PLATO-Invasive, Including Stent Thrombosis Data for Ticagrelor
January 27, 2010 (London, United Kingdom) — Results of the PLATO-Invasive substudy--showing a significant reduction in the composite end point of cardiovascular death, myocardial infarction (MI), or stroke with ticagrelor (Brilinta, AstraZeneca) over clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis)--have now been published online in TheLancet [1].Key findings for the analysis mirror those of the overall trial [2] and those reported by heartwire when the invasive substudy was first presented at Transcatheter Cardiovascular Therapeutics (TCT) 2009. But as lead author on the analysis, Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA), emphasized to heartwire, the paper also includes new subset analysis details that may help answer some of the lingering questions about the study.
A full 72% (13 408) of the acute coronary syndrome (ACS) patients in the overall PLATO trial were deemed to be candidates for invasive management. As reported at TCT, PLATO investigators found that the primary composite end point in this subset of PLATO patients was significantly reduced in the ticagrelor group at one year (9% vs 10.7%; hazard ratio [HR] 0.84; 95% CI 0.75–0.94, p=0.0025). Total major bleeding and severe bleeding, however, were no different between the two groups. According to Cannon, a nonsignificant increase in non–coronary artery bypass graft (CABG)–related bleeding was offset by a nonsignificant decrease in CABG-related bleeding. Dyspnea was significantly more common among ticagrelor-treated patients than in clopidogrel-treated patients (13.9% vs 8%; p<0.0001); permanent discontinuations related to dyspnea ranged from 0.8% in the ticagrelor group to 0.2% in the clopidogrel group.
Details on Stent Thrombosis, Clopidogrel Loading Dose
Cannon highlighted new data in the published paper that may help resolve some of the concerns raised by commentators when PLATO was first presented. One such concern was that ticagrelor results may have been less impressive if the comparator arm had been the now-more-widely-used 600-mg loading dose of clopidogrel. Fleshing out details also reported at TCT, the paper looked specifically at the 3634 patients in the study who received a clopidogrel loading dose of 600 mg or greater; at one year, the benefits of ticagrelor-treated patients vs this higher-loading-dose subgroup were similar to those of the overall cohort.
Addressing a point also raised at TCT, the Lancet paper also provides data on stent thrombosis--a more reliable way to ascertain whether the more potent ticagrelor is actually reducing early repeat MIs, Cannon explained. "In this population, when almost everyone is having an MI early, you can't detect another MI early because you still have the first one going on, for the first day or two, with the enzymes rising. But what you can document is angiographically determined stent thrombosis."
In the PLATO-Invasive subset, rates of definite, definite or probable, and definite, probable, or possible stent thrombosis were all lower in the ticagrelor-treated patients, both within 30 days and at one year. "The [event] curves show that the benefit starts in the first day," Cannon said. While the analysis is underpowered, he acknowledged, "[Stent thrombosis is] an ascertainable event, showing that in the first few days, as you'd anticipate, the higher level of platelet inhibition is having an early effect, although obviously it continues for the whole year."
Clearing the Clouds
Cannon says the invasive data from PLATO, in particular, will help with what he calls the "dominant question that clouds everything in this field"--that is, deciding on the best antiplatelet therapy for ACS patients admitted to the emergency department.
"Should we preload with clopidogrel or not, and what if the patient needs to go for bypass surgery?" Cannon explained. "So here, if [ticagrelor] becomes available, we'll have an agent where we have the flexibility to stop it if the patient needs CABG, without incurring any bleeding risk."
Data Needed on 150-Mg Maintenance Dose and Aspirin Variations
Commenting on the results for heartwire, Dr Shamir Mehta (McMaster University, Hamilton, ON) called the analysis "impressive and consistent with the main study results published earlier in the [New England Journal of Medicine]."
He noted, however, that the data on the 300-mg vs 600-mg clopidogrel loading dose need to be considered with caution. The main benefit of double-dose clopidogrel in preventing stent thrombosis, Mehta pointed out, is likely due not only to the higher loading dose but also to the doubling of the standard maintenance regimen for the week following percutaneous coronary intervention, as tested in the CURRENT OASIS-7 trial (150 mg, instead of 75 mg). "The 150-mg maintenance dose was not tested in the PLATO trial, so we do not know whether the early benefit would have been present if ticagrelor was compared with the full double-dose regimen of clopidogrel," Mehta commented, adding, "The late benefit, beyond 30 days, is clear."
Mehta also drew attention to a point raised previously, that when stratified by geographical region, the point estimate for benefit in North American patients seems to go conspicuously in the wrong direction, favoring clopidogrel. "This interaction was nominally significant at the 0.05 level in the main study, and the trend is still present in the invasive population," he told heartwire. "While I believe this is probably due to the play of chance, other explanations, such as aspirin dose--which is generally higher in North America compared with the rest of the world--should be ruled out as a potential cause." Ongoing analyses are trying to tease out an answer to the question of geographic variation and aspirin dose.
In an accompanying editorial [3], Dr Gregg Stone (Columbia University, New York, NY) highlights the reduced all-cause mortality with ticagrelor seen in the PLATO study (4.5% vs 5.9%; 95% CI 0.69-0.89; p<0.001), a secondary end point in the trial. "It is unlikely that this 22% reduction in mortality (an absolute difference of 1.4%, or 107 deaths prevented in the entire study cohort with ACS) is due to chance in view of the tight point estimate and high statistical significance observed in a double-blind randomized trial of more than 18 000 patients," he writes. While "off-target" effects of ticagrelor that might explain this mortality benefit need to be further explored, says Stone, he postulates that PLATO helps reinforce mounting evidence that strategies that reduce bleeding events without increasing the risk of MI translate into better overall survival.
Stone advocates an "individualized" approach to patient care that might include use of already-approved agents in certain circumstances but concludes that the introduction of ticagrelor is "a landmark event that should redefine the care of patients with ACS."
AstraZeneca submitted a new drug application for ticagrelor to the US Food and Drug Administration (FDA) last November; there is no word yet from the FDA as to when it will ask its advisory panel to review the application.
January 27, 2010 (London, United Kingdom) — Results of the PLATO-Invasive substudy--showing a significant reduction in the composite end point of cardiovascular death, myocardial infarction (MI), or stroke with ticagrelor (Brilinta, AstraZeneca) over clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis)--have now been published online in TheLancet [1].Key findings for the analysis mirror those of the overall trial [2] and those reported by heartwire when the invasive substudy was first presented at Transcatheter Cardiovascular Therapeutics (TCT) 2009. But as lead author on the analysis, Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA), emphasized to heartwire, the paper also includes new subset analysis details that may help answer some of the lingering questions about the study.
A full 72% (13 408) of the acute coronary syndrome (ACS) patients in the overall PLATO trial were deemed to be candidates for invasive management. As reported at TCT, PLATO investigators found that the primary composite end point in this subset of PLATO patients was significantly reduced in the ticagrelor group at one year (9% vs 10.7%; hazard ratio [HR] 0.84; 95% CI 0.75–0.94, p=0.0025). Total major bleeding and severe bleeding, however, were no different between the two groups. According to Cannon, a nonsignificant increase in non–coronary artery bypass graft (CABG)–related bleeding was offset by a nonsignificant decrease in CABG-related bleeding. Dyspnea was significantly more common among ticagrelor-treated patients than in clopidogrel-treated patients (13.9% vs 8%; p<0.0001); permanent discontinuations related to dyspnea ranged from 0.8% in the ticagrelor group to 0.2% in the clopidogrel group.
Details on Stent Thrombosis, Clopidogrel Loading Dose
Cannon highlighted new data in the published paper that may help resolve some of the concerns raised by commentators when PLATO was first presented. One such concern was that ticagrelor results may have been less impressive if the comparator arm had been the now-more-widely-used 600-mg loading dose of clopidogrel. Fleshing out details also reported at TCT, the paper looked specifically at the 3634 patients in the study who received a clopidogrel loading dose of 600 mg or greater; at one year, the benefits of ticagrelor-treated patients vs this higher-loading-dose subgroup were similar to those of the overall cohort.
Addressing a point also raised at TCT, the Lancet paper also provides data on stent thrombosis--a more reliable way to ascertain whether the more potent ticagrelor is actually reducing early repeat MIs, Cannon explained. "In this population, when almost everyone is having an MI early, you can't detect another MI early because you still have the first one going on, for the first day or two, with the enzymes rising. But what you can document is angiographically determined stent thrombosis."
In the PLATO-Invasive subset, rates of definite, definite or probable, and definite, probable, or possible stent thrombosis were all lower in the ticagrelor-treated patients, both within 30 days and at one year. "The [event] curves show that the benefit starts in the first day," Cannon said. While the analysis is underpowered, he acknowledged, "[Stent thrombosis is] an ascertainable event, showing that in the first few days, as you'd anticipate, the higher level of platelet inhibition is having an early effect, although obviously it continues for the whole year."
Clearing the Clouds
Cannon says the invasive data from PLATO, in particular, will help with what he calls the "dominant question that clouds everything in this field"--that is, deciding on the best antiplatelet therapy for ACS patients admitted to the emergency department.
"Should we preload with clopidogrel or not, and what if the patient needs to go for bypass surgery?" Cannon explained. "So here, if [ticagrelor] becomes available, we'll have an agent where we have the flexibility to stop it if the patient needs CABG, without incurring any bleeding risk."
Data Needed on 150-Mg Maintenance Dose and Aspirin Variations
Commenting on the results for heartwire, Dr Shamir Mehta (McMaster University, Hamilton, ON) called the analysis "impressive and consistent with the main study results published earlier in the [New England Journal of Medicine]."
He noted, however, that the data on the 300-mg vs 600-mg clopidogrel loading dose need to be considered with caution. The main benefit of double-dose clopidogrel in preventing stent thrombosis, Mehta pointed out, is likely due not only to the higher loading dose but also to the doubling of the standard maintenance regimen for the week following percutaneous coronary intervention, as tested in the CURRENT OASIS-7 trial (150 mg, instead of 75 mg). "The 150-mg maintenance dose was not tested in the PLATO trial, so we do not know whether the early benefit would have been present if ticagrelor was compared with the full double-dose regimen of clopidogrel," Mehta commented, adding, "The late benefit, beyond 30 days, is clear."
Mehta also drew attention to a point raised previously, that when stratified by geographical region, the point estimate for benefit in North American patients seems to go conspicuously in the wrong direction, favoring clopidogrel. "This interaction was nominally significant at the 0.05 level in the main study, and the trend is still present in the invasive population," he told heartwire. "While I believe this is probably due to the play of chance, other explanations, such as aspirin dose--which is generally higher in North America compared with the rest of the world--should be ruled out as a potential cause." Ongoing analyses are trying to tease out an answer to the question of geographic variation and aspirin dose.
In an accompanying editorial [3], Dr Gregg Stone (Columbia University, New York, NY) highlights the reduced all-cause mortality with ticagrelor seen in the PLATO study (4.5% vs 5.9%; 95% CI 0.69-0.89; p<0.001), a secondary end point in the trial. "It is unlikely that this 22% reduction in mortality (an absolute difference of 1.4%, or 107 deaths prevented in the entire study cohort with ACS) is due to chance in view of the tight point estimate and high statistical significance observed in a double-blind randomized trial of more than 18 000 patients," he writes. While "off-target" effects of ticagrelor that might explain this mortality benefit need to be further explored, says Stone, he postulates that PLATO helps reinforce mounting evidence that strategies that reduce bleeding events without increasing the risk of MI translate into better overall survival.
Stone advocates an "individualized" approach to patient care that might include use of already-approved agents in certain circumstances but concludes that the introduction of ticagrelor is "a landmark event that should redefine the care of patients with ACS."
AstraZeneca submitted a new drug application for ticagrelor to the US Food and Drug Administration (FDA) last November; there is no word yet from the FDA as to when it will ask its advisory panel to review the application.
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