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

Figures & data

Figure 1 Flow diagram of the literature search and study selection process.

Table 1 Baseline characteristics of included trials

References	Participants (n)	Race (%)	Study design	Study type	Study duration	Study groups (n)	Background antithrombotic therapy
Li et al, 2012^Citation19	Healthy subjects (26)	Chinese (100%)	Two-cohort, open-label, sequential, single-center study	PK	10 days (day 1: single dose^*; days 2–3: washout period; days 4–9: BID; day 10: single dose)	Ticagrelor 90 mg (12) Ticagrelor 180 mg (14)	None
Hiasa et al, 2014^Citation23	Stable CAD patients (139)	Japanese (84.9%) Other Asians (15.1%)	RCT, double-blinded, multicenter, parallel-group study	PK/PD	4 weeks	Ticagrelor 45 mg BID (50) Ticagrelor 90 mg BID (43) Clopidogrel 75 mg daily (46)	Aspirin 75–100 mg daily
Bonaca et al, 2015^Citation1 (PEGASUS-TIMI 54)	Patients 1–3 years post MI (21,162)	European (58.7%) North American (18.5%) South American (11.6%) Asian (11.0%)	RCT, ITT, double-blinded, double-dummy, multicenter, multinational, parallel-group study	Clinical study	Median follow-up of 33 months	Ticagrelor 60 mg BID (7,045) Ticagrelor 90 mg BID (7,050) Placebo (7,067)	Aspirin 75–150 mg daily
Li et al, 2015^Citation21	Patients with unstable angina pectoris and non-revascularization (351)	Chinese (100%)	RCT, parallel-group study	PD/clinical study	Follow-up of 12 months	Ticagrelor 90 mg LD/45 mg BID MD (108) Ticagrelor 180 mg LD/90 mg BID MD (132) Clopidogrel 300 mg LD/75 mg daily MD (111)	Aspirin 100 mg daily
Li et al, 2016^Citation24	Stable CAD patients (36)	Chinese (100%)	RCT, open-label, single-center study	PK/PD	7 days (day 1: single dose; days 3–6: BID; day 7: single dose)	Ticagrelor 45 mg (12) Ticagrelor 60 mg (12) Ticagrelor 90 mg (12)	Aspirin 75–100 mg daily
Li et al, 2016^Citation20	Healthy subjects (30)	Chinese (100%)	RCT, open-label, single-center study	PK/PD	4 days	Ticagrelor 90 mg LD/45 mg BID MD (10) Ticagrelor 180 mg LD/90 mg BID MD (10) Clopidogrel 600 mg LD/75 mg daily MD (10)	None
Xue et al, 2016^Citation22	NSTE-ACS patients (61)	Chinese (100%)	RCT, double-blinded, single-center, parallel-group study	PD	5 days	Ticagrelor 90 mg LD/45 mg BID MD (20) Ticagrelor 180 mg LD/90 mg BID MD (21) Clopidogrel 300 mg LD/75 mg daily MD (20)	Aspirin daily

Note:

* For the purposes of this review, only the results of the single dose study were included.

Abbreviations: CAD, coronary artery disease; ITT, intention to treat; LD, loading dose; MD, maintenance dose; MI, myocardial infarction; NSTE-ACS, non-ST segment elevation acute coronary syndrome; PK, pharmacokinetics; PD, pharmacodynamics; RCT, randomized controlled trial.

Table 2 Pharmacokinetic data of low dose versus standard dose of ticagrelor in East Asians

References	Ticagrelor dose	Time	Ticagrelor			AR-C124910XX			Main findings
			Cmax (ng/mL)	AUC0-inf (ng·h/mL)	t½ (h)	Cmax (ng/mL)	AUC0-inf (ng·h/mL)	t½ (h)
Li et al, 2012^Citation19	90 mg	Day 1 (LD)	602 (32)	3,855 (31)	10.9 (36)	183 (25)	1,797 (25)	9.5 (29)	Cmax and AUC0-inf of ticagrelor and AR-C124910XX increased dose-proportionally
	180 mg		1,198 (30)	7,738 (33)	11.7 (28)	345 (25)	2,997 (25)	9.1 (15)
Hiasa et al, 2014^Citation23,*	45 mg	Day 1 (LD)	283 (51)	1,640 (46)^#	5.10 (27)	62.8 (48)	445 (39)^#	8.16 (38)	Cmax and AUC0–t of ticagrelor and AR-C124910XX increased dose-proportionally in both Japanese and non-Japanese Asian patients
	90 mg	Day 28 (MD)	612 (39)	3,310 (36)^#	4.83 (27)	156 (45)	1,080 (30)^#	7.13 (43)
	45 mg		422 (50)	3,050 (55)^#	9.72 (29)	135 (40)	1,180 (42)^#	15.57 (36)
	90 mg		931 (43)	6,080 (41)^#	8.78 (22)	326 (36)	2,720 (31)^#	14.41 (30)
Li et al, 2016^Citation24	45 mg	Day 1 (LD)	464 (38)	3,220 (51)	10.72 (16.18)	88.3 (24.6)	922 (29)	12.65 (22.94)	Cmax and AUC0–12 of ticagrelor and AR-C124910XX increased dose-proportionally between ticagrelor 45 mg and 90 mg doses, but differences between ticagrelor 45 mg and 60 mg doses were not significant
	60 mg		414 (34)	3,633 (32)	9.42 (13.53)	77.1 (54)	1,108 (35)	11.38 (24.27)
	90 mg		822 (37)	6,234 (54)	10.14 (17.54)	139 (38)	1,644 (31)	11.62 (24.64)
	45 mg	Day 7 (MD)	616 (37)	3,882 (42)^‡	N/A	144 (26)	1,069 (25)^‡	N/A
	60 mg		689 (34)	4,351 (37)^‡	N/A	180 (50)	1,314 (41)^‡	N/A
	90 mg		1,273 (43)	8,206 (51)^‡	N/A	301 (32)	2,254 (37)^‡	N/A
Li et al, 2016^Citation20	90 mg	Day 1 (LD)	470 (48)	3,330 (22)	N/A	154 (39)	887 (25)^#	N/A	Cmax and AUC0-inf of ticagrelor and AR-C124910XX increased dose-proportionally
	180 mg	Day 4 (MD)	1,447 (27)	6,905 (30)	N/A	445 (35)	2,120 (34)^#	N/A
	45 mg		322 (18)	3,128 (18)	8.4 (37)	142 (35)	2,467 (33)	16.6 (54)
	90 mg		921 (46)	8,023 (55)	8.9 (31)	361 (35)	6,407 (46)	11.7 (32)

Notes: All data are provided as geometric mean (coefficient of variation %) unless otherwise indicated.

* Japanese patient data (n=38);

# AUC_0–t (AUC from time 0 to end of the dosing interval);

‡ AUC_0–12.

Abbreviations: LD, loading dose; MD, maintenance dose; N/A, not available; PK, pharmacokinetics; AUC, area under the curve.

Table 3 Pharmacodynamic data of low dose versus standard dose ticagrelor in East Asians

References	Treatment	Time	PD		Main findings
			Final extent IPA	PRU
Hiasa et al, 2014^Citation23	Ticagrelor 45 mg	Day 28	57%	N/A	Final extent IPA was greater at every time point on days 1 and 28 with ticagrelor 90 mg than 45 mg. Both doses of ticagrelor had greater final extent IPA than clopidogrel 75 mg at all time points
	Ticagrelor 90 mg		67%
	Clopidogrel 75 mg		42%
Li et al, 2015^Citation21	Ticagrelor 45 mg	Days 1–7	N/A	N/A	IPA of ticagrelor 90 mg was higher than ticagrelor 45 mg, which was higher than clopidogrel 75 mg. PRU and PRI of ticagrelor 90 mg were lower than ticagrelor 45 mg, which was lower than clopidogrel 75 mg. All differences were statistically significant
	Ticagrelor 90 mg		N/A	N/A
	Clopidogrel 75 mg		N/A	N/A
Li et al, 2016^Citation24	Ticagrelor 45 mg	Day 1	27% (26)	N/A	IPA increased dose-dependently. Reductions in mean PRU values were dose dependent
	Ticagrelor 60 mg		26% (26)	N/A
	Ticagrelor 90 mg		33% (31)	N/A
	Ticagrelor 45 mg	Day 7	>85%	48–98
	Ticagrelor 60 mg		>90%	36–81
	Ticagrelor 90 mg		>95%	17–32
Li et al, 2016^Citation20	Ticagrelor 45 mg	Days 1–4	N/A	97.1%^*	No significant differences in PRU were observed between low- and standard-dose ticagrelor, but both doses of ticagrelor were significantly higher than clopidogrel at 0.5, 1, 2, 4, 8, and 48 h after loading and maintenance doses (p<0.05)
	Ticagrelor 90 mg		N/A	98.7%^*
	Clopidogrel 75 mg		N/A	77%^*
Xue et al, 2016^Citation22	Ticagrelor 45 mg	Day 5	N/A	44.55±32.88^#	PRU of ticagrelor 45 mg was similar to ticagrelor 90 mg (p=0.3085), but both doses of ticagrelor had significantly lower PRU than clopidogrel (p<0.0001)
	Ticagrelor 90 mg		N/A	39.10±40.02^#
	Clopidogrel 75 mg		N/A	189.20±65.22^#

Notes:

* Peak mean percentage inhibition of PRU;

# mean ± SD.

Abbreviations: IPA, inhibition of platelet aggregation; N/A, not available; PD, pharmacodynamics; PRI, platelet reactivity index; PRU, P2Y₁₂ reactivity unit.

Table 4 Clinical efficacy outcomes of low-dose versus standard-dose ticagrelor in East Asians

References	Participants	Clinical efficacy outcomes
Bonaca et al, 2015^Citation1 (PEGASUS-TIMI 54)	All patients	Composite of cardiovascular death, MI, or stroke	Ticagrelor 60 mg 7.77%, HR^* 0.84 (95% CI 0.74–0.95)
			Ticagrelor 90 mg 7.85%, HR^* 0.85 (95% CI 0.75–0.96)
			Placebo 9.04%
	Asians only	Composite of cardiovascular death, MI, or stroke	Ticagrelor 60 mg 7.11%, HR^* 0.90 (95% CI 0.60–1.34) p=0.83^‡
			Ticagrelor 90 mg 6.08%, HR^* 0.82 (95% CI 0.54–1.23) p=0.99^‡
			Placebo 6.86%
Li et al, 2015^Citation21#	(Chinese)	CV death	Low-dose ticagrelor 2.8%
			Standard-dose ticagrelor 2.3%, HR 1.108 (95% CI 0.974–1.259), p=0.118
		MI	Low-dose ticagrelor 3.7%
			Standard-dose ticagrelor 3.9%, HR 1.108 (95% CI 0.974–1.259), p=0.118
		Stroke	Low-dose ticagrelor 0.9%
			Standard-dose ticagrelor 0.8%, HR 1.106 (95% CI 0.974–1.257), p=0.121
		PCI	Low-dose ticagrelor 1.9%
			Standard-dose ticagrelor 1.5%, HR 1.107 (95% CI 0.974–1.258), p=0.120
		Recurrent angina	Low-dose ticagrelor 7.4%
			Standard-dose ticagrelor 6.8%, HR 1.109 (95% CI 0.973–1.264), p=0.119

Notes:

* Compared to placebo;

# low-dose ticagrelor: 90 mg LD/45 mg BID MD and standard-dose ticagrelor: 180 mg LD/90 mg BID MD; ^‡interaction p-value (for region).

Abbreviations: CI, confidence interval; CV death, cardiovascular death; HR, hazard ratio; PCI, percutaneous coronary intervention; MI, myocardial infarction; LD, loading dose; MD, maintenance dose.

Table 5 Safety and tolerability of low-dose versus standard-dose ticagrelor in East Asians

References		Major bleeding (%)	Minor/minimal bleeding (%)	Dyspnea (%)	Any adverse events (%)
Li et al, 2012^Citation19		None	Minor bleeding: Ticagrelor 90 mg 8.3% (epistaxis) Ticagrelor 180 mg 7.1% (gingival bleeding)	Ticagrelor 90 mg 0% Ticagrelor 180 mg 21.4%	Ticagrelor 90 mg 25.0% Ticagrelor 180 mg 50.0%
Hiasa et al, 2014^Citation23		Ticagrelor 45 mg 2% Ticagrelor 90 mg 0% Clopidogrel 75 mg 0%	Minor bleeding: None Minimal bleeding: Ticagrelor 45 mg 26.0% Ticagrelor 90 mg 39.5% Clopidogrel 75 mg 21.7%	Ticagrelor 45 mg 0% Ticagrelor 90 mg 4.7% Clopidogrel 75 mg 0%	Ticagrelor 45 mg 56.0% Ticagrelor 90 mg 74.4% Clopidogrel 75 mg 47.8%
Bonaca et al, 2015^Citation1 (PEGASUS-TIMI 54)	All patients	Ticagrelor 60 mg 2.3%, HR^* 2.32 (95% CI 1.68–3.21) Ticagrelor 90 mg 2.6%, HR^* 2.69 (95% CI 1.96–3.70) Placebo 1.1%	Minor bleeding: Ticagrelor 60 mg 1.2%, HR^* 3.31 (95% CI 1.94–5.63) Ticagrelor 90 mg 1.3%, HR^* 4.15 (95% CI 2.47–7.00) Placebo 0.4%	Ticagrelor 60 mg 15.8% Ticagrelor 90 mg 18.9% Placebo 6.4%	Ticagrelor 60 mg 76.3% Ticagrelor 90 mg 76.9% Placebo 70.0%
	Asians only	Ticagrelor 60 mg 3.7%, HR^* 3.23 (95% CI 1.45–7.18) Ticagrelor 90 mg 3.0%, HR^* 2.37 (95% CI 1.02–5.50) Placebo 1.4%	N/A	N/A	N/A
Li et al, 2015^Citation21		Ticagrelor 45 mg 4.6%, HR^# 0.352 (95% CI 0.125–0.994) Ticagrelor 90 mg 12.1% Clopidogrel 75 mg 3.6%	Minor bleeding: Ticagrelor 45 mg 5.6%, HR^# 0.311 (95% CI 0.121–0.801) Ticagrelor 90 mg 15.9% Clopidogrel 75 mg 4.5%	Ticagrelor 45 mg 3.7% Ticagrelor 90 mg 11.4% HR 1.086 (95% CI 0.952–1.237) Clopidogrel 75 mg N/A	N/A
Li et al, 2016^Citation24		None	Minor bleeding^‡: Ticagrelor 45 mg 8.3% Ticagrelor 60 mg 16.7% Ticagrelor 90 mg 8.3%	Ticagrelor 45 mg 0% Ticagrelor 60 mg 16.7% Ticagrelor 90 mg 8.3%	Ticagrelor 45 mg 33.3% Ticagrelor 60 mg 33.3% Ticagrelor 90 mg 41.7%
Li et al, 2016^Citation20		None	Minimal bleeding: Ticagrelor 90 mg LD, 45 mg BID MD 10.0% Ticagrelor 180 mg LD, 90 mg BID MD 20.0% Clopidogrel 600 mg LD, 75 mg daily MD 0%	None	Ticagrelor groups N/A Clopidogrel 600 mg LD, 75 mg daily MD 10.0% (sinus bradycardia)
Xue et al, 2016^Citation22		None	Minor bleeding: Ticagrelor 45 mg 0% Ticagrelor 90 mg 9.5% Clopidogrel 75 mg 0%	Ticagrelor 45 mg 10.0% Ticagrelor 90 mg 14.3% Clopidogrel 75 mg 0%	Ticagrelor 45 mg 15.0% Ticagrelor 90 mg 33.3% Clopidogrel 75 mg 0%

Notes:

* Compared to placebo;

# compared to ticagrelor 90 mg; bleeding events compared to clopidogrel were not statistically significant (p>0.05);

‡ composite of several minor bleeding results (positive occult bleeding, hemoptysis, gingival bleeding, epistaxis).

Abbreviations: CI, confidence interval; HR, hazard ratio; N/A, not available; TIMI, thrombolysis in myocardial infarction; LD, loading dose; MD, maintenance dose.

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