were retested the next morning after ad- mission. All other data were collected after two and six days in hospital. Echocardiography was repeated ten to fourteen days after treatments.

Sample calculation and statistical analysis

Sample size was calculated for the primary endpoints using the Sam- ple Size Calculations in Clinical Research tool (2013-2015 HyLown Con- sulting LLC, Atlanta, GA). Previously, it has been shown that compared with routine treatments, TMZ may reduce myocardial injury markers substantially [17]. In the present study, we expected a greater improve- ment in the TMZ group. Based on prior data, and considering a signifi- cance level of 5% and power of 80%, 40 patients per group were needed to evaluate the benefits and side effects of TMZ vs. routine treat- ments. Taking into account the number of hospitalized patients, exclu- sion criteria, loss to follow-up, and a study design incorporating multiple outcome variables, we increased the sample size to 180, with 90 in each group.

All data analyses were performed using SPSS v16.0 (SPSS Inc., Chica- go, IL). The continuous variables were expressed as mean +- SD and analyzed using the Student’s t-test. The dichotomous variables were analyzed using chi-square test. All comparisons were two-tailed, and p b 0.05 was considered statistically significant.

Results

Patient characteristics

Included in the parent trial were 180 patients with AMI who underwent PCI, comprising of 90 in TMZ group and 90 in control group. One patient was excluded from the TMZ group (lost to follow- up after patients left hospital). Six patients were excluded from the con- trol group: two were lost to follow-up, two were suspected of having mechanical complications of AMI, one was diagnosed with renal dys- function, one declined to participate. The seven patients excluded from the study were not followed. All other patients’ data were collect- ed

in follow-up (Fig. 1).	Statins	89	83	0.977
Within our study, 89 DM patients with AMI undergoing PCI were in-	Nitrates	69	66	0.868

cluded in the experimental group, matched with 84 patients as a control group. All 173 patients completed this study. The patients’ baseline

Number of stents	1.2 +- 0.4	1.2 +- 0.4	0.709
PPCI	55(62)	48(57)	0.533
TIMI grade 0-2 before PCI (%)	54(61)	46(55)	0.431
Manual Thrombus aspiration (%)	8 (9)	8 (10)	0.903

HbA1c, glycosylated hemoglobin; MI, myocardial infarction; TIA, transient ischemic at- tack; PPCI, primary percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

characteristics were similar and are presented in Tables 1 and 2. 69% were males, 57% had hypertension, and 42% had dyslipidemia. The groups had similar rates of TIMI grade 0-2 flow before PPCI, and similar levels of glycosylated hemoglobin. The target vessels and number of stents used were similar between the groups. All patients received sim- ilar in-hospital management including PCI treatments (Table 2). There was some cause for concern in that all of the baseline measured vari- ables (CK, CK-MB, cTNI, AST, and ALT) were higher in the control popu- lation than in the TMZ population prior to PCI, while other variables (Cr, Glu) were lower in the control group before PCI. The groups’ baseline myocardial injury markers, liver function tests, renal function tests and glucose all showed visible but non-statistically significant differ- ences (Table 3).

Study endpoints

No significant effects of TMZ on renal function (Cr and serum urea) were detected. Myocardial injury markers including CK and CK-MB on the second day in hospital, cTNI on the second day in hospital, and cTNI after six days in hospital, liver function (ALT, AST) after six days and Glu after six days were all significantly reduced by TMZ treatment in AMI patients with type 2 diabetes mellitus compared with controls (Table 4). LVEF was increased by TMZ treatment although no significant differences were detected in LA, LVEDD, and CO (Table 5).

Table 2

Pharmacotherapeutic management.

TMZ group (n = 89) Control group (n = 84) P value

Aspirin 89 84 -

Ticagrelor 89 84 -

Anticoagulant (LWHC) 89 84 -

?-Blockers 51 53 0.437

ACEIs/ARBs 45 49 0.305

LWHC, low-molecular-weight heparin calcium; ACEI, angiotensin-converting enzyme in- hibitor; ARB, angiotensin receptor blocker.

Table 3

Baseline laboratory values upon admission.

	TMZ group (n = 89)	Control group (n = 84)	P value
CK	189 +- 91	218 +- 128	0.096
CKMB	25 +- 11	27 +- 14	0.388
TNI	1.7 +- 1.4	1.9 +- 1.7	0.464
ALT	33.7 +- 21.6	40.7 +- 26.1	0.057
AST	96.7 +- 97.0	125.2 +- 102.0	0.062
Cr	80.6 +- 22.6	78.8 +- 18.4	0.553
Urea	7.3 +- 2.1	7.4 +- 12.9	0.962
Glu	10.2 +- 2.9	9.9 +- 2.8	0.485

CK and CK-MB, serum creatine kinase and its isoenzyme; cTNI, cardiac troponin I; Cr, serum creatinine; Glu, glucose; ALT, serum glutamic pyruvic transaminase; AST, serum glutamic oxaloacetictransaminase.

Discussion

AMI and DM are synergistic threats to Life expectancy and life quality for people worldwide [1,5,7,17]. TMZ appears to improve clinical symp- toms and cardiac function, reduces the area of myocardial infarction and decreases hospitalization for cardiac causes [15-18,22] in acute coro- nary syndrome (ACS) patients. Other investigators reported that TMZ decreased BNP levels, reduced LVEDD, and increased the myocardial performance index (MPI) [23].

No previous investigation has focused on the efficacy of TMZ in pa- tients with AMI and DM. Though our study did not confirm that TMZ could decrease LVEDD in DM patients with AMI, it did confirm that TMZ decreased the size of infarcted myocardium and improved heart function, reflective of findings reported in ACS, including AMI, but only some of the patients included here suffered from DM during this period [15-18,24]. In addition, our study showed that TMZ significantly reduced myocardial enzymes including cTNI on the second day in hos- pital, though we did not compare the differences in the peak levels of cardiac enzymes between these two groups.

?-Blockers and statins are recommended for AMI patients if there are no contraindications, in accordance with the guidelines for the man- agement of acute myocardial infarction [20,21]. However, ?-blockers af- fect glucose metabolism and increase glucose concentrations [25-27]. Statins present adverse renal effects (acute renal failure), and increase liver enzymes and the incidence of type 2 DM [28,29]. In our study, TMZ significantly improved liver function and lowered elevated glucose levels. There were other interventions (such as insulin) also used in this study to lower glucose. However, because the insulin was prescribed to the participants in a single-blind fashion (the physicians prescribing in- sulin were blinded to the test), the confounding effect of insulin was considered similar between the experimental and control groups. The noted improvements represent substantial benefits for the recovery of AMI in dysMetabolic syndrome patients, and may offset adverse effects of ?-blockers and statins on metabolism.

Table 4

Laboratory values and In-hospital echocardiogram data during hospitalization.

	TMZ group (n = 89)	Control group (n = 84)	P value
CK	797 +- 582	1092 +- 1114	0.029
CKMB	80 +- 60	105 +- 100	0.041
TNI	13.5 +- 12.7	19.8 +- 19.2	0.012
TNI	3.3 +- 3.2	4.8 +- 4.7	0.012
ALT	29.0 +- 11.6	42.4 +- 24.5	0.000
AST	39.8 +- 17.3	69.2 +- 70.0	0.000
Cr	81.0 +- 20.5	81.1 +- 20.5	0.988
Urea	6.5 +- 2.6	7.6 +- 17.7	0.569
Glu	6.8 +- 2.1	7.6 +- 2.2	0.019
LA (mm)	36.3 +- 4.5	37.0 +- 4.1	0.264
LVEDD (mm)	52.0 +- 4.9	53.1 +- 4.6	0.128
CO (L/min)	5.4 +- 0.9	5.4 +- 0.9	0.929
LVEF	58.4 +- 8.6	54.9 +- 8.4	0.008

LVEF, left ventricular ejection fraction; LVEDD, Left ventricular end-diastolic dimension; LA, left atrial dimension; CO, cardiac minute output.

Table 5

In-hospital echocardiogram data (x s).

	TMZ group (n = 89)	Control group (n = 84)	P value
LA (mm)	36.3 +- 4.5	37.0 +- 4.1	0.264
LVEDD (mm)	52.0 +- 4.9	53.1 +- 4.6	0.128
CO (L/min)	5.4 +- 0.9	5.4 +- 0.9	0.929
LVEF	58.4 +- 8.6	54.9 +- 8.4	0.008

LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic dimension; LA, left atrial dimension; CO, cardiac minute output.

In contrast with a previous trial [30], TMZ had no effect on renal function tests. It is likely that the reason we did not observe significant differences in these clinical events between the two groups is because of the small sample size of the current study. A high-quality randomized controlled trial with a large sample size should be performed to clarify these conflicting results as well as evaluate the cost-effectiveness of TMZ.

Overall, there were positive effects of TMZ in AMI that occurred in patients with type 2 DM. This was evidenced not just by blood markers such as CK, CK-MB, cTNI on hospital day #2 and day #6 and blood glu- cose, but also by heart functional measurement, such as LVEF. Therefore, treatment with TMZ may be beneficial for AMI patients with type 2 DM.

Study limitations

Our study had a small sample size with a short follow-up of fourteen days; larger, high-quality randomized controlled trials with longer follow-up periods are required to verify of our findings. We did not compare the differences in the peak levels of cardiac enzymes between the two groups to more accurately assess the size of myocardial infarc- tion. Future clinical studies are required to compare the differences in the peak levels of cardiac enzymes to better assess the size of myocardi- al infarction. We also did not assess total exercise time. Finally, our study did not evaluate mortality. Future clinical studies are required to assess total exercise time and mortality to allow observation of the in- fluence of long-term outcome of TMZ for AMI patients with type 2 DM.

Conclusions

Among DM patients with AMI undergoing PCI, TMZ, as a supplemen- tation to standard anti-ischemic therapy, reduces serum myocardial en- zyme, improves liver function, moderates glucose levels, and improves cardiac function.

Conflict of interest statement

This study was not supported by any drug manufacturing company. The authors declared that they have no conflicts of interest with regard to the content of this article.

Acknowledgments

We would like to thank Professor QMJ for his kind assistance with the revision of this article. Conceived and designed the experiments: XYT, RJL, and QMJ. Performed the experiments: RJL, XYT, XYH and JYZ. Analyzed the data: HMY and RJL. Wrote the paper: XYT.

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