Systematic Review and Meta-Analysis Medicine ®

Safety of Vitamin K in mechanical heart valve

patients with supratherapeutic INR
A systematic review and meta-analysis
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Bannawich Sapapsap, PharmDa, Chansinee Srisawat, PharmDb, Pornsinee Suthumpoung, PharmDc,

Onjira luengrungkiat, PharmDd, Nattawut Leelakanok, BPharm, PhDa, Surasak Saokaew, PharmD, PhDe,f,g,h,i,j,
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 01/10/2024

Sukrit Kanchanasurakit, PharmDf,g,h,k,l,*

Abstract
Background: Patients who had mechanical heart valves and an international normalized ratio (INR) of >5.0 should be managed
by temporary cessation of vitamin K antagonist. This study aimed to investigate the safety of low-dose vitamin K1 in patients with
mechanical heart valves who have supratherapeutic INR.
Methods: CINAHL, Cochran Library, Clinical trial.gov, OpenGrey, PubMed, ScienceDirect, and Scopus were systematically
searched from the inception up to October 2021 without language restriction. Studies comparing the safety of low-dose vitamin
K1 treatment in patients with placebo or other anticoagulant reversal agents were included. We used a random-effect model for
the meta-analysis. Publication bias was determined by a funnel plot with subsequent Begg's test and Egger's test.
Results: From 7529 retrieved studies, 3 randomized control trials were included in the meta-analysis. Pooled data demonstrated
that low-dose vitamin K was not associated with thromboembolism rate (risk ratio [RR] = 0.94; 95% CI: 0.19–4.55) major bleeding
rate (RR = 0.58; 95% CI: 0.07–4.82), and minor bleeding rate (RR = 0.60; 95% CI: 0.07–5.09). Subgroup and sensitivity analysis
demonstrated the nonsignificant effect of low-dose vitamin K on the risk of thromboembolism. Publication bias was not apparent,
according to Begg's test and Egger's test (P = .090 and 0.134, respectively).
Conclusion: The current evidence does not support the role of low-dose vitamin K as a trigger of thromboembolism in
supratherapeutic INR patients with mechanical heart valves. Nevertheless, more well-designed studies with larger sample sizes
are required to justify this research question.
Abbreviations: 95% CI = 95% confidence interval, ACC/AHA = American College of Cardiology/American Heart Association
Guideline, FFP = fresh frozen plasma, GRADE = Grading of Recommendations, Assessment, Development and Evaluations,
HR = hazard ratio, INR = international normalized ratio, N/A = not available, NOS = The Newcastle-Ottawa Scale, NS = not serious,
OR = odds ratio, RCT = randomised control trial, RR = risk ratio, RoB 2.0 = Cochrane Risk-of-bias tool 2.0, ROBINs = The Risk
Of Bias In Non-randomized Studies of Interventions, S = serious, VKA = vitamin K antagonist
Keywords: heart valve prosthesis, hemorrhage, thromboembolism, vitamin K

The authors have no financial conflicts of interest.
The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
The systematic review or meta-analysis is exempt from ethics approval because it
collecting and synthesizing data from the previous studies. In addition, patient data
is anonymized and data are available in the public domain so that ethical permission
is not needed. The authors followed applicable EQUATOR Network (https://www.
equator-network.org) guidelines during the conduct of research project.
Supplemental Digital Content is available for this article.
a
Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Burapha
University, Chonburi, Thailand, b Division of Pharmaceutical care, Department of
Pharmacy, Banphaeo General Hospital, Samut Sakhon, Thailand, c Division of
Pharmaceutical care, Department of Pharmacy, Fort Khuncheangthammikkarat
Hospital, Phayao, Thailand, d Division of Pharmaceutical Care, Department of
Pharmacy, Wichaivej International Omnoi Hospital, Samutsakhon, Thailand,
e
Division of Social and Administration Pharmacy, Department of Pharmaceutical
Care, School of Pharmaceutical Sciences, University of Phayao, Phayao,
Thailand, f Center of Health Outcomes Research and Therapeutic Safety
(Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao,
Thailand, g Unit of Excellence on Clinical Outcomes Research and IntegratioN
(UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao,
Thailand, h Unit of Excellence on Herbal Medicine, School of Pharmaceutical
Sciences, University of Phayao, Phayao, Thailand, i Biofunctional Molecule
Exploratory Research Group, Biomedicine Research Advancement Centre,
School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor
Darul Ehsan, Malaysia, j Novel Bacteria and Drug Discovery Research Group,
Microbiome and Bioresource Research Strength, Jeffrey Cheah School of
Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway,
Selangor Darul Ehsan, Malaysia, k Division of Clinical Pharmacy, Department of
Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao,
Phayao, Thailand, l Division of Pharmaceutical care, Department of Pharmacy,
Phrae Hospital, Phrae, Thailand.
*Correspondence: Sukrit Kanchanasurakit, PharmD, Division of Clinical Pharmacy,
Department of Pharmaceutical Care, School of Pharmaceutical Sciences,
University of Phayao, Phayao, Thailand 56000. (e-mail: sukrit.ka@up.ac.th,
sukrit_rx@hotmail.com).
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to
download, share, remix, transform, and buildup the work provided it is properly cited.
The work cannot be used commercially without permission from the journal.
How to cite this article: Sapapsap B, Srisawat C, Suthumpoung P, luengrungkiat
O, Leelakanok N, Saokaew S, Kanchanasurakit S. Safety of Vitamin K in
mechanical heart valve patients with supratherapeutic INR: A systematic review
and meta-analysis. Medicine 2022;101:36(e30388)
Received: 7 January 2022 / Received in final form: 21 July 2022 / Accepted:
22 July 2022
http://dx.doi.org/10.1097/MD.0000000000030388

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 Sapapsap et al. • Medicine (2022) 101:36Medicine
1. Introduction
Over 4 million people worldwide have received prosthetic heart
valves. An estimated 300,000 valves are implanted every year,
mainly to improve the quality of life and survival of patients
with severe valvular heart disease.[1] According to the guidelines,
all patients who are diagnosed with valvular heart disease, par-
ticularly those who have mechanical heart valves, should use
oral vitamin K antagonists (VKAs) to prevent thromboembo-
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lism in either artery or vein.[2] VKAs inhibit vitamin K-dependent
g-carboxylation of several coagulation factors, for example, II,
VII, IX, and X[3], preventing blood coagulation. International
normalized ratio (INR) is used as a surrogate for the monitoring
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of VKA therapy. In patients with mechanical heart valves, the
target of INR should be ranging between 2.5 and 3.5.[4]
Supratherapeutic INR during VKA treatment can be caused by
multiple reasons, for example, interactions with other drugs or
food, inappropriate VKA dosing, or poor adherence to the VKA
regimen.[5] Patients with prosthetic heart valve implantation expe-
riencing an increased INR of >4.0 to 4.5 are at risk of bleeding,
especially when anticoagulant treatment is not ceased.[6] Bleeding
can be inevitable if the INR elevation is not properly managed.[7]
The 2020 American College of Cardiology (ACC)/American
Heart Association (AHA) Guideline[2] suggested that for patients
with mechanical valves and uncontrollable bleeding, 4-factor
prothrombin complex or fresh frozen plasma (FFP) is preferred to
high-dose vitamin K for the management of bleeding. Vitamin K
administration with temporary cessation of vitamin K antagonist
has been suggested in individuals with mechanical heart valves
and INR of >5.0 who are not actively bleeding. However, the evi-
dence on whether vitamin K1 should be used for managing supra-
therapeutic INR, which is >5.0, in patients with prosthetic heart
valves is still conflicting. Evidence shows that using vitamin K1
as an antagonist in such patients increases the risk of prosthetic
valve thrombosis.[8] On the contrary, some randomized controlled
trials have proved that using low doses of vitamin K to reverse
anticoagulation in patients tends to reduce bleeding and does not
link to a higher risk of having thrombosis.[9–11]
Although this topic is not new since vitamin K has been used
for warfarin overdose for a long time, there are still misunder-
standings that low dose vitamin K can cause thromboembolism
in patients with mechanical heart valves with warfarin overdose.
The information supporting the use of warfarin in such patients
derives from small RCTs. Therefore, conducting this systematic
review and meta-analysis increases the power of the analysis on
this topic and provides valuable data for healthcare providers
treating patients with mechanical heart valves.
2. Methods
2.1. Search strategy
This study adhered to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) 2020.[12] The study pro-
tocol was registered with PROSPERO (CRD42022289966) in
December 2020. Systematic searches were conducted in 7 data-
bases including CINAHL, Cochran Library, Clinical trial.gov,
OpenGrey, PubMed, ScienceDirect, and Scopus. The searches
were conducted without language and study design restrictions
and from their inception to October 30, 2021. The following
search strategy was used: “anticoagulant OR warfarin OR ‘vita-
min K’ antagonist AND ‘heart valve prosthes’ OR ‘mechan-
ical heart valve’ AND ‘vitamin K’ OR phytonadione” (Table 1,
Supplemental Digital Content 1, http://links.lww.com/MD/H179).
2.2. Study eligibility criteria
This study included randomized controlled trials, cohort studies,
and case-control studies in which patients received vitamin K
(phytomenadione). In those studies, controls were no treatment,
placebo, or other anticoagulant reversal agents. The included
2
studies had to ostensibly illustrate statistics necessitate for the
meta-analysis, for example, risk ratio (RR), odds ratio (OR), haz-
ard ratio with a 95% confidence interval (95% CI), or the num-
ber of thromboembolism and bleeding with the total number of
the patients. The definition of thromboembolism and bleeding
outcomes are detailed in (Table S2, Supplemental Digital Content
2, http://links.lww.com/MD/H180).[11] We excluded nonresearch
articles, nonhuman studies, case series or case reports, cross-sec-
tional studies, and retrospective studies. Studies whose effect esti-
mates could not be extracted were also excluded.
2.3. Data extraction
Two investigators independently screened titles, abstracts, and
full texts of the retrieved articles independently. Disagreements
were resolved by consulting the third author. Also, three inves-
tigators independently extracted the author's name, country,
study design, sample size, effect estimates, participant char-
acteristics, comorbidities, treatment regimens, controls, and
outcomes. Data that were not available were retrieved by con-
tacting the corresponding authors of selected articles. If the cor-
responding authors did not respond in a reasonable time, the
articles were excluded.
2.4. Quality assessment
Three investigators independently assessed the risk of bias or
quality of the included studies. For RCTs, the Cochrane Risk-
of-bias tool 2.0 (RoB 2.0)[13] and Grading of Recommendations,
Assessment, Development and Evaluations (GRADE) for ran-
domized control trials were used for evaluating the risk of bias
and the quality of evidence, respectively. The Risk Of Bias In
Non-randomized Studies of Interventions (ROBINS-I tool) were
used to evaluate the risk of bias in nonrandomized trials because
it was accessible and easy to use.[14] The Newcastle-Ottawa
Scale[15] were used to assess the quality of the observational
studies because of its reliability, validity, and ease of use.[16]
2.5. Statistical analysis
Pooled risk ratio and 95% CI were calculated using the
DerSimonian-Laird random-effect models[15] (STATA, ver-
sion 16.0, StataCorp LLC, USA) to explain the risk of throm-
boembolism from using low-dose vitamin K in the patients.
Heterogeneity was assessed using Cochrane Q statistic and
I2 values. The P value of Cochrane Q of <.10 or I2 of >75%
indicated high heterogeneity while the P value of >.01 or I2 of
lower than 25% indicated low heterogeneity.[16] The funnel plot
was used to observe for the publication bias. Further tests were
conducted using (RevMan 5.3, The Nordic Cochrane Center,
Copenhagen, Denmark). Begg's test and Egger's test were used
to further detect[17,18] and the trim-and-fill method was per-
formed to further justify the publication bias.[19]. A value of 0.5
was used to impute the data points that were zero.[20]
2.6. Subgroup analysis and meta-regression
The influence of baseline characteristics, which can be the cause
of heterogeneity, was determined by subgroup and sensitiv-
ity analyses, and meta-regression. The following strata were
planned priori: age ≥ 65 years or <65 years, sex, and types of val-
vular. Meta-regression was calculated using OpenMetaAnalyst
for Windows 8[21] posthoc.
3. Results
3.1. Studies retrieved and characteristics
We retrieved 7529 studies from the databases. After the
removal of duplicate articles (n = 341) and impertinent
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articles (n = 6863), 3 articles, all of which were randomized
controlled trials studies (RCT),[9–11] were included for data
synthesis. The PRISMA diagram for the study screening is
shown in Figure 1. The essential characteristics of included
studies are exhibited in Table 1. In brief, the PICO of the
included studies was described as the following. The total
number of participants from the 3 included studies was 241.
The majority of them were East Asian with the mean age of
59 years (range: 50.08 years–66.00 years). More than 50%
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of participants were female. All studies measured the efficacy
and safety of oral or intravenous vitamin K and used FFP[10],
no treatment[9] or placebo[11] as comparators. The outcomes
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measured were thromboembolism, major bleeding, and
minor bleeding in all studies.[9,11]
3.2. Quality assessment
Since all included studies were RCTs, RoB 2.0, and GRADE
were used to analyze the risk of bias. The risk of bias was high
in 1 study, concerned in 1 study, and low in 1 study, according
to RoB 2.0 (Figure 1A and 1B, Supplemental Digital Content 3,
http://links.lww.com/MD/H181). The quality of included stud-
ies according to GRADE criteria was moderate because of the
Figure 1. The PRISMA flow chart of the study selection process. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
3
serious imprecision in the pooled estimate (Table 3, Supplemental
Digital Content 4, http://links.lww.com/MD/H182).
3.3. Thromboembolism
The forest plot for the risk of thromboembolism in 241
mechanical heart valve patients with supratherapeutic INR
who were treated with low-dose vitamin K and compara-
tors is shown in Figure 2. Using random-effect model, low-
dose vitamin K was not associated with thromboembolism
rate (RR = 0.94; 95% CI: 0.19–4.55; P = .94; I2 = 0.0%).
Heterogeneity among RCT trials was low.
3.4. Bleeding
The forest plot for the risk of major bleeding and minor bleed-
ing in 241 and 139 patients who had mechanical heart valves,
had supratherapeutic INR, and were treated with low-dose vita-
min K is shown in Figure 2. Using random-effect model, low-
dose vitamin K also was not associated with major bleeding
rate (RR = 0.58; 95% CI: 0.07–4.82; P = .62; I2 = 0.0%) and
minor bleeding rate (RR = 0.60; 95% CI: 0.07–5.09; P = .64;
I2 = 45.0%). Heterogeneity among RCT trials was low.
 Sapapsap et al. • Medicine (2022) 101:36Medicine

Table 1
Characteristics of studies included in the meta-analysis.
Author (year)
Characteristic Ageno et al [9]
Yiu et al[10] Zhang et al[11]

Region Italy, Mexico Hong Kong, China China

Study design Randomized, controlled trial Randomized, controlled trial Randomized, double-blind, placebo-controlled trial
Sample size 59 102 80
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No. of participants Interventions 29 57 40

Comparators 30 45 40
Duration of study 4 ± 1 weeks 6 hours and 1 week later 3 months
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Age (year) 64.50* 61.0 ± 1.93* 50.24 ± 7.69*

Male (%) 27
Characteristics of participants -Patients with mechanical heart
valves who were receiving warfa-
rin therapy and who presented
-INR values between 6.0 and 12.0 -international normalized ratios (INRs)
Comorbidity of participants - Atrial fibrillation
Valvular type - Aortic prosthetic valve(50.85%)
- Aortic prosthetic valve(44.07%)
- Mitral and aortic position(5.08%) - Mitral and aortic position(16%)
Treatment regimen Oral administration of
1-mg vitamin K
Comparison group No treatment
Effect size (95% CI) 1.03 (0.07–15.79)
Outcome measurement - Mean INR day 0, 1
- Number of patients with INR 2.3 to - Thromboembolic stroke, other
4.5 on day 1
- Number of patients with INR < 1.8
on day 1
- Major/minor bleeding
- Thrombotic events
* Mean ± SD.
N/A = not available.
35 33
-Patients with mechanical heart -Adult patients aged ≥ 18 years with bileaflet mechanical
valves receiving long-term valve prostheses who were undergoing warfarin
warfarin sodium treatment
-INR values from 4.0 to 10.0
from 4 to 7
N/A - Hypertension
- Prior stroke
- Diabetes
- Peripheral vascular disease
- Coronary artery disease
- Aortic prosthetic valve(24%) - Aortic prosthetic valve (13%)
- Mitral prosthetic valve (60%) - Mitral prosthetic valve(53%)
- Mitral and aortic position(35%)
Intravenous administration of Oral administration of
1-mg Vitamin K 2.5 mg vitamin K
Fresh frozen plasma (FFP) 1 U Placebo
0.80 (0.05–12.40) 1.00 (0.06–15.47)
- Major bleeding Primary outcome
- Percentage of patients that achieved an INR value of
systemic thromboembolic events 1.5 to 2.5 on the day following treatment
- Adverse reaction to treatment - The time necessary to achieve an INR < 2.5
(anaphylaxis, fever, rash). Secondary outcome
- The INR at 6 hours and 1 week - The number of patients having INR values < 1.5
after treatment or > 2.5 on any day following drug administration
- The variation in INR values after drug administration
- The incidence of resistance to warfarin, as described by
the mean of the final 2 INR values determined during
the study period being < 1.5
- Adverse event incidence

3.5. Sensitivity and subgroup analysis 4. Discussion

The results of the subgroup analysis are shown in Table 2. The
data were stratified by age, sex, and types of valvular. The risk of
thromboembolism in patients with mechanical heart valves who
had supratherapeutic INR and were treated with vitamin K was
consistent across all subgroups. In addition, sensitivity analysis
by influence plot is shown in (Figure 2, Supplemental Digital
Content 5, http://links.lww.com/MD/H183). The result of a
meta-regression supported no association between selected vari-
ables (sample size, age, percentage of male participant, aortic
prostatic heart valve, route of administration, and study dura-
tion) and the outcomes (Table 4, Supplemental Digital Content
6, http://links.lww.com/MD/H184).
3.6. Publication bias
The funnel plot was asymmetrical, suggesting the existence of
the publication bias (Figure 3, Supplemental Digital Content
7, http://links.lww.com/MD/H185). However, the results from
Begg's test and Egger's test were not statistically significant, sug-
gesting that publication bias may have not affected this analy-
sis (Figure 4, Supplemental Digital Content 8, http://links.lww.
com/MD/H186, P = .090 and .134, respectively).
According to the AHA/ACC guideline for the management of
patients with valvular heart disease 2020,[2] vitamin K admin-
istration with temporary cessation of vitamin K antagonist has
been suggested in individuals with mechanical heart valves and
INR of >5.0 who are not actively bleeding. This study did not
find the association between the use of low dose vitamin K and
the risk of thromboembolism thus, supporting the use of vitamin
K in such patients. This finding agrees with a previous systematic
review and meta-analysis that compared the rate of major bleed-
ing in nonvalvular patients with supratherapeutic INR using oral
anticoagulants.[22] Moreover, the onset of action for vitamin K
in warfarin reversal is approximately 8 to 40 hours,[23] which is
the time required for the synthesis of vitamin K-dependent coag-
ulation factors in the liver. On the contrary, FFP immediately
replaced coagulation factors. The rapid replacement of FFP can
lead to the sudden reduction of INR which can lead to thrombo-
sis.[24] This might explain the nonassociation between the use of
vitamin K and thrombosis. In fact, vitamin K can be beneficial
over the use of FFP in some scenarios. For example, FFP can
cause transfusion reactions.[25] In addition, vitamin K can be an
interesting alternative in patients with cardiac dysfunction since
FFP can increase the risk of pulmonary edema.[26]

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Figure 2. Forest plot showing risk ratio of thromboembolism, major bleeding, and minor bleeding in patients with mechanical heart valves, who have suprath-
erapeutic INR receiving Vitamin K or placebo—use using random-effect model. INR = international normalized ratio.
Table 2
Subgroup and sensitivity analysis.
All studies
Subgroup Pooled risk ratio (95% CI)
Age
 ≥65 years N/A
 <65 years 0.94 (0.19, 4.55)
Sex
 Male N/A
 Female 0.94 (0.19, 4.55)
Types of valvular
 AVR 1.03 (0.07, 15.79)
 MVR 0.89 (0.13, 6.21)
AVR = aortic valve replacement, CI = confidence interval, MVR = mitral valve replacement,
N/A = not available.
Although vitamin K is an interesting treatment option, there
is no consensus in doses use for treating patients with the over-
dosage of vitamin K antagonists in patients with mechanical
heart valves. The study by Ageno et al[9] and Yiu et al[10] are
published early and investigated the use of 1-mg vitamin K. This
is different from the dose used by the newer study by Zhang et
al[11] which used 2.5 mg vitamin K. Moreover, in the study by
Yiu et al,[10] vitamin K was administered intravenously which is
different from other studies which used oral vitamin K. In addi-
tion, Zhang et al[11] provide more details on patients’ comor-
bidities including prior stroke, and coronary artery disease. The
discrepancy in the dose used in among studies may have resulted
in differences in the major/minor bleeding outcome.
There are some limitations worth mentioning in this
study. First of all, the majority of the participants were Asian
(182/241) which was highly homogeneous. This might limit
the generalization of the result to other populations. Although
there is no direct support for the racial difference in vitamin
K response, plenty of evidence shows the difference in the
baseline vitamin K among ethnicities.[27,28] Therefore, more
studies in other populations are warranted before the role of
races in vitamin K response can be ignored. Second, there is
an insufficient number of studies that answer this research
question, reflected by the low number of included studies in
our meta-analysis. In addition, the included studies were of
Heterogeneity moderate quality since most of the articles did not specify the
methods for randomization, allocation, and blinding. These
I value (%)
2
P 2 factors can directly affect the quality of our meta-analysis.
Third, the included studies fail to mention how they control
the factors that affect INR including diarrhea, fever, and food/
N/A N/A
0.0 0.990
drug-VKA interactions.[9–11] However, this study still has sev-
eral implications. Our findings reinforce the use of vitamin K
N/A N/A as an INR reversal agent in patients with mechanical heart
0.0 0.990 valves with VKA overdose. Our study also suggests the scar-
city of research on the risk of thromboembolism in vitamin K
N/A N/A users. RCTs with a larger sample size that clearly specifies the
0.0 0.908 process of randomization, allocation, and blinding or well-de-
signed large cohort studies that observe the use of vitamin K
or other anticoagulant reversal agents should be conducted to
further ensure the safety of vitamin K as an antidote for supra-
therapeutic INR occurred in patients with mechanical heart
valves. In addition, participants with diverse ethnicities should
also be included.
In conclusion, using low-dose vitamin K in patients with
mechanical heart valves and supratherapeutic was not asso-
ciated with the risk of thromboembolism. This study also
shows no association between low-dose vitamin K and bleed-
ing. Further studies are required to confirm the benefits over
the risk for the use of low-dose vitamin K to reduce the INR
in patients with mechanical heart valves and supratherapeu-
tic INR.
Author contributions
B.S., S.K., C.S., P.S., O.L., N.L., and S.S. contributed to the
research idea and design. B.S. and S.K. created the search strat-
egy. B.S., C.S., and P.S. screened titles, abstracts, and full texts.
B.S., C.S., and O.L. contributed to data extraction. B.S., S.K.,
and N.L. contributed to quality assessment. B.S., S.K., and N.L.
contributed to statistical analysis and interpretation of data. B.S.
and N.L. wrote the first draft of the article. B.S., S.K., N.L., and
5
 Sapapsap et al. • Medicine (2022) 101:36Medicine
S.S. edited the draft of the article. All authors contributed to the
critical revision of the article for important intellectual content,
approved and reviewed the final article.
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