Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled phase II trialBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l2211 (Published 06 June 2019) Cite this as: BMJ 2019;365:l2211
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Re: Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled phase II trial
A unique study focusing on acute minor ischemic stroke and moderate to high stroke titled “Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled
phase II trial” by Yilong Wang et al.,
Earlier study by same author in proved that combination of aspirin was superior over aspirin alone in the CHANCE trial in reducing the risk of subsequent stroke.  But this study period was one year, therefore long term benefit was not proved. It has been observed that CYPC19 activity decreases over a period of time.
Clopidogrel and Ticagrelor are the P2Y 12 Receptor Antagonists. Platelets contain two purinergic receptors, P2Y1 and P2Y12 both are G-Protein Coupled Receptors (GPCR) for Adenosine diphosphate receptor (ADP). Clopidogrel is an irreversible inhibitor ,whereas ticagrelor is a reversible inhibitor. Clopidogrel is a prodrug, whereas ticagrelor active drug. Clopidogrel activated by CYPC19 enzyme.
Earlier studies proved that ticagrelor can cause more side effects than clopidogrel. Ticagrelor can cause dysponea in 17% patients without involving pulmonary system, also a high incidence of intracranial bleed. 
In this study National Institute of Health Stroke Scale of ≤3 was included under acute minor stroke and the ABCD stroke risk score was used for inclusion in Transient Ischemic Attack (TIA). To bring uniformity and to ensure the validity and reproducibility of the assay, a separate training session was conducted among study experts. This is an important step to reduce researcher bias.
High platelet reactivity (HPR) is an important surrogate marker for recurrent ischemic events in patients with history of coronary heart disease (CHD) or who are undergone per cutaneous intervention(PCI). To assess the HPR there are different tests available these are Light Transmission Aggregometry (LTA) assay, Vasodilator Stimulated Phosphoprotein Phosphorelation (VASP), and VeryfyNow P2Y12 assay. LTA is considered as the gold standard test because it identify P2Y1 and P2Y12 effect. VeryfyNow P2Y12 assay simple bedside test easy to perform.  In this HPR is a primary endpoint in this situation if LTA could be better test than VeryfyNow P2Y12 assay.
Efficacy wise ticagrelor plus aspirin group superior than the clopidogrel plus aspirin group. But hard endpoints of this study did not proved similar efficacy outcomes. This may be due to the shorter duration of the study or smaller sample size.
Subgroup analysis in patients with genetic variant in CYP2C19 favored the ticagrelor plus aspirin group. This is direct correlation because clopidogrel is a pro drug, which requires activation. If we could say that the impact of genetic analysis in improving therapy with clopidogrel will be more valuable.
Another subgroup analysis is with respect to intracranial Large Artery Atherosclerosis (LAA). In this group stroke recurrence at 90 days significantly higher in clopidogrel group. It is one of the important findings to prevent risk of recurrence in the future by using ticagrelor plus aspirin than the clopidogrel plus aspirin.
The adverse effects ticagrelor plus aspirin group significantly high, especially with respect to bleeding.  Incidence of bleeding, less in the clopidogrel plus aspirin group may be due to reduced activity of CYP2C19 with chronic use. This analysis will avoid misconception that ticagrelor associated with more adverse effects.
1. Wang Y, Pan Y, Zhao X, Li H, Wang D, Johnston SC, Liu L, Meng X, Wang A, Wang C, Wang Y. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: one-year outcomes. Circulation. 2015 Jul 7;132(1):40-6.
2. Brunton LL, Knollmann BC. As Bases Farmacológicas da Terapêutica de Goodman e Gilman-13. Artmed Editora; 2018 Dec 19.
3. Garabedian T, Alam S. High residual platelet reactivity on clopidogrel: its significance and therapeutic challenges overcoming clopidogrel resistance. Cardiovascular diagnosis and therapy. 2013 Mar;3(1):23.
4. Cannon CP, Harrington RA, James S, Ardissino D, Becker RC, Emanuelsson H, Husted S, Katus H, Keltai M, Khurmi NS, Kontny F. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. The Lancet. 2010 Jan 23;375(9711):283-93.
Competing interests: No competing interests
Re: Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or TIA - uncertain interactions between genetics, HOPR and clinical outcomes.
Thank you for this very interesting phase II study which helps shed additional light on the complexity of genetics, platelet reactivity and outcomes.
It is not unexpected that Ticagrelor is superior to Clopidogrel in efficacy (ref 1 and 2) but potentially more bleeding/harmful too (ref 3 and 4). The reported associations between allelle phenotype, HOPR (high on-treatment platelet reactivity), and clinical outcomes is interesting.
Figure 3: In the HOPR poor metaboliser category, more than half of those in the clopidogrel group had suppressed activity. The Stroke (and composite) outcomes, stratified by metaboliser status, seems to suggest that ticagrelor+aspirin is potentially superior to clopidogrel + aspirin irrespective of the genetic profile (i.e. unrelated to the allele phenotype). If this is shown to be reproduced in future studies, then our current hypothesis of using genetics based just on HOPR to select antiplatelet choice is probably too simplistic and potentially incorrect.
This seems to be confirmed by the non LAA subgroup 90 d outcomes in figure 4 where there is no difference in outcome at 90d in the ticagrelor +aspirin vs clopidogrel + aspirin groups (despite the differences in the metaboliser status/ HOPR expected between the two groups).
Incidentally, the net benefit of 1.2% (composite events and significant bleeds combined) for the ticagrelor group needs to weighed against the morbidity of dyspnoea, numerous minor bleeding and other safety outcomes events (as noted in the paper, Table 2), suggesting the subgroup in which ticagrelor/aspirin combination is likely to be overall most beneficial still needs elucidating (perhaps LAA or those with IACS) (ref 4).
1. https://www.ahajournals.org/doi/10.1161/JAHA.115.002490 (JAHA, 2015)
2. https://heart.bmj.com/content/104/19/1575 (Heart, 2018)
3, https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.112.668988 (Stroke, 2012)
4. https://www.internationaljournalofcardiology.com/article/S0167-5273(13)01194-7/abstract (Int J Cardiol, 2013)
5, https://n.neurology.org/content/85/13/1154.short (Neurology, 2015)
Competing interests: No competing interests