Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany

Abstract

Background

Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran.

Aims

To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage.

Methods

Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used.

Results

Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0–3 in 67%. Overall, mortality was low with 6.5% (one patient in each group).

Conclusion

Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Keywords

Idarucizumab dabigatran ischemic stroke intracranial hemorrhage thrombolysis outcome

Introduction

Neurologists use the direct thrombin inhibitor dabigatran most frequently in secondary stroke prevention in patients with atrial fibrillation. The RE-LY study^1–3 showed superiority of dabigatran 150 mg bid for the prevention of ischemic stroke compared to warfarin, and in the subgroup of patients with prior TIA or stroke, dabigatran was non-inferior to warfarin.⁴ Three other non-vitamin-K-antagonizing oral anticoagulants (NOACs) are approved for stroke prevention in patients with atrial fibrillation.^5–7 As a group, NOACs have lower rates of bleeding complications in comparison to warfarin, in particular when considering intracranial hemorrhage.⁸ A major concern for the use of oral anticoagulation is the lack of specific and rapidly acting reversal agents for vitamin-K antagonists or NOACs.

This has changed for dabigatran with the approval of idarucizumab, a humanized Fab fragment of a monoclonal antibody which binds specifically dabigatran with very high affinity. It is indicated in dabigatran-treated patients with life-threatening or uncontrolled bleeding or those in need of urgent surgery or intervention.^9,10 To date, the use of idarucizumab in patients with acute ischemic stroke who qualify for systemic thrombolysis with rt-PA is limited to single case reports.^11–15

Aims

This report summarizes national experience with idarucizumab administration in dabigatran-treated patients suffering from acute ischemic stroke or intracranial hemorrhage in Germany following market launch in January 2016, for the first eight months until August 2016. We provide data about feasibility, potential efficacy and safety of idarucizumab application in these two important patient cohorts.

Methods

We retrospectively collected data from all German neurological/neurosurgical departments who used idarucizumab for the reversal of dabigatran for the first eight months from when it became available in the clinic in January 2016. The anonymized patient data collected included baseline characteristics, clinical findings, laboratory and coagulation parameters upon admission, imaging diagnostics, clinical course and status upon discharge from hospital and further co-medication. In case of intracranial hemorrhage, we collected information on hematoma growth with clinical deterioration, adverse events of idarucizumab application and outcome measured by modified Rankin score (mRS) pre- and post-treatment. For ischemic stroke, we considered NIHSS, mRS, bleeding and thrombotic complications, clinical outcome and further co-medication. All data were retrospectively collected, anonymized and transferred for analysis. A few previously reported single case reports were included in this analysis as these cases are still rare and were considered important for this multicenter collection of patients.^11–13,16 The study was approved by the independent Ethics Committee (IEC), Medical Faculty of Essen University.

Results

Our retrospective study retrieved 31 patients presenting with either intracranial hemorrhage or ischemic stroke from German Stroke Units, who received idarucizumab between January and August 2016.

Ischemic stroke patients

Nineteen patients (58% female, 42% male; median age 78 years; median NIHSS upon admission 7) presented with ischemic stroke (Table 1). Eighteen of these stroke patients presented within the 4.5 h window for systemic thrombolysis, and one patient suffered a wake-up stroke. They did not display signs of bleeding or early infarct signs on initial CT scan (see Table 1 for baseline characteristics, laboratory examinations, clinical course and outcome). All patients were on dabigatran, 14 receiving 110 mg bid; 17 had a history of non-valvular atrial fibrillation (NVAF). Upon admission, the activated partial thromboplastin time (aPTT) values were normal in 68% of patients (13 out of 19 patients). Initial thrombin time (TT) was available in 12 out of 19 patients. TT was prolonged above the upper limit of normal in 92% (11 out of 12 patients). All individuals received idarucizumab according to the prescribing information. All coagulation parameters were normalized in the patients where coagulation parameters were available post idarucizumab administration (Table 1). rt-PA was given to all patients according to prescription protocol and local SOPs, and one patient underwent additional thrombectomy. Fifteen out of 19 individuals benefitted from i.v. thrombolysis with a median improvement of 5 points in NIHSS (mean from 8 to 3.6 points; median from 7 to 2 points). One patient had no change in NIHSS prior and after thrombolysis. Two patients had an unfavorable outcome. Patient #10 presented with signs of acute vertebrobasilar stroke and deteriorated 24 h following admission from NIHSS 7 to 18 due to a large brainstem, cerebellar and PCA infarction, while treated with ASA 100 mg. Patient #9 died five days after idarucizumab application, rt-PA thrombolysis and additional endovascular thrombectomy after initial neurological improvement due to severe pneumonia, deep vein thrombosis, and bilateral pulmonary embolism. The clinical complications developed a few days following the index event under treatment with enoxaparin 40 mg/d and ASA 100 mg/d.

Table 1.

Idarucizumab for reversal of Dabigatran activity prior to iv. rt-PA treatment of acute ischemic stroke

Case No.	Sex	Age	Dabigatran dose	Indication for OAC	CrCl (ml/min)	aPTT Adm (s)	aPTT Post Idarucizumab (s)	TT Adm (s)	TT Post Idarucizumab (s)	Restart Antithrombotic Treatment (drug)	NIHSS Ad.	NIHSS Dis.	mRS Ad.	mRS Dis.
1	M	75	110 mg bid	NVAF	69.2	38.0	31.9	66.8	n.a	24 h D110 mg bid	5	1	3	1
2	F	40	110 mg bid	CMP†	102	24.3	24.1	69.1	n.a	7 d VKA	12	1	4	0
3	M	83	110 mg bid	NVAF	58.4	34.6	30.9	45.4	17	8 d D110 mg bid	4	2	2	1
4	M	76	110 mg bid	NVAF	75	73	n.a.	218	n.a.	3 d D150 mg bid	11	1	4	1
5	F	67	150 mg bid	NVAF	n.a.	26	n.a.	129.8	n.a.	10 d Apixaban 2.5 mg bid 20 d Apixaban 5 mg bid	10	8	4	4
6	F	86	110 mg bid	NVAF	52.2	34.6	35.7	n.a.	n.a.	24 h D110 mg bid	5	2	2	1
7	F	86	110 mg bid	NVAF	n.a.	45	28	n.a.	n.a.	Edoxaban Dose not specified	12	2	4	1
8	F	58	150 mg bid	ESUS†	89	35.8	26.8	87.5	0,0	3 d Argatroban	3		3
9^a	M	53	150 mg bid	NVAF	112	25.9	28.1	19.2	n.a.	n.a.	17	n.a.	5	6
10	F	75	110 mg bid	NVAF	64	35.6	n.a.	>150	n.a.	24 h ASA 100 mg 21d-28 d OAC not specified	7	18	5	5
11	M	80	110 mg bid	NVAF	47	59	33	>150	17	24 h D110 mg bid	5	2	2	0
12	F	94	110 mg bid	NVAF	48.3	69	33	>150	n.a	30 h D150 mg bid	6	0	4	0
13	M	85	150 mg bid	NVAF	73.5	48	29	n.a	n.a.	24 h ASA 100 mg Certoparin 3.000 IE 7 d D150 mg bid	7	1	3	1
14	F	78	110 mg bid	NVAF	52	84	35	n.a	n.a.	48 h D150 mg bid	7	1	2	1
15	F	84	110 mg bid	NVAF	112	25.6	n.a.	n.a.	n.a.	48 h ASA 100 mg	14	14	4	4
16	M	77	110 mg bid	NVAF	79	43.6	n.a.	n.a.	n.a.	48 h D150 mg bid	4	1	4	1
17	M	54	150 mg bid	NVAF	72	26.1	38.5	24.1	n.a.	24 h D150 mg bid	11	2	3	2
18	F	89	110 mg bid	NVAF	57.5	38.9	28.2	n.a.	n.a.	8 d D110 mg bid	5	2	2	2
19	F	90	110 mg bid	NVAF	64	37	n.a.	>120	n.a.	24 h ASA 100 mg 7d D110 mg bid	7	3	3	1

OAC: oral anticoagulation; NVAF: non-valvular atrial fibrillation; CrCl: creatinine clearence; rt-PA: recombinant tissue type plasminogen activator (alteplase); ATT: antithrombotic treatment; VKA: vitamin-K-antagonist; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; aPTT: activated partial thromboplastin time; TT: thrombin time; dTT: diluted thrombin time;

CMP (Cardiomyopathy); ESUS (Embolic Stroke of Undetermined Source) †: off-label indication

Including mechanical thrombectomy.

The majority of patients with signs of ischemic stroke had a CrCl above 50 ml/min. Anticoagulation was restarted between 24 h and 10 days post-ischemia depending on infarct size in all surviving patients. In total, 73.7% of patients (14 out of 19) were restarted on NOAC (dabigatran n = 12, apixaban n = 1, edoxaban n = 1).

Patients with intracranial bleeding

Twelve patients presented with intracranial hemorrhage (Table 2). Among these, the majority presented with intracerebral hemorrhage (n = 8). Three cases showed a subdural hemorrhage on CT scans. One patient presented with subarachnoidal hemorrhage. Surgical intervention was necessary in four individuals. All patients were taking dabigatran for stroke prevention in atrial fibrillation, and 5 of 12 patients were on the 150 mg bid dose. The median age was 77 years, 50% were female and median NIHSS upon admission was 8 points. Creatinine clearance (CrCl) was above 50 ml/min in 9 out of 12 of cases. TT upon admission was elevated substantially in all cases examined (n = 9) while aPTT was normal or slightly above reference (n = 11; see Table 2). There was no hematoma growth in 10 out of 12 patients on follow-up CT scans. One patient died; this patient presented with massive bleeding (134.5 ml hematoma volume) and signs of herniation on admission. Overall, outcome was favorable with a median NIHSS improvement of 5.5 points (mean from 11.5 to 5.9 points; median from 8 to 2.5 points) and mRS 0–3 in 67% of patients (8 out of 12; Table 2).

Table 2.

Idarucizumab for reversal of Dabigatran activity in patients with intracranial bleeding

Case No.	Sex	Age	Dabigatran dose	Indication for OAC	ICH type	CrCl	aPTT admission	aPTT post Idarucizumab	TT admission	TT post idarucizumab	Restart ATT (drug)	Volume Adm. (ml)	Hematoma growth	NIHSS Ad.	NIHSS Dis.	mRS Ad.	mRS Dis.
1	M	71	150 mg bid	NVAF	SAH	90.8	30.3	20.7	>120	18.1	36 h Enox 40 mg	n.a.	n.a.	10	0	5	1
2	M	56	150 mg bid	NVAF	ICB	104.8	26.5	22.7	53.4	18.2	12 h Enoxaparin 20 mg	29	+27 ml Intraventricular extension	2	3	3	3
3	F	86	110 mg bid	NVAF	ICB	59.8	34	n.a.	>200	n.a.	None	7	No	4	2	4	3
4	F	78	150 mg bid	NVAF	ICB	n.a.	44	n.a.	n.a.	n.a.	None	134.5	n.a.	33	n.a.	5	6
5	F	83	110 mg bid	NVAF	SDH	112	30	27	73.1	17.6	Enoxaparin Dose not specified	R: 155.05 L: 36.4	No	6	0	5	1
6	M	78	110 mg bid	NVAF	SDH	75	47.3	29.9	n.a.	n.a.	24 h ASA 100 mg	n.a.	No	n.a.	n.a.	2	3
7	F	82	110 mg bid	NVAF	ICB Pons	n.a.	44.2	n.a.	>150	n.a.	n.a.	10	None	4	2	3	2
8	F	74	110 mg bid	NVAF	ICB	66.8	30.3	23.9	81.6	20.6	n.a.	6.2 × 3.9 × 5.8 cm	No	18	9	5	5
9	M	76	110 mg bid	NVAF	ICB	64.6	32.6	28.2	77.8	n.a.	n.a.	3.7 × 3.5 × 2.0 cm	No	32	22	5	5
10	M	83	110 mg bid	NVAF	ICB	69	n.a.	n.a.	119	n.a.	n.a.	8 ml + ventricular extension	No	9	9	2	3
11	F	73	150 mg bid	NVAF	ICB	58	22.4	25	n.a.	n.a.	n.a.	45 × 24 × 26 mm	Yes 24 h following admission	8	12	5	5
12	M	65	150 mg bid	NVAF	SDH bilateral	108	28.8	25.3	93.3	19.1	24 h 3.000 IE Certoparin		No	1	0	1	0

OAC: oral anticoagulation; CrCl: creatinine clearence; rt-PA: recombinant tissue type plasminogen activator (alteplase); ATT: antithrombotic treatment; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale; aPTT: activated partial thromboplastin time; TT: thrombin time; dTT: diluted thrombin time.

Discussion

Thrombolysis with rt-PA is well established and the recommended therapy for acute ischemic stroke according to guidelines. Lack of antidotes for patients on effective oral anticoagulants has to date excluded patients with acute ischemic stroke, who would otherwise have been eligible for intravenous thrombolysis with rt-PA, due to the potential risk of bleeding. Prothrombin complex concentrates (PCC) are recommended by cardiology and neurology guidelines for the treatment of bleeding complications under oral anticoagulation with VKAs and NOACs; however, the efficacy of this therapy has not been established in patients with intracranial hemorrhage.^17–19 In addition, PCC has partial prothrombotic effects. A specific antidote is now available for the reversal of the anticoagulant effect of dabigatran. Idarucizumab is a humanized monoclonal antibody fragment that binds dabigatran ∼350 times more avidly than dabigatran binds thrombin. The standard dose of 5 g immediately reverses the anticoagulant activity of dabigatran.^9,20 Thrombolysis in ischemic stroke is considered an urgent procedure and intracranial bleeding is usually life-threatening. Idarucizumab can be applied on-label for both disease entities. Here, we report the first case collection from clinical experience with idarucizumab for two important neurological conditions: ischemic stroke and intracranial hemorrhage under effective oral anticoagulation.

Ischemic stroke patients

The administration of rt-PA in ischemic stroke requires absence of effective anticoagulation proven by appropriate laboratory tests. For patients on dabigatran, aPTT is recommended as an appropriate test to provide qualitative rather than quantitative information about the presence and anticoagulant activity of dabigatran. We suggest taking a blood sample for aPTT immediately after idarucizumab infusion to ensure an on-label application of rt-PA. Thrombolysis with rt-PA may be started without delay and only terminated if one of the coagulation parameters proves still to be prolonged when analysis of the samples has been performed (see Expert Opinion in this journal issue). Thrombolysis with rt-PA was highly effective in our patient series with a median NIH-SS improvement of 5 points and a median mRS of 1 point at discharge. This improvement was achieved without a bleeding event. One thrombotic adverse event (bilateral pulmonary embolism) leading to death occurred five days after idarucizumab/rt-PA infusion. The pulmonary embolism appeared most probably due to the fact that effective anticoagulation was not restarted in this patient. Idarucizumab infusion was generally well tolerated and anticoagulation with dabigatran could be re-established after 24 h in the majority (66.7%) of patients.

Patients with intracranial bleeding

Five out of 12 patients with primary intracranial bleeding were taking high-dose dabigatran (150 mg twice daily). However, hematoma growth could only be documented in two patients. This is an important finding, as previous data from the RE-LY trial showed that the incidence of ICH was significantly lower in patients on dabigatran; however, mortality was similar under VKA or dabigatran treatment.²¹ In addition, data from a subgroup of patients with intracranial hemorrhage were recently presented from the interim analysis of the RE-VERSE AD trial, focusing on the ability of idarucizumab to reverse the anticoagulant effects of dabigatran in this patient group. The analysis showed a rapid reversal of the anticoagulant activity and a mortality rate similar to patients with non-ICH included in the RE-VERSE AD trial.²²

The mortality after idarucizumab treatment was 6.5% in this case collection of patients with hemorrhagic stroke as compared to 35% (D150 mg) to 41% (D110 mg) mortality in the RE-LY trial.²¹ A recent report by Purrucker and colleagues²³ summarizes 61 consecutive patients with non-traumatic NOAC-associated intracerebral bleeding. In this case cohort, the mortality rate was 28% and hematoma expansion was observed in 38%.

Multinational registries are necessary to quantify effects on bleeding complications, hematoma growth, thrombotic events, outcome and mortality in cases of ischemic stroke and intracranial bleeding from patients treated with dabigatran receiving idarucizumab or other NOACs and anti-factor Xa inhibitor-antidotes when they become available. In Germany, the RASUNOA prime (registry of acute stroke under novel oral anticoagulants, NCT02533960) study was started in 2015 and plans to enroll 4000 patients with atrial fibrillation receiving vitamin K antagonists, NOAC or no therapy and suffering from ischemic or hemorrhagic stroke. They will be monitored for acute treatment and hematoma characteristics. With the case series reported here, we hope to encourage activities in other countries to evaluate and further develop guidelines for the treatment of cerebrovascular complications under NOAC therapy.

In summary, our case collection illustrates:

Intravenous thrombolysis with rt-PA after antagonizing dabigatran with idarucizumab is feasible, easy to manage in an emergency room or stroke-unit setting, appears to be safe and should therefore be considered in cases where ischemic stroke occurs in patients under effective dabigatran therapy.

Idarucizumab application appears to prevent hematoma growth and might reduce mortality and/or improve outcome in cases of hemorrhagic stroke or intracranial hemorrhage and should therefore be given in all patients presenting with intracranial bleeding and effective dabigatran anticoagulation.

Clearly, this study has limitations with regard to the small number of patients included in the analysis and the retrospective nature of the study. However, this case collection of administration of idarucizumab in acute neurological emergencies displays the largest real world experience available to date. Thus, this case collection adds important clinical information until further robust data from large prospective registries will be available.

Footnotes

Acknowledgement

We thank Joanne van Ryn, Boehringer Ingelheim, for critically reading the manuscript.

Authors’ contributions

PK, CCE, H-CD and MG Took part in the study design, data collection, data analysis, data interpretation, and writing. YA, KA, JB, HC, MD, SE, KG, CGH, AH, VH, AK, PK, AL, WM, MO, SP, JP, PAR, JR, RR, NS, AS, RS, RJS, KS, and RW made substantial contribution to the study by local acquisition of data and interpretation of data, critical reading of the manuscript with critical revision and approved the version to be published.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P Kermer received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbvie, Bayer Vital, Biogen, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Genzyme, Novartis, Pfizer, TEVA and UCB.

CC Eschenfelder is an employee of Boehringer Ingelheim.

H-C Diener received honoraria in the last two years for participation in clinical trials, contribution to advisory boards or oral presentations from: Bayer Vital, BMS, Boehringer Ingelheim (significant), Covidien, Daiichi-Sankyo, Medtronic, Pfizer, Sanofi-Aventis and WebMD Global. Financial support for research projects was provided in the last two years by Boehringer Ingelheim. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation.

Martin Grond received honoraria for participation in clinical trials, advisory boards or speakers’ bureau for Boehringer Ingelheim, Bayer Vital, Bristol-Myers Squibb, Pfizer, Daichii-Sankyo, Medtronics and Sanofi Aventis.

Yasser Abdalla reports no conflict of interests.

Katharina Althaus reports no conflict of interests.

Jörg Berrouschot received in the last two years honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Sanofi-Aventis.

Hakan Cangür received honoraria for oral presentations and participation in advisory boards from Boehringer Ingelheim, Bayer and Bristol-Myers Squibb.

Michael Daffertshofer reports no conflict of interests.

Sebastian Edelbusch received travel support for participation in national medical update sessions from Boehringer Ingelheim.

Klaus Gröschel received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer.

Claus G Haase reports no conflict of interests.

Andreas Harloff has received honoraria for oral presentations by Bayer Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Pfizer and Sanofi-Aventis.

Valentin Held reports no conflict of interests.

Andreas Kauert received honoraria for oral presentations from Bayer Vital, Novartis, and Pfizer.

Peter Kraft received honoraria for oral presentations, advisory boards and travel grants from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, and Bristol-Myers Squibb.

Arne Lenz received honoraria for oral presentations from Boehringer Ingelheim.

Wolfgang Müllges received honoraries for lectures and travel expenses from Boehringer Ingelheim, Bayer, KoMed GbR, diverse hospitals, German Society of Neurology, Antibiotic stewardship programme and Travel expenses from German Society of Neurocritical Care, German Interdisciplinary Society of Intensive Care, German Soc. of Neurology, German Soc. of Anesthesiology, German Soc. of Pneumology, German Soc. of Organ Transplant, German Soc of Clin. Neurophysiology.

Mark Obermann received scientific support, travel support and/or honoraria from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme, Pfizer, Teva and Heel. He received research grants from Allergan, Electrocore, Heel, and the German Ministry for Education and Research (BMBF).

Someieh Partowi reports no conflict of interests.

Jan Purrucker received travel support and personal fees from Pfizer and Boehringer Ingelheim.

Peter A Ringleb received lecture-fees and travel-expenses from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer and compensation for advisory board participation from Boehringer Ingelheim, Covidien, and Daiichi Sankyo.

Joachim Röther received honoraria for participation in clinical trials from Astra Zeneca and Servier, contribution to advisory boards or oral presentations from Sanofi Aventis, Pfizer, Lundbeck, Boehringer Ingelheim. Bristol-Myers Squibb, Bayer Vital and as advisor from DAK – Deutsche Allgemeine Krankenversicherung.

Raluca Rossi reports no conflict of interests.

Niklas Schäfer received travel fees and honoraria for oral presentation from Roche.

Andreas Schneider reports no conflict of interests.

Ramona Schuppner reports no conflict of interests.

Rüdiger J Seitz reports no conflict of interests.

Kristina Szabo reports no conflict of interests.

Robert Wruck reports no conflict of interests.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection

Abstract

Background

Aims

Methods

Results

Conclusion

Keywords

Introduction

Aims

Methods

Results

Ischemic stroke patients

Patients with intracranial bleeding

Discussion

Ischemic stroke patients

Patients with intracranial bleeding

Footnotes

Acknowledgement

Authors’ contributions

Declaration of conflicting interests

Funding

References