Efficacy of Dual Antiplatelet Therapy for Preventing Recurrence of Arterial Thrombosis in Patients With Antiphospholipid Syndrome

Naoki Ohnishi; Yuichiro Fujieda; Ryo Hisada; Hiroyuki Nakamura; Masaru Kato; Kenji Oku; Toshiyuki Bohgaki; Olga Amengual; Shinsuke Yasuda; Tatsuya Atsumi

Disclosures

Rheumatology. 2019;58(6):969-974. 

In This Article

Results

One hundred and twelve patients out of the 206 patients in the APS cohort had a history of arterial thrombosis as the first thrombotic event and received a prophylactic regimen. Ninety patients met the inclusion criteria and were enrolled in this analysis. Patients were divided into four groups according to the regimen as follows: Wf (n = 13), AP (n = 41), Wf + AP (n = 21) or DAPT (n = 15) (Supplementary Figure S1, available at Rheumatology online).

Baseline Characteristics

Patients' baseline characteristics are summarized in Table 1. Seventy-three out of 90 (81%) were female, and cerebral infarction [(81/90 patients (90%)] was the most frequent incident thrombotic event. The median observation period was 8 years (interquartile range 5–13 years). No statistically significant differences were found in risk factors for arterial thrombosis among the four groups (Table 1 and Supplementary Table S2, available at Rheumatology online). The frequency of coronary heart disease, deep vein thrombosis, pulmonary embolism and superficial thrombophlebitis was statistically significantly different among the four groups at baseline (P = 0.025, 0.022, 0.004 and 0.017, respectively).

Recurrence Rate

Recurrent events were observed in 40 patients (recurrence rate 4.96 per 100 patient-years) with 35 arterial and 5 venous thromboses (Supplementary Table S3, available at Rheumatology online). The most common arterial and venous thrombotic recurrence was cerebral infarction and deep vein thrombosis in 29 (32.2%) and 3 patients (3.3%), respectively. There were statistically significant differences in the recurrence rates of cerebral infarction among the four groups (P = 0.004), with AP (P= 0.024), Wf + AP (P = 0.034) and DAPT (P = 0.001) having significantly lower incidences relative to Wf.

Thrombosis-free intervals during treatment calculated by the Kaplan–Meier method are presented in Figure 1. Wf was less effective for prevention of thrombosis than other treatment options (log-rank P = 0.0027). INR levels in Wf group were for moderate intensity: PT-INR between 1.5 and 2.5 [on recurrence; median PT-INR (range), 2.17 (1.75–2.39)]. The frequency of thrombotic recurrence between Wf and DAPT, and also between Wf and Wf + AP was statistically significantly different (log-rank P = 0.001 and 0.009, respectively). Wf had the highest rate of recurrence (11.58 per 100 patient-years). In the other group, the recurrence rate expressed per 100 patient-years was as follows: AP: 5.47, Wf + AP: 3.72, DAPT: 1.81. Wf was identified as an independent risk factor in adjusted Cox proportional hazards models (hazard ratio 4.23, 95% confidence interval: 1.69–10.38, P = 0.003; Supplementary Table S4, available at Rheumatology online). Since the patients with high risk of ischaemic heart disease might have an impact on the results, a sub-analysis excluding patients with recurrence of cardiac events was performed; Wf monotherapy was still identified as an independent risk factor (Supplementary Figure S2, available at Rheumatology online).

Figure 1.

Ten-year thrombosis-free survival
Data were estimated using Kaplan–Meier curves. P values <0.05. Ten-year thrombosis-free survival rate was 62%. Warfarin was less effective for prevention of thrombosis than other treatment options (log-rank P = 0.0027). There was statistically significant difference in the frequency of thrombotic recurrence events between Wf and DAPT (**log-rank P = 0.001) or Wf + AP combination therapy (*log-rank P = 0.009). The intensity of warfarin therapy on recurrence was at a moderate-intensity level [median PT-INR (range), 2.17 (1.75–2.39)]. DAPT: dual antiplatelet therapy; PT-INR: PT-International normalized ratio; Wf: warfarin monotherapy; Wf + AP: warfarin and antiplatelet combination therapy.

Figure S2.

Ten-years thrombosis-free survival (sub-analysis)
Data were estimated using the Kaplan-Meier curves. P-values <0.05. The sub-analysis excluding patients with recurrence of cardiac events were performed. Warfarin (Wf) was less effective for prevention of thrombosis than other treatment options.

Safety Assessment

Severe bleeding events and/or mortality occurred in 20 patients (22.2%, 3.58 per 100 patient-years) (Supplementary Table S3, available at Rheumatology online). During the follow-up period, there were nine patients (10%) with severe bleeding events and 14 deaths (15.6%). Three patients died of severe bleeding (aortic dissection in AP, alveolar haemorrhage in Wf + AP, aortic aneurysm rupture in DAPT), and two patients died of cerebral infarction. Other causes of death were interstitial pneumonia (n = 2), and infection/sepsis, lung cancer, amyotrophic lateral sclerosis and drowning (n = 1 each). In three patients, the causes of death could not be identified. No statistically significant differences in frequency of severe bleeding or death were observed among the four groups (Supplementary Figure S3, available at Rheumatology online). Per 100 patient-years, serious bleeding events and/or mortality rate in the four groups were as follows: Wf: 0.59, AP: 2.14, Wf + AP: 2.21, DAPT: 2.89.

Figure S3.

Ten-years adverse events-free survival
Data were estimated using the Kaplan-Meier curves. P-values <0.05. Adverse events-free survival curves. Adverse events were defined as severe bleeding and death. No statistically significant difference in frequency of adverse events was observed between the 4 groups (Log-rank p = 0.174). The case of mortality in Wf monotherapy died 15 years later from the start of the observation. N: number of patients, Wf: warfarin monotherapy, AP: antiplatelet monotherapy, Wf + AP: warfarin and antiplatelet combination therapy, DAPT: dual antiplatelet therapy.

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