Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation

Key Points

Question  Are oral anticoagulants differentially associated with risk of fracture among patients with atrial fibrillation?

Findings  In this comparative effectiveness cohort study of 167 275 patients with atrial fibrillation, direct oral anticoagulants (ie, dabigatran, rivaroxaban, and apixaban) were associated with modestly lower fracture risk compared with warfarin. This protective association was more pronounced among patients with atrial fibrillation who also had a diagnosis of osteoporosis; among the direct oral anticoagulants, fracture risk was lowest among apixaban users.

Meaning  These findings add to speculation that warfarin may be harmful to bone health and suggest that direct oral anticoagulants may be preferred among patients with atrial fibrillation and high fracture risk.

Importance  Warfarin is prescribed to patients with atrial fibrillation (AF) for the prevention of cardioembolic complications. Whether warfarin adversely affects bone health is controversial. The availability of alternate direct oral anticoagulant (DOAC) options now make it possible to evaluate the comparative safety of warfarin in association with fracture risk.

Objective  To test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident fracture.

Design, Setting, and Participants  This comparative effectiveness cohort study used the MarketScan administrative claims databases to identify patients with nonvalvular AF and who were prescribed oral anticoagulants from January 1, 2010, through September 30, 2015. To reduce confounding, patients were matched on age, sex, CHA₂DS₂-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score, and high-dimensional propensity scores. The final analysis included 167 275 patients with AF. Data were analyzed from February 27, 2019 to September 18, 2019.

Exposures  Warfarin and DOACs (dabigatran etexilate, rivaroxaban, and apixaban).

Main Outcomes and Measures  Incident hip fracture, fracture requiring hospitalization, and all clinical fractures (identified using inpatient or outpatient claims) defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes.

Results  In the study population of 167 275 patients with AF (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), a total of 817 hip fractures, 2013 hospitalized fractures, and 7294 total fractures occurred during a mean (SD) follow-up of 16.9 (13.7) months. In multivariable-adjusted, propensity score–matched Cox proportional hazards regression models, relative to new users of warfarin, new users of DOACs tended to be at lower risk of fractures requiring hospitalization (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96) and all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), whereas the association with hip fractures (HR, 0.91; 95% CI, 0.78-1.07) was not statistically significant. When comparing individual DOACs with warfarin, the strongest findings were for apixaban (HR for hip fracture, 0.67 [95% CI, 0.45-0.98]; HR for fractures requiring hospitalization, 0.60 [95% CI, 0.47-0.78]; and HR for all clinical fractures, 0.86 [95% CI, 0.75-0.98]). In subgroup analyses, DOACs appeared more beneficial among patients with AF who also had a diagnosis of osteoporosis than among those without a diagnosis of osteoporosis.

Conclusions and Relevance  In this real-world population of 167 275 patients with AF, use of DOACs—particularly apixaban—compared with warfarin use was associated with lower fracture risk. These associations were more pronounced among patients with a diagnosis of osteoporosis. Given the potential adverse effects of warfarin on bone health, these findings suggest that caution should be used when prescribing warfarin to patients with AF at high risk of fracture.

An estimated 1 in 3 to 1 in 5 individuals will develop atrial fibrillation (AF) in their lifetime,^1,2 and the prevalence of AF in the United States is projected to exceed 12 million by 2030.³ In addition to rhythm and/or rate control, anticoagulant therapy for the prevention of stroke and cardioembolic complications is a mainstay of nonvalvular AF management.⁴ Oral anticoagulant (OAC) options now include vitamin K antagonists (typically warfarin in the United States) and several direct OACs (DOACs), namely dabigatran etexilate, rivaroxaban, apixaban, and edoxaban tosylate. Direct OACs have been shown to be as effective as warfarin for the prevention of stroke and cardioembolic complications in patients with nonvalvular AF and have been associated with a lower risk of bleeding events in randomized clinical trials^5-8 and large, observational comparative effectiveness studies.^9,10

Concerns have been raised about whether warfarin use may be associated with impaired bone quality¹¹ and increased fracture risk, although the existing evidence is inconsistent. This hypothesis was bolstered by a 2017 publication¹² that, using a population of patients with AF from Hong Kong, reported that dabigatran was associated with a significantly lower risk of fracture compared with warfarin. However, only 32 events were reported among dabigatran users. Conversely, a 2019 meta-analysis of 4 studies¹³ found no difference in fracture risk between use of a DOAC vs warfarin. Likewise, findings from comparisons of warfarin users and individuals not prescribed an OAC have been inconsistent.^13,14 To our knowledge, no studies have yet conducted comparisons among different DOAC users, although doing so is important¹⁵ because prescribers and patients must decide among the various OAC options.

Given present uncertainty regarding whether fracture risk differs according to type of OAC therapy and the need to optimize AF management to avoid unintended consequences and maximize quality of life, we used data from the MarketScan administrative claims databases to test the hypothesis that, among patients with nonvalvular AF, use of DOACs vs warfarin is associated with lower risk of incident clinical fracture. Head-to-head comparisons of individual DOACs were also conducted.

We used MarketScan Commercial Claims and Encounters and MarketScan Medicare Supplemental and Coordination of Benefits databases (IBM Corporation) from January 1, 2010, through September 30, 2015. The Commercial Claims and Encounters database consists of employer- and health plan–sourced data, whereas the Medicare Supplemental and Coordination of Benefits database includes beneficiaries with Medicare supplemental insurance paid for by employers.¹⁶ Missing from these databases are individuals with no insurance, and individuals working at small companies are underrepresented. Because this is a commercially insured population, age at AF is younger than that typically seen in clinical practice. The databases contain individual-level, deidentified health care claims information compliant with the Health Insurance Portability and Accountability Act, inclusive of enrollment records and inpatient, outpatient, ancillary, and drug claims, which are linked via individual-level identifiers. The University of Minnesota institutional review board deemed this analysis exempt from review and informed consent because the data were deidentified. This comparative effectiveness cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

To identify AF, we required at least 1 inpatient claim for AF or 2 outpatient claims for AF from 7 to 365 days apart (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 427.3, 427.31, and 427.32 in any position). The positive predictive value (PPV) of this definition is approximately 90%, and the sensitivity is approximately 80%.¹⁷ We excluded patients with ICD-9-CM codes indicating valvular disease or valve repair or replacement owing to the lack of approval of DOACs for valvular AF.

The initial sample included 956 884 patients with nonvalvular AF aged 18 to 99 years. The analytic sample consisted of 546 214 patients once we restricted the population to individuals receiving OACs from January 1, 2010, to September 30, 2015; 217 962 patients after requiring at least 3 months of continuous enrollment before the first OAC prescription; and 212 995 patients after excluding those with fracture codes (any fracture in any position) in the 90-day run-in period. These 212 995 patients were eligible for matching (eFigure 1 in the Supplement).

New users of OACs (ie, individuals without known prior exposure to OACs) were categorized according to the first OAC they were prescribed. To mimic the intention-to-treat approach of a randomized clinical trial,¹⁸ participants remained in this drug category for the entire analysis. Validity of warfarin claims in administrative databases is excellent (sensitivity, 94%; PPV, 99%).¹⁹ Validity for DOACs claims has not yet been established.

We matched each DOAC new user with as many as 3 warfarin-only new users by age (±3 years), sex, time since database enrollment (±90 days), and drug initiation date (±90 days). Matching was performed separately for each DOAC by using an automated greedy matching algorithm.²⁰ The matching process was repeated for each head-to-head DOAC comparison using 1:1 matching.

Outcomes of interest were (1) hip fractures (inpatient ICD-9-CM code 820), (2) fractures requiring hospitalization (inpatient codes only), and (3) all clinical fractures (inpatient and outpatient codes). Only fractures in the primary position were counted. The all-clinical and hospitalized fracture outcomes were identified by the presence of ICD-9-CM codes 733.1x, 733.93 to 733.98, or 800 to 829. Fractures associated with E codes (E800-E848) were not included, nor were fractures of toes, fingers, and skull or face (ICD-9-CM codes 733.94, 800, 801, 802, 803, 815, 816, 817, 825, or 826).

Prespecified covariates were derived using information before the date of initiation of OAC therapy (minimum, 90 days) obtained from all MarketScan data sources (ie, demographic data, inpatient, outpatient, and pharmacy claims). Validated published algorithms were used to define numerous prespecified comorbidities, prior procedures, and medications (pharmacy prescription fills).^21,22Table 1 lists prespecified covariates; eTable 1 in the Supplement provides details of the codes used to derive these variables. Osteoporosis was defined by ICD-9-CM inpatient or outpatients codes 715 or 733 or by pharmacy claims indicative of osteoporosis treatment (ie, bisphosphonates [alendronate sodium, risedronate sodium, zoledronic acid, and ibandronate sodium], raloxifene hydrochloride, denosumab, and teriparatide). The CHA₂DS₂-VASc (congestive heart failure, hypertension, age [>65 years = 1 point; >75 years = 2 points], diabetes, and previous stroke/transient ischemic attack [2 points], vascular disease) score²³ and a frailty index²⁴ were calculated.

Separate high-dimensional propensity scores (HDPS)²⁵ were calculated for each of the 6 main comparisons (individual DOACs vs warfarin or vs other DOACs) using the following steps²⁵:

1. MarketScan information was categorized into 5 domains: inpatient diagnostic codes, inpatient procedure codes, outpatient diagnostic codes, outpatient procedure codes, and medications. Within each domain, we selected the 200 most prevalent conditions, resulting in 1000 covariates.

2. Covariates were then empirically ranked based on their potential for controlling confounding (ie, strength of the covariate-outcome association and prevalence of the covariate).²⁶ The top 500 covariates were selected based on this ordering.

3. The 500 covariates along with the prespecified covariates (also listed in Table 1) were included in a regression model to calculate the probability of exposure (ie, receiving a specific DOAC vs warfarin or the reference DOAC).

As noted above, for the purpose of defining an index date and collecting covariate information at the time of initiation of drug therapy, we initially matched OAC users by age, sex, enrollment date, and OAC therapy initiation date. After computing the HDPSs, we rematched patients according to each outcome-specific HDPS to make the participant characteristics even more similar at the time of therapy initiation. A greedy matching technique with a caliper of 0.25 SD of each HDPS was used,²⁰ with patients matched with 1 comparison patient (ie, users of warfarin or the reference DOAC).

Data were analyzed from February 27, 2019 to September 18, 2019. Cox proportional hazards regression was used to compare the OACs according to risk of incident fracture. Follow-up began at the date of the first OAC prescription, and person-time accrued until incident fracture, health plan disenrollment (including due to death), or the end of study follow-up (September 30, 2015), whichever came first. Models were adjusted for age (continuous), sex, CHA₂DS₂-VASc score, HDPS, and frailty. Separate models also compared DOACs by dosage. Multiplicative interactions were evaluated by sex, age (<75 vs ≥75 years), and whether the claims indicated a diagnosis of osteoporosis (yes vs no). The Cox proportional hazards regression assumption was checked using Schoenfeld residuals, and there was no evidence of violations.

Sensitivity analyses were also conducted by (1) adjusting for prevalent fracture (claims indicating fracture before the 90-day run-in period), (2) adjusting for diagnosis of osteoporosis, (3) excluding those with any prevalent fracture, (4) requiring at least 180 days (compared with 90 days in the primary analysis) of continuous enrollment before the first OAC prescription, and (5) censoring participants on evidence of nonadherence (ie, a gap in prescription refills). E values were also calculated to gauge the likelihood that unmeasured confounding explained our findings.^27,28 Statistical analyses were performed with SAS, version 9.3 (SAS Institute Inc).

Among the 212 995 patients with AF eligible for initial matching, a total of 167 275 patients were matched (38.0% women and 62.0% men; mean [SD] age, 68.9 [12.5] years), initially and by HDPS, and are included in the present analysis (eFigure 1 in the Supplement). Of these, 18.9% were prescribed dabigatran; 21.1%, rivaroxaban; 10.6%, apixaban; and 49.4%, warfarin. Table 1 displays characteristics of these matched participants by OAC initially prescribed. Individuals prescribed warfarin (mean [SD] age, 70.2 [12.3] years) and apixaban (mean [SD] age, 69.1 [12.6] years) tended to be older than patients prescribed dabigatran (mean [SD] age, 67.0 [12.4] years) and rivaroxaban (mean [SD] age, 67.7 [12.3] years). The mean (SD) CHA₂DS₂-VASC scores followed a similar pattern: 3.6 (2.0) for warfarin, 3.4 (2.0) for apixaban, 3.0 (1.9) for dabigatran, and 3.1 (1.9) for rivaroxaban.

During a mean (SD) follow-up of 16.9 (13.7) months, 817 hip fractures, 2013 fractures requiring hospitalization, and 7294 clinical fractures occurred. The incidence per 1000 person-years was 3.7 for hip fracture, 9.3 for hospitalized fracture, and 35.7 for any clinical fracture. Adjusted hazard ratios (HRs) and 95% CIs for incident fracture according to DOACs vs warfarin are shown in Table 2. Relative to warfarin, being prescribed a DOAC was generally associated with lower risk of fractures requiring hospitalization (HR, 0.87; 95% CI, 0.79-0.96), all clinical fractures (HR, 0.93; 95% CI, 0.88-0.98), and hip fractures (HR, 0.91; 95% CI, 0.78-1.07). When comparing dabigatran with warfarin, there was some evidence of lower risk of fractures requiring hospitalization with dabigatran (HR, 0.88; 95% CI, 0.78-1.00), although for hip and all clinical fractures, the estimates were near the null. Rivaroxaban use compared with warfarin use was associated with lower risk of fractures requiring hospitalization (HR, 0.80; 95% CI, 0.69-0.93) and all clinical fractures (HR, 0.82; 95% CI, 0.76-0.89), although the estimate for hip fractures (HR, 0.89; 95% CI, 0.71-1.12) was not statistically significant. Apixaban use was associated with lower risk of all fracture outcomes compared with warfarin, including hip fractures (HR, 0.67; 95% CI, 0.45-0.98), fractures requiring hospitalization (HR, 0.60; 95% CI, 0.47-0.78), and all clinical fractures (HR, 0.86; 95% CI, 0.75-0.98). These findings were robust to a number of sensitivity analyses, including adjusting for prevalent fracture, adjusting for the diagnosis of osteoporosis, excluding those with prevalent fracture, and requiring a 6-month run-in (eTable 2 in the Supplement). Likewise, findings were similar when we censored participants at evidence of nonadherence; with a mean (SD) follow-up of 7.1 (8.0) months, there were 220 hip fractures, 525 fractures requiring hospitalization, and 2232 clinical fractures. The HRs for DOAC users vs matched warfarin users were 0.91 (95% CI, 0.70-1.19) for hip fracture, 0.81 (95% CI, 0.69-0.97) for inpatient fracture, and 0.91 (95% CI, 0.84-0.99) for all fractures.

In analyses stratified by subgroups of interest (Figure 1 and eTable 3 in the Supplement), risk of hip fracture associated with DOAC use was lower among patients with AF who had claims indicating an osteoporosis diagnosis (HR, 0.74; 95% CI, 0.58-0.96) compared with those without osteoporosis (HR, 1.06; 95% CI, 0.86-1.30) (P = .03 for interaction). This finding was similar when evaluating fractures requiring hospitalization (HR for no osteoporosis, 0.97 [95% CI, 0.85-1.11]; HR for osteoporosis, 0.75 [95% CI, 0.64-0.88]; P = .59 for interaction) (Figure 2 and eTable 3 in the Supplement). Although interactions were not always significant, some evidence suggested that the lower risk associated with DOAC use was more pronounced in women than in men. Subgroup analyses for the all clinical fractures outcome are provided in eTable 3 and eFigure 2 in the Supplement. Table 3 provides head-to-head comparisons of the specific DOACs associated with fracture risk. Little evidence suggested that fracture risk varied according to type of DOAC prescribed.

Precision was poorer for analyses comparing the association of different DOAC doses and warfarin with fracture risk (eTable 4 in the Supplement). Nevertheless, we found some evidence of dose response, whereby risk (vs warfarin) was lower for standard doses than for reduced doses of rivaroxaban. For example, the standard dose of rivaroxaban (20 mg) had an HR of 0.78 (95% CI, 0.58-1.05), while for the 15 mg dose, the HR was 1.02 (95% CI, 0.74-1.40).

E values were calculated to evaluate how strong unmeasured confounding would have to be to negate the observed results. For the association of DOACs vs warfarin with fractures requiring hospitalization, the E value was 1.56, indicating that residual confounding could explain the observed association if an unmeasured covariate had a relative risk association at least as large as 1.56 with OAC choice (DOACs vs warfarin) and fractures requiring hospitalization. For all clinical fractures and hip fractures, the E values were 1.36 and 1.43, respectively. To put these results in context, in a model adjusted for Table 1 covariates, hypertension was associated with an HR for fracture of 0.79 (95% CI, 0.69-0.91), diabetes with an HR for fracture of 1.16 (95% CI, 1.02-1.31), and ischemic stroke with an HR for fracture of 1.09 (95% CI, 0.92-1.28). Even established risk factors for fracture, such as dementia (HR, 1.43; 95% CI, 1.08-1.91), had an association weaker than the E value, although the upper limit of the confidence interval exceeds the E value.

Use of the DOACs, and particularly apixaban, was associated with lower incidence of clinical fracture relative to warfarin in this retrospective analysis of patients with AF who had health care insurance coverage. Although the lower risk in DOAC users vs warfarin users did not reach statistical significance for the outcome of hip fracture, precision was poorer for this outcome. In general, associations were more pronounced among patients with AF with a diagnosis of osteoporosis relative to those without. The strongest effect estimates were observed when comparing apixaban and warfarin; this finding was not hypothesized and, as such, warrants further scrutiny. We found no apparent differences in fracture risk in head-to-head DOAC comparisons. Collectively, our findings support the notion that warfarin may be harmful to bone health.

Speculation that long-term warfarin use might increase fracture risk stems from warfarin’s role as a vitamin K antagonist.²⁹ Vitamin K is important in posttranslational glutamination of osteocalcin, the major noncollagenous bone matrix protein. Warfarin interferes with this process and consequently inhibits the activation of bone matrix proteins.³⁰ Experimental rat models³¹ and observational human studies^32,33 have suggested that warfarin reduces blood osteocalcin levels and may impair bone quality. Few studies have directly compared the effects of DOACs vs warfarin on indicators of bone health. Switching from warfarin to rivaroxaban was associated with an increase in bone formation markers and a decrease in bone resorption markers in a study of 21 patients with AF.¹¹ An animal study also found dabigatran to be advantageous over warfarin on numerous markers of bone health.³⁴

Our findings that warfarin is associated with greater fracture risk relative to DOACs is consistent with the evaluation of patients with AF from Hong Kong¹² that showed greater fracture risk with use of warfarin than dabigatran. Conversely, a smaller study of patients with AF in the Florence, Italy, metropolitan area³⁵ identified no difference in fracture risk by OAC. In post hoc analysis of the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 trial,³⁶ findings suggested that edoxaban vs warfarin lowered fracture risk (HR, 0.88; 95% CI, 0.75-1.03) among participants at increased risk of falls but not among those at low fall risk. The present findings enhance the current literature in that we had far more fracture events among DOAC users (ie, 356 hip, 863 requiring hospitalization, and 3350 all clinical) than previous analyses and therefore reasonable precision to evaluate subgroups of interest.

Head-to-head DOAC comparisons yielded no statistically significant differences in fracture risk, although findings suggested that apixaban was the most advantageous. The lack of robust association in comparisons of DOACs is not surprising given the hypothesis that warfarin has a detrimental effect on bone health and the lack of known pathways by which DOACs may influence bone metabolism. To our knowledge, no previous studies have yet evaluated head-to-head comparisons of DOACs and fracture risk.

The hypothesis that warfarin is deleterious to bone health is not without controversy. Comparisons of warfarin users with individuals not prescribed an OAC have provided inconsistent results,¹⁴ with some studies reporting a link between warfarin and fracture^37,38 and others showing no association.^13,39,40 An alternate hypothesis is that perhaps instead of warfarin being harmful, DOACs may be beneficial. Although the mechanism is unclear, DOACs may influence the likelihood of fracture by reducing fall risk.^12,15,36

Our findings were robust to numerous sensitivity analyses, including when censoring at evidence of nonadherence, which is important given high OAC discontinuation rates among patients with AF.⁴¹ Some evidence suggests a dose-response association, although this effect may be due to uncontrolled confounding because patients prescribed reduced doses tend to be older and have more comorbidities.⁴ In subgroup analyses, a significant interaction occurred whereby DOACs were more beneficial among participants with diagnosed osteoporosis than those without. Differential effects of DOACs by osteoporosis status were not expected and should be evaluated in independent populations.

Strengths of the present analysis are the novel head-to-head DOAC comparisons, the large sample of patients with AF who had insurance coverage and consequent relatively large number of fracture events, and evaluation of the risks associated with these OACs in a real-world population that may be more generalizable across patients with AF and health care professionals than a randomized clinical trial population. Uncontrolled confounding is a chief potential limitation; as such, we used a multipronged approach to minimize confounding (ie, initially matching on key patient characteristics, creating and then rematching on empirically derived HDPS, and finally adjusting for the HDPS and other key patient characteristics). Misclassification is also an important consideration. Unfortunately, we were unable to locate a fracture definition that had been validated in a US population. As such, our definition was based on codes identified in a Taiwanese validation study (PPV, 100% for hip fracture, 86% for vertebral fracture, 100% for wrist and forearm fracture, and 100% for humerus fracture)¹² and expert opinion. Last, edoxaban was not included in the present analysis because there were few users in our database.

Optimizing care of patients with AF is paramount. In the present study, use of DOACs, and particularly apixaban, was associated with lower fracture risk than use of warfarin. Furthermore, some evidence suggested that this association was more pronounced among patients with AF who had a diagnosis of osteoporosis. Given the detrimental effects of fracture in the elderly,^42-44 caution should be used when prescribing warfarin to patients with AF at elevated fracture risk.

Accepted for Publication: September 26, 2019.

Corresponding Author: Pamela L. Lutsey, PhD, Division of Epidemiology and Community Health, University of Minnesota School of Public Health, 1300 S Second St, Ste 300, Minneapolis, MN 55454 (lutsey@umn.edu).

Published Online: November 25, 2019. doi:10.1001/jamainternmed.2019.5679

Author Contributions: Dr Lutsey and Ms Norby had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lutsey, Norby, MacLehose, Alonso.

Acquisition, analysis, or interpretation of data: Lutsey, Norby, Ensrud, Diem, Chen, Alonso.

Drafting of the manuscript: Lutsey.

Critical revision of the manuscript for important intellectual content: Norby, Ensrud, MacLehose, Diem, Chen, Alonso.

Statistical analysis: Lutsey, Norby, MacLehose.

Obtained funding: Alonso.

Administrative, technical, or material support: Lutsey, Alonso.

Supervision: Lutsey, MacLehose, Alonso.

Conflict of Interest Disclosures: Dr Lutsey reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr MacLehose reported receiving grants from the NIH during the conduct of the study. Dr Diem reported receiving grants from the NIH during the conduct of the study. Dr Chen reported receiving grants from the NIH during the conduct of the study. Dr Alonso reported receiving grants from the NIH and American Heart Association during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by grants R01HL131579 (principal investigator, Dr Lutsey) and R01-HL122200 (principal investigator, Dr Alonso) from the National Heart, Lung, and Blood Institute, NIH; by grant R21 AG058445 from the National Institute on Aging; and grant 16EIA26410001 from the American Heart Association (Dr Alonso).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.