NPC Archive Item: Pre-planned analysis of PLATO study of aspirin plus ticagrelor or clopidogrel in patients undergoing early invasive intervention for ACS

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18 August 2010

Early invasive intervention for acute coronary syndrome was planned for 13,408 patients in this pre-specified analysis of the PLATO study (total n=18,624). After 12 months, ticagrelor plus aspirin was more effective than clopidogrel plus aspirin for the primary composite endpoint of death from vascular causes, myocardial infarction (excluding silent MI), or stroke (NNT=59). There was no significant difference in the rates of PLATO-defined total major bleeding, fatal or life threatening bleeding or other major bleeding between the two groups. However, while there was no significant difference in non-CABG-related major bleeding, the non-CABG-related major or minor bleeding events were more commonly seen in ticagrelor patients (NNH=56).

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

The place of ticagrelor in therapy is unclear at present. This analysis suggests that ticagrelor plus aspirin may reduce the risk of CV events compared with clopidogrel plus aspirin when early invasive intervention is necessary, and its rapid reversibility may give it advantages for acute treatment of patients who require surgery. As we mentioned in the blog of the full PLATO study, ticagrelor patients were at 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, which raises questions about its safety, particularly over the longer term. As yet there is no direct clinical evidence for any advantage/disadvantage compared with prasugrel.

Patients with acute coronary syndrome (ACS) require careful risk assessment, whichever 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). As the effects of ticagrelor are reversible, compliance may be particularly important for effective treatment, and patients may need additional counselling and surveillance in this respect.

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 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 acute myocardial infarction, in combination with aspirin, in medically treated patients eligible for thrombolytic therapy.

Prasugrel, co-administered with aspirin, is licensed for patients with both ACS and ST-segment-elevation myocardial infarction who are undergoing primary or delayed percutaneous coronary intervention (PCI). NICE guidance recommends prasugrel, as an option, 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 to the PLATO trial this provides potential advantages for ticagrelor where a patient with ACS needs non-deferrable surgery, such as urgent coronary artery bypass graft (CABG).

What does this study claim?
The PLATO study compared the effects of ticagrelor and clopidogrel, both in combination with aspirin, on CV events in patients admitted to hospital with ACS. The analysis reported here was pre-planned and included those patients for whom an early invasive strategy (coronary angiography followed by revascularisation) was required.

At 12 months, the primary composite endpoint of death from vascular causes, myocardial infarction (MI), or stroke was seen in 9.0% of ticagrelor patients and 10.7% of clopidogrel patients: hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75 to 0.94, P=0.0025. Therefore, if 1,000 patients like those in the trial are treated with ticagrelor rather than clopidogrel then 17 of them will be prevented from having a primary composite outcome after 12 months i.e. a number needed to treat (NNT) of 59 over 12 months.

This composite endpoint was driven by reductions in MI and CV death, but there was no difference in the risk of stroke: 1.2% vs. 1.1% (HR 1.08, 95%CI 0.78 to 1.50, P=0.6460). There was also a significant reduction in all-cause mortality (a secondary endpoint) for ticagrelor compared to clopidogrel at 12 months: 3.9% vs. 5.0%, (HR 0.81, 95% CI 0.68 to 0.95, P=0.0103), NNT =91.

There was no difference in the risk of PLATO-defined total major bleeding (11.5% vs. 11.6%, P=0.8803), fatal or life threatening bleeding (6.0% vs. 5.9%, P=0.6095) or other major bleeding (5.9% vs. 6.2%, P=0.4030) between ticagrelor compared to clopidogrel, respectively. However, while there was no significant difference in non-CABG-related major bleeding (4.7% vs. 4.0%, P=0.1040), the non-CABG-related major or minor bleeding events were more commonly seen in ticagrelor patients (8.9% vs. 7.1%, HR 1.26 95%CI 1.11 to 1.43, P=0.0004) giving a number need to harm (NNH) of 56 over 12months.

How does this relate to other studies?
NICE recommends the use of clopidogrel in combination with low-dose aspirin for 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 NNT for clopidogrel in combination with aspirin to prevent one additional CV death, non-fatal MI or stroke was 48 over 9 months. However, there was a significantly increased risk of CURE-defined major bleeding (NNH 100 over 9 months).

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 45), but there was an increased risk for the key safety end point of TIMI-defined non-CABG-related major bleeds (NNH 167).

The Summary of Product Characteristics for clopidogrel recommends that if a patient needs elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be stopped seven days before surgery. In CURE, there was no excess in CURE-defined major bleeds with clopidogrel and aspirin within seven days after CABG surgery in patients who stopped therapy more than five days before surgery.

A NICE clinical guideline on the management of patients with unstable angina and non-ST-segment-elevation MI was published in March 2010 and a NICE appraisal is planned for ticagrelor with the Appraisal Consultation Document anticipated in March 2011. Further information on the management of ACS can be found on the antiplatelets section of NPC.

So what?
The place in therapy of 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 who require early invasive intervention. 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 ticagrelor, 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 accompanying this paper 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 potential limitations to the PLATO study, which also need to be considered when interpreting the results of this analysis:

  • Not all patients received the same duration of treatment, with some patients receiving treatment for six or nine months, as the pre-specified number of events had been reached. Length of treatment was well balanced in both arms.
  • The loading dose of clopidogrel was different among patients, depending on whether or not they had already received open-label clopidogrel. .

Although the 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 to its efficacy compared with clopidogrel or prasugrel. Ticagrelor requires twice-daily dosing.

Study details
Cannon CP, Harrington RA, James S et al for the PLATelet inhibition and patient Outcomes (PLATO) investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375:283-93

Design: PLATO was a randomised, double-blind, double-dummy trial with concealed allocation.

Patients: High-risk patients hospitalised for ACS, with or without ST-segment-elevation, were included. Early invasive management had to be indicated by the investigator before patients were randomly assigned to treatment. Of the 18,624 patients recruited into PLATO, an invasive strategy was planned for 13,408 (72%). These patients (mean age 61 years) were the subject of this pre-planned analysis.

Intervention and comparison: A 180mg loading dose of ticagrelor was followed by 90mg taken twice a day (n=6,732). Clopidogrel was administered as a 300mg loading dose followed by 75mg daily (n=6,676). Placebo tablets were given to maintain blinding. 98% of patients took aspirin daily. Patients were treated with ticagrelor for a median of 277 days and clopidogrel for 279 days.

Outcomes and results: The primary composite endpoint was death from vascular causes, MI, or stroke. At 12 months, this was seen in 9.0% of ticagrelor patients and 10.7% of clopidogrel patients, HR 0.84 (95%CI 0.75 to 0.94), P=0.0025.

In the secondary outcomes, CV death was reduced by ticagrelor: 3.4% vs. 4.3%, HR 0.82, 95%CI 0.68 to 0.98, P=0.0250); the incidence of myocardial infarction was less with ticagrelor (5.3%) as compared to 6.6% in clopidogrel patients (HR 0.80, 95%CI 0.69 to 0.92, P=0.0023; but there was no difference in the risk of stroke (1.2% vs. 1.1% respectively, HR 1.08, 95%CI 0.78 to 1.50, P=0.6460). In addition, patients treated with ticagrelor were at lower risk of definite stent thrombosis: 1.3% vs. 2.0% with clopidogrel, HR 0.64 (95%CI 0.46 to 0.88), P=0.0054.

The main safety outcome was PLATO-defined total major bleeding. This was not different between the groups: seen in 11.5% of ticagrelor and 11.6% of clopidogrel patients (HR 0.99, 95%CI 0.89 to 1.10, P=0.8803).

21.8% of clopidogrel patients and 23.1% of ticagrelor patients stopped the study drug early. 29.4% of all patients in this analysis withdrew due to an adverse effect, but there was no great difference between the two groups in withdrawal rate for that reason.

Dyspnoea was more common in ticagrelor patients: 13.9% vs. 8.0% (P<0.0001). However, only 0.8% of ticagrelor, and 0.2% of clopidogrel, patients stopped therapy due to this adverse reaction.

Sponsorship: AstraZeneca

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