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. E-mail: [email protected].
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. E-mail: [email protected].
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 ATV group (80mg 12h before PCI, with a further 20mg every day to 30th days after PCI, n=44) or the pretreatment with ATV (as the ATV group) 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 ATV group and 4.2% of those in the ATV+TMZ group (P=0.189). NT-pro-BNP of the two groups were decreased 30th days after PCI, however, NT-pro-BNP in the ATV+TMZ group were significantly lower than those in the ATV group (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 ATV+TMZ (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: Atorvastatin; Trimetazidine; Percutaneous coronary intervention; NT-pro-BNP; Cardiac function
Citation: 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;8:68-72.
DOI: 10.17987/icfj.v8i0.245
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, placebo-controlled 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 ATV group (80mg 12h before PCI, with a further 20mg every day to 30th days after PCI) or the pretreatment with ATV (as the ATV group) 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 (300-600mg) 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 (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.
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 NT-pro-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
(Consolidated Standards of Reporting Trials) flow diagram is shown in Figure 1. Clinical and procedural variables in the ATV and ATV+TMZ 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 ATV+TMZ group (P=0.189).
LVEF (ATV+TMZ group 51.24±5.63 % at baseline and 55.62±4.89 % at 30 days; ATV group 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 (ATV+TMZ group 52.62±4.53mm and 42.53±5.84mm; ATV group 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 (ATV+TMZ 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 ATV+TMZ treatment and LVFS was higher in the group administered ATV+TMZ treatment. NT-pro-BNP (ATV+TMZ group-456.82±89.53 pg/ml and 219.64±72.82 pg/ml; ATV group- 438.52±82.94 pg/ml and 279.35±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 150.67±63.48, respectively). However, the decrease of NT-pro-BNP levels was higher in the group administered ATV+TMZ 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).
Discussion
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, 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 ATV+TMZ compared to ATV alone.
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
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
Table 1. Clinical characteristics of the study population
Variables ATV group (n=44)
ATV+TZM
group(n=48) P Value
Mean age in years ±SD 63.21±12.35 62.34±15.58 0.849
Male, n (%) 28(64) 32(67) 0.760
History, n (%)
Earlier myocardial
infarction 4(9) 6(13) 0.742
Earlier PCI 6(14) 9(19) 0.507
Earlier CABG 2(5) 3(6) 1.000
Unstable angina 25(57) 23(48) 0.393
NSTEMI 19(43) 25(52) 0.393
Risk factors, n (%)
Smoking (past or current) 26(59) 28(58) 0.941
Hypercholesterolaemia 23(52) 25(52) 0.986
Hypertension 28(64) 33(69) 0.604
Diabetes mellitus 16(36) 19(43) 0.751
Family history 8(18) 7(15) 0.641
Mean BMI in kg/m2±SD 26.23±3.28 25.75±3.16 0.783
Medication, n (%)
ACE inhibitors or ARB 35(80) 40(83) 0.640
β Blockers 36(82) 41(85) 0.641
Calcium antagonist 12(27) 11(23) 0.630
Aspirin 44(100) 48(100) 1.000
Clopidogrel 18(41) 22(46) 0.509
Ticagrelor 26(59) 26(54) 0.634
Insulin 6(14) 8(17) 0.686
Nitrates 36(82) 38(80) 0.749
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 intra-mitochondrial 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 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 Table 2. Angiographic characteristics of the study population
Variable, n (%) ATV group (n=44)
ATV+TMZ
group(n=48) P Value
Lesion class*
A+B1 32(73) 36(75) 0.804
B2+C 12(27) 12(25) 0.804
Artery involved
Left main artery 0 0 1.000
Left anterior
descending artery 33(75) 35(73) 0.820
Left circumflex artery 24(55) 28(58) 0.714
Right coronary artery 30(68) 30(63) 0.568
Single-vessel disease 12(27) 15(31) 0.676
Double-vessel disease 21(48) 21(44) 0.702
Three-vessel disease 11(25) 12(25) 1.000
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 ATV group (n=44)
ATV+TMZ
group(n=48) P Value
Stent length (mm) 23.26±3.82 21.89±2.87 0.553
Stent diameter (mm) 2.82±0.64 2.93±0.58 0.686 Total inflation time (s) 38.42±8.96 42.32±5.75 0.162
Inflation maximal
pressure (atm) 14.36±3.67 15.42±4.26 0.737 TIMI flow grade≤1,
n (%) 2(5) 1(2) 0.328
TIMI flow grade=2,
n (%) 5(7) 2(4) 0.328
TIMI flow grade = 3,
n (%) 37(88) 45(94) 0.328
ST change during
inflation, n (%) 8(18) 11(23) 0.575
Procedural complications, n (%)
Side-branch occlusion 4(9) 4(10) 1.000
Coronary dissection 2(5) 2(4) 1.000
Coronary spasm 5(11) 6(13) 0.867
Coronary embolisation 1(2) 1(2) 1.000
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
Variables Baseline 30 days
ATV+TMZ
(n=48)
NT-pro-BNP
(pg/ml) 456.82±89.53 219.64±72.82ab LVEF (%) 51.24±5.63 55.62±4.89
LVEDd (mm) 52.62±4.53 42.53±5.84ab
LVFS (%) 27.53±3.59 35.53±3.72ab
ATV
(n=44)
NT-pro-BNP
(pg/ml) 438.52±82.94 279.35±68.26a LVEF (%) 52.46±4.82 54.29±3.29
LVEDd (mm) 53.27±3.86 47.46±4.28a LVFS (%) 28.31±3.48 31.42±3.26a
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 ATV groupꜝbp<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 8 0 4 0 12
ATV+TMZ 10 0 5 0 15
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) ATV+TMZ 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].
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;49:1272-8. DOI:10.1016/j. jacc.2007.02.025
2. 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;54:558-65. DOI:10.1016/j.jacc.2009.05.028 3. 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;48:1560-6. DOI:10.1016/j.jacc.2006.06.061
4. Di Pasquale P, Lo verso P, Bucca V, et al.Effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: short-term and long short-term results.Cardiovasc Drug Ther1999;13:423–8.
5. 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;77:263–73. DOI: http:// dx.doi.org/10.1016/S0167-5273(00)00443-5
6. Demirelli S, Karakelleoglu S, Gundogdu F, et al. The Impact of Trimetazidine Treatment on Left Ventricular Functions and Plasma Brain Natriuretic Peptide Levels in Patients with Non-ST Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention. Korean Circ J 2013;43:462-7. DOI: http://dx.doi.org/10.4070/kcj.2013.43.7.462 7. Smith SC, Jr., Dove JT, Jacobs AK, et al. ACC/AHA guidelines for
percutaneous coronary intervention. Circulation 2001;103:3019-41. 8. Effects of tissue plasminogen activator and a comparison of early invasive
and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994;89:1545-56.
9. Argaud L, Gomez L, Gateau-Roesch O, et al. Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury. J Mol Cell Cardiol 2005;39:893-9. DOI: http:// dx.doi.org/10.1016/j.yjmcc.2005.09.012
10. Kober G, Buck T, Sievert H, Vallbracht C. Myocardial protection during percutaneous transluminal coronary angioplasty: effects of trimetazidine. Eur Heart J 1992;13:1109-15.
11. Pornin M, Harpey C, Allal J, Sellier P, Ourbak P. Lack of effects of trimetazidine on systemic hemodynamics in patients with coronary artery disease: a placebo-controlled study. Clin Trials Metaanal 1994;29:49-56. 12. Lopaschuk GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of
trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res 2003;93:e33-7. DOI: 10.1161/01. RES.0000086964.07404.A5
13. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580-8. DOI: 10.1161/01. RES.86.5.580
14. Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001;103:2885-90. DOI:10.1016/S1062-1458(01)00462-7
15. Jones SP, Trocha SD, Lefer DJ. Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol 2001;21:2059-64. DOI: 10.1161/hq1201.099509 16. Bell RM, Yellon DM. Atorvastatin, administered at the onset of reperfusion,
and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol 2003;41:508-15. 17. Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns
of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464-9. DOI: 10.1161/01. CIR.87.2.464
18. Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002;40:437-45. DOI:10.1016/S0735-1097(02)01986-1
