Results of the PLATO substudy of ACS patients undergoing an invasive strategy have been published in the Lancet, accompanied by a comment from Gregg Stone hailing  the introduction of ticagrelor as a landmark event that will redefine the care of ACS patients. The results of the substudy were originally presented by Chris Cannon at TCT and reported by CardioBrief at the time. The main results of PLATO in 18,624 ACS patients were presented last summer at the ESC.

The substudy demonstrates that ticagrelor was more effective than clopidogrel in preventing events in the 13,408 ACS patients in PLATO for whom an invasive strategy was planned.

The primary endpoint, the rate of CV death, MI, and stroke, was reduced from 10.7% in the clopidogrel arm to 9.0% in the ticagrelor arm, a highly significant (p=0.0025) reduction of 16%. MIs were reduced from 6.6% in the clopidogrel group to 5.3% in the ticagrelor group. CV death was cut from 4.3% to 3.4%. All cause mortality was 5.08% in the clopidogrel group versus 3.94% in the ticagrelor group. Stent thrombosis was also reduced by ticagrelor (definite ST 1% versus 1.6%, probable or definite ST 1.7% versus 2.3%).

The superior efficacy of ticagrelor was not achieved at the expense of more bleeding. Major bleeds occurred in 11.6% of clopidogrel patients and 11.5% of ticagrelor patients. There were also no significant differences in life threatening of fatal bleeds, or bleeding associated with CABG.

The results were consistent across a broad range of subgroups, with one notable and potentially troubling exception. The primary endpoint in the 1,627 patients enrolled in North America occurred in 9.1% of clopidogrel-treated patients compared to 11.1% of ticagrelor patients (HR- 1.21, 0.88-1.66). As reported last October in CardioBrief, AstraZeneca had previously disclosed this subgroup result, and speculated on “a possible association between aspirin dose and the primary efficacy results, such that reduced efficacy was observed with ticagrelor and increasing aspirin doses.” The Lancet paper included no discussion of this finding.

The authors estimated that using ticagrelor instead of clopidogrel for 1 year in 1000 patients would result in 11 fewer deaths, 13 fewer MIs, and 6 fewer cases of stent thrombosis, with no increase in major bleeding or transfusion.

In an accompanying editorial, Gregg Stone discussed the advantages of ticagrelor over clopidogrel and prasugrel, in particular the value of its reversible platelet inhibition in preventing bleeding associated with CABG. Stone wrote that the drug’s 22% reduction in mortality is most likely not due to chance.

According to Stone, the trial’s “compelling results support ticagrelor as a new standard of care in acute coronary syndromes.” However, Stone noted, clopidogrel might still be useful in low risk patients or in patients for whom cost or the twice-daily dosing of ticagrelor may be an issue. Stone concluded with a ringing endorsement: “the introduction of ticagrelor, a more potent and effective agent which is as safe as its predecessor, is a landmark event that should redefine the care of patients with acute coronary syndromes.”

Here is the press release from the Lancet:

TICAGRELOR FOR HEART ATTACK PATIENTS—A LANDMARK EVENT THAT SHOULD REDEFINE PATIENT CARE (PLATO trial)

New research shows that the stronger anticlotting medication tricagrelor reduces death rates without increasing bleeding compared with the current standard treatment of clopidogrel for heart attack patients. This new analysis of the PLATO* trial is reported in an Article Online First (www.thelancet.com) and in an upcoming edition of The Lancet. The Article is by Dr Christopher P Cannon, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA, and colleagues.

Dr Cannon says**: “Heart attacks are caused by blood clots in the heart artery. We see today that using a stronger anticlotting drug lowered the chance of having a second heart attack—and reduced the risk of dying from one. This is a key advance for heart attack patients.” An accompanying Comment describes the introduction of ticagrelor as ‘a landmark event that should redefine the care of patients with acute coronary syndromes’.

Clopidogrel is an antiplatelet drug that is used in combination with aspirin in patients with acute coronary syndrome (heart attack/unstable angina), in order to prevent clots forming—thus reducing the risk of further heart attacks, stroke, and death. Ticagrelor is an antiplatelet drug that has a greater and more consistent antiplatelet effect than does clopidogrel, with a faster onset and offset of action. In this study, the authors compared the two drugs in patients with acute coronary syndromes patients who were planned to undergo invasive procedures (such as angioplasty and stenting of the coronary artery).

At the beginning of the study, an invasive strategy was planned for 13 408 (72·0%) of 18 624 patients hospitalised for acute coronary syndromes. Patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300–600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6–12 months. All patients were given aspirin. The primary endpoint was any of cardiovascular death, myocardial infarction, or stroke.

Patients in the ticagrelor group were 16% less likely to experience the primary endpoint than those in the clopidogrel group. The endpoint of cardiovascular death, heart attack, or stroke occurred in fewer patients in the ticagrelor group than in the clopidogrel group (event rate at 360 days 9.0% vs 10.7%). The risk of death was also significantly reduced from 5.0% (clopidogrel) to 3.9% (ticagrelor), a reduction in the risk of dying over one year of around one fifth. Blood clots developing inside heart stents were also significantly reduced. On the other hand, there was no statistically significant difference between clopidogrel and ticagrelor groups between clopidogrel and ticagrelor groups in the rates of total major bleeding (12% each group), or severe bleeding (3% both groups).

The authors say: “Patients given ticagrelor had significant and clinically relevant reductions in cardiovascular and total deaths, myocardial infarction, and stent thrombosis, without an increase in risk of major bleeding. The benefits with respect to clinical events and stent thrombosis were consistent whether or not patients were given standard or higher loading doses of clopidogrel, as advocated for patients undergoing invasive strategies.Thereby, ticagrelor has important advantages, and improves the early invasive and long-term management of patients with acute coronary syndromes.”

They conclude: “We estimate that use of ticagrelor instead of clopidogrel for 1 year in 1000 patients with acute coronary syndromes and who are planned to undergo an invasive strategy at the start of drug treatment would lead to 11 fewer deaths, 13 fewer myocardial infarctions, and six fewer cases of stent thrombosis without an increase in the rates of major bleeding or transfusion.”

In an accompanying Comment, Dr Gregg W Stone, Columbia University Medical Center, Cardiovascular Research Foundation, New York, USA, says: “These compelling results support ticagrelor as a new standard of care in acute coronary syndromes. However, a personalised approach to drug selection should be used wherein each patient’s individualised risk of ischaemia versus bleeding is considered. Clopidogrel might still be appropriate for selected patients who are at relatively low risk of myocardial infarction or stent thrombosis and/or high risk of major bleeding, and/or for whom non-compliance with ticagrelor because of cost or other considerations (eg, twice daily dosing) is a concern. Nonetheless, the introduction of ticagrelor, a more potent and effective agent which is as safe as its predecessor, is a landmark event that should redefine the care of patients with acute coronary syndromes.”

For Dr Christopher P Cannon, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA, please contact Kevin Myron, Media Relations T) +1 617 534 1605 E) cpcannon@partners.org / kmyron@partners.org

Dr Gregg W Stone, Columbia University Medical Center, Cardiovascular Research Foundation, New York, USA. T) +1 212-851-9304 E) gstone@crf.org

For full Article and Comment, see: http://press.thelancet.com/ticagrelor.pdf

Note to editors: * PLATO: PLATelet inhibition and patient Outcomes

**a quote direct from Dr Cannon which cannot be found in the text of the Article