Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome

Figures & data

Figure 1. Overall design of the WILL lOWer dose aspirin be more effective in ACS? (WILLOW ACS) study. ACS, acute coronary syndrome; BD, twice daily; mg, milligrams; OD, once daily; R, point of randomization.

Table I. Baseline demographics of the 20 randomized patients.

Characteristic	–
Sex, male, n (%)	16 (80%)
Age, years, mean (SD)	64.3 (11.9)
Race	–
Caucasian	18 (90%)
Black	2 (10%)
Other	0 (0%)
Height, cm, mean (SD)	171.4 (10.4)
Weight, kg	–
Mean (SD)	83.6 (15.5)
Median (range)	86 (55–106)
BMI, kg/m^2	–
Mean (SD)	28.3 (3.9)
Median (range)	28.6 (22.6–37.1)
Systolic BP, mmHg, mean (SD)	134.8 (20.1)
Diastolic BP, mmHg, mean (SD)	71.7 (11.7)
Pulse rate, bpm, mean (SD)	59.2 (5.6)
Diagnosis	–
STEMI	7 (35%)
NSTEMI	13 (65%)
Unstable angina	0 (0%)
Management of ACS	–
PCI	16 (80%)
CABG	0 (0%)
Conservative	4 (20%)
Smoking status	-
Current	2 (10%)
Past	11 (55%)
Never	7 (35%)
Diabetes mellitus	3 (15%)
Hypertension	11 (55%)
Hypercholesterolaemia	9 (45%)
Time from ACS event to randomization, days, mean (SD)	123.8 (82.8)
Concurrent medication	–
Beta-blocker	17 (85%)
ACE inhibitor/ARB	19 (95%)
Statin	19 (95%)
Regular nitrate	1 (5%)
Nicorandil	1 (5%)
Proton pump inhibitor	13 (65%)

ACE, angiotensin converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; UA, unstable angina

Table II. Comparison of study medication period duration, sampling times and compliance between the 20 mg BD and 75 mg OD aspirin regimens. Values are shown as mean ± SD and p values were generated by paired t-tests.

–	20 mg BD	75 mg OD	p value
Time from aspirin dose to post-aspirin venepuncture (mins)	124.7 ± 18.2	123.1 ± 10.2	0.68
Time from last ticagrelor dose to pre-aspirin venepuncture (mins)	214.0 ± 208.5	184.9 ± 160.2	0.36
Time from aspirin dose to bleeding time measurement (mins)	122.2 ± 21.0	122.8 ± 19.6	0.88
Time from last aspirin dose to collection of urine sample (mins)	133.9 ± 24.7	136.2 ± 24.6	0.76
Time of aspirin dose on day of sampling from previous dose (hrs)	13.7 ± 2.4	26.2 ± 1.8	NA
Compliance with aspirin therapy (% of doses taken)	99.9 ± 0.7	100.0 ± 0.0	0.33
Compliance with ticagrelor therapy (% of doses taken)	100.0 ± 0.0	99.7 ± 1.3	0.33
Time on study medication (days)	14.95 ± 2.0	14.80 ± 1.47	0.55
Systolic BP (mmHg)	127.3 ± 12.9	128.8 ± 15.5	0.67
Diastolic BP (mmHg)	72.2 ± 10.2	71.1 ± 10.2	0.53
Heart rate (bpm)	60.7 ± 6.0	62.3 ± 10.3	0.49

BD, twice daily; BP, blood pressure; bpm, beats per minute; hrs, hours; mmHg, millimeters of mercury; Mins, minutes; NA, not applicable; OD, once daily

Table III. Results of analyses of pharmacodynamic endpoints during each aspirin dosing regimen at steady state. Values shown are mean ± SD. p values were generated from paired t-tests.

–		20 mg BD	75 mg OD	p value
PRE-DOSE (TROUGH EFFECT)
Serum TXB2 (ng/mL)		3.51 ± 4.07	2.48 ± 3.14	0.23
Light transmittance aggregometry—maximum aggregation (%)
Agonist	[Agonist]	–
AA (mmol/L)	0.1	2.5 ± 1.8	2.4 ± 1.6	0.62
	0.3	2.2 ± 1.3	1.7 ± 1.5	0.10
	1	8.7 ± 14.2	6.6 ± 5.3	0.41
Collagen (µg/mL)	1	26.3 ± 20.3	15.5 ± 9.4	0.03
	4	57.0 ± 15.7	51.0 ± 18.1	0.16
	16	72.1 ± 11.8	73.5 ± 9.1	0.60
ADP (µmol/L)	20	44.6 ± 11.7	41.5 ± 12.0	0.21
POST-DOSE (PEAK EFFECT)
Serum TXB2 (ng/mL)		3.03 ± 3.64	0.83 ± 1.93	0.018
Urinary TxM (pg/mg creatinine)		430.0 ± 269.7	371.5 ± 176.6	0.17
Urinary PGI-M (pg/mg creatinine)		109.9 ± 143.3	86.68 ± 54.58	0.41
Urinary 8-iso-PGF2α (pg/mg creatinine)		2713 ± 1534	2834 ± 1945	0.77
Bleeding time (s)		679.5 ± 305.5	833.9 ± 385.7	0.04
Light transmittance aggregometry—maximum aggregation (%)
Agonist	[Agonist]	–
AA (mmol/L)	0.1	2.3 ± 1.5	2.6 ± 1.5	0.50
	0.3	2.1 ± 1.6	1.7 ± 0.9	0.23
	1	8.5 ± 14.3	5.1 ± 3.6	0.24
Collagen (µg/mL)	1	16.5 ± 15.6	9.0 ± 5.7	0.03
	4	44.6 ± 23.3	29.6 ± 14.9	0.007
	16	65.6 ± 12.0	58.4 ± 13.7	0.11
ADP (µmol/L)	20	40.9 ± 15.5	40.6 ± 12.1	0.86

AA, arachidonic acid; ADP, adenosine diphosphate; BD, twice-daily; PGI-M, prostacyclin metabolite; OD, once-daily; s, seconds; TXB₂, thromboxane B₂

Figure 2. Serum TXB₂ (a) and bleeding time (b) in ACS patients receiving two regimens of aspirin and ticagrelor in the WILLOW ACS study. Bars represent mean + SD. Dots and lines represent paired values for the individual participants. p values shown were generated by paired t-tests between the groups (see text and tables for further details). BD, twice-daily; OD, once-daily s, seconds; sTXB2, serum thromboxane B2. the groups (see text and tables for further details). Scale on the y-axis in Figure 2(a) is logarithmic. BD, twice-daily; OD, once-daily s, seconds; TXB₂, thromboxane B₂.

Figure 3. Maximum platelet aggregation responses to arachidonic acid, adenosine diphosphate and collagen assessed by light transmittance aggregometry pre- and post-aspirin dose at the end of each treatment period in the WILLOW ACS study. Bars indicate mean + SD. p values were generated using prespecified paired t-tests. AA, arachidonic acid; ADP, adenosine diphosphate; BD, twice-daily; OD, once-daily.

Figure 4. Urinary levels of TX metabolite, PGI₂ metabolite 8-iso-PGF_2α measured at the end of each treatment period. Bars represent mean + SD. Dots and lines represent paired values for the individual participants. p values shown were generated by paired t-tests between the groups. Scale on the y-axis is logarithmic. 8-iso-PGF_2α, 8-iso prostaglandin F_2α; BD, twice- daily; PGI-M, prostacyclin metabolite; OD, once-daily; TxM, thromboxane metabolite.

Figure 5. Conceptual figure summarizing the anticipated profiles of COX-1 inhibition and hemostasis provided by maintenance aspirin doses of 75 mg OD or 20 mg BD in combination with ticagrelor 90 mg BD, during steady-state. Figure for illustrative purposes only, scale on the y-axis is arbitrary. Dashed line represents effects on COX-1 and hemostasis at steady-state trough levels. BD, twice-daily; COX-1, cyclo-oxygenase 1; mg, milligrams; OD, once-daily.