Inferiority of ticagrelor in the PHILO trial: Play of chance in East Asians or nightmare confirmation of PLATO-USA?

Serebruany, Victor L.; Tomek, Aleš; Pya, Yuriy; Bekbossynova, Makhabbat; Kim, Moo Hyun

doi:10.1016/j.ijcard.2016.04.125

Cited by 16 publications

(17 citation statements)

References 24 publications

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“…As mentioned earlier, differences in efficacy and safety in clinical studies of different therapies have been reported between Asian and non-Asian populations 20 – 23 and demonstrate the need to carefully assess all therapies in Asian populations.…”

Section: Discussionmentioning

confidence: 96%

“…19 For example, in the PHILO trial of the blood thinner ticagrelor, Asian patients had notably worsened outcomes compared to other ethnic populations. 20 In cancer patients, the incidence of severe neutropenia following treatment with the chemotherapy drug docetaxel was demonstrated to be 19 times greater than in non-Asian patients in Phase II and III clinical trials, 21 leading to the proposal of dose reduction in Asian patients treated with docetaxel. 22 A 10% dose reduction in Asian patients with head and neck squamous cell cancer receiving induction chemotherapy with dose-modified docetaxel, cisplatin, and 5-fluorouracil achieved similar survival figures compared to the original recommended dose regimen.…”

Section: Introductionmentioning

confidence: 99%

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Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease

Bai

Ichinose

Lee

et al. 2017

COPD

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Background and purposeWhile the efficacy and safety of combined tiotropium and olodaterol in patients with COPD was established in a large clinical trial program, it is important to assess whether clinical data can be applied to geographic patient groups, particularly for East Asian patients who may have a different phenotypic profile to the global trial population. This study aimed to compare the lung function and safety profiles of tiotropium/olodaterol and monocomponents in East Asian and global populations from the TONADO® trials.Materials and methodsIn the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase III TONADO studies, patients received tiotropium/olodaterol, tiotropium, or olodaterol. We assessed the forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response and trough FEV1 response at 24 weeks for the approved doses, tiotropium/olodaterol 5/5 μg, tiotropium 5 μg, and olodaterol 5 μg. Treatment-emergent adverse events were recorded throughout treatment and ≤21 days after study medication.ResultsIn the East Asian population, 1,152 patients were randomized (5,163 overall). After 24 weeks, FEV1 AUC0–3 and trough FEV1 responses were greater (P<0.0001) with tiotropium/olodaterol 5/5 μg in both populations versus tiotropium or olodaterol. The East Asian population showed slightly greater trough FEV1 treatment differences between tiotropium/olodaterol 5/5 μg and tiotropium compared to the overall population. Generally, no increase in adverse events was seen with tiotropium/olodaterol 5/5 μg compared to tiotropium and olodaterol in either population.ConclusionThe efficacy and safety profile of tiotropium/olodaterol 5/5 μg has been demonstrated for both East Asian and global populations.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease

Bai

Ichinose

Lee

et al. 2017

COPD

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“…Moreover, the bleeding concerns were particularly evident in Korea, China, and Taiwan, where standard-dose prasugrel or ticagrelor is recommended in parallel with the ESC and the ACC/AHA recommendations. 19,20 Considering the critical need for the development of appropriate antiplatelet treatment strategies for East Asian patients with ACS, our study contributes to a growing body of literature on dose adjustments of novel P2Y12 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Ischemic and Bleeding Events Among Patients With Acute Coronary Syndrome Associated With Low-Dose Prasugrel vs Standard-Dose Clopidogrel Treatment

et al. 2020

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IMPORTANCE Prasugrel was approved at a lower dose in 2014 in Japan than in the West because East Asian patients are considered more susceptible to bleeding than Western patients. However, real-world outcomes with low-dose prasugrel treatment remain unclear. OBJECTIVE To investigate the association of low-dose prasugrel vs standard-dose clopidogrel administration with short-term outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). DESIGN, SETTING, AND PARTICIPANTS This study used data from the Japan Cardiovascular Database-Keio Interhospital Cardiovascular Studies registry, a large, ongoing, multicenter, retrospective cohort of consecutive patients who underwent PCI. The present cohort study evaluated 2770 patients with acute coronary syndrome who underwent PCI and received either low-dose prasugrel (loading dose, 20 mg; maintenance dose, 3.75 mg) or clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg) in combination with aspirin between 2014 and 2018. Propensity score-matching analysis was conducted to balance the baseline characteristics of patients receiving low-dose prasugrel and those receiving clopidogrel. Data analysis was conducted in June 2019. EXPOSURES Prescription of either low-dose prasugrel or standard-dose clopidogrel prior to PCI. MAIN OUTCOMES AND MEASURES Primary ischemic events (in-hospital death, recurrent myocardial infarction, and ischemic stroke) and primary bleeding events, defined as bleeding complications within 72 hours after PCI consistent with the National Cardiovascular Data Registry CathPCI Registry definition. RESULTS Of 2559 patients included in the study, the mean (SD) age was 67.8 (12.7) years, and 78.2% were male. In total, 1297 patients (50.7%) received low-dose prasugrel, and 1262 patients (49.3%) received clopidogrel. After propensity score matching, primary ischemic events among patients receiving low-dose prasugrel and those receiving clopidogrel were comparable (odds ratio [OR], 1.42; 95% CI, 0.90-2.23), but primary bleeding events were significantly higher among patients receiving prasugrel (OR, 2.91; 95% CI, 1.63-5.18). This increase in bleeding events was associated with the presence of a profile of high-bleeding risk (Ն75 years of age, body weight <60 kg, or history of stroke or transient ischemic attack) (OR, 4.08; 95% CI, 1.86-8.97), being female (OR, 3.84; 95% CI, 1.05-14.0), or the presence of ST-segment elevation myocardial infarction (OR, 2.07; 95% CI, 1.05-4.09) or chronic kidney disease (OR, 4.78; 95% CI, 1.95-11.7). CONCLUSIONS AND RELEVANCE Since its approval, low-dose prasugrel has been used by nearly 80% of patients who undergo PCI. Despite the modified dose, bleeding events were higher among patients receiving low-dose prasugrel than among patients receiving clopidogrel, with no difference (continued) Key Points Question Are there differences in ischemic and bleeding outcomes among East Asian patients with acute coronary syndrome who undergo percutaneous coronary intervention associated with admin...

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“… 8 From this study, superior efficacy of ticagrelor, as observed in the PLATO trial, was questioned in East Asian patients, and more alarmingly, the risk of higher bleeding rates in the ticagrelor group suggested a need for further evaluation of a lower dose of ticagrelor in East Asian population. 9 …”

Section: Introductionmentioning

confidence: 99%

Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low-dose ticagrelor versus standard dose in East Asians: a systematic review

Lee

Kim

Choi

et al. 2018

TCRM

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East Asians are prone to higher systemic exposure and increased risk of bleeding compared to other races after administration of antiplatelet agent(s). The aim of this systematic review was to compare and evaluate the appropriateness of a lower dose versus standard dose of ticagrelor in East Asians. A systematic search was conducted in PubMed, EMBASE, and Cochrane databases for studies comparing low versus standard doses of ticagrelor in East Asian populations; a total of seven studies were included in the review. Pharmacokinetic (PK), pharmacodynamic (PD), clinical efficacy, and safety data were collected. PK data demonstrated that the Cmax and area under the curve (AUC) of ticagrelor increased dose-proportionally. PD data indicated that while the low dose of ticagrelor resulted in less antiplatelet activity in three of the five PD studies, in the other studies, there were no differences between low and standard doses. There were two clinical studies included in this review, which showed that the efficacy was similar between the low and standard doses, but both studies were limited by the number of patients included. While there were generally greater incidence of adverse events observed in the standard ticagrelor dose, the magnitude or actual difference between the two doses is difficult to determine due to lack of consistent data. In East Asians, the appropriateness of the low-dose ticagrelor cannot be determined based on the currently available evidence. Additional large-scale and longer duration studies are warranted.

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Inferiority of ticagrelor in the PHILO trial: Play of chance in East Asians or nightmare confirmation of PLATO-USA?

Cited by 16 publications

References 24 publications

Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease

Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease

Ischemic and Bleeding Events Among Patients With Acute Coronary Syndrome Associated With Low-Dose Prasugrel vs Standard-Dose Clopidogrel Treatment

Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low-dose ticagrelor versus standard dose in East Asians: a systematic review

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