Comparison of Ticagrelor versus Prasugrel for inflammation, vascular function, and circulating endothelial progenitor cells in Diabetic patients with NON-ST-Segment Elevation Acute coronary syndrome requiring coronary stenting.

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Jeong HS, et al. "Comparison of Ticagrelor Versus Prasugrel for Inflammation, Vascular Function, and Circulating Endothelial Progenitor Cells in Diabetic Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Requiring Coronary Stenting: A Prospective, Randomized, Crossover Trial". JACC: Cardiovascular Interventions. 2017. 10(16):1646-1658.
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Clinical question

Among type 2 diabetes patients with NSTE-ACS, does the use of Ticagrelor improve vascular function, reduce inflammatory status, and enhance circulating endothelium progenitor cells in comparison with Prasugrel?

Bottom line

Compared with Prasugrel, Ticagrelor has been shown to have pleiotropic effects beyond platelet inhibition. It significantly reduces inflammatory markers, such as Interleukin-6 and tumor necrosis factor-α, enhances circulating endothelial progenitor cells and improves vascular endothelial function in diabetes type 2 patients with NSTE-ACS at 10 weeks follow up.

Major points

1- Acute coronary syndrome patients subjected to coronary stenting are at high risk of developing stent thrombosis. Therefore, the American heart association and American college of cardiology recommend providing patients with NSTE-ACS underwent coronary stenting with dual antiplatelet therapy. They particularly recommend Ticagrelor or Prasugrel over clopidogrel with aspirin as platelet function inhibitors medications. Ticagrelor is a reversible P2Y12 receptor blocker, whereas Prasugrel is a prodrug that needs hepatic metabolism first to produce the active metabolite that irreversibly blocks P2Y12 receptor.

2-Ticagrelor is thought to block Equilibrative nucleoside transporter 1, inhibit adenosine uptake, and subsequently enhance the circulating adenosine concentration.


3-The trial randomized 62 patients to a cross over design so that the group of patients who received Ticagrelor (180 mg loading dose, 90 mg twice daily) for the first 5 weeks would be crossed over to a Prasugrel (60 mg loading dose, 10 mg once daily) for the next 5 weeks. Patients were evaluated at 5 weeks and 10 weeks.

4-Ticagrelor notably mitigates inflammatory status, enhances endothelial progenitor cells and ameliorates vascular endothelial function at 5 weeks and 10 weeks follow up.

Guidelines

As of November 2017, no recommendations have been published to that reverberate the result of this trial.

Design

Prospective, open-label, randomized, crossover trial Sample size = 62. Setting: Korea University Anam Hospital Cardiovascular Center. Enrollment: from July 2015 to April 2016. Follow-up: 10 weeks. Analysis: Analysis of variance with adjusted sequence effect and period effect test to adjust for carryover effects.

Population

Inclusion criteria: 1-Patients aged 35 to 74 years old. 2-Newly diagnosed with type 2 diabetes or had type 2 diabetes and take hypoglycemic agents. 3-Diagnosed with Non St-segment acute coronary syndrome and underwent successful coronary stenting. 4-Patients’ thrombolysis in myocardial infraction(TIMI)flow grade 3 after the PCI procedure.

Exclusion criteria

1-Body weight < 60Kg. 2-Patients didn’t provide consent. 3-Unsuccessful reperfusion after PCI. 4-Stable angina. 5-STEMI. 6-History of PCI or CABG. 7- History of stroke or transient ischemic attack. 8-Gastrointestinal bleeding within 6 months. 9-Previous use of Ticagrelor or Prasugrel within a month before randomization. 10-Heart failure. 11-Renal dysfunction. 12-Hepatic dysfunction. 13-HbA1c>9% 14-Platelet level<100,000µL 15-Expected life expectancy of less than 1 year. 16-Pregnant. 17-Intention to be pregnant during the study period.

Baseline Characteristics

There are no significant differences between two groups regarding baseline characteristics:

Age, Yrs: 61.0 ± 9.1 Male: 45 (72.6%) Height, Cm: 163±8.8 BMI, KG/m²: 26.0±3.2 Waist circumference, CM: 90.3±7.8 Smoking: 29(46.8%) Hypertension: 44 (71.0%) Total Cholesterol, mg/dl:165.3±40.6 Triglyceride, gm/dl: 165.1 ± 96.8 HDL, mg/dl: 40.3 ± 8.4 LDL, mg/dl: 112.8 ± 31.6 Uric acid, mg/dl: 5.5 ± 1.0 Creatinine: .95 ± .019 WBC, 10³/mm³: 8.5 ±3.1 WBC lymphocyte,%: 27.1 ±12.5 Verify now P2Y12: 241.3 ±35.4 Medication on admission: Aspirin: 61(98.4%) Beta-Blocker: 11(17.7%) Calcium channel blocker: 21(33.9%) ACE inhibitor/ARB: 26 (41.9%) Statin: 61 (98.4%)

Interventions

A prospective crossover design where patients randomly assigned to; Group 1: 31 patients received Ticagrelor (180 mg loading dose, 90 mg twice daily) for 5 weeks, and then crossed over to Prasugrel (60 mg loading dose, 10 mg once daily) for another 5 weeks. Group 2: 31 patients received Prasugrel (60 mg loading dose, 10 mg once daily for the first 5 weeks, then crossed over to Ticagrelor (180 mg loading dose, 90 mg twice daily) for another 5 weeks.

Outcomes

Primary outcomes

  • There is a significant improvement in baFMD in ticagrelor group in comparison with Prasugrel group at 5 weeks and 10 weeks follow up (4.3 ± 0.6 mm vs. 3.9 ±0.5 mm; p = 0.037) and (4.2 ±0.6 mm vs. 4.1 ±0.6 mm; p < 0.001), respectively.
  • There is no difference in brachial artery dilation after nitroglycerin in both groups.
  • There is no detected difference in pulse wave velocity, ankle-brachial index, central blood pressure, or augmentation index.

Secondary outcomes

Inflammatory cytokines: Ticagrelor significantly decreased IL-6, TNF-α and increased adiponectin compared with Prasugrel at 10 weeks follow up(0.58 0.43 pg/ml vs. 0.05 0.24 pg/ml; p < 0.001), (5.62 4.40 pg/ml vs. 0.42 2.64 pg/ml; p < 0.001) and (2.31 2.00 mg/ml vs. 0.08 1.50 mg/ml; p < 0.001), respectively. Endothelial progenitor cells: There is a significant increase in circulating endothelial progenitor cells in the Ticagrelor group in comparison with Prasugrel group at 10 weeks follow up; CD34+/KDR+ (42.5 ±37.8 per ml vs. 28.2 ±23.7 per ml; p < 0.001), CD34+/CD117+ (51.9 ± 77.2 per ml vs. 66.3± 45.2 per ml; p < 0.001), and CD34+/CD133+ (55.2 ±69.2 per ml vs. 28.0 ±34.1 per ml; p < 0.001).

Additional outcomes

Plasma Adenosine concentration and Adenosine deaminase activity
Plasma adenosine concentration was 1.7-fold higher in ticagrlor group after the loading doses of both medications.
Adenosine deaminase activity didn’t differ in both groups at 5-weeks follow up.
Platelet function
Despite platelet inhibition was higher in the ticagrelor group, the difference between both groups was not significantly different. Platelet reactivity units were 90 ± 84.7 vs. 81.9 ± 99.3 in ticagrelor versus Prasugrel, respectively.
Serum Uric acid and Creatine
There is a significant elevation in serum Uric acid and creatinine level in the ticagrelor group compared with Prasugrel group; (0.42 0.37 mg/dl vs. 0.24 0.34 mg/dl, p < 0.001 for uric acid; 0.07 0.07 mg/dl vs. 0.08 0.11 mg/dl, p < 0.001 for creatinine).

Comments

  • The significant improvement in arterial endothelial function and decrease in inflammatory cytokines in the ticagrelor group prove the hypotheses of the pleiotropic effects of ticagrelor over prasugrel which may have contributed to this improvement.
  • There is an increase in the plasma adenosine level in the ticagrelor group.

Adenosine acts one A2A and A2B receptors which subsequently downregulate inflammatory cytokines and enhance coronary vasodilation. Furthermore, A2A receptor particularly promotes endothelial progenitor cells migration.

  • Adenosine acts on A1 receptor which leads to a vasoconstriction in the renal afferent arterioles and justify the significant elevation in serum creatinine level in the ticagrelor group.
  • Despite previous reports found no significant anti-inflammatory properties to the ticagrelor, this could be explained by the relative difference of the inclusion criteria of this study. Unlike previous studies, this study included diabetic patients with NS-ACS which have extremely inflammatory status enough to elucidate the anti-inflammatory properties of the ticagrelor.
  • Adenosine up-regulates phospholipase A2, cyclooxygenase2 and endothelial nitric oxide which improve baFMD.

The use of Ticagrelor among dual anti-platelet therapy after PCI in patients with acute coronary syndrome may reduce the currently recommended duration of dual anti-platelet therapy

Criticism

1-Short follow- up period that can’t translate the observed improvement in endothelial function into a significant mortality benefits. 2-The study team didn’t report data regarding plasma adenosine level and adenosine deaminase activity at follow-up time points. 3-The study has a small sample size that’s not enough to provide adequately powered data. 4-Despite a washout period is required in such a design, it’s plausible that they didn’t provide subjects a time for washout since this could expose stented patients to a high risk of stent thrombosis.

Funding

This study is funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (no. NRF-2014R1A2A1A11051998)

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