PLATO Shows Benefits of Ticagrelor Over Clopidogrel

August 30, 2009

(Updated August 30, 2009) (Barcelona, Spain) — Treatment of patients with acute coronary syndrome (ACS) with the investigational oral antiplatelet agent ticagrelor (AstraZeneca) has significantly reduced the rate of MI/stroke/cardiovascular death compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in the phase 3 Platelet Inhibition and Patient Outcomes (PLATO) study, reported here at the European Society of Cardiology 2009 Congress during a hotline session and published online simultaneously in the New England Journal of Medicine [1].

The preliminary results of PLATO were first released by AstraZeneca in May, as reported by heartwire .

Unlike clopidogrel and another newer antiplatelet agent, prasugrel (Effient, Lilly/Daiichi), which has just been approved, ticagrelor is not a thienopyridine, and its mechanism of action is unique in that it is reversible, although it does have the drawback of twice-daily dosing. There was no increase in the rate of overall major bleeding with ticagrelor as compared with clopidogrel in PLATO, said the lead investigator Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), who presented the findings here. Excess bleeding with prasugrel compared with clopidogrel is one of its drawbacks.

Wallentin told heartwire : "The reduction in total mortality [with ticagrelor] was the most striking result. We saved 14 lives per 1000 treated patients, and this has not been seen over the past 20 years with a new antiplatelet agent. So I think the combination of a reduction in mortality and ischemic events, without a cost in bleeding, is very impressive." In PLATO, the rates of death from any cause were 4.5% with ticagrelor and 5.9% with clopidogrel (p<0.001), with a significant relative risk reduction (22%).

Other experts polled by heartwire were similarly upbeat about the PLATO results. American College of Cardiology president Dr Doug Weaver (Henry Ford Health System, Detroit, MI), said: "I think it's the best result we've seen since aspirin, which was the last time we saw an antiplatelet drug with a mortality benefit. It could not have come out better. I really do think it's going to surpass clopidogrel and pass prasugrel--it looks safer than prasugrel. In my own personal opinion, clopidogrel is too expensive for what you get. This is much, much better." Weaver said he would "absolutely" use ticagrelor if it becomes available.

I think it's the best result we've seen since aspirin. It could not have come out better. It's going to surpass clopidogrel and pass prasugrel.

"I thought the results were very compelling," Dr Marc Sabatine (Brigham and Women's Hospital, Boston, MA) commented. "To be able to see a reduction in CV mortality and all-cause mortality is extremely rare in cardiovascular trials." And Dr Shamir R Mehta (McMaster University, Hamilton, ON) said: "The overall results are clearly impressive, and I think it's going to have a major impact."

But in an editorial accompanying the publication of the PLATO results [2], Dr Albert Schömig (Deutsches Herzzentrum, Munich, Germany) says the reduction in death seen with ticagrelor in PLATO "may simply reflect the play of chance, because [PLATO] was not powered to detect differences in the mortality rate."

There was also debate about varying aspects of the PLATO trial, such as bleeding, side effects, and whether the reversible nature of ticagrelor may actually be a disadvantage in some circumstances. But discussant of the hotline session, Dr Steen D Kristensen (Aarhus University Hospital, Aarhus, Denmark), concluded that, overall, ticagrelor is "a promising drug, with better efficacy than clopidogrel."

Benefits of Ticagrelor Seen Without Increase in Bleeding

In PLATO, 18 624 patients admitted to the hospital with ACS in 43 countries around the world, with or without ST-segment elevation, were randomized to receive either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) in a double-blind, double-dummy fashion for one year, although patients left the study at their six- or nine-month visit if the targeted number of 1780 primary end points had occurred by that time. Patients also received aspirin, at a dose of 75 mg to 100 mg day, unless they could not tolerate the drug.

At 12 months, the primary end point--a composite of death from vascular causes, MI, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those taking clopidogrel (hazard ratio 0.84; p<0.001). Predefined secondary end points were also significantly reduced with ticagrelor as compared with clopidogrel, such as MI and death from vascular causes. But there was no significant difference in the risk of stroke between the two groups.

Wallentin also stressed that the benefits of ticagrelor seen over and above those of clopidogrel "were continuous over time" and that for every 1000 patients admitted to the hospital because of ACS, use of ticagrelor instead of clopidogrel for up to one year led to 14 fewer deaths, 11 fewer MIs, or eight fewer cases of stent thrombosis, without an increase in major bleeds.

Major Efficacy End Points at 12 Monthsa

End point Ticagrelor (%) Clopidogrel (%) Hazard ratio for ticagrelor pb
Primary end point: death from vascular causes, MI, or stroke 9.8 11.7 0.84 <0.001
Secondary end points        
Death from any cause, MI, or stroke 10.2 12.3 0.84 <0.001
Death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event 14.6 16.7 0.88 <0.001
MI 5.8 6.9 0.84 0.005
Death from vascular causes 4.0 5.1 0.79 0.001
Stroke 1.5 1.3 1.17 0.22
--Ischemic 1.1 1.1   0.74
--Hemorrhagic 0.2 0.1   0.10
--Unknown 0.1 0.02   0.04
a. The percentages are Kaplan-Meier estimates of the rate of the end point at 12 months. Patients could have had more than one type of end point. Death from vascular causes included fatal bleeding. Only traumatic fatal bleeding was excluded from the category of death from vascular causes.

b. p values were calculated by means of Cox regression analysis.

He added that the superiority of ticagrelor over clopidogrel with regard to the primary end point as well as the similarity in rates of major bleeding were "consistent in 62 of 66 subgroups."

Bleeding Discussions

In his discussion following Wallentin's presentation, Kristensen said the study investigators came up with a new bleeding definition for this trial-–the "PLATO bleeding definition." While he said that there would be questions as to whether another bleeding definition was required, he acknowledged this one "was as good as or even better than any others" and that the investigators also supplied TIMI bleeding definitions for comparison.

No significant difference in the rates of major bleeding were found between the two agents (11.6% and 11.2% respectively; p=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to CABG than clopidogrel (4.5% vs 3.8%; p=0.03) by the PLATO definition of bleeding, including more instances of fatal intracranial bleeding, but fewer of fatal bleeding of other types.

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) pointed out to heartwire this higher rate of major bleeding not related to CABG, which was increased by 25% with ticagrelor compared with clopidogrel in PLATO (HR 1.25; p=0.03 using TIMI bleeding definition), is similar to the 32% increase in the same end point seen with prasugrel compared with clopidogrel in TRITON-TIMI 38.

Mehta raised the same issue: "It's reassuring that overall bleeding was not increased, but there was an increase in non-procedure–related bleeding." He also wondered why a reversible agent like ticagrelor did not actually lower bleeding in CABG surgery (bleeding in CABG patients was similar between the two agents in PLATO). But Wallentin said: "One way of looking at it is that patients [on ticagrelor] tolerated a more intense platelet inhibition without an increase in bleeding."

Mehta also mentioned the "slight imbalance in intracranial hemorrhage [ICH] between the two groups, something that would need to be discussed further, but it's reassuring that overall bleeding was not increased." Wallentin said that one patient in a 1000 [taking ticagrelor] had ICH, "and this led to fatalities, but overall the number of fatal bleeds was not different between the two arms--there were other fatal bleeds that were concerning in the clopidogrel group. In comparison with, for example, fibrinolytic treatment with tPA--where you have one patient per 100 with ICH--this is one in 1000, and you still have no overall difference in fatal bleeds."

Kristensen said one of the challenges for ticagrelor will be whether there will be more bleeding "in the real world" and also whether compliance will be an issue, given the twice-daily dosing regimen required: "Compliance is the backside of the coin for a reversible inhibitor," he noted.

Kaul said that although the "rapid and reversible inhibition" of ticagrelor might be an advantage in patients requiring CABG or other procedures, "it could potentially put patients, especially those with [drug-eluting stents] DES, at risk for thrombotic events in case of noncompliance."

Are the Side Effects of Concern?

There was a much higher incidence of dyspnea with ticagrelor as compared with clopidogrel in PLATO (14.2% of patients vs 9.2%; p<0.001), something that had been observed in earlier phase 2 trials with the investigational agent. But the PLATO investigators say that "most episodes lasted less than a week, [and] discontinuation of the study drug because of dyspnea occurred in 0.9% of patients in the ticagrelor group." In terms of other side effects, Holter monitoring did detect more frequent ventricular pauses during the first week in the ticagrelor group than in the clopidogrel group, but such episodes were infrequent at 30 days and were rarely associated with symptoms, they note. "There were no significant differences in the rates of clinical manifestations of bradyarrhythmia between the two treatment groups."

Schömig says in his editorial that dyspnea "may have a negative effect on quality of life," but others questioned by heartwire appeared less concerned. Weaver said: "The side-effect profile is great--yes, people will notice dyspnea, but it didn't limit people taking it in the trial, it's short-lived most of the time." Wallentin stressed that dyspnea "will have to be explained to patients, so they understand it is not related to disease. If patients know that this is transient, they will tolerate it more. Still, one patient in a 100 needs to switch to something else, but that's not uncommon for any treatment."

Schömig says: "The whole story concerning the adverse effects of ticagrelor may require evaluation in a much larger number of patients, something that may be beyond the capacity of a randomized trial. We should carefully monitor patients receiving this drug to establish the overall impact of its side effects."

Ticagrelor a Potential Blockbuster, But Caution in Patient Selection Needed

As a potential competitor in the antiplatelet field, ticagrelor is a prospective blockbuster drug: last year, clopidogrel was the second-biggest-selling drug in the world, with global revenues of more than $8 billion. However, generic versions of clopidogrel are already available in Europe and are expected to appear in the US within a few years, which will make competition much harder. But there are a number of patients who do not respond to clopidogrel, and these people likely represent the initial market for those trying to promote newer antiplatelet drugs, such as prasugrel and ticagrelor, should it be approved.

When it first announced that the PLATO data were positive earlier this year, AstraZeneca said it would submit the drug for approval in the fourth quarter of this year.

Schömig says the potential availability of three agents for antagonizing platelet ADP receptors "may make it possible to individualize antiplatelet therapy."

In particular, ticagrelor "may be preferred in patients whose coronary anatomy is unknown and for whom a CABG procedure is deemed probable." And if patients who are receiving clopidogrel or prasugrel need elective surgery, it would seem reasonable to switch them to ticagrelor five to seven days before surgery, Schömig says. Kristensen concurs, stating that ticagrelor would be "easier to manage in patients who are undergoing operations." Kaul agrees: "I see ticagrelor as the antiplatelet agent of choice in situations where surgical procedures cannot be deferred, because of its reversible platelet inhibition."

But like prasugrel, the use of ticagrelor should probably be avoided in those with a history of stroke or transient ischemic attack (TIA) and in those with an excessively high risk of bleeding, Schömig advises. And ticagrelor therapy should also be discouraged in those with chronic obstructive pulmonary disease, hyperuricemia, renal failure, bradyarrhythmias unprotected by pacemakers, a history of syncope, or need for treatment with antiplatelet agents for more than one year.

"For all remaining patients with ACS, either ticagrelor or prasugrel may be preferred, at least until data from studies specifically comparing these two agents become available," he concludes.

Kaul says prasugrel would be a desirable option in patients who experience recurrent events on clopidogrel and/or in patients who are unlikely to tolerate ticagrelor, while for patients at high risk of bleeding, "clopidogrel would be the treatment of choice."

Wallentin reports receiving consulting fees from Regado Biosciences and Athera Biotechnologies; lecture fees from Boehringer Ingelheim, AstraZeneca, and Eli Lilly; and grant support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough. Disclosures for the coauthors are listed in the paper. Schömig reports no conflicts of interest.