Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation

Abstract

Background: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).

Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01–3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant.

Conclusions: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

The risk of early recurrence of ischemic stroke is higher in patients with non-valvular atrial fibrillation (NVAF) than in those without.^1,2 Vitamin K antagonists to prevent recurrence of ischemic stroke in patients with NVAF take a few days to reach a therapeutic anticoagulant effect. Thus, a temporary therapy with heparin can be performed alongside warfarin, termed “bridging therapy”.³ However, numerous studies and meta-analyses showed that anticoagulant therapy with heparin in the acute phase of ischemic stroke was associated with bleeding events.^4–18 Direct oral anticoagulants (DOACs) have a therapeutic anticoagulant effect within a few hours of administration. However, some clinicians also perform bridging therapy before starting DOACs. Few studies addressed the association between bridging therapy before starting DOACs and clinical outcomes after ischemic stroke. The present post-hoc analysis of the Recurrent Embolism Lessened by rivaroxaban, an Anti-Xa agent, of Early Dosing for acute ischemic stroke and transient ischemic attack (TIA) with atrial fibrillation (RELAXED) study^19,20 aimed to clarify the association between bridging therapy before starting rivaroxaban and clinical outcomes after ischemic stroke or TIA in patients with NVAF.

Editorial p 964

Methods

Study Design

The RELAXED study is a prospective, multicenter, observational study performed to establish efficacy, safety, and the optimal timing for starting rivaroxaban in patients with NVAF who experienced acute ischemic stroke or TIA. Detailed rationale and design of the RELAXED study are described elsewhere.¹⁹ Written informed consent was obtained from all patients. The RELAXED study was registered at ClinicalTrials.gov (NCT02129902) and in the UMIN clinical trials registry (UMIN000013932).

Study Population

Patients with NVAF who experienced acute ischemic stroke or TIA were enrolled in the RELAXED study between February 2014 and April 2016 if they met the following inclusion criteria: aged ≥20 years; hospitalization within 48 h after onset; ischemic stroke with a fresh infarct in the middle cerebral artery territory or TIA with a symptom corresponding to this territory; and anticoagulant therapy with rivaroxaban started within 30 days after onset. Major exclusion criteria were defined as: hypersensitivity to rivaroxaban; clinically significant hemorrhage such as gastrointestinal hemorrhage; liver failure with a Child-Pugh class of B or C; renal failure with a creatinine clearance of <15 mL/min; poorly controlled hypertension with a blood pressure of ≥180/100 mmHg; pregnant or potentially pregnant women; treatment with human immunodeficiency virus (HIV) protease inhibitors; treatment with azole antifungal drugs; and acute bacterial endocarditis. Patients were followed up for 90 days.

Clinical Characteristics

Data regarding clinical characteristics including age, sex, NVAF (identified vs. unidentified at baseline), hypertension, diabetes mellitus, previous stroke or TIA, congestive heart failure, creatinine clearance, the National Institutes of Health Stroke Scale (NIHSS) score at baseline, the CHADS₂ score at baseline, the HAS-BLED score at baseline, bridging therapy, antiplatelet therapy, the time for starting rivaroxaban, and the follow-up duration were obtained from our web-based registration system. Bridging therapy was defined as any temporary administration of unfractionated or low-molecular-weight heparin between admission and starting rivaroxaban. Antiplatelet therapy was defined as any temporary administration of oral antiplatelet agents during the follow-up period.

Outcome Measures

Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Major bleeding was defined as symptomatic intracranial hemorrhage, hemorrhagic infarction with a European Cooperative Acute Stroke Study classification²¹ of parenchymal hematoma type 2 showing exacerbation with a NIHSS score of ≥4, or other major bleeding according to the International Society on Thrombosis and Hemostasis criteria.²² Disability was defined as a modified Rankin Scale score of 3 to 5.

Statistical Analysis

Clinical characteristics stratified by the presence or absence of bridging therapy were compared using the t-test, the chi-squared test, or the Mann-Whitney U-test, as appropriate. Cumulative incidence rates of ischemic events, major bleeding, and their composite stratified by the presence or absence of bridging therapy were compared using the Kaplan-Meier method and the log-rank test. Associations between bridging therapy and ischemic events, major bleeding, or their composite were assessed using age- and sex-adjusted and multivariable-adjusted Cox proportional hazards models. The association between bridging therapy and death or disability 90 days after onset was assessed using age- and sex-adjusted and multivariable-adjusted logistic regression models after patients lost to follow up 90 days after onset were excluded. Age, sex, the CHADS₂ score at baseline, the NIHSS score at baseline, and bridging therapy were entered into multivariable-adjusted models. Firth’s penalized likelihood approach was used to address issues caused by the small sample size. All reported P values are 2-sided. A P value of <0.05 was considered to indicate statistical significance. Statistical analyses were performed using JMP software (version 12.2.0; SAS Institute Inc., Cary, NC, USA).

Results

Of 1,333 patients enrolled in the RELAXED study, 25 ineligible patients were excluded (Figure 1). Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin (unfractionated, 620; low-molecular-weight, 17; unknown, 1), with a median of 10,000 IU/day (unfractionated, 10,000 IU/day; low-molecular-weight, 10,000 IU/day), for a median of 3 days. The median time for starting heparin was 1 day. The NIHSS score at baseline was significantly lower (median, 7 vs. 9; P=0.002), the time for starting rivaroxaban was significantly longer (median, 5 vs. 2 days; P<0.001), and the follow-up duration was significantly shorter (median, 100 vs. 103 days; P=0.024) in patients receiving bridging therapy than in those who did not (Table 1).

Figure 1.

Flow of patients in the present study. NVAF, non-valvular atrial fibrillation; TIA, transient ischemic attack.

Table 1. Clinical Characteristics of Patients Stratified by the Presence or Absence of Bridging Therapy

	Bridging therapy (n=638)	No bridging therapy (n=670)	P value
Age, years	77±9	77±10	0.311
Female sex	258/638 (40)	295/670 (44)	0.189
Identified NVAF at baseline	301/638 (47)	307/670 (46)	0.623
Hypertension	432/628 (69)	430/658 (65)	0.190
Diabetes mellitus	110/632 (17)	102/664 (15)	0.320
Previous stroke or TIA	113/636 (18)	118/658 (18)	0.938
Congestive heart failure	41/599 (7)	53/616 (9)	0.251
Creatinine clearance, mL/min	62±24	63±26	0.621
NIHSS score at baseline	7 [3–16]	9 [3–18]	0.002
CHADS2 score at baseline	4 [3–4]	4 [3–4]	0.494
HAS-BLED score at baseline	2 [2–3]	2 [2–3]	0.670
Antiplatelet therapy	170/638 (27)	205/670 (31)	0.114
Time for starting rivaroxaban, days	5 [3–8]	2 [1–6]	<0.001
Follow-up duration, days	100 [92–115]	103 [93–118]	0.024

Data are presented as mean±standard deviation, number (%), or median [interquartile range]. NIHSS, National Institutes of Health Stroke Scale; NVAF, non-valvular atrial fibrillation; TIA, transient ischemic attack.

During the follow-up period, 38 patients experienced ischemic events (bridging therapy, 24; no bridging therapy, 14), and 11 experienced major bleeding (bridging therapy, 7; no bridging therapy, 4). Numbers and incidence rates of each event stratified by the presence or absence of bridging therapy are shown in Table 2. The incidence rate of ischemic events (P=0.074) (Figure 2A) or major bleeding (P=0.323) (Figure 2B) was not significantly higher in patients receiving bridging therapy than in those who did not individually, but the incidence rate of their composite was significantly higher in patients receiving bridging therapy than in those who did not (P=0.042) (Figure 2C). Associations between bridging therapy and ischemic events (age- and sex-adjusted hazard ratio [HR], 1.77; 95% confidence interval [CI], 0.93–3.52; multivariable-adjusted HR, 1.73; 95% CI, 0.90–3.44) or major bleeding (age- and sex-adjusted HR, 1.88; 95% CI, 0.57–7.19; multivariable-adjusted HR, 2.02; 95% CI, 0.61–7.72) were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (age- and sex-adjusted HR, 1.80; 95% CI, 1.02–3.28; multivariable-adjusted HR, 1.80; 95% CI, 1.01–3.29) (Table 3).

Table 2. Numbers and Incidence Rates of Each Event Stratified by the Presence or Absence of Bridging Therapy

	Bridging therapy (n=638)	No bridging therapy (n=670)
Ischemic event	24 (5.9)	14 (3.5)
Ischemic stroke	19 (4.7)	11 (2.7)
Transient ischemic attack	3 (0.7)	2 (0.5)
Systemic embolism	2 (0.5)	1 (0.3)
Major bleeding	7 (1.7)	4 (1.0)
Symptomatic intracranial hemorrhage	3 (0.7)	1 (0.3)
Hemorrhagic infarction	2 (0.5)	1 (0.3)
Other major bleeding	2 (0.5)	2 (0.5)
Total	31 (7.6)	18 (4.4)

Data are presented as number (incidence rate per 100 person-years).

Figure 2.

(A) Cumulative incidence rate of ischemic events stratified by the presence or absence of bridging therapy. (B) Cumulative incidence rate of major bleeding stratified by the presence or absence of bridging therapy. (C) Cumulative incidence rate of the composite of ischemic events and major bleeding stratified by the presence or absence of bridging therapy.

Table 3. Associations Between Bridging Therapy and Outcome Measures

	Age- and sex-adjusted			Multivariable-adjusted*
	HR	95% CI	P value	HR	95% CI	P value
Event
Ischemic events	1.77	0.93–3.52	0.083	1.73	0.90–3.44	0.099
Major bleeding	1.88	0.57–7.19	0.304	2.02	0.61–7.72	0.255
Composite	1.80	1.02–3.28	0.043	1.80	1.01–3.29	0.044
	OR	95% CI	P value	OR	95% CI	P value
Functional outcome
Death or disability	0.80	0.64–1.01	0.063	0.90	0.69–1.18	0.449

*Adjusted for age, sex, the CHADS₂ score at baseline, and the National Institutes of Health Stroke Scale score at baseline. CI, confidence interval; HR, hazard ratio; OR, odds ratio.

Ninety days after onset, 5 patients were lost to follow up (Figure 1), 517 had a disability (bridging therapy, 234; no bridging therapy, 283), and 28 died (bridging therapy, 13; no bridging therapy, 15). The association between bridging therapy and death or disability 90 days after onset was not statistically significant (age- and sex-adjusted odds ratio, 0.80; 95% CI, 0.64–1.01; multivariable-adjusted odds ratio, 0.90; 95% CI, 0.69–1.18) (Table 3).

Discussion

The present post-hoc analysis of the RELAXED study showed that bridging therapy with low-dose heparin before starting rivaroxaban was associated with the composite of ischemic events and major bleeding and was not associated with functional outcome after ischemic stroke or TIA in patients with NVAF.

Numerous studies and meta-analyses of randomized controlled trials showed that anticoagulant therapy with unfractionated or low-molecular-weight heparin or heparinoids in the acute phase of ischemic stroke was associated with bleeding events including intracranial hemorrhage and major extracranial hemorrhage^4–18 (for a relatively low number of patients with major bleeding in the present study, this may have been derived from underdosing of heparin). These studies and meta-analyses also showed that anticoagulant therapy with heparin in the acute phase of ischemic stroke did not improve the functional outcome. However, few studies addressed the association between bridging therapy before starting DOACs and clinical outcomes after ischemic stroke.

Apart from the present study, the post-hoc analysis of the Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation (RAF) and Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) studies showed that bridging therapy with low-molecular-weight heparin before starting DOACs was associated with ischemic events including recurrence of ischemic stroke, TIA, and systemic embolism after ischemic stroke in patients with NVAF.²³ Considering the onset of the therapeutic anticoagulant effect within a few hours, ease of administration via a nasogastric tube (except dabigatran), and immediate reversibility of the anticoagulant effect by specific antidotes, bridging therapy before starting DOACs seems to confer few benefits for patients with ischemic stroke and adequate renal function.²⁴ The high number of patients receiving bridging therapy in the present study (638 of 1,308 patients) may be partly owing to the fact that little evidence concerning early administration of DOACs in patients with ischemic stroke existed during the study period of the RELAXED study.

Increases of ischemic events and major bleeding in patients receiving bridging therapy may have been derived from underdosing and the anticoagulant effect of heparin, respectively. However, the timing of these events should be paid attention to. In many randomized controlled trials, the follow-up period for assessing occurrences of adverse events was longer than the dosing period for heparin,^{5,10,13,15,17} and adverse events observed in these trials should include those that occurred after the dosing period for heparin. In the present study, bridging therapy was performed for a median of 3 days, but differences in incidence rates of ischemic events and major bleeding between patients receiving bridging therapy and those who did not, continued to increase throughout the follow-up period (Figure 2). Thus, some background factors that led patients to receive bridging therapy may have contributed to increases of ischemic events and major bleeding in patients with bridging therapy, but such factors could not be identified because of limited numbers of patients and events in the present study. Further study, such as a meta-analysis with other observational studies, is required.

The present study has some limitations. First, patients were not randomized by the presence or absence of bridging therapy because the RELAXED study was an observational study. Second, the number of patients enrolled in the RELAXED study (n=1,333) was lower than planned (n=2,000), which may have resulted in statistically underpowered results. For instance, the association between bridging therapy and ischemic events or major bleeding was not statistically significant individually although incidence rates of ischemic events and major bleeding were numerically higher in patients receiving bridging therapy than in those who did not (Table 2). Third, most of the heparin type used for bridging therapy was unfractionated (97%), and the dose of heparin was low (median, 10,000 IU/day), which may have contributed to an increase of ischemic events in patients receiving bridging therapy. Fourth, the dose of rivaroxaban approved in Japan (15 or 10 mg/day) differs from that approved in Western countries (20 or 15 mg/day); however, pharmacokinetic and pharmacodynamic profiles of rivaroxaban at a dose of 15 or 10 mg/day in Japanese patients were reported to be similar to those of 20 or 15 mg/day in Caucasians.^25,26 Fifth, a significant difference was identified in the follow-up duration between patients receiving bridging therapy and those who did not. Finally, we have no data regarding intracardiac thrombus or craniocervical atherosclerotic lesion, which greatly affects the frequency of ischemic events.

In conclusion, the composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Acknowledgment

Teruyuki Hirano received a grant from JSPS KAKENHI (Grant Number 25461320, PI, 2014-2016; Grant Number 16K09731, PI, 2016-2017).

Disclosures

The present study was planned by the Japan Cardiovascular Research Foundation and funded by Bayer Yakuhin Ltd. (Contract number: 017926). Dr. Tokunaga has no conflicts of interest. Dr. Yasaka received lecture fees from Bayer, BMS, Boehringer Ingelheim, Boston Scientific, CSL Behring, Daiichi-Sankyo, Eisai, Medtronic, Otsuka, Pfizer, Sanofi, Sekisui Medical, Sumitomo Dainippon, Takeda, and Tanabe Mitsubishi and research support from Boehringer Ingelheim, Daiichi Sankyo, and Sanofi. Dr. Toyoda received lecture fees from Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, and Takeda. Dr. Mori received lecture fees from Daiichi-Sankyo, Johnson & Johnson, Kyowa Kirin, Medtronic, Nihon Medi-Physics, Novartis, Otsuka, Sosei, Sumitomo Dainippon, and Toshiba and research support from Daiichi Sankyo, Eisai, Fuji Film, General Electric, JSPS, MEXT, MHWL, and Novartis. Dr. Hirano received lecture fees from Astellas, Bayer, BMS, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Eisai, Medtronic, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda, and Tanabe Mitsubishi and research support from Astellas, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eisai, MSD, Otsuka, and Tanabe Mitsubishi. Dr. Hamasaki received lecture fees from Johnson & Johnson and research support from Teikoku Pharmaceuticals. Dr. Yamagami received lecture fees from Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Johnson and Johnson, Medico’s Hirata, Medtronic, Otsuka, Striker, Terumo, and Tanabe Mitsubishi and research support from BMS. Dr. Nagao received lecture fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, FP, Kyowa Kirin, Medtronic, Mochida, Novartis, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda, and Tanabe Mitsubishi. Dr. Yoshimura received lecture fees from Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Medico’s Hirata, Medtronic, Otsuka, Pfizer, Sanofi, Stryker, Takeda, and Tanabe Mitsubishi and research support from BMS and Takeda. Dr. Uchiyama received lecture fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Otsuka, Sanofi, Shionogi, Sumitomo Dainippon, Takeda, and Tanabe Mitsubishi and research support from the Japan Cardiovascular Research Foundation. Dr. Minematsu received lecture fees from Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Kowa, Kyowa Kirin, Medico’s Hirata, MSD, Nihon Medi-Physics, Nippon Chemiphar, Otsuka, Pfizer, Sanofi, Sawai, Stryker, Sumitomo Dainippon, Tanabe Mitsubishi, and Towa Pharmaceutical.

IRB Information

Study procedures and associated documents were reviewed and approved by the Institutional Review Board of the National Hospital Organization Kyushu Medical Center (Reference number: 14-50).

Data Availability

The deidentified participant data will not be shared.

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