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Figure.
Association of Ticagrelor With Reactive Hyperemia Index (RHI) and Augmentation Index Normalized to Heart Rate (AI75)
Association of Ticagrelor With Reactive Hyperemia Index (RHI) and Augmentation Index Normalized to Heart Rate (AI75)

Reactive hyperemia index (A) and augmentation index normalized to heart rate (AI75) (B); at baseline visit and after treatment with ticagrelor at trough (12 hours after last dose) and peak (2 hours after ticagrelor administration) drug levels. The horizontal lines between the upper and lower whisker marks indicate the mean, while the top and bottom whisker marks represent SD.

1.
Rubinshtein  R, Kuvin  JT, Soffler  M,  et al.  Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.  Eur Heart J. 2010;31(9):1142-1148.PubMedGoogle ScholarCrossref
2.
Bonaca  MP, Bhatt  DL, Cohen  M,  et al; PEGASUS-TIMI 54 Steering Committee and Investigators.  Long-term use of ticagrelor in patients with prior myocardial infarction.  N Engl J Med. 2015;372(19):1791-1800.PubMedGoogle ScholarCrossref
3.
Bonello  L, Laine  M, Kipson  N,  et al.  Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome.  J Am Coll Cardiol. 2014;63(9):872-877.PubMedGoogle ScholarCrossref
4.
Alemayehu  M, Kim  RB, Lavi  R,  et al.  Effect of ticagrelor versus clopidogrel on vascular reactivity.  J Am Coll Cardiol. 2017;69(17):2246-2248.PubMedGoogle ScholarCrossref
5.
clinicaltrials.gov. Effect of ticagrelor on endothelial function. NCT01805596. https://clinicaltrials.gov/ct2/show/NCT01805596. Accessed June 15, 2017.
6.
Parviz  Y, Hsia  C, Alemayehu  M,  et al.  The effect of fresh versus standard blood transfusion on microvascular endothelial function.  Am Heart J. 2016;181:156-161.PubMedGoogle ScholarCrossref
7.
van den Berg  TN, El Messaoudi  S, Rongen  GA,  et al.  Ticagrelor does not inhibit adenosine transport at relevant concentrations: a randomized cross-over study in healthy subjects in vivo.  PLoS One. 2015;10(10):e0137560.PubMedGoogle ScholarCrossref
Research Letter
September 2017

Association Between Administration of Ticagrelor and Microvascular Endothelial Function

Author Affiliations
  • 1London Health Sciences Centre, London, Ontario, Canada
  • 2Western University, London, Ontario, Canada
JAMA Cardiol. 2017;2(9):1042-1044. doi:10.1001/jamacardio.2017.2378

Impaired endothelial function has been associated with an increased risk of adverse cardiovascular events,1 while ticagrelor use has been associated with reduced risk.2 Ticagrelor's effect may be partially facilitated via adenosine-mediated pleiotropic actions. Ticagrelor stimulates rapid release of adenosine triphosphate from red blood cells, inhibits adenosine uptake, and is associated with increased circulating adenosine levels in patients with acute coronary syndrome.3 Ticagrelor administration has been shown to augment adenosine-induced coronary blood flow velocity and is associated with improved vascular reactivity compared with clopidogrel.4 Our study aimed to describe the association between ticagrelor and vascular reactivity in relation to timing of drug administration.

Methods

In this prospective, open-label, clinical trial5 of 45 participants, we assessed the association of ticagrelor administration with endothelial function and arterial stiffness. The study was approved by Western University Research Ethics Board, and written informed patient consent was obtained.

Inclusion criteria were an age of 18 years or older, coronary artery disease with at least 2 cardiovascular risk factors, and abnormal endothelial function defined as a reactive hyperemia index (RHI) of less than 2.0. Exclusion criteria were heart block, bleeding, stroke, dyspnea, valvular heart disease, anticoagulants, treatment with CYP3A4 inhibitors, alcohol or other drug abuse, liver disease, hypersensitivity to the study drug, pregnancy, and latex allergy.

Microvascular endothelial function was determined using a noninvasive assessment of endothelial function (EndoPAT2000; Itamar Medical Inc) as previously described.6 Plethysmographic probes placed on the index fingers of each hand sense volume changes to measure peripheral arterial tonometry (PAT). The normalized augmentation index (AI75), a measure of arterial stiffness, was calculated from PAT waveforms recorded prior to cuff inflation using the formula

(P2−P1)/P1,

where P1 is the systolic peak and P2 is the reflected wave peak. The result is normalized to heart rate.

Reactive hyperemia index and AI75 were assessed in the absence of ticagrelor (baseline) and twice following ticagrelor administration for 21 days, at 12 hours after the last dose of ticagrelor (trough), and 2 hours after ticagrelor administration (peak).

Continuous variables are summarized by mean and SD. Categorical variables are presented as counts and percentages. Continuous variables were compared using the paired t test or 1-way analysis of variance when appropriate.

Results

Forty-five participants (mean [SD] age, 64 [8] years; 41 men and 4 women) completed the study. Risk factors included diabetes (12 [27%]), dyslipidemia (34 [76%]), and hypertension (29 [64%]). Medical therapy included the use of aspirin (44 [98%]), a statin (38 [84%]) and/or a β-blocker (34 [76%]).

The RHI was improved in the short term with administration of ticagrelor (mean [SD] index, 2.02 [0.63] at peak vs 1.74 [0.45] at trough; P = .002, Figure, A). The AI75 did not change with long-term or short-term ticagrelor administration (P = .71, Figure, B).

Discussion

We assessed endothelial function before and after a dose of ticagrelor, timed to reflect the drug’s peak and trough levels. During peak ticagrelor levels, there was significant improvement in endothelial function compared with baseline and compared with the time of low drug levels. Reactive hyperemia index during trough was nonsignificantly higher compared to baseline. Considering the twice-daily drug administration, endothelial function may be improved during the dosing cycle of ticagrelor. However, this effect is not sustained for the duration of the 12 hours between drug dosing times and is maintained only while patients continue taking the drug. Our results contrast the lack of effect of ticagrelor therapy on reactive hyperemia in healthy young patients.7 It is possible that the potential beneficial effect of ticagrelor is seen only in patients with established cardiovascular disease and endothelial dysfunction.

The lack of effect of ticagrelor on arterial stiffness, measured simultaneously with RHI, underscores the fact that the effect on RHI is real and not related to repeated measurements. In conclusion, short-term administration of ticagrelor is associated with improvement in microvascular endothelial function. Use of ticagrelor did not affect arterial stiffness.

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Article Information

Accepted for Publication: June 2, 2017.

Corresponding Author: Shahar Lavi, MD, Division of Cardiology, Western University, 339 Windermere Rd, PO Box 5339, London, ON N6A 5A5, Canada (shahar.lavi@lhsc.on.ca).

Published Online: July 26, 2017. doi:10.1001/jamacardio.2017.2378

Author Contributions: Dr S. Lavi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: S. Lavi, R. Lavi

Concept and design: S. Lavi, R. Lavi.

Acquisition, analysis, or interpretation of data: S. Lavi, Alemayehu, Puka, Wall.

Drafting of the manuscript: S. Lavi.

Critical revision of the manuscript for important intellectual content: Alemayehu, Puka, Wall, R. Lavi.

Statistical analysis: S. Lavi, Puka.

Obtained funding: S. Lavi.

Administrative, technical, or material support: Alemayehu, Wall, R. Lavi.

Study supervision: R. Lavi.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: AstraZeneca provided funding for the study.

Role of the Funder/Sponsor: AstraZeneca reviewed the initial draft and provided scientific comments. However, AstraZeneca had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Rubinshtein  R, Kuvin  JT, Soffler  M,  et al.  Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.  Eur Heart J. 2010;31(9):1142-1148.PubMedGoogle ScholarCrossref
2.
Bonaca  MP, Bhatt  DL, Cohen  M,  et al; PEGASUS-TIMI 54 Steering Committee and Investigators.  Long-term use of ticagrelor in patients with prior myocardial infarction.  N Engl J Med. 2015;372(19):1791-1800.PubMedGoogle ScholarCrossref
3.
Bonello  L, Laine  M, Kipson  N,  et al.  Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome.  J Am Coll Cardiol. 2014;63(9):872-877.PubMedGoogle ScholarCrossref
4.
Alemayehu  M, Kim  RB, Lavi  R,  et al.  Effect of ticagrelor versus clopidogrel on vascular reactivity.  J Am Coll Cardiol. 2017;69(17):2246-2248.PubMedGoogle ScholarCrossref
5.
clinicaltrials.gov. Effect of ticagrelor on endothelial function. NCT01805596. https://clinicaltrials.gov/ct2/show/NCT01805596. Accessed June 15, 2017.
6.
Parviz  Y, Hsia  C, Alemayehu  M,  et al.  The effect of fresh versus standard blood transfusion on microvascular endothelial function.  Am Heart J. 2016;181:156-161.PubMedGoogle ScholarCrossref
7.
van den Berg  TN, El Messaoudi  S, Rongen  GA,  et al.  Ticagrelor does not inhibit adenosine transport at relevant concentrations: a randomized cross-over study in healthy subjects in vivo.  PLoS One. 2015;10(10):e0137560.PubMedGoogle ScholarCrossref
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