1 Introduction

Arthrofibrosis following total knee arthroplasty (TKA) is a major source of patient dissatisfaction, with a prevalence rate of approximately 15 %.¹ Characterized by excessive fibrous tissue formation around the knee joint, arthrofibrosis is a debilitating cause of pain and functional limitation. Although there is debate regarding the precise definition of arthrofibrosis, it typically involves deposition of dense scar tissue around the joint leading to reduced knee range of motion (ROM) and interference with a patient's ability to engage in activities of daily living such as sitting in a chair, getting into a car, or navigating stairs.² First line treatment consists of aggressive physical therapy with an emphasis on ROM exercises and multimodal pain control.³ Manipulation under anesthesia (MUA) is warranted if conservative management fails, followed by open or arthroscopic lysis of adhesions and revision TKA.³

Despite the availability of numerous treatment modalities, success rates are limited. Furthermore, this complication poses a considerable economic burden, accounting for 28 % of hospital readmissions within 90-days and 10 % of revisions within 5 years.^4,5 As a result, there has been a growing interest in the use of targeted preventative measures. Since fibrotic processes are mediated by signaling cascades and regulatory proteins such as angiotensin, inhibition of this pathway has shown potential anti-fibrotic effects in both in vitro and in vivo studies.^6,7 These early findings have led to the exploration of angiotensin II receptor blocker (ARBs) as a prophylactic medication to mitigate against the development of postoperative arthrofibrosis.

However, there is currently no consensus regarding the efficacy of perioperative ARBs as potential anti-fibrotic agents in the setting of TKA. Thus, the purpose of this systematic review and meta-analysis was to evaluate the effectiveness of perioperative ARBs in mitigating against the development of arthrofibrosis. We sought to determine if ARBs were effective at (1) providing superior postoperative ROM compared to controls; and (2) reducing MUA rates compared to controls.

2 Material and methods

3 Results

The search generated 64 studies. Of these, 7 met the inclusion and exclusion criteria (Fig. 1).

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Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

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3.3

3.3 Postoperative knee range of motion

Postoperative knee ROM was reported in 2 studies.^15,17 The weighted mean postoperative knee ROM in the ARB cohort was 114.6° (range, 114.3°–115.6°) and the weighted mean postoperative knee ROM in the control cohort was 114.3° (range, 112.8°–115.6°). There was no statistically significant difference in postoperative knee range of motion between the ARB cohort and the non-ARB cohort; SMD = −0.089 (95 % CI; −0.354, 0.1751; P = 0.5086), with low heterogeneity (I² = 0 %) (Fig. 2).

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Fig. 2 Meta-analysis of post-operative knee range of motion between angiotensin II receptor antagonist cohort and control cohort.

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3.4

3.4 Manipulation under anesthesia

There were 6 studies that evaluated postoperative MUA rates following TKA.^11–16 In total, 3486 patients (2.8 %) underwent an MUA following TKA in the ARB cohort and 37,008 patients (2.1 %) underwent an MUA following TKA in the control cohort. There was no difference in the rates of postoperative MUA between the ARB cohort and the non-ARB cohort; OR = 1.0408 (95 % CI; 0.6408, 1.6715; P = 0.8370), with high heterogeneity (I² = 98 %) (Fig. 3).

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Fig. 3 Meta-analysis of manipulation under anesthesia rates between angiotensin II receptor antagonist cohort and control cohort.

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3.5

3.5 Revision total knee arthroplasty

There were 3 studies that evaluated revision TKA rates.^12,13,15 In total, 1243 patients (1.2 %) underwent a revision TKA in the ARB cohort and 14,081 patients (1.6 %) underwent revision TKA following TKA in the control cohort. There was no difference in the revision TKA rates between the ARB cohort and the non-ARB cohort; OR = 0.7133 (95 % CI; 0.2249, 2.2621; P = 0.3349), with high heterogeneity (I² = 79 %) (Fig. 4).

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Fig. 4 Meta-analysis of revision total knee arthroplasty rates between angiotensin II receptor antagonist cohort and control cohort.

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4 Discussion

The most important finding of this systematic review and meta-analysis was that the utilization of perioperative ARBs was not associated with superior postoperative knee ROM nor lower rates of MUA in patients undergoing TKA. Additionally, no difference in revision TKA rates existed between patients in the ARB cohort compared to the control cohort.

Arthrofibrosis is a complex pathological process involving excessive scar tissue formation within and around a joint due to an exaggerated healing response triggered by the surgical trauma.³ A critical pathway in arthrofibrosis is mediated by transforming growth factor-beta (TGF-β1), which binds to cell-surface receptors and initiates a signaling cascade to drive extracellular matrix (ECM) production.^18,19 TGF- β1 drives fibroblast differentiation which is modulated by angiotensin II, therefore enhancing its pro-fibrotic effects.^20,21 Given this interaction, ARBs have shown promise as anti-fibrotic agents by reducing angiotensin II-mediated TGF-β1 upregulation in various pre-clinical studies. An in vivo study by Bedair et al. evaluated the effects of ARBs on muscle tissue fibrosis in a mouse gastrocnemius laceration model.⁷ The authors found that administration of losartan resulted in a statistically significant reduced gastrocnemius muscle tissue fibrosis compared to controls in a dose-dependent fashion.

However, contrary to encouraging evidence from early pre-clinical studies, this current systematic review found that the perioperative utilization of ARBs did not lead to a reduction in arthrofibrosis following TKA. Overall, there was no superiority in postoperative knee ROM nor reduction in MUA rates between patients who received perioperative ARBs and the non-ARB cohort. There are several factors which may account for the lack of efficacy of ARBs as potent anti-fibrotic agents. Firstly, patients within the included studies were likely prescribed ARBs at a dose that may be insufficient to reduce the risk of arthrofibrosis. According to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines, the recommended starting dose of losartan for patients is 25 mg per day, titrating up to a maximum dose of 100 mg per day for patients with hypertension or 150 mg per day for patients with heart failure.²² An in vivo study of a tibialis anterior muscle fibrosis rodent model by Garg et al. found that the minimum dose of losartan required to modulate the expression of pro-fibrotic genes and reduce the deposition of type I collagen was 10 mg per kilogram per day,²³ significantly higher than the maximum recommended dose of losartan recommended by the AHA/ACC. This suggests that typical dosages of ARBs in patients with hypertension and heart failure may fall below the threshold necessary to effectively inhibit fibrosis. Secondly, the precise dose of ARBs necessary to mitigate against the development of fibrosis in both peri-articular soft tissue structures and within the joint itself has not been described to date, thus it is likely that the ARB cohort were not receiving the correct dose of ARBs to adequately permeate the joint. Thirdly, elevated BMI, a known risk factor for arthrofibrosis, is common in patients prescribed ARBs and may have reduced the potential anti-fibrotic effects in this cohort. Finally, none of the included patients received perioperative ARBs for the sole purpose of reducing the risk of arthrofibrosis, with many of the included cohort prescribed ARBs for a prolonged period of time prior to undergoing TKA. Thus, it is possible that this cohort may have experienced a less robust anti-fibrotic effect compared to an ARB naïve cohort.

Three studies in this review reported that the perioperative utilization of ARBs resulted in statistically significant improvement in various postoperative markers of arthrofibrosis, including MUA rates.^12,13,16 Rana et al. found that patients who received perioperative ARBs were 1.15 times less likely to warrant an MUA at 1-year postoperatively compared to the non-ARB cohort.¹² Similarly, Albright et al. reported that there was a statistically significant lower likelihood of patients who received perioperative ARBs warranting an MUA at 1-year postoperatively compared to the non-ARB cohort (P < 0.001).¹³ Premkumar et al. also described that there was a statistically significant lower likelihood of patients who received perioperative ARBs requiring an MUA at 1-year postoperatively compared to the non-ARB cohort (P < 0.001).¹⁶ However, it must be noted that all 3 studies were large database studies with sample sizes ranging from 101,366 to 921,078, with the authors utilizing odds ratios to highlight the lower likelihood of the ARB cohort requiring an MUA. Calculating odds ratios with large sample sizes enhances the precision of the estimated effect size by narrowing the confidence intervals around the odds ratio, thereby reducing the standard error.²⁴ As a result, even small differences in the odds of an outcome between groups are more likely to yield statistically significant findings, as the increased sample size facilitates the detection of true associations with greater confidence. Upon examining the MUA rates in each individual study, marginal differences between the cohorts were observed. For example, Rana et al. reported a 2.5 % MUA rate in the ARB cohort compared to a 2.8 % MUA rate in the non-ARB cohort.¹² Similarly, Albright et al. recorded a 2.8 % MUA rate in the ARB cohort compared to a 3.8 % MUA rate in the non-ARB cohort.¹³ The minimal differences in MUA rates between the ARB and non-ARB cohorts suggest that, despite statistical significance, the observed findings may not hold substantial clinical relevance.

Although ARBs may have limited anti-fibrotic effects, there are numerous inherent risks and limitations associated with ARB usage in the setting of TKA. Firstly, like many anti-hypertensive medications, there is a risk of dizziness and light-headedness associated with ARB usage which could increase the risk of a fall whereby a periprosthetic fracture could be sustained.²⁵ Furthermore, multiple studies have demonstrated that perioperative ARBs are independent risk factors for development of an acute kidney injury (AKI) following TKA and total hip arthroplasty (THA).^26,27 Shahi et al. reported that preoperative ARB utilization was associated with an increased risk of developing an AKI following TKA and THA (OR: 3.8).²⁶ Additionally, Kimmel et al. found that perioperative ARB utilization was associated with an increased risk of developing an AKI following TKA and THA (OR: 2.64).²⁷ Although these AKIs are typically mild-to-moderate and self-resolving in nature, the presence of the AKI has implications for postoperative pain management, as prescribed NSAIDs may exacerbate the AKI and, therefore, must be avoided.²⁸ Thus, given the absence of meaningful improvements in ROM, MUA rates, or revision risk, in addition to the lack of substantial anti-fibrotic effects, it is the opinion of the authors that perioperative ARB utilization for the sole purpose of preventing postoperative arthrofibrosis following TKA cannot currently be recommended.

5 Conclusion

This systematic review and meta-analysis found that the utilization of perioperative ARBs were not associated with superior postoperative knee ROM nor lower rates of MUA in patients undergoing TKA. Additionally, no difference in revision TKA rates existed between patients in the ARB cohort compared to the control cohort. Based on the current available data, it is the author's current recommendation that perioperative ARB usage is not indicated in the setting of TKA for the prevention of arthrofibrosis. However, this analysis should be interpreted in light of the low level of evidence and under-reporting of data of the included studies. Thus, higher-level evidence, prospective, comparative studies should be conducted to definitively identify if perioperative ARBs can be utilized as effective anti-fibrotic agents in the setting of TKA.

Patient consent

There was no guardian or patient consent for this study as it was a systematic review and did not use primary patient data.

Ethics approval statement

No ethical approval was required for this study.

CRediT authorship contribution statement

James Butler: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization; Utkarsh Anil: Writing – review & editing, Supervision, Project administration, Methodology, Data curation, Conceptualization. Theodor Di Pauli Von Treuheim: Writing – original draft, Writing – review & editing, Validation, Supervision, Investigation, Conceptualization. Kendall Derry: Writing – review & editing, Data curation, Validation. Maxwell Trudeau: Writing – original draft, Writing – review & editing, Data curation. Jared Rubin: Writing – original draft, Writing – review & editing, Data curation. Ran Schwarzkopf: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation. Claudette Lajam: Writing – review & editing, Validation, Supervision, Project administration, Formal Analysis. Joshua Rozell: Writing – review & editing, Writing – original draft, Validation, Supervision, Resources, Project administration, Methodology, Investigation.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.