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2 December 2009
Ticagrelor plus aspirin was significantly more effective than clopidogrel plus aspirin in preventing vascular events in patients with acute coronary syndrome in the PLATO trial (NNT=53). There was no significant difference in the rates of major bleeding between the two groups, although more patients taking ticagrelor withdrew from the study, mainly due to adverse effects. Patients taking ticagrelor were significantly more likely to suffer from non-procedure related bleeding (NNH=143) and breathlessness than those taking clopidogrel.
Level of evidence:
Level 1 (good quality, patient-orientated evidence) according to the SORT criteria
Action
Patients with ACS require careful risk assessment, whichever dual antiplatelet regimen is being considered. It is important to balance the benefits of treatment (i.e. reduced risk of CV events) against any adverse effects (e.g. increased risk of bleeding).
Ticagrelor’s place in therapy is unclear at present. This study suggests that ticagrelor plus aspirin may reduce the risk of CV events compared with clopidogrel plus aspirin, and its rapid reversibility may give it advantages for acute treatment of patients who require surgery. However the greater risk of non-procedural major bleeding and other treatment-related side-effects (dyspnoea, bradyarrhythmia, increased serum levels of uric acid and creatinine) compared with clopidogrel, raise questions about its safety, particularly over the longer term. As yet there is no direct clinical evidence for any advantage/disadvantage compared with prasugrel▼.
As the effects of ticagrelor reverse rapidly, compliance may be particularly important for effective treatment, and patients may need additional counselling and surveillance in this respect.
AstraZeneca is hoping to file ticagrelor with the regulatory authorities in the fourth quarter of 2009. If ticagrelor is granted a marketing authorisation, local decision makers will need to agree a protocol for its use.
What is the background to this?
Dual antiplatelet therapy is commonly used in patients with acute coronary syndromes (ACS). Clopidogrel in combination with aspirin is licensed, and recommended by NICE for, non-ST-segment elevation ACS. Clopidogrel is also licensed for patients with ST-segment-elevation ACS, in combination with aspirin, in medically treated patients eligible for thrombolytic therapy.
Prasugrel is licensed for patients with both non-ST and ST-segment-elevated ACS who are undergoing primary or delayed percutaneous coronary intervention (PCI). The current NICE FAD recommends prasugrel only when immediate primary PCI is necessary or when stent thrombosis has occurred with clopidogrel or for patients with diabetes mellitus.
Both clopidogrel and prasugrel, are irreversible inhibitors of adenosine diphosphate receptor P2Y12 on platelets. Unlike clopidogrel and prasugrel, ticagrelor does not require metabolic activation, and its effects are more rapidly reversible. As pointed out in the accompanying Editorial, this provides potential advantages for ticagrelor where a patient with ACS needs non-deferrable surgery, such as urgent CABG. The PLATO study compared the effects of ticagrelor and clopidogrel, both in combination with aspirin, on CV events in patients admitted to hospital with an ACS.
What does this study claim?
In patients who have had an ACS, with or without ST-segment elevation, treatment with ticagrelor plus aspirin significantly reduced the risk of death from vascular causes, myocardial infarction [MI] or stroke (primary composite outcome) compared with clopidogrel plus aspirin. The primary composite outcome occurred in 9.8% of the ticagrelor patients and 11.7% of those on clopidogrel at 12 months (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.77 to 0.92, P<0.001. This gives an absolute risk reduction of 1.9% and a number needed to treat (NNT) of 53 over 12 months. The rate of death from any cause was also reduced by ticagrelor (4.5% vs. 5.9%, P<0.001; NNT 72).
No significant difference in major bleeding (the primary safety variable) was found between groups (ticagrelor 11.6%, clopidogrel 11.2%, P=0.43). However, ticagrelor was associated with a significantly increased risk of major bleeding not related to CABG (4.5% vs. 3.8%, P=0.03; number needed to harm [NNH] 143).
Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (7.4% vs. 6.0%, P<0.001; NNH 72)
How does this relate to other studies?
In 2004, NICE recommended use of clopidogrel in combination with low-dose aspirin for up to 12 months in the management of non-ST-segment-elevation ACS in people who are at moderate to high risk of MI or death. This recommendation was largely based on the results of the CURE study, which demonstrated a significant reduction in the incidence of death from CV causes, non-fatal MI or stroke with clopidogrel plus aspirin compared with aspirin alone. The number of patients who would need to be treated (NNT) with clopidogrel in combination with aspirin to prevent one additional CV death, non-fatal MI or stroke was 48. However, there was a significantly increased risk of major bleeding (NNH 100).
Key clinical evidence for prasugrel in ACS comes from the TRITON-TIMI 38 study. This demonstrated improved efficacy for prasugrel over clopidogrel, both given with aspirin, in reducing CV death or non-fatal MI or stroke (NNT 46), but there was an increased risk of major bleeds (NNH 125).
A NICE technology appraisal on ticagrelor is anticipated in May 2011 and a clinical guideline on the management of patients with ACS is due in February 2010. Further information on the management of ACS can be found on the Antiplatelets section of NPC.
So what?
The place in therapy for ticagrelor is currently unclear. The study suggests a possible advantage of ticagrelor over clopidogrel when used with aspirin in the treatment of patients with ACS. However, any benefit in the reduction of CV events has to be balanced against the increased risk of adverse effects. Although the reduced risk of CV deaths compared with clopidogrel without any apparent increased risk of major bleeding (overall) is encouraging for ticagralor, the increased risk of non-CABG-related bleeding and other treatment-related adverse effects, raises concerns about it safety and may limit its use, especially over the long-term. At present there is no clinical evidence with which to directly compare the benefits and risks of ticagrelor with those of prasugrel.
As the Editorial points out, it is possible that by considering the advantages and disadvantages of each antiplatelet agent, it may be possible to individualise treatment for patients with ACS. However, further trials, including a direct comparison with prasugrel would be useful for guiding ticagrelor’s place in therapy.
There are a number of other limitations to the PLATO study, which also need to be considered when interpreting the results of this study:
- Not all patients received the same duration of treatment, with some patients discontinuing treatment at six or nine months, if the pre-specified number of events had been reached.
- The loading dose of clopidogrel was different among patients, depending on whether or not they had already received open-label clopidogrel.
Although the rapid reversibility of ticagrelor may give advantages in some clinical situations (e.g. prior to CABG), it also means that compliance with treatment may be more of an issue in its efficacy compared with clopidogrel or prasugrel. Ticagrelor requires twice-daily dosing.
Design: Randomised, multicentre, double-blind, phase III trial.
Patients: 18,624 patients hospitalised because of ACS with (38%) or without (43%) ST-segment elevation (17% unstable angina). Patients were eligible if onset of symptoms had been within the previous 24 hours. Patients had a median age of 62 years.
Intervention and comparison: Ticagrelor or clopidogrel were given in a double-dummy fashion to maintain blinding. Ticagrelor patients (n=9,333) received 180mg loading dose followed by 90mg twice a day. In the clopidogrel group (n=9,291), patients who had not received an open-label loading dose and had not been taking clopidogrel for at least 5 days before randomisation received 300mg as a loading dose then 75mg thereafter. Otherwise patients in this group received 75mg daily. All patients received aspirin 75–100mg daily, unless intolerant.
Outcomes and results: The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months, 9.8% of ticagrelor patients and 11.7% of those receiving clopidogrel had a primary outcome (HR 0.84; 95% CI 0.77 to 0.92; P<0.001).
The rate of death from any cause was reduced in the ticagrelor group (4.5% vs. 5.9%; HR 0.78 (95% CI 0.69 to 0.89, P<0.001). Although statistically significant fewer MIs were identified in the ticagrelor group (5.8% vs. 6.9%; HR 0.84 (95%CI 0.75 to 0.95, P=0.005), the rate of stroke did not differ significantly between the two treatment groups. Definite stent thrombosis was seen in 1.3% of the ticagrelor patients and 1.9% of those on clopidogrel (HR 0.67, 95% CI 0.50 to 0.91, P=0.009).
No significant difference in major bleeding (the primary safety variable) was found between groups (ticagrelor 11.6%, clopidogrel 11.2%; HR 1.04 (95%CI 0.95 to 1.13, P=0.43). Ticagrelor was associated with an increased risk of major bleeding not related to CABG (4.5% vs. 3.8%; HR 1.19 (95%CI 1.02 to 1.38, P=0.03).
23.4% and 21.5% of ticagrelor and clopidogrel patients, respectively, stopped treatment early (P=0.002). 7.4% and 6.0% stopped due to adverse events (P<0.001).
Dyspnoea was reported by 13.8% of ticagrelor patients compared to 7.8% of clopidogrel patients (P<0.001). In most cases the dyspnoea lasted less than one week. Discontinuation because of dyspnoea occurred in 0.9% of patients in the ticagrelor group. Greater increases in both serum uric acid and creatinine from baseline were seen in the ticagrelor group than in the clopidogrel group at both one and 12 months (all P<0.001). Holter monitor detected more ventricular pauses (greater than or equal to 3 sec) during the first week in the ticagrelor group than in the clopidogrel group (P=0.01), but not at day 30 of treatment.
Sponsorship: AstraZeneca
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This Rapid Review is an amended version of the original which was posted on 6 October 2009. It incorporates further details supplied by the sponsoring company of trial design and limited amendments to the results presented. In particular, allocation concealment was not reported in the paper. Main results and key messages are unchanged from the original review.
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