Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial

BMJ 2011; 342 doi: http://dx.doi.org/10.1136/bmj.d3527 (Published 17 June 2011)
Cite this as: BMJ 2011;342:d3527

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I read with interest in this issue, the PLATO groups' study of the cohort (n=5216) of patients in the PLATO study managed in a conservative manner. Mirroring the findings in the study as a whole, they report a significant (p=0.04) 16% relative risk reduction in the occurrence of the primary end point of death from vascular causes, MI or stroke.

One must interpret this result in light of recent questions surrounding the index study PLATO, which seem to suggest that the incidence of the primary endpoint varied greatly according to the country of enrolment in to the study. In the US and Canadian cohort in PLATO (1814 of the total 18624 patients) there was a non significant trend toward worse outcomes in those taking ticagrelor compared with those taking clopidogrel. This finding directly contradicts the findings of the study as a whole. As a result, Ticagrelor is yet to be approved by the Food and Drugs Administration. [1] Some, including the manufacturers, ascribe this difference to a significantly higher daily dose of aspirin in the north American cohort which was a median of 325mg (compared to 100mg in the non - US group) [2]. Differing aspirin usage alone, may however be unlikely to account for this difference [2,3]. In PLATO, North American sites were monitored by independent clinical research organisations (CROs), whereas in countries such as Poland and Hungary, which together enrolled 21% of patients but accounted for 46% of positive endpoints favouring Ticagrelor, trial sites were monitored by manufacturer hired monitors. [3,4]

Ticagrelor has been approved for use in the European union but its' approval for use in North America is still pending approval in the United States by the FDA. I find it encouraging that patients treated with Ticagrelor as part of an initially non invasive conservative approach show similar benefits over clopidogrel treatment when compared with the PLATO ACS cohort in its entirety. It was also encouraging to note that this difference was not being driven by a difference in rates of eventual percutaneous coronary intervention between the clopidogrel and ticagrelor groups.

I await with great anticipation the FDAs decision on the drugs approval due on the 20th July 2011.

1) Ohman EM and Roe MT. Explaining the unexpected: insights from the PLATelet inhibition and clinical Outcomes (PLATO) trial comparing ticagrelor and clopidogrel. Thromb Haemost 2011; DOI:10.1160/TH11-03-0159

2) Fiorentino RP (2010) Brilinta (Ticagrelor) Efficacyreviewhttp://www.fda.gov /downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM221383.pdf

3) Serebruany VL. Aspirin dose and Ticagrelor Benefit in PLATO: fact of fiction? Cardiology 2010;117(4):280-3. Epub 2011 Feb 8.

4) Nainggolan L, Miller R (2010) No US approval for ticagrelor yet; FDA requests further analysis of PLATO. http://www.theheart.org/article /1164221.do

Competing interests: None declared

Andrew P Apps, ST1 in Cardiology.

Harefield Hospital

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Some preliminary remarks:
i) The STICH trial (1) showed that patients with coronary artery disease and left ventricular dysfunction do not benefit from medical therapy plus coronary-artery bypass grafting (CABG) compared with medical therapy alone,
ii)PLATO trial by James and Colleagues (2) supported that in a population with acute coronary syndrome, managed with a non-invasive treatment strategy, the benefits of ticagrelor over clopidogrel were consistent,
iii) These data accord with CURRENT - OASIS 7 trial (3), not reported in the text from James and Colleagues; in patients undergoing percutaneous coronary intervention for acute coronary syndromes a 7-days double-dose regimen of clopidogrel was more effective than was the standard-dose regiment in reduction of ischemic events and stent trombosis. We would be grateful if the Authors could comment:

First, the application of bone marrow cells (BMC) as therapeutic regimen in addition to convention therapy. Crucially in the BALANCE study Yousef and Colleagues (4) demonstrated significant decreased in mortality of BMC treated patients with acute myocardial infarction in comparison with the control group (P=0.03) over a median follow-up time of 4.6 +_2.1 yrs which also goes parallel to improve LV ejection fraction by 7.9% (P value was less than 0.01). However a meta-analysis has demonstrated that intracoronary infusion of BMC has the potential to recover contractile function and to counteract end-systolic volume expansion within 6 months after acute myocardial infarction.(5)

Second, the clinical trials comparing BMC effects and other procedures (repeat PTCA, CABG or stent implantation) in coronary artery disease merit consideration.

Third, the impact of transplanted apoptotic cells developing less myocardial inflammation, less myocardial apoptosis and scar formation as well as enhanced angiogenesis.

Finally, we believe that BMC trials might focus on critically ill patients who stand to benefit dramatically.


1.Velasquez EJ, Lee KL, Deja MA, et al. Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction. N Engl J Med. 2011; 28;364(17):1607-16.

2.James SK, Roe MT, Cannon CP Cornel JH , Horrow J, Husted S, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial BMJ 2011;342:d3527 doi: 10.1136/bmj.d3527

3.Metha SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT -OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233-43

4.Yousef M, Schnannwell CM, Kostering M, Zeus T, Brehm M, Strauer EB. The BALANCE study. Clinical benefit and long-term outcome after intracoronary autologous bone marrow cells. Transplantation in patients with acute myocardial infarction. J Am Coll Cardiol 2009; 53: 2262-9.

5.Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J. 2008;29:1807-1818.

Competing interests: None declared

Roberto G Carbone MD, FCCP, ACCP Leadership

Rosangela Filiberti PhD, National Cancer Research Institute, Genoa Italy,Assaf Monselise MD, PhD,University Tel Aviv Israel

DIMI,University of Genoa Italy

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21 June 2011

As a junior doctor I was interested to read this subgroup analysis comparing Ticagrelor to Clopidogrel in those initially randomised to a non -invasive treatment strategy with ACS.(1) Ticagrelor has been approved by the Scottish Medicines Consortium for this very indication within NHS Scotland, where I practice.(2)

I noted in the editorial on the paper that further cost effectiveness analyses need to be considered.(3) Using the data provided in the paper, we can calculate that the Number Needed to Treat to prevent one primary outcome of vascular death, non-fatal myocardial infarction or non-fatal stroke over 12 months, comparing Ticagrelor and Clodpidogrel is 53 (95% CI 53, 53).

The cost of one year's treatment with Ticagrelor is ?711, compared to ?39 for Clopidogrel (2), and therefore to prevent one primary outcome a year this will cost the NHS an extra ?35 616. Clearly further research needs to look at improvements in health related quality of life associated with this indication, however on first glance it looks a wee bit expensive.


1) James SK et al Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial BMJ 2011; 342:d3527

2) www.scottishmedicines.org.uk

3) Timmis A. Non-interventional management of acute coronary Syndromes Ticagrelor shows promise compared with clopidogrel but the absolute added benefit is small. BMJ 2011;342:d3263

Competing interests: None declared

Jamie Catlow, Foundation Year 1 Doctor

NHS Lanarkshire

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