Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation.

Several direct oral anticoagulants have been developed to prevent cardiogenic thrombosis in patients with atrial fibrillation, on the other hand, have the complication of bleeding. Since clinical course after bleeding with direct oral anticoagulant remains unclear, the present retrospective cohort study was to clarify the course after hemorrhage among patients receiving direct oral anticoagulants. Among all 2005 patients prescribed dabigatran, rivaroxaban, apixaban, or edoxaban between April 2011 and June 2017, subjects comprised 96 patients with non-valvular atrial fibrillation who experienced relevant bleeding during direct oral anticoagulant therapy (Bleeding Academic Research Consortium type 2 or above). The clinical course after hemorrhage was reviewed to examine whether rebleeding or thrombotic events occurred up to the end of December 2019. Gastrointestinal bleeding was the most frequent cause of initial bleeding (57 patients, 59%). Rebleeding occurred in 11 patients (4.5%/year), with gastrointestinal bleeding in 10 and subarachnoid hemorrhage in 1. All rebleeding occurred in patients who resumed anticoagulation therapy. Another significant factor related with rebleeding included past history of gastrointestinal bleeding. On the other hand, major adverse cardiac and cerebrovascular events occurred in 6 patients older than 75 years old or more (2.5%/year), with systemic thrombosis in 4 and cardiac death in 2. All 4 patients with systemic thrombosis withheld anticoagulants after index bleeding, although only 10 patients withheld anticoagulation therapy. Rebleeding should be taken care of when anticoagulants are resumed after bleeding, particularly among patients who initially experienced gastrointestinal bleeding. Systemic thrombosis occurred at a high rate when anticoagulant therapy was withheld after bleeding.

Introduction

With the continued rapid aging of society, the number of patients suffering from atrial fibrillation (AF) has increased in developed countries [1, 2]. Several direct oral anticoagulants (DOACs) have recently emerged for the prevention of thrombosis in patients with AF. DOACs have characteristics of improved adherence, easier handling and effectiveness comparable to that of vitamin K antagonists, whereas a drawback could be a higher risk of bleeding especially in the gastrointestinal tract, a common site of bleeding during antithrombotic therapy. The incidence of major gastrointestinal bleeding (GIB) among patients taking DOACs has been reported as 1–3% in randomized controlled trials [3-7]. Previous studies have indicated an increased incidence of GIB among AF patients taking dabigatran and rivaroxaban compared with those taking warfarin [8-12].

In addition, continuation of warfarin is considered important for preventing thrombotic adverse events, even after serious bleeding developed. Restarting warfarin after major GIB is reportedly associated with significant reductions in thromboembolism and all-cause mortality [13-15]. Meanwhile, anticoagulant interruption is known to be related to increased risks of all-cause mortality and thrombosis, but no decrease in risk of major bleeding [16, 17]. However, information on the clinical course after bleeding during DOAC therapy remains limited, and both the incidences of rebleeding and thrombosis and factors associated with the development of such adverse events are uncertain [18]. The present study was to clarify the occurrence of rebleeding and thrombotic events in post-bleeding patients and the relation with clinical factors such as resumption or discontinuation of anticoagulation therapy.

Materials and methods

Study subjects

This was a single-center, retrospective cohort study. Study subjects were selected from patients at Teikyo University Hospital in Japan. The patients who had been prescribed a DOAC in the form of dabigatran, rivaroxaban, apixaban, or edoxaban between April 2011 and June 2017 were identified from prescription lists. From them, the patients who had been prescribed DOAC for non-valvular atrial fibrillation (NVAF) and experienced clinically relevant bleeding (Bleeding Academic Research Consortium (BARC) type 2–5) [19] during DOAC therapy were included. The exclusion criteria were involved prescribing DOAC except non-valvular atrial fibrillation, inpatients, less than 1 month from prescribed DOAC, unable to follow up after bleeding and bleeding caused by medical procedures.

BARC proposes 5 bleeding types. Type 0 is no bleeding. Type 1 is bleeding that is not actionable and does not cause the patient to seek medical attention. Type 2 bleeding includes any clinically overt sign of hemorrhage that is actionable and requires diagnostic studies, hospitalization, or treatment by a healthcare professional. Type 3 bleeding is divided into 3 categories. Type 3a bleeding includes any transfusion with overt bleeding plus a hemoglobin drop of 3 to < 5 g/dL (provided the hemoglobin drop is related to bleeding). Type 3b bleeding includes overt bleeding plus a hemoglobin drop of ≥ 5 g/dL (provided the hemoglobin drop is related to bleeding), cardiac tamponade, bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid), and bleeding requiring intravenous vasoactive agents. Type 3c bleeding includes intracranial hemorrhage and intraocular bleeding compromising vision. Type 4 bleeding is associated with procedures of coronary artery bypass grafting, such as perioperative intracranial bleeding within 48 h and reoperation after closure of sternotomy for the purpose of controlling bleeding. Type 5 bleeding is fatal.

Data collection

The medical records of subjects were reviewed to identify whether bleeding or major adverse cardiac and cerebrovascular events (MACCE), including systemic thrombosis, myocardial infarction and cardiac death, had developed up to the end of December 2019 (primary endpoint). Observations ceased when bleeding or MACCE occurred, or the patient stopped visiting our institution for >6 consecutive months without a documented reason (dropout cases). Baseline characteristics of subjects, meaning data at the time of the index bleeding event, were also investigated, including biographic data (age, sex, height, weight), type of DOAC, comorbidities (hypertension, dyslipidemia, diabetes mellitus, chronic heart failure, ischemic heart disease, cerebrovascular disease, peripheral artery disease, chronic kidney disease, chronic obstructive pulmonary disease, liver cirrhosis, advanced malignant diseases), and concomitant medications (steroids, nonsteroidal anti-inflammatory drugs, low-dose aspirin, adenosine diphosphate receptor P2Y12 antagonists, or proton pump inhibitors (PPIs)). CHADS2 score and HAS-BLED score were also obtained from the background data.

Statistics

All statistical analyses were performed using SPSS Statistics version 24 (IBM Japan, Tokyo, Japan). Continuous variables are presented as median (interquartile range [IQR]) and categorical variables were shown by number and/or percentage. In order to minimize effects of confounders, differences in ratios between groups were evaluated by linear correlation model using inverse probability weighting methods. Differences with two-sided alpha levels of <0.05 were determined as statistically significant.

Ethics

This protocol was approved by the institutional review board of Teikyo University prior to the study (approval number TU-18-216). All methods were carried out in accordance with relevant guidelines and regulations. The need to obtain informed consent was waived by the ethics committee that approved the study, given the retrospective design of the study.

Results

Characteristics of subjects at index bleeding

Fig 1 depicted the details of study flow. First of all, 2005 patients who had been prescribed DOAC were obtained. There were 172 patients prescribed DOAC for NVAF and experienced clinically relevant bleeding. Among those, 76 patients were excluded due to prescribed only in the hospital (n = 48), prescribed less than 1 month (n = 12), unable to follow up after bleeding (n = 10) and bleeding after medical procedures (n = 6).

Fig 1

Flowchart for selection of study subjects.

Abbreviations: DOAC, direct oral anticoagulant; NVAF, non-valvular atrial fibrillation.

Table 1 shows the characteristics of subjects, and Table 2 shows the site and severity of bleeding. As shown in Table 1, 96 patients were eligible to the subjects. The median age was 76 years old, and male dominant. Prescribed DOACs were rivaroxaban in 51 (53%), dabigatran in 22 (23%), apixaban in 18 (19%), and edoxaban in 5 (5%). The median CHADS2 score was 2, and HAS-BLED score was 3. Regarding comorbidities, hypertension, dyslipidemia, chronic heart failure and chronic kidney disease coexisted with high rate more than 50%. As for concomitant drugs, low-dose aspirin was given in 27% and P2Y12 was in 17%. The rate of concomitant prescription of proton pump inhibitors reached to 51%.

Table 1

Characteristics of study subjects at index bleeding.

Characteristics	Total
Number of patients	96
Age (years), median (IQR)	76 (70–81)
Sex (male), n (%)	57 (59.3)
Height (m), median (IQR)	1.59 (1.50–1.67)
Weight (kg), median (IQR)	58.3 (48.6–67.0)
CHADS2 score, median (IQR)	2 (2–3)
HAS-BLED score, median (IQR)	3 (3–4)
DOAC before bleeding, n (%)
Dabigatran	22 (22.9)
Rivaroxaban	51 (53.1)
Apixaban	18 (18.8)
Edoxaban	5 (5.2)
Comorbidities, n (%)
Hypertension	82 (85.4)
Diabetes mellitus	22 (229)
Dyslipidemia	56 (58.3)
Chronic heart failure	60 (62.5)
Ischemic heart disease	27 (28.1)
Cerebrovascular disease	13 (13.5)
Peripheral arterial disease	6 (6.3)
Chronic obstructive pulmonary disease	8 (8.3)
Liver cirrhosis	0 (0.0)
Advanced malignancy	13 (13.5)
Chronic kidney disease	63 (65.6)
Medications, n (%)
Low-dose aspirin	27 (28.1)
P2Y12	16 (16.7)
Nonsteroidal anti-inflammatory drugs	8 (8.3)
Steroids	4 (4.2)
Proton pump inhibitor	51 (52.1)

IQR: interquartile range, n: number, DOAC: direct oral anticoagulants,* P2Y12: adenosine 2 phosphate receptor P2Y12 antagonist.

Table 2

Cause and severity of index bleeding in study subjects.

Site of bleeding	Number of patients	Severity of bleeding (BARC type 2/type 3 or more)
Total	96	64/32
Gastrointestinal tract	57	31/26
Upper	17	6/11
Peptic ulcer	12	3/9
Gastric polyp	2	1/1
Gastric cancer	2	1/1
Vascular ectasia	1	1/0
Lower	40	25/15
Diverticulum	14	7/7
Vascular ectasia	9	6/3
Hemorrhoid	8	6/2
Cancer	4	2/2
Inflammation	4	3/1
Rectal ulcer	1	1/0
Other site	39	33/6
Intracranial	5	0/5
Nasal cavity	9	9/0
Urinary tract	7	7/0
Oral cavity	6	6/0
Cutaneous/Subcutaneous	7	7/0
Ocular region	4	3/1
Joint	1	1/0

Abbreviation: BARC, criteria of the Bleeding Academic Research Consortium.

Table 2 shows that 57 of all the subjects had experienced GIB (59%), with lower GIB representing the majority, while upper GIB had a higher rate of BARC type 3 or more, meaning that upper GIB tended to be more serious. The major cause of upper GIB was peptic ulcer, and reasons for lower GIB included diverticulum, hemorrhoids, malignancy, and vascular ectasia. Other sites of bleeding included cutaneous, ocular, nasal, oral, urological, and intracranial bleeding. Most episodes of bleeding remained mild in severity, excluding intracranial bleeding.

Rebleeding and thrombosis after initial bleeding

Table 3 summarizes data concerning rebleeding and thrombotic events after initial bleeding in subjects. The observation period was 242.6 patient-years. Of all 96 patients, 11 developed rebleeding (4.5%/year), including GIB in 10 and subarachnoid hemorrhage in 1. The lower GI tract was the majority site of rebleeding, and the most common cause was colonic diverticulum. On the other hand, MACCE occurred in 6 patients (2.5%/year), with systemic thrombosis in 4 (2 death) and cardiac death in 2. There was no case of cardiac infarction.

Table 3

Rebleeding and thrombotic events after initial bleeding in patients on direct oral anticoagulant therapy.

Data
Observation data
Number of patients	96
Period, patient-years	242.6
median (IQR)	2.3 (0.8–3.7)
Dropout, n (%)	3 (3.1)
Adverse events; n (%/year)
Rebleeding	11 (4.5)
Gastrointestinal	10 (4.1)
Gastric vascular ectasia	1
Colonic diverticula	7
Colonic cancer	1
Hemorrhoid	1
Intracranial	1 (0.4)
Subarachnoid hemorrhage	1
Major adverse cardiac and cerebrovascular event	6 (2.5)
Cardiac death	2 (0.8)
Myocardial infarction	0 (0)
Systemic thrombosis	4 (1.6)

Abbreviations: IQR, interquartile range; n, number.

Table 4 describes status of anticoagulation therapy after initial bleeding. Most patients had resumed anticoagulation therapy after bleeding, excluding 10 patients for whom prescription of all oral anticoagulants was withheld. About half of the subjects resumed the same drug with the same dosage as before initial bleeding, while 40% of them changed drugs to other OAC. The duration of withdrawal was less than 14 days in 90% of patients resuming anticoagulant therapy.

Table 4

Status of anticoagulation therapy after initial bleeding during direct oral anticoagulants in patient with nonvalvular atrial fibrillation.

Anticoagulation therapy after index bleeding, n (%)
Restart with same drug on same dose	46 (47.9)
Restart with same drug on reduced dose	3 (3.1)
Restart with other drugs	37 (38.5)
To dabigatran	2
To rivaroxaban	3
To apixaban	16
To edoxaban	4
To warfarin	12
Withhold medication	10 (10.4)
Total	96 (100)
Duration from bleeding to resume therapy (n = 86)
≤ 7 days	69 (80.2)
8–14 days	9 (10.5)
15–30 days	5 (5.8)
≥ 31 days	3 (3.5)

Table 5 shows the impact of factors on development of rebleeding. Rate of resumption of anticoagulation therapy was 100% in patients experienced rebleeding. Past history of GIB was a significant factor predicting the development of rebleeding. Concomitant prescription of antiplatelet was not significantly related to rebleeding. In patients with rebleeding, HAS-BLED scores tended to be higher than those in patients without rebleeding, although it remained statistically insignificant.

Table 5

Relationship between occurrence of rebleeding and major factors in patients with non-valvular atrial fibrillation.

Characteristics	Rebleeding (+)	Rebleeding (-)	Adjusted hazard ratio* (95% Confidence interval)	P-value
Number of patients	11	85	-	-
Time to rebleeding, month (range)	18 (1–60)	-	-	-
Past GIB, n (%)	10 (91.0)	53 (62.3)	11.672 (1.390–98.009)	0.024
Resumption of anticoagulant, n (%)	11 (100)	75 (88.2)	9.6x108 (3.7x108-24.1x108)	<0.001
Concomitant antiplatelet, n (%)	6 (54.5)	25 (29.4)	0.925 (0.216–3.961)	0.916
HAS-BLED score, median (IQR)	4 (3.5–4.5)	3 (3–4)	1.672 (0.924–3.023)	0.089

* Evaluated by generalized linear model using propensity score weighting by inverse probability weighting method. Abbreviations: n, number; GIB, gastrointestinal bleeding, IQR, interquartile range.

Table 6 describes the occurrence of MACCE and possible relating factors. All 6 patients suffering from MACCE were 75 years of age or more. Anticoagulation therapy was withheld in 4 of 6 patients experiencing MACCE. Especially, all 4 patients with systemic thrombosis did not resume anticoagulants after initial bleeding events.

Table 6

Relationship between occurrence of MACCE after initial bleeding and major factors in patients with non-valvular atrial fibrillation.

Characteristics	MACCE (+)	MACCE (-)	Adjusted hazard ratio* (95% Confidence Interval)	P-value
Number of patients	6	90	-	-
Time to MACCE, month (range)	8.5 (5–23)	-	-	-
75 years old or more, n (%)	6	48	7.0x108	<0.001
	(100%)	(53.3%)	(2.6x107-1.8x1010)
Sex (male), n (%)	2	61	0.132	0.057
	(33.3)	(63.5)	(0.016–1.064)
Withhold of anticoagulant, n (%)	4 (66.7)	6 (6.7)	3.243	0.290
			(0.367–28.624)
CHADS2 score, Median (IQR)	2.5 (2–3)	3 (2–3)	0.985	0.965
			(0.499–1.446)

*: generalized linear model using propensity score weighting by inverse probability weighting method. Abbreviations: MACCE, major adverse cardiac and cerebrovascular events; IQR, interquartile range.

Discussion

The present results showed that the gastrointestinal tract was the most frequent site of index bleeding, and GIB tended to be more serious than bleeding from other sites. HAS-BLED score, which represents factors associated with bleeding during warfarin treatment, indicates that a past history of bleeding is an obvious risk for future bleeding [20-24]. Our previous study indicated that a history of GIB was one of the significant risk factors for rebleeding from gastrointestinal tract among patients who have received DOACs [25]. Since the rebleeding rate was higher than the incidence of MACCE, the risk of rebleeding should be kept in mind, especially in the gastrointestinal tract.

Concerning the site of GIB, a high proportion of cases showed sites other than the upper gastrointestinal tract. Previous studies have reported that simultaneous PPI with DOAC has prophylactic effects against the onset of upper GIB [26-30]. In the present study, the upper GIB would have been suppressed probably because the rate of concomitant PPI use was high, in more than half of patients. On the other hand, no solution to prevent bleeding has been established for other parts of the gastrointestinal tract. Lanas et al. mentioned that concomitant use of PPIs among patients on antithrombotic drugs was associated with a reduced risk of upper GIB, but not a lower risk of GIB [30]. Although the severity of lower GIB tended to be lower than that of upper GIB, as shown in Table 2, lower GIB sometimes becomes life-threatening because of the risk of interruption to pharmacotherapy. Lower GIB warrants caution, even if these symptoms and signs are not serious.

For the resumption of anticoagulant therapy after bleeding, a previous study indicated no increase in the risk of embolism development if warfarin is resumed within 30 days after bleeding, while restarting warfarin within 7 days was associated with an increased risk of recurrent GIB compared to restarting after 30 days [16]. As for DOAC, Sengupta et al. reported that in 1338 patients with GIB during DOAC therapy, restarting DOAC therapy within 30 days after admission due to GIB was not associated with thromboembolism or recurrent GIB within either 90 days or 6 months [18]. In the present study, the resumption rate within 30 days was approximately 90%. However, although only 10 patients were still withheld DOACs after initial bleeding, MACCE occurred in 4. Especially, all 4 patients with systemic thrombosis withheld anticoagulants. In the literature, the strongest predictors for withholding anticoagulants were concomitant antiplatelet agents and a history of bleeding, and 40–50% of patients with AF are regarded as being in a state of anticoagulant under-use [22, 31–33]. On the other hand, it is to be noted that all cases of rebleeding resumed anticoagulation therapy, and more than half of them were also on antiplatelet drugs concurrently. The necessity for combined use of antithrombotic drugs may be considered carefully in patients with a history of bleeding.

Limitations of this study included the use of a single facility, the small number of subjects, and the retrospective study design. In retrospective studies, the number of dropouts is often problematic, but was only 4 patients in this study, and was thus considered to have had little effect on the results. Research involving multiple facilities is desirable in the future.

Conclusions

The present study showed that GIB was common and serious among patients taking DOACs. The incidence of rebleeding seemed high, while withholding of anticoagulants was associated with a high rate of developing thromboembolism.

22 Feb 2021

PONE-D-20-38582

Clinical course after hemorrhage in patients taking direct oral anticoagulants

PLOS ONE

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Reviewer #1: In this manuscript, Yanagisawa et al describe the bleeding and ischemic events in a cohort of DOAC-treated patients after a first hemorrhage. It is a retrospective, descriptive, chart review study that is nonetheless clearly written and informative. It is well curated and attention has been paid to the details. I have (very few) suggestions touching upon a number of structural issues.

Major comments

-This is a descriptive study or patients who have already bled. It cannot speak to incidence of first bleeding, risk factors for bleeding etc. The authors are generally cautious about this throughout the manuscript yet in the final conclusions the state that “the present study showed that GIB was common and serious among patients taking DOACs,” which would require knowing the incidence of bleeding among the 2005 patients mentioned in the methods section that were prescribed DOAC during this period. They then go on to state that “clinicians should endeavor to…” this study cannot speak to what should be done in practice. It is clear that patients who do not resume anticoagulation are generally of greater hemorrhagic and thrombotic risk than those who do not resume and that therefore, retrospective data cannot resolve the question over what clinicians should or should not do when facing a patient who had a major bleeding. Indeed, precisely because this is the case, a number of trials are ongoing randomizing resuming vs. not resuming anticoagulation in patients with intracranial hemorrhage (I am less sure about those with gastrointestinal bleed, but the question over confounders stands). While I am sympathetic to the idea that resuming should be the default position based on the best data we have, this study cannot be used to advise clinicians on what to do.

Minor concerns/suggestions:

-A distinction between spontaneous and traumatic and surgical bleedings should be made throughout the manuscript. At least some are procedure-related based on the table (polypectomy). Nasal bleeding may be related to ENT examinations etc etc. I would judge these patients to have a lower re-bleeding risk (other than related to further procedures) and would rarely hesitate to recommend re-starting anticoagulation; at least it would give me less pause than a spontaneous major bleed would. This is important data.

-I have some misgivings about splitting the cohort into GI bleeding and “other.” I worry that this was a post-hoc split the authors may have made after finding a statistical difference in severity or to have a “comparison” in what is really a descriptive study. The group of other is very heterogeneous to the extent that it becomes a meaningless category (what do nasal bleedings have to do with intracranial hemorrhages). I suggest focusing on the description of all hemorrhages, rather than on the comparison between these two groups, which should just be a side issue. In line with this, it is very hard to know what to do with figure 2, and I suggest removing it. Comparing these two groups, which are otherwise not comparable, is not useful. An informative comparison between these two very different groups would require taking into account many variables, both known and unknown, and this cannot be done in this small patient cohort. A crude comparison between patients who bleed from the GI tract and those who bleed from other sites can be deceiving

Reviewer #2: The authors have reported outcomes in a cohort of patients taking DOACs. The data contained in the paper are not particularly bovel. There are trials and metaanlaysis already reporting bleeding rates in patients taking DOACs but the autjors have added some mroe "real world" data to the body of the literature. Although the overall size of the group is small, once getting down to the subgroups, it is unteresting to see the outcomes in those following reintroduction of anticoagulant after a bleeding episode. Overall the data once again confirm that decsions about reintroduction of anticoagulation need to balance the risk of rebleeding, troublemsome but rarely life-altering against the risk of thromboembolism which can be more clinicaly signficant. The equation usually falls in favour of restarting anticoagulation and this study provides some real workd data to support this. Overall the manuscipt is adequately structured and presented. The writing is suficiently concise. There are a few areas that would benefit from further clarification.

1. In the abstract, it would be very informative to actually give the numerical data for rebleeding and thrombosis speparately for those that had anticoagulation resumed and those that did not. As currently writen it is not clear what these figures for complications after the initial bleeding episode represent.

2. The flow chart explaining subject flow through the study needs more clarity. The reasons for exclusion need to be given and the disposition of subjects made clearer. Simialrly from over 2000 patients with atrial fibrillation there appear to be no deaths during the follow-up period. Is this really the case?

3. Although the authors have usedthe data they have available. The paper should contain a formal statement about samoke size and power calculation related to the planned primary outcome, this will enable the reader to determine if the study is really able to answer the question that the authors have raised. The methods section needs to be clearer about what the primary hypothesis being examined in this study is.

4. The discussion about subjects excluded from the study, currently placed in data collection, more appropriatelyly belongs in the study design and subjects section.

5. Although the focus of this study is on outcomes after the 1st bleeding episode, it is unfortunate given the comprehensive follow up that Table 1 does not include the data for the group that had no bleeding, to allow clearer comparsion.

6. The data of most interest to clinicians will be the outcomes after the 1st bleed, and the differenttiation between those restarted and those without anticoagulation. Hence burying the combined data at the bottom of a summary table 3 is rather unhelpful. These data should be represented separately, although the numbers are small.

7. The authors have provided a lot of data on the co-morbidities of the group post-index bleeding. I am not sure such granualr detail helps at all, especially as the authors have not clearly defined what they consider the inclusions for each of their criteria. Including the data on HAS-BLED scores for the rebleeding and non-rebleeding groups is essntial. This would allow greater generarisation.

8. The overall rebleeding rate seems comparable to other studues, again the authors should be able to estimate from HAS-BLED scores whether the rebleeding rate in their cohort is higer or lower than anticipiated.

9. The authors seem rather over reliant in "p" values to assess differences between groups. It would be more appropriate to repesent these differences a odds ratio/hazaed ratio with 95% confidence intervals. Hence tables 5 and 6 should have these data included For clarity, it would be reasonable to leave out the OR/HR where there is clearly no difference but where the paper cites a "p" value the OR/HR with confidence interval is the correct way to represent this.

Reviewer #3: Comments to authors

This is a neat descriptive study of patients on NOAC who experience bleeding.

There are three points where we need more detailed information.

1. It would be very useful to present more details as to how the anticoagulant drug was restarted. In Table 3 we are informed that 45 pts restarted same drug and 45 changed medication. I believe that this is very vague. We should know if the dose was reduced, if the NOAC was changed (and also from which agent to which agent the change was made) or if warfarin was recommended. A table with the number of pts who remained on same NOAC dose, who restarted lower dose of NOAC and who switched NOAC (or went back to warfarin) would do.

2. A large number of pts was also receiving concomitantly antiplatelet drugs. And it appears that AFTER the bleeding episode many (or all?) continue on them. For example 28 pts were on aspirin (and 17 on P2Y12) before bleeding (table 1) and, surprisingly, 28 remain on aspirin (and 17 on P2Y12) after bleeding (table 5 and 6). Similarly the same number of pts is on PPI before and after bleeding (55 pts) which is odd. The common practice in AF pts who bleed is to withdraw the antiplatelet therapy first rather than stop the NOAC.

3. The rate of MACCE in this group of 102 pts is 2.5%/year. It would be interesting to have the rate for the 2005 pts overall (to confirm that pts who bleed are a high risk group)

4. Accordingly the above issues should be commented in the discussion.

Reviewer #4: The authors report on a cohort of patients with DOAC-related bleeding at a single hospital site in Japan. Previous literature in this area is based on similar observational cohorts at high risk of bias. Some comments are included below for consideration prior to publication.

Introduction

- DOACs have been approved for clinical use for over 10 years (i.e. no longer "recent"). In light of this, what additional information does this study provide beyond existing literature?

- Anticoagulant discontinuation after bleeding is associated with a higher risk of thrombosis and death, but studies were limited by baseline confounding and likely differences in prognosis among patients who resumed versus those who did not resume anticoagulation after bleeding

- it would be helpful to provide specific objectives for readers. As written, "clarify the course after bleeding" is vague.

Methods

- In general, additional details regarding the methods are required.

- Further, some results are included in the methods section (i.e. 2005 patients)

- Please list specific inclusion/exclusion criteria at the beginning of the Study Population section. Patients with AFib? Any dose of DOAC? Why were patients receiving DOACs for less than one month excluded?

- Were these patients identified by outpatient prescriptions?

- Did patients have both reliable inpatient and outpatient follow-up?

- What does "able to be followed up" mean? This indicates that they may not have captured all potential patients. What about patients who weren't able to be followed? It would be important to document loss to follow-up.

- Please clarify the reason BARC was selected as opposed to ISTH definitions which are commonly used in this population

- What does "clinical course was examined every month" mean?

- Did you collect information about DOAC dosing?

- No adjustment for baseline confounding was done (e.g. by regression). Some justification should be provided about why associations were not explored using regression analysis.

- What was the duration of follow-up?

Results

- the rate of clinically relevant bleeding in this cohort seems low (102 out of 2005 patients) over 6 years

- Table 1 should indicate the type of bleeding at cohort entry. Not sure why GI bleeding and "Other bleeding" were separated out into columns. Please include individual DOACs on separate lines (as opposed to D/R/A/E)

- What is meant by "upper GIB tended to be more serious"? Hospitalization? ICU admission? Hemodynamic instability?

- "Tendency to become serious" is vague

- "Little difference was seen between patients with GIB and those with other bleeding" with respect to comorbidities is also vague

- Any differences in dose for restarting anticoagulation?

- Did severity of bleeding or site of bleeding influence therapy?

- Did you capture all-cause death within your cohort? HOw was cardiac death adjudicated?

- When did re-bleeding occur?

- Remove comorbidites from Tables 5 and 6

- What about loss to follow-up?

Discussion

- the conclusions are overstated. It is not clear how the authors showed conclusively that resumption of anticoagulation was not associated with rebleeding as it is stated and based on the analyses conducted

- what does this study add to existing literature?

- The COMPASS trial showed that prophylactic PPI did not influence bleeding (factorial randomization)

- Anticoagulant related GI bleeding is more than "troublesome" with mortality rates of ~10% at 30 days in some cohorts

- Clinical recommendations about the timing of treatment re-initiation is beyond the scope of this paper and remains highly uncertain

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Ian L. P. Beales

Reviewer #3: No

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

16 Jul 2021

I am sorry that it took a lot of time to revise our manuscript. As you pointed out, the first paper we submitted had many problems with study design, data presentation and data analyses. We have changes substantially of the data presentation and statistical analysis, and corrected according to the indications as much as possible.

Submitted filename: Response To Reviewers.docx

Click here for additional data file.

24 Aug 2021

PONE-D-20-38582R1

Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants

PLOS ONE

Dear Dr. Abe,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Your paper was reevaluated by the previous reviewers. Though the manuscripts was improved, minor points still need to be clarified. Please read the comments carefully and address the issues accordingly.

Please submit your revised manuscript by Oct 08 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have tackled some of the issues I (and others reviewers have raised). I appreciate their effort and I thank them. I do think this is a more balanced manuscript and important details have been added in response to comments other reviewers have raised. As far as I go, I have a few minor issues and a comment that pertains to the major issue I raised in the previous draft

Major comments

-The authors have removed a comment that spoke to the clinical decisions that physicians should make based on this retrospective study, given the potential biases. However, another such comment is present in the current version. Page 14 line 246 “clinicians should resume anticoagulants after bleeding events….” I still think this study (or any of the other studies published, which are all retrospective and/or observational) cannot be used to reach this conclusion. I suggest removing this statement

Minor concerns/suggestions:

-Most importantly for clarity I think the authors should use consistently bleeding for the first bleeding (the one leading to study entry) and rebleeding for subsequent hemorrhages. While they occasionally do, this is not consistent (e.g., section title “Bleeding and thrombosis after initial bleeding” would be “Rebleeding and thrombosis…”), page 9 line 163 “…11 developed rebleeding”, table 3 (title and table itself) etc . I think this would help follow the text more easily.

-Methods. Page 4 lines 76-78 and page 5 lines 92 -93 are redundant (same exclusion criteria are mentioned)

-Statistics section fail to mention most of the analyses conducted

-Table 1 title is confusing as “baseline” and “at index bleeding” seem contradictory (baseline would generally mean at the time of starting anticoagulation)

-Tables 5 and 6 include “E8” on several occasions in the aOR column. Meaning is unclear. Does that mean 10 raised to the power of 8? This seems unplausible but in any event meaning should be cleared up.

Reviewer #2: The revised manuscript is much improved and presents some more data examining the relative safety of restarting DOACs after a bleeding episode. The overall cohort is small and the data are not really any different from several other reports. The data again emphasize the overall safety of early reintroduction of DOACs in this situation. The size of the cohort makes it difficult to draw strong conclusions on the relative risks.

There are no major sticking points.

Some relatively minor points to consider addressing.

1. Amend the title to include......for non-valvular atrial fibrillation. The study specifically focuses on this group of patients taking DOACs, and although the results are likely to have some generalisability, the risk stratification for other indications for DOACs may be different.

2. The authors give rates of bleeding events and thrombotic events per year, in the Results section. Given the small cohort and limited number of events (especially thrombotic) the confidence intervals around these rates are likely to be high. By just giving a single figure, this suggests that rates of bleeding a nearly three times higher than thromboembolism. I doubt that the data are rich enough to say that for certain. Please include some marker of the range or confidence intervals around these calculations of event rates.

Reviewer #3: the paper is now more informative. My only concern is again related to the use of antiplatelet drugs. It is not clear if rebleeding was mainly recorded in pts who remained on combination therapy. It is unfair to attribute a bleeding (or re-bleeding) on DOAC rather than on antiplatelet if this was also given. At least a comment in the discussion is needed.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: marc sorigue

Reviewer #2: Yes: Ian L. P. Beales

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

11 Sep 2021

We appreciate your repeated careful guidance. We feel that our manuscript is of high quality owing to your cooperation.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

10 Nov 2021

PONE-D-20-38582R2Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillationPLOS ONE

Dear Dr. Abe,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Your paper was reevaluated by the previous two reviewers. One reviewer did not respond to my invitation for review but the reviewer seems to be satisfied with your answer and revised manuscript. There is one minor modification suggested by one reviewer this time. I would recommend adding a description to discussion (please see the comment).

Please submit your revised manuscript by Dec 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: I think that a brief comment in the discussion should adress the fact that some pts restarted not only the NOAC but the antiplatelet as well.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: marc sorigue

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Nov 2021

I am very grateful for the careful proofreading and the accurate advice.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

15 Nov 2021

Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation

PONE-D-20-38582R3

Dear Dr. Abe,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

17 Nov 2021

PONE-D-20-38582R3

Thrombotic events and rebleeding after hemorrhage in patients taking direct oral anticoagulants for non-valvular atrial fibrillation

Dear Dr. Abe:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tomohiko Ai

Academic Editor

PLOS ONE