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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 4  |  Page : 154-159

Assessment of coronary flow reserve by Doppler flow wIre in patients with acute coronary syndrome undergoing percutaneous coronary intervention: differences between the LoAding dose of Ticagrelor versus prasugrEl (DILATE): study protocol for a randomized controlled trial


1 Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
2 Cardiology Unit, Ospedali Riuniti Anzio-Nettuno, Rome, Italy

Date of Web Publication30-Dec-2016

Correspondence Address:
Massimo Mancone
Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, "Sapienza" University of Rome, Rome
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5658.196982

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  Abstract 

Background: Percutaneous coronary intervention (PCI) is the main treatment in patients with acute coronary syndromes (ACS). Current guidelines recommend the administration of a loading dose of clopidogrel, ticagrelor or prasugrel during the procedure. Ticagrelor and prasugrel have proven to overcome some limitation related to clopidrogrel administration as of pharmacological resistance. P2Y12 antagonists increase adenosine concentration by inhibiting red blood cells reuptake and induces adenosine triphosphate release from human red blood cells, which is further degraded to adenosine. Ticagrelor has been demonstrated to increase the coronary blood flow velocity more than prasugrel, as assessed by transthoracic Doppler echocardiography after incremental doses of adenosine administration. Currently, no data are available on comparison between prasugrel and clopidrogrel in term of vasodilation effect evaluated invasively.
Methods/Design: This prospective, single-center, investigator-initiated, randomized controlled trial will compare the adenosine induced coronary dilatation after the treatment with ticagrelor (180 mg) versus prasugrel (60 mg) in patients with ACS undergoing PCI. A total of 90 patients, aged ≥ 18 and ≤ 75 years, admitted with ACS, treated by PCI with stent implantation and with a second intermediate non-culprit lesion will be included and randomized 1:1 to prasugrel (60 mg) or ticagrelor (180 mg). Coronary flow reserve (CFR), the study endpoint, will be recorded before the stent implantation on the intermediate lesion, then immediately after the stent implantation and during the adenosine intravenous administration at incremental doses of 50, 80, 110 and 140 μg/kg/min with 2-minute interval between infusions.
Discussion: Our clinical trial, for the first time, will evaluate the supposed adenosine induced effect of the ticagrelor in terms of coronary vasodilatation calculated by CFR. Currently, CFR represents the gold standard to assess the ability of the myocardium to increase blood flow in response to maximal exercise. Furthermore, this trial will be the first to compare the effects of ticagrelor versus prasugrel on patients ACS. This trial will allow to better understand the physiological pathway of coronary vasodilatiation induced by ticagrelor versus prasugrel using invasive methods.
Trial registration: ClinicalTrials.gov identifier: NCT02032303; registered on December 18, 2013.
Ethics: The study was approved by the Ethics Committee of Policlinico Umberto I Rome Hospital (approval No. 2322/15) and will be performed in accordance with the ethical standards of the responsible committee on human experimentation and the Declaration of Helsinki.
Informed consent: A signed informed consent will be given by each patient with ACS before undergoing angiography.

Keywords: clinical trial; percutaneous coronary intervention; acute coronary syndrome; ticagrelor; prasugrel; coronary flow reserve; randomized controlled trial


How to cite this article:
Cicenia M, Ceccacci A, Calcagno S, Maestrini V, Salvi N, Cinque A, Stio RE, Pulcini M, Sardella G, Mancone M, Fedele F. Assessment of coronary flow reserve by Doppler flow wIre in patients with acute coronary syndrome undergoing percutaneous coronary intervention: differences between the LoAding dose of Ticagrelor versus prasugrEl (DILATE): study protocol for a randomized controlled trial. Clin Trials Degener Dis 2016;1:154-9

How to cite this URL:
Cicenia M, Ceccacci A, Calcagno S, Maestrini V, Salvi N, Cinque A, Stio RE, Pulcini M, Sardella G, Mancone M, Fedele F. Assessment of coronary flow reserve by Doppler flow wIre in patients with acute coronary syndrome undergoing percutaneous coronary intervention: differences between the LoAding dose of Ticagrelor versus prasugrEl (DILATE): study protocol for a randomized controlled trial. Clin Trials Degener Dis [serial online] 2016 [cited 2019 Dec 10];1:154-9. Available from: http://www.clinicaltdd.com/text.asp?2016/1/4/154/196982


  Introduction Top


P2Y12 receptor antagonists represent a well-established antiplatelet therapy for patients undergoing percutaneous coronary intervention (PCI) procedure. Currently, in patients with acute coronary syndrome (ACS), the P2Y12-receptor antagonists ticagrelor and prasugrel, in addition to aspirin, are the recommended antiplatelet drugs according to European guidelines (Steg et al., 2012; Roffi et al., 2016).

As a third generation thienopyridine, prasugrel' metabolite is hepatically activated in a single cytochrome P (CYP)-dependent step. Accordingly, it exerts a more rapid and stable inhibitory effect on platelet aggregation than clopidogrel.

Ticagrelor is an oral reversible P2Y12 antagonist that belongs to a novel chemical class, cyclopentyltriazolopyrimidine. Ticagrelor undergoes hepatic metabolism and produces its metabolite AR-C124910XX; both ticagrelor and its metabolite are pharmacologically active (Storey et al., 2011).

Few trials compared clopidrogrel with prasugrel or ticagrelor. In the "trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38" (TRITON-TIMI 38) prasugrel was compared with clopidogrel, showing significantly reduction of ischemic event rate (including stent thrombosis), but with an increasing risk of major bleeding (including fatal bleeding) (Wiviott et al., 2007).

In the "Platelet Inhibition and Patient Outcomes" trial (PLATO), ticagrelor significantly reduced the rate of death from vascular causes, myocardial infarction or stroke compared with clopidogrel, without an increase in the rate of overall major bleedings (Wallentin et al., 2009). Furthermore, ticagrelor seems to determine an increased adenosine-induced coronary blood flow velocity (Wittfeldt et al., 2013). The potential effect of ticagleor on adenosine-mediate dilatation derived also from results of the PLATO trial. It has been supposed that the increased rate of dyspnea and asymptomatic ventricular pausesare due to increased adenosine plasmatic concentration (Schneider, 2011; Serebruany, 2011).

Currently, there are no studies comparing ticaglelor versus prasugrel in term of vasodilatation evaluated invasively, specifically there are no data on the effect of ticaglelor versus prasugrel on microvascular dysfuction reduction.

Objective

The aim of the trial is to compare the adenosine induced coronary dilatation following the treatment with ticagrelor (loading dose [180 mg] + standard treatment [90 mg b.i.d.] and prasugrel (loading dose [60 mg] + standard treatment [10 mg]) in patients presenting ACS undergoing PCI.


  Methods/Design Top


Study design

This is a prospective, single-center, investigator-initiated, randomized controlled study to compare the adenosine-induced coronary vasodilatation effect following ticagrelor versus prasugrel treatment in patients with ACS undergoing PCI [Figure 1].
Figure 1: Flow chart of the DILATE trial.
Note: ACS: Acute coronary syndrome; CFR: coronary flow reserve; FFR: fractional flow reserve.


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Patients admitted to the Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, "Sapienza" University of Rome with ACS will be screened for participation in the study according to the inclusion and exclusion criteria. Written informed consent will be obtained from all participants considered eligible, before the angiography. During angiography, the patient satisfying the inclusion and exclusion criteria will be randomized.

Patients with ACS undergoing PCI on the culprit lesion and with at least another intermediate non-culprit lesion will be enrolled and randomized, in a 1:1 ratio, to receive a loading dose of ticagrelor (180 mg) or prasugrel (60 mg). PCI will be performed according to a standard procedure.

A second angiography to evaluate the intermediate non-culprit lesion will be performed within seven days. The coronary dilatation of the intermediate non-culprit lesion will be calculated by coronary flow reserve (CFR) with an intracoronary Doppler Flow Wire "Combowire" (currently considered the gold standard technique) and hemodynamically by fractional flow reserve (FFR). The lesion will be considered significant if FFR will be more than 0.8, accordingly to the current guidelines (Kaluski et al., 2012; Montalescot et al., 2013; Van Nunen et al., 2015).

CFR will be recorded before the stent implantation and after the procedure at baseline and after adenosine intravenous administration at incremental doses of 50, 80, 110 and 140 μg/kg/min with 2-minute interval between infusions.

Inclusion criteria

  • Patients admitted with ACS undergoing angiography treated for they culprit lesion
  • Presence of an intermediate non-culprit lesion requiring FFR/CFR evaluation according to international guidelines (Montalescot et al., 2013; Kolh et al., 2014; Van Nunen et al., 2015)
  • Age ≥ 18 and ≤ 75 years


Exclusion criteria

  • Patients with stable angina
  • Prior myocardial infarction
  • Prior revascularization (PCI or coronary artery bypass grafting-CABG)
  • Contraindications for ticagrelor (history of intracranial haemorrhage, active pathological bleeding, severe hepatic impairment)
  • Contraindications for prasugrel (patients weigh < 60 kg, previous stroke or transient ischemic attack, patients > 75 years)
  • Major periprocedural complications
  • Glomerular filtration rate (GFR) < 30 mL/min or requiring haemodialysis
  • Severe chronic obstructive pulmonary disease (COPD)
  • Risk of bleeding or bradycardic events
  • Cardiogenic shock
  • Refusal to signed informed consent


Sample size

Assuming an awaited mean value of coronary flow reserve of 3.0 ±0.5 and 2.7 ±0.5 in patients treated with ticagrelor and prasugrel, respectively and aiming for a 2-tailed 5% alpha and 80% power, it is estimated that at least 45 patients for each group (total 90 patients) needed to be enrolled in this study. We will increase 10% of the number of enrolled patients for each group under consideration of dropout rates.

Baseline evaluation

Patient baseline evaluation will be performed at admission and before angiography. Evaluation will include the following data:

  • Demographic and antropometric data
  • Medical history
  • Therapy
  • Blood test
  • Eclectrocardiogram
  • Fast echocardiography


Recruitment

Informed consent form will be collected before the angiography. Furthermore, patients will be recruited and screened using inclusion (verified during angiography) and exclusion criteria.

Randomization and blinding

The randomization will be performed during angiography. The list of assignment to ticagrelor or prasugrel will be generated by an on-line randomization program (randomization.com) according to a 1:1 randomization.

Interventions

All patients will be treated according to European Society of Cardiology (ESC) guidelines. In particular anti-platelet therapy will be administered according to the following scheme:

- Ticagrelor: loading dose of 180 mg and maintaining dose of 90 mg twice daily in acute coronary syndrome (ACS) (Class I B) patients for 6 months in case of implantation of a drug eluting stent (DES), for at least one month in case of implantation of a bare metal stent (BMS) (Kolh et al., 2014).

- Prasugrel: loading dose of 60 mg and maintaining dose of 10 mg daily in ACS(Class I B) patients for six moths in case of implantation of a drug eluting stent (DES), for at least one month in case of implantation of a bare metal stent (BMS) (Kolh et al., 2014).

Both prasugrel and ticagrelor will be supplied by the referring pharmacy of our department.

All patients will be pre-treated with aspirin 300 mg orally, heparin i.v. to maintain an activated clotting time of > 250 seconds, and a loading dose of ticagrelor (180 mg) or prasugrel (60 mg) immediately before the revascularization PCI will be performed according to standard clinical practice using femoral or radial artery Judkins approach via six or seven French heath insertion. After crossing the target lesions, coronary stenting will be performed based on standard practice. Patients will subsequently receive heparin for 48 hours, aspirin 100 mg daily, and prasugrel (10 mg/d) or ticagrelor (90 mg twice daily) for at least 12 months in case of DES, for one month in case of BMS. Other adjunctive pharmacotherapy in intensive care unit (ICU) will be administered according to operator discretion. The course of thienopyridine treatment will be done according to the current guidelines (Class IB) (Steg et al., 2012; Roffi et al., 2016).

Before and after PCI, a 12-lead electrocardiogram (ECG) and an echocardiogram will be performed as standard practice. Then, all the pre-, intra-, and post-procedure data of patients will be collected in a database.

Study endpoint

The enhancement of adenosine-induced coronary vasodilatation in terms of coronary flow reserve (CFR) on a non-culprit lesion after treatment with ticagrelor (180 mg) versus prasugrel (60 mg) in patients with ACS undergoing PCI at gradually increasing doses of adenosine.

Data management

All required data for this registry will be collected prospectively on a dedicated case report form by a research co-ordinator at the clinical site. A copy of angiography compact disc will also be collected.

Regulations require that the investigator keeps the record of clinical information on the study patients' medical records. In order to comply with these regulatory requirements, the following information will be maintained (for at least 5 years) and made available, as required by monitors and/or regulatory inspectors:

  • Medical history and physical condition of the study patient before recruitment in the study to verify protocol entry criteria;
  • Signed informed consent;
  • Record of any abnormal lab test results and adverse events reported and their resolution;
  • Record of any concomitant medications taken during the study (including starting/finishing dates);
  • Reasons for withdrawal from the study.


Statistical analysis

Continuous variables will be expressed as mean ± SD and categorical variables will be reported as percentage. Hazard ratios (HR) will be presented along their 95% confidence interval (CI). Unless specified otherwise, a 2-tailed P value of 0.05 will be considered statistically significant. A multivariate logistic regression model will be constructed using variables selected according to the corresponding significant univariate analysis. All statistical analyses will be performed using SPSS version 13.0 for Windows (SPSS Inc., Chicago, IL, USA).

Ethical considerations

Medical Ethics Committee Approval Institutional review board (IRB), medical ethics committee (MEC) approval for the protocol and informed consent form will be obtained by the investigator prior to participation in this study.

The study will be explained to the patients in native language. Patients will sign a copy of an informed consent form prior to study participation. Patients will be assured that they may withdraw from the study at any time for any reason and receive alternative conventional therapy as indicated.


  Discussion Top


Ticagrelor and its metabolites increase adenosine concentration by inhibiting red blood cell reuptake (Van Giezen et al., 2012) and induce adenosine triphosphate release from human red blood cells, which is further degraded to adenosine (Ohman et al., 2012). Ticagrelor has been demonstrated to significantly increase adenosine-induced cardiac blood flow in a dose dependent manner in an animal expeirment (Van Giezen et al., 2012). In addition, in a clinical study, ticagrelor has been proven to increase coronary blood flow velocity (CBFV) after adenosine infusion using transthoracic Doppler echocardiography (Wittfeldt et al., 2013) and increase coronary blood flow velocity compared with prasugrel, as assessed by transthoracic Doppler echocardiography after administration of incremental doses of adenosine (Alexopoulos et al., 2013).

In this clinical trial, for the first time, we will directly compare the supposed adenosine induced effect of ticagrelor versus prasugrel in terms of coronary vasodilatation using the intracoronary Doppler flow wire, currently considered the gold-standard.

Accordingly, this trial will allow to better understand the physiological pathway of ticagrelor versus prasugrel to induce a coronary vasodilatiation by an invasive assessment in subjects presenting with ACS.

Although prompt reperfusion treatment restores normal epicardial flow, microvascular dysfunction may persist in some patients with ACS. The presence of microvascular dysfunction is considered a poor prognostic factor for ACS (Schnorbus et al., 2014). Adenosine acts as a cytoprotector in response to stress to an organ or tissue, with potential therapeutic applications due to its anti-inflammatory, cardioprotective, cerebroprotective, antisclerotic, and antifibrotic properties.

There is also evidence that elevated levels of adenosine reduce the inflammatory response in the different phases after revascularized myocardial infarction, by interfering with the production of inflammatory mediators and oxygen species and neutrophil trafficking (Barletta et al., 2012); it may have a stimulatory effect on endothelial healing, which may be particularly favorable in patients who underwent successful primary PCI for ACS (Janssens et al., 2016). In this setting, future study may include the assessment of the cardioprotective effect of the antiplatelets by imaging modalities.

Limitations: This is a single centre and unblinded trial and the sample size is relatively small for the evaluation of the clinical effects.


  Trial Status Top


Enrollment into the DILATE trial will start in November 2016. The study is expected to be completed by the end of November 2017. [18]

 
  References Top

1.
Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, Davlouros P, Hahalis G (2013) Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. Circ Cardiovasc Interv 6:277-283.  Back to cited text no. 1
    
2.
Barletta KE, Ley K, Mehrad B (2012) Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 32:856-864.  Back to cited text no. 2
    
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Janssens GN, van Leeuwen MAH, van der Hoeven NW, de Waard GA, Nijveldt R, Diletti R, Zijlstra F, von Birgelen C, Escaned J, Valgimigli M, van Royen N (2016) Reducing microvascular dysfunction in revascularized patients with ST-elevation myocardial infarction by off-target properties of ticagrelor versus prasugrel. Rationale and design of the REDUCE-MVI study. J Cardiovasc Trans Res 9:249-256.   Back to cited text no. 3
    
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Kaluski E, Waller AH, Rudzinski W, Nasur A, Dehnee A, Gerula C, Maher J, Dhruvakumar S, Mazza V (2012) Fractional flow reserve (FFR): changing the practice of interventional cardiology. Minerva Cardioangiol 60:539-548.  Back to cited text no. 4
    
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Kolh P, Windecker S, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Jüni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, et al. (2014) 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg 46:517-592  Back to cited text no. 5
    
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Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, et al. (2013) 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 34:2949-3003.   Back to cited text no. 6
    
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Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D (2012) Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun 418:754-758.  Back to cited text no. 7
    
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Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, et al. (2016) 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 37:267-315.  Back to cited text no. 8
    
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Schnorbus B, Daiber A, Jurk K, Warnke S, König J, Krahn U, Lackner K, Munzel T, Gori T (2014) Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. BMJ Open 4:e005268.  Back to cited text no. 10
    
11.
Serebruany VL (2011) Adenosine release: a potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial? Am Heart J 161:1-4.  Back to cited text no. 11
    
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Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, et al. (2012) ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33:2569-2619.  Back to cited text no. 12
    
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Storey RF, Bliden KP, Ecob R, Karunakaran A, Butler K, Wei C, Tantry U, Gurbel PA (2011) Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses. J Thromb Haemost 9:1730-1737.  Back to cited text no. 13
    
14.
Van Giezen JJ, Sidaway J, Glaves P, Kirk I, Bjorkman JA (2012) Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 17:164-172.  Back to cited text no. 14
    
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Van Nunen LX, Zimmermann FM, Tonino PA, Barbato E, Baumbach A, Engstrøm T, Klauss V, MacCarthy PA, Manoharan G, Oldroyd KG, Ver Lee PN, Van′t Veer M, Fearon WF, De Bruyne B, Pijls NH (2015) FAME study investigators fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. Lancet 386:1853-1860.  Back to cited text no. 15
    
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Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA and PLATO Investigators, Freij A, Thorsén M (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045-1057.  Back to cited text no. 16
    
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Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, Gan LM (2013) Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 61:723-727.  Back to cited text no. 17
    
18.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001-2015.  Back to cited text no. 18
    

Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
All authors participated in the intellectual content, conception and design, and the writing of the manuscript. All authors approved the final version of the manuscript for publication.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


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