CardioBrief

Updated with links to slides–Ticagrelor (Brillanta, AstraZeneca) appears to offer improved antiplatelet efficacy without excess bleeding, according to the results of PLATO, which were presented this morning at the ESC and published simultaneously in the New England Journal of Medicine.

Ticagrelor is an oral, reversible drug  with a stronger antiplatelet effect than clopidogrel and a more rapid onset of action. PLATO compared ticagrelor (180 mg loading dose followed by 90 mg twice daily) to clopdigrel (300-600 mg loading dose following by 75 mg daily) in 18,624 ACS patients. At one year, the primary endpoint, which was a composite of death from vascular causes, MI, or stroke, was reached in 9.8% of ticagrelor patients versus 11.7% of clopidogrel patients [CI 0.77-0.92, p<0.001].

Secondary endpoints were also lower in the ticagrelor group than in the clopidogrel group, including death from any cause (4.5% vs 5.9%, p<0.001) and MI (5.8% vs 6.9%, P= 0.005). The primary endpoint was also lower in the subgroup of patients for whom invasive therapy was planned. In addition, the rate of stent thrombosis was lower in patients who received a stent.

There were no significant differences in major bleeding or fatal or life-threatening bleeding, although there was an excess of non-CABG-related major bleeding in the ticagrelor group. There were also more intracranial bleeds (26 vs 14, p=0.06) and fatal intracranial bleeds (11 vs 1, p=0.02) in the ticagrelor group as well as higher rates of dyspnea and ventricular pauses on Holter monitoring in the ticagrelor group.

The investigators speculated that “the improved survival rate with ticagrelor might be due to the decrease in the risk of thrombotic events without a concomitant increase in the risk of major bleeding” seen with clopidogrel and prasugrel.

In an accompanying editorial in the NEJM, Albert Schömig makes a similar speculation, writing that “ticagrelor may reduce the mortality rate by reducing the risk of death from ischemia without increasing the risk of death from bleeding.”

Schömig also proposes that the availability of clopidogrel, prasugrel, and ticagrelor “may make it possible to individualize antiplatelet therapy.” Ticagrelor, he writes, “may be preferred in patients whose coronary anatomy is unknown and for whom a CABG procedure is deemed probable.”

Sanjay Kaul provided the following commentary to CardioBrief:

Overall, the results of the PLATO trial demonstrate a favorable benefit-risk for ticragelor with a significant 16 percent relative risk reduction in the primary efficacy endpoint and a nonsignificant 4 percent increase in the risk of major bleeding compared with clopidogrel. The reduced bleeding risk was primarily related to lack of CABG-related bleeding reflecting the advantage of a short-acting reversible P2Y inhibitor. However, non-CABG TIMI major bleeding, the primary safety endpoint in TRITON trial which evaluated prasugrel vs. clopidogrel, was significantly increased to a similar degree as with prasugrel (25 percent vs. 32 percent increase with prasugrel). This coupled with the fact that ticragelor produced an equivalent reduction in the combined endpoint of all-cause death, nonfatal MI or nonfatal stroke as prasugrel compared with clopidogrel (16 vs. 17 percent relative risk reduction) suggests that ticragelor might offer an advantage only in patients with unknown coronary anatomy who are likely to undergo CABG–a relative minority of patients with ACS. The adverse effects of dyspnea, bradycardia/ventricular pause, and increase in serum uric acid and creatinine are worrisome enough to consider restricting its use in patients without these conditions. Moreover, its short half life and rapidly reversible effect places the patients, especially those with DES, vulnerable to adverse consequences of noncompliance, thereby requiring careful monitoring. Finally, whether ticragelor would be superior to optimal clopidogrel treatment that utilizes a higher loading dose and minimizes the use of PPI (which might potentially attenuate the effectiveness of clopidogrel) remains to be seen.

(As CardioBrief reported previously, in May AstraZeneca announced preliminary results of the PLATO trial.)

Click here to download the slides of the PLATO presentation.

Click here to download the slides of the PLATO discussant, Steen Kristensen.

Here is the press release issued by the ESC:

NEW ORAL ANTIPLATELET AGENT TICAGRELOR FIRST TO SHOW REDUCTION IN CARDIOVASCULAR DEATH OVER PLAVIX IN ACUTE CORONARY SYNDROME

Barcelona, Spain, 30 August: The presentation of the PLATO (A Study of Platelet Inhibition and Patient Outcomes), showed that ticagrelor (Brilinta®) reduced the rate of cardiovascular (CV) events (CV death, myocardial infarction or stroke) from 11.7% to 9.8% compared clopidogrel (Plavix®) XX% (p<0.001, RRR = 16%), without an increase in major bleeding. This efficacy endpoint was driven by a statistically significant reduction in both CV death and myocardial infarction (MI) with no difference in stroke. Ticagrelor is the first antiplatelet agent to demonstrate a reduction in CV death across all major acute coronary syndromes (ACS) patient types.

For every 1,000 patients admitted to the hospital because of an ACS event, use of ticagrelor instead of clopidogrel, for up to one year, led to 14 fewer deaths, or 11 fewer MI’s, or 8 fewer cases of stent thrombosis, without an increase in major bleeds. In the PLATO study, the reduction in risk of cardiovascular events appears early and the benefit over clopidogrel grows with time. Ticagrelor demonstrated a consistent benefit
across multiple secondary efficacy endpoints including CV death and total mortality; myocardial infarction; the composite of myocardial infarction, stroke, and total mortality; and a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, recurrent cardiac ischemia, severe recurrent cardiac ischemia, and other arterial thrombotic events.

“Ticagrelor is the first antiplatelet therapy to achieve a significant reduction in CV mortality in ACS patients versus clopidogrel and perhaps most importantly without an increase in major bleeding,” commented Professor Lars Wallentin, co-chair of the PLATO Executive Committee. “PLATO has redefined what is possible in the prevention of recurrent events in patients with acute coronary syndromes.”

The PLATO study confirmed the clinical safety profile of previous ticagrelor studies by showing an efficacy advantage without an increase in major bleeding. Across all the important patient subgroups (e.g. gender, weight, history of stroke/TIA) in PLATO, ticagrelor showed no difference versus clopidogrel in the incidence of major bleeding. When minor bleeding was added, ticagelor showed a small increase in PLATO defined major plus minor bleeding versus clopidogrel. At continuous ECG monitoring wile in hospital, but not at later follow-up in the outpatient setting, pauses in the heart rhythm were seen more frequent with ticagrelor. However such pauses were not associated with any symptoms or clinical consequences for the patient. Transient symptoms of dyspnoea were reported more often by patients on ticarelor but only one in 100 ticagrelor treated patients overall stopped taking study medication due to dyspnoea.

PLATO was a head-to-head outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel plus aspirin, and was designed to establish whether ticagrelor could achieve meaningful cardiovascular endpoints in ACS patients. 18,624 patients at 893 sites in 43 countries across all continents were sucessfully recruited. All patients were admitted to hospital because of acute coronary syndrome, one third with ST-elevation myocardial infarction and two thrirds without ST-elevation. Shortly after admission to hospital, the patients started their long-term anti-platelet treatment with either ticagrelor (90 mg twice daily) or clopidogrel (75 mg daily) in a randomized, double-blind fashion for 6 – 12 months. The PLATO study was led by the Executive Committee co-chairs, Professor Lars Wallentin, Sweden (Uppsala Clinical Research Center) and Professor Robert Harrington, USA (Duke Clinical Research Institute).

The PLATO study was sponsored by AstraZeneca which has developed and manufactures ticagrelor (Brilinta®). AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services.

- Ends –

Click here to read the AstraZeneca press release on PLATO.

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