Tejaswini Yeshala^*,1, Anudeep Reddy Annem², Pragna Gajawada³

¹MBBS- Maheshwara Medical College

²MBBS-Kurnool Medical College

³Kazakh National Medical University, Almaty, Kazakhstan

^*Corresponding Author: Tejaswini Yeshala, MBBS, Maheshwara Medical College, India

Received: 20 July 2025; Accepted: 31 July 2025; Published: 07 August 2025

Article Information

Citation: Tejaswini Yeshala, Anudeep Reddy Annem, Pragna Gajawada. A Systematic Review and Meta-Analysis on Anticoagulants and Vascular Calcification. Archives of Internal Medicine Research. 8 (2025): 233-245.

DOI: 10.26502/aimr.0216

Abstract

Keywords

Cardiovascular Calcifications, Atherosclerosis, Coronary Artery Disease, Breast Arterial Calcifications (BAC), Peripheral Arterial Disease (PAD), Aortic Calcification Index

Article Details

Introduction

The way that vascular calcification is a free indicator of cardiovascular sickness (CVD) and mortality (1) is a finding that has gotten inescapable acknowledgment. Various investigations have shown a relationship among's calcification and clinically huge coronary course illness (computer aided design) (2-4), intense heart and cerebrovascular occasions (5, 6), blood vessel solidness and hypertension (7), and aortic valve sickness (8). Cardiovascular infection is the significant reason for death, representing in excess of about a third of all passings worldwide. With the coming of coronary corridor calcium scoring, a harmless imaging stage has developed with the end goal of atherosclerotic cardiovascular illness risk evaluation and the direction of lipid-bringing down drugs for essential counteraction (9, 10). During the 1950s, the anticoagulant known as warfarin, which is a vitamin K bad guy (VKA), was first brought into clinical practice (11). Warfarin and other VKAs have been authorized for the anticipation of thrombotic occasions in patients with repetitive venous apoplexy, atrial fibrillation, valvular coronary illness, and valve substitution (12). This endorsement has been conceded throughout the span of numerous years. Notwithstanding the way that the use of VKA has diminished throughout recent years because of the advancement of more secure non-vitamin K oral anticoagulants (NOAC or DOAC, which represents direct oral anticoagulants), VKAs keep on being widely given and are the sole drug that is shown by rules for patients who have prosthetic valves (13-16). Furthermore, patients who are more seasoned and patients who have been determined to have a few circumstances are bound to be endorsed warfarin for anticoagulation (17).

Through the concealment of vitamin K-subordinate post-translational gamma-carboxylation, which is essential for the movement of coagulation factors II, VII, IX, and X, as well as various different proteins, VKA can obstruct these proteins (18). Under typical physiological settings, calcification is restrained by various endogenous inhibitors. These inhibitors incorporate network Gla protein (MGP), pyrophosphate, and plasma fetuin-A (19). The gamma-carboxylation process is essential for the inhibitory capability of MGP, which is an individual from a similar gathering of gamma-carboxylated proteins as coagulation factors (18). It is guessed that the decline in vitamin K-subordinate gamma-carboxylation of MGP that happens because of drawn out use of VKA is answerable for the expanded vascular calcification that is related with its utilization (20, 21). There is as of now an absence of acknowledgment about the capability that VKA plays in vascular calcification, and the clinical significance of this not entirely settled (22). Introduced here is the absolute first meta-examination of clinical exploration that have been directed regarding this matter. In this review, our motivation was to offer information that upholds the speculation that the utilization of VKA is related with cardiovascular calcification.

Methods

Search strategy

There was no limitation put on the incorporation of a specific sign for the utilization of VKA; rather, all clinical examinations, except for contextual investigations and case series, were thought about. The essential results were calcification of the coronary courses, calcification of the corridors beyond the coronary conduits (like the stomach or thoracic aorta, carotid veins, bosom supply routes, and corridors of the limits), and calcification of the valve device. Between the dates of Walk 29, 2022 and Walk 29, 2022, the center efficient writing search was completed in PubMed utilizing a stepwise catchphrase search technique (Beneficial Table 1). A bunch of PubMed channels was applied to the query items to reject surveys, case reports, proposals, and exploration conventions from the gathering. Also thought about were the reference arrangements of the pertinent papers as well as the "comparative articles" that were suggested by PubMed. Different data sets, for example, CINAHL, the Cochrane Register of Studies, and Google Researcher, were looked through to track down additional references. The accompanying incorporation standards were applied to the digests: (1) treatment with VKA; and (2) the presence of no less than one blood vessel or valvular calcification result, for example, calcium score or record, calcified plaque volume, presence or nonappearance of calcification, calcification seriousness grade, or a yearly pace of movement. The digests were audited by two specialists, and any distinctions that emerged were dealt with by getting everybody to settle on something.

Data extraction and management

The determination of the information depended on an examination of the general text. The information that was extricated incorporated a review identifier, the country, the review plan, the example size, the mean or middle age, the level of guys, the term of VKA treatment, the calcification outcome(s), the strategies for evaluation of calcification, the impact size gauges, and a concise portrayal of the measurable models that were utilized for the impact gauges. Occurrence, pervasiveness, chances proportions (OR), mean change from gauge, relapse coefficients, proportions of anticipated counts (REC), and F insights were the factual measures that were utilized to separate the meaning of the effect sizes. coronary course calcium (CAC) score, which was surveyed by registered tomography (CT), calcified plaque volume, still up in the air by coronary CT angiography (CCTA), and coronary supply route calcium file, which was gained by intravascular ultrasonography (IVUS) were the consequences of the coronary review. The presence or nonattendance of calcification, seriousness grade, calcification score, or a yearly pace of (not entirely set in stone by CT, X-beam, mammography, or histology) were all instances of extra-coronary results. All in all, the outcomes of calcification of the aortic valve contained the presence or nonattendance of calcification on transthoracic ultrasonography (US), the quantity of aortic valve flyers that were harmed, the CT calcification score, or positive outcomes on histology.

Statistical Analysis

The Survey Chief PC device, rendition 5.4 (RevMan5, the Cochrane Joint effort, 2020), was utilized to do the investigation on the information base. Utilizing either the RevMan5 impact size adding machine or an internet based impact size mini-computer apparatus [Practical Meta-Examination Impact Size Number cruncher (25)], the impact sizes were addressed as chances proportions (OR) and standard blunders (SE). Information amalgamation was achieved through the utilization of backwards change irregular impacts models. To order the investigations, coronary, extra-coronary, and valvular calcification were the three classifications that were utilized. The joined evaluations were figured as chances proportions (OR) and certainty stretches (95% CI) comparative with the presence of vascular or valvular calcification in patients who were treated with VKA in contrast with patients who were not treated with VKA. This gathering of patients included patients who were treated with anticoagulants that were not related with VKA as well as patients who had no signs for anticoagulation and were not given any anticoagulants. Using the I2 test that was registered in RevMan5, the factual heterogeneity was examined and characterized. Utilizing the Meta-Fundamentals program, which was gotten on February 9, 2022 from https://www.erim.eur.nl/research-support/meta-basics, an Egger relapse and Begg and Mazumdar rank relationship test were acted to assess the potential for distribution inclination (26). Also, the Meta-Basics instrument was used for the univariate meta-relapse investigations. These examinations considered the time of distribution, the geological district (mainland), the review plan, the example size, the patient attributes, the middle age, the proportion of members by sex, the length of the VKA treatment, the calcium imaging methodology, and whether the impact gauges were adapted to frustrating elements. Each critical modifier that was found by meta-relapse was utilized to direct the sub-bunch concentrates on that were completed. To additional intricate, the responsiveness examination was completed by disposing of each exploration in turn from the meta-examination that compared to it. An importance level of p < 0.05 was taken on for the review.

Results

Search results and characteristics of the included studies

In the wake of doing a pursuit on PubMed, a sum of 330 papers were found, and five additional articles were gotten from their separate sources. These 335 pieces included 114 audits and publications, 22 case reports, two review conventions, and two clinical proposals. Moreover, there were two clinical rules. Another 152 were proclaimed immaterial by an understanding arrived at between two specialists (NDK and OVS) on the off chance that the papers didn't have a place with human subjects, didn't give VKA treatment or impact gauges, or didn't have a normalized strategy of distinguishing and estimating calcification. Following an assessment of the total texts of the excess 43 distributions, seven extra were ignored for the accompanying reasons: (1) they needed information (n = 1), they didn't meet the incorporation measures (n = 4), they were an optional examination of a generally included research (n = 2), or they were a continuous examination (n = 1). This brought about the consideration of 35 preliminaries and 15,594 individuals in the examination, of whom 6,251 were treated with VKA (27-61). There were a sum of 32 observational examinations, with 38 partners, 15,261 members, and 6,082 VKA clients. Three of these investigations were randomized preliminaries, with four unmistakable examination associates, 333 patients, and 169 VKA clients (29, 32, 39). The other 32 investigations were observational examinations (27, 28, 30, 31, 33-38, 40-61). Thirteen exploration were directed to investigate the impacts of VKA on coronary corridor calcification. These examinations went from 27 to 38 and included 15 accomplices, 23,768 members, and 2,625 people who got VKA. 18 accomplices, 4,740 members, and 1,595 patients who were treated with VKA (40-54) were remembered for the sixteen examinations that showed extra-coronary calcification, which alludes to calcification in any course other than the coronary supply route. Finally, nine examinations (31, 49, 55-61) were led to survey the impacts of VKA drug on aortic valve calcification. The all out number of members in these examinations was 15,594. Table 1 shows the attributes of the examinations that were remembered for the investigation.

From 2005 to 2022, studies were distributed in scholastic diaries. In Europe, twenty examinations were completed (29-31, 34-36, 38, 41-43, 46-51, 53, 55, 57-59), thirteen investigations were done in North America (27, 28, 32, 33, 37, 39, 40, 44, 45, 52, 56, 58, 60), and two examinations were done in Asia (54, 61). As referenced before, we tracked down three randomized preliminaries (29, 32, 39), one meta-investigation of patient-level information from eight randomized preliminaries (27), 21 review accomplice studies (30, 31, 34-38, 40-42, 45, 48-52, 54, 55, 57, 59, 60), one forthcoming partner (61), and nine cross-sectional examinations (28, 33, 43, 44, 46, 47, 53, 56, 58). These examinations were led in the US. The quantity of members in the example fluctuated from 37 to 17,254 altogether. The interquartile range (IQR) of the example size went from 108 to 387 patients, with 207 being the middle example size. 77% (interquartile range: 72-95%) of the members were men, and the typical age of the members was 66.2 years with a standard deviation of 3.6 years. There were 33 gatherings of patients who were either tentatively or reflectively followed, and the weighted middle length of VKA prescription was 2.3 years (interquartile range somewhere in the range of 1.2 and 4.0) (27, 29-32, 34-42, 45, 48-52, 54, 55, 57, 59-61). Cross-sectional examinations were led on nine different exploration partners, and the length of treatment was not shown for any of them (28-58).

Quality assessment

There were three randomized preliminaries, and one of them was a "per-convention" study (29), which had a critical gamble of predisposition inferable from missing result information. Then again, two extra "aim to-treat" studies had issues about missing result information (32) and specific detailing (32, 39) (Advantageous Table 2). An assessment of the potential for predisposition in observational examinations was done utilizing a Newcastle-Ottawa quality scale with nine places. Notwithstanding, there were five examinations in which the gamble of predisposition was appraised low to direct on the Newcastle-Ottawa quality scale (31, 33, 44, 47, 53) (Beneficial Table 3). Most of the examinations were of basically moderate quality (27, 28, 30, 31, 34-38, 40-43, 45, 46, 48-59, 61) [median score 7 (interquartile range 5-9)]. The impacts of the utilization of VKA on the calcification of the coronary, extra-coronary, and aortic valves. There was a relationship between's the use of VKA and an expansion in vascular and valvular calcification. Contrasting patients who were not treated and VKA to the individuals who were treated with VKA, the chances proportion (OR) for coronary corridor calcification was 1.21 (95% certainty stretch [CI]: 1.08, 1.36), with a p-worth of 0.001. Moreover, the utilization of VKA was connected to the presence of extra-coronary vascular calcification in the corridors of the aorta, carotid conduits, bosom veins, and courses of the lower limits [odds proportion 1.86 (1.43, 2.42), p < 0.00001]. Moreover, we found a relationship between's the utilization of VKA and the improvement of aortic valve calcification, [odds proportion 3.07 (1.90, 4.96), p < 0.00001]. The discoveries of the coronary (n = 15), extra-coronary vascular (n = 18), and aortic valve (n = 9) examinations uncovered that the degree of heterogeneity between the investigations was genuinely critical at I2 upsides of 69, 78, and 90%, separately.

Table 1: Characteristics of the included studies

Meta-regression and subgroup analysis

The distinguishing proof of conceivable effect modifiers was achieved through the utilization of meta-relapse investigation. We utilized univariate arbitrary impacts relapses to dissect the impacts of the accompanying variables: the extended time of distribution, the geographic district (landmass), the review plan, the example size, the patient attributes, the middle age, the proportion of members by sex, the span of VKA treatment, the calcium imaging methodology, and whether the impact gauges were accounted for adapted to the bewildering factors (Table 1). The appraisals of coronary supply route calcification were impacted by three logical factors. The extended time of distribution had a B relapse coefficient of - 0.04 (95% certainty stretch: - 0.08, 0.00), with a p-worth of 0.035. Moreover, the orientation proportion communicated as a level of male members had a B worth of - 0.01 (- 0.03, 0.00), with a p-worth of 0.039. Then again, the length of VKA treatment had a B worth of 0.08 (0.03, 0.13), with a p-worth of 0.0005 to be viewed as in Table 2. It was seen that the consequences for the extra-coronary vascular calcification were changed relying upon whether the gave gauges were amended to the bewildering factors [B = - 0.63 (- 1.19), - 0.08; p = 0.016, Table 2]. We led a meta-relapse examination and found that the impact gauges were conceivably impacted by the example size [B = - 0.32 (- 2.35, - 0.04), p = 0.009, Table 2]. This was in spite of the way that the quantity of examinations relating to aortic valves was moderately low (n = 9), and there was an impressive gamble of distribution predisposition. Thus, we completed subgroup examinations in which we thought about the top portion of the investigations to the base portion of the investigations concerning every one of the recognized modifiers (distribution year, sex proportion, length of VKA treatment, and factual change). We found that the effect of the length of VKA on the calcification of the coronary conduits was very nearly being critical while contrasting investigations and a more drawn out term (>1.7 years) to review with a span of ≤1.7 years (bunches distinction test I2 = 72%, p = 0.06; Table 3). We additionally found that, as was normal by meta-relapse, the appraisals of VKA impacts of the extra-coronary calcification were modified relying upon whether the introduced models were adapted to likely bewildering factors.

Discussion

The motivation behind this precise survey, which has an emphasis on randomized controlled preliminaries and contains a significant example size of 15,594 individuals, was to explore the connection among anticoagulants and blood vessel (and valvular) calcification. Our discoveries show that there is a significant relationship between the utilization of vitamin K bad guys (VKAs) and expanded blood vessel and valvular calcification. This is rather than the way that different anticoagulants didn't exhibit a relationship of a similar kind.

Table 2: Coronary Calcifications

Figure 1: Effect size of Coronary calcifications

Table 3: Extra-Coronary Calcifications

Figure 2: Effect size of Extra-Coronary Calcifications

Table 4: Aortic Valve Calcifications

Figure 3: Effect Size of Aortic Valve Calcifications

To stay away from calcification in the veins and heart valves, vitamin K-subordinate proteins are totally fundamental. Vitamin K bad guys, like warfarin, block the actuation of these proteins. As per the system of activity that VKAs are accepted to have, it is accepted that they accelerate the course of calcification. This thought is affirmed by past examination, which our review approves. More specifically, VKAs block the network Gla-protein (MGP), which is a strong inhibitor of vascular calcification, from being carboxylated. Calcification of the vascular and valvular designs happens all the more rapidly when MGP isn't completely carboxylated, which prompts a lessening in the inhibitory impact of the compound. There have been countless observational examinations assessing the impacts of VKA on vascular calcification that have been accounted for. These investigations are of a top notch. In these preliminaries, calcification was assessed in many people who had been treated with VKA. The utilization of calcium imaging in demonstrative examinations, along with the advancement of further developed imaging modalities, made it conceivable to lead more exact examinations on greater patient associates. The end of the conceivable bewildering factors was achieved by various journalists by means of the utilization of a penchant matching methodology. Still others involved extra broad factual methodologies to limit the effect of bewildering factors on calcification assessments. Furthermore, the nature of distributions on the use of VKA and vascular calcification is upheld by the shortfall of a significant gamble of distribution inclination and the way that we had the option to distinguish the length of treatment as a modifier of the effect gauges. To wrap things up, the assessment of calcification in the primary no holds barred randomized preliminaries with VKA was made conceivable by the new send off of another class of non-vitamin K oral anticoagulants known as NOAC. This was the situation in spite of the way that every one of the three randomized examinations assessed a similar peculiarity.

Figure 4: CT Scan Effect Size

As indicated by our exploration, in any case, there was no perceptible connection between vascular or valvular calcification and non-vitamin K oral anticoagulants (NOACs), which incorporate direct thrombin inhibitors and variable Xa inhibitors. This was the situation. There are different instruments that are answerable for the working of these anticoagulants. These exercises don't obstruct the digestion of vitamin K or the carboxylation of macrocyclic G-protein. The meaning of this differential lies in the way that it exhibits how NOACs might be more useful than VKAs for people who are in danger of encountering complexities connected with calcification issues. This information is useful for going with choices applicable to clinical practice. It is vital to take note of that the aftereffects of the survey have significant clinical outcomes. With regards to the cardiovascular results of patients, the decision of an anticoagulant for long haul use might have a critical effect, especially on patients who are at a high gamble of blood vessel or valvular calcification. Clinical experts should give cautious thought to both the dangers and advantages related with VKAs, especially in populaces where calcification is an issue. VKAs have been related with an expansion in calcification, which features the need of cautious checking and, in certain cases, the investigation of elective anticoagulant treatments in patients who are vulnerable. Moreover, it raises the issue of whether patients who need VKAs yet can't change to NOACs would profit from supplemental treatment that is pointed toward decreasing how much calcification that happens in their bodies. While it is vital to recognize the constraints of this audit, which remember changeability for research plans, socioeconomics, and calcification appraisal techniques, it is additionally essential to recognize that this assessment gives educational data. There will be an improvement in the likeness of results in future examination assuming that these boundaries are normalized. Furthermore, research that is led over a more extended timeframe is fundamental to see the value in the effect of anticoagulant medicine on the general movement of calcification and clinical results completely. Furthermore, it is the very pinnacle of need to accomplish other things research to investigate the basic systems that are liable for the calcification that is brought about by VKAs and to make practical medicines that could diminish the seriousness of this effect. Almost certainly, new treatment choices might open up assuming researchers examine the job that vitamin K admission from food plays and the possible advantages of vitamin K supplementation in individuals with VKA.

Conclusion

Because of the reasonable association that exists between these medications and expanded blood vessel and valvular calcification, our far reaching investigation has reached the resolution that patients who need long haul anticoagulation with vitamin K bad guys (VKAs) face a huge gamble. Then again, it doesn't appear to be that different anticoagulants have a similar unfriendly impact as the one recently referenced. Future examination tries that are pointed toward working on understanding results according to anticoagulant medication ought to be directed by the discoveries of this review, which ought to help direct such undertakings.

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