Abstract
Background
Angiotensin II receptor blockers (ARBs) antagonize the effects of transforming growth factor-β1, a cytokine mediator for fibrosis and fatty infiltration in skeletal muscle. The objective of this study was to determine (1) if postoperative ARB use is associated with reduced rates of secondary surgery 2 years following arthroscopic rotator cuff repair, and (2) whether there are differences in these outcomes within male-, female-, and non–sex-specific cohorts.
Methods
The TriNet X national database was queried to identify patients between 2015 and 2022 who were prescribed an ARB (losartan, valsartan, or olmesartan) within 3 months of arthroscopic rotator cuff repair. ARB patients were propensity matched 1:1 with a non-ARB control. Analyses were conducted to assess outcomes differences within male-, female-, and non–sex-specific cohorts. Two-year secondary surgery rates (manipulation under anesthesia, revision rotator cuff repair, conversion to reverse or anatomic total shoulder arthroplasty, and non-rotator cuff repair arthroscopic shoulder procedures) were evaluated and compared using odds ratios (OR).
Results
In total, 2,883 matched ARB and non-ARB rotator cuff repair patients were included, with a mean age of 62.5 years, and 42% female in each cohort. In the non–sex-specific analysis, within 2 years after surgery, the non-ARB cohort had similar rates of revision rotator cuff repair as the control. In the female-specific analysis, 1,228 matched ARB and non-ARB females were included, with an average age of 63.2 years, and there were no statistically significant differences in secondary surgery rates. In the male-specific analysis, 1,562 matched males were included, with an average of 62 years. The male non-ARB cohort reported significantly higher rates of undergoing revision rotator cuff repair (OR 1.33, 95% confidence interval [1.01-1.75], P = .039) and significantly higher rates of undergoing total non–rotator cuff repair arthroscopic shoulder procedures (OR 1.35, 95% [confidence interval] [1.04-1.75], P = .025) compared to the ARB male cohort.
Conclusion
The findings of this study suggest that ARB use may be associated with lower rates of secondary shoulder surgeries in patients undergoing rotator cuff repair, with the effects predominantly observed in male patients.
Keywords: Arthroscopic rotator cuff repair, Angiotensin II receptor inhibitor, Shoulder, Fibrosis, Tendon healing, Reoperation rates
Rotator cuff repair is one of the most commonly performed arthroscopic shoulder procedures with favorable clinical, functional, and patient-reported outcomes.7,10,13 Despite its success, it has been associated with variable rates of retear, which can range from 13% to 79%.4 Risk factors such as increased age, severity of tear or retraction, or poor bone stock may also negatively impact tendon healing.1
In addition to the aforementioned risk factors, postoperative scar tissue development with disorganized fibrotic connective tissue formation is implicated in failure of rotator cuff repairs.16,20 Basic science studies have shown that transforming growth factor-β1 (TGF-β1) can promote muscle fibrosis and fatty infiltration by inhibiting fibrogenic and adipogenic progenitor cell apoptosis.8 Mice and rabbit studies have demonstrated that disrupting this signaling pathway in rotator cuff repairs results in decreased muscle fibrosis and fatty infiltration with improved postoperative tendon morphology.8,16 Angiotensin II receptor inhibitors (ARBs), such as losartan or valsartan, have been reported to decrease TGF-β1 levels via antagonizing the renin–angiotensin system (RAS) and have exhibited potential anti-fibrotic effects via inhibiting its downstream signaling pathway.6,9,11,15 Further, basic science models have also demonstrated postoperative ARB use may promote tendinous healing by modulating oxidative stress and inflammatory cytokines, while also improving collagen composition.16,24,33 In rat models, this has been associated with enhanced biomechanical properties such as ultimate load and tensile strength following repair.16,24,33
There is also increasing evidence that ARBs and RAS-antagonizing therapeutics may also exhibit variable effects based on patient sex, attributable in part to increased RAS dysregulation in males compared to females.21,28 In their systematic review of randomized controlled trials evaluating sex-specific efficacy of RAS antagonists in treating hypertension, Rabi et al found that seven of nine trials reported angiotensin-converting enzyme (ACE) inhibitor or ARBs to be modestly more beneficial in men.27 On the other hand, multiple studies have also suggested increased ARB efficacy in females for treatment of congestive heart failure.12,31
In the clinical orthopedic literature, ARBs have been prescribed prophylactically for capsulolabral adhesions after hip arthroscopy; however, there are limited outcomes studies on their efficacy.19,25 Studies have also demonstrated postoperative ARB use to be associated with decreased stiffness and lower rates of manipulation under anesthesia (MUA) after total knee arthroplasty.3,26 In shoulder arthroscopy, a recent single-center study examining perioperative ACE inhibitor and ARB use found similar rates of postoperative MUA and diagnosis of adhesive capsulitis between the prescribed cohort and control.5 However, to date, multi-institutional studies evaluating the rates of postoperative revision and secondary surgeries in patients prescribed ARBs following arthroscopic rotator cuff repair remain limited. Moreover, studies investigating postoperative ARB use in orthopedics have offered limited discussion on potential sex-based differences in clinical outcomes following administration.
The objective of this study was to determine (1) if postoperative ARB use is associated with reduced rates of secondary surgery 2 years following arthroscopic rotator cuff repair, and (2) whether there are differences in these outcomes within male-, female- and non–sex-specific cohorts. It was hypothesized that postoperative ARB use would be associated with decreased secondary surgery and revision rates in patients undergoing arthroscopic rotator cuff repair.
Methods
Study design and data collection
All queries were performed on the TriNetX US Collaborative Network database (TriNetX, LLC, Cambridge, MA, USA), which collects deidentified electronic health records from 65 health care organizations with an aggregate of over 116 million patients across the United States. TriNetX was queried on August 28, 2024, to identify patients who underwent arthroscopic rotator cuff repair between October 1, 2015, and August 1, 2022. All queries were performed utilizing International Classification of Disease, 10th revision, Clinical Modification (ICD-10), RxNorm, and Current Procedural Terminology (CPT) codes. This study was exempt from institutional review board approval as all data utilized from the database was anonymized. Supplementary Appendix SA describes all the CPT and ICD-10 codes utilized to identify patients.
The index event was indicated as the patient's first arthroscopic rotator cuff repair between October 1, 2015, and August 1, 2022. Patients with any postoperative prescription of at least one of the three most commonly prescribed ARBs (losartan, valsartan, olmesartan) within 3 months after surgery were placed into one cohort, and patients without in the same timeframe were placed in the other cohort.2 Although some patients in the control group had prior ARB prescriptions, they were not considered exposed in the absence of postoperative use. This distinction was made to focus specifically on the postoperative period of biologic healing, and prior ARB use was not used as matching or exclusion criterion. A 1:1 propensity match analysis based on age at surgery, sex (if applicable), and diagnoses of hypertension, overweight or obesity (≥25 body mass index), and diabetes mellitus (type I or type II) was performed. Two year secondary surgery rates (MUA, second rotator cuff repair, conversion to reverse or anatomic total shoulder arthroplasty (TSA) (both CPT: 23472), and non–rotator cuff repair arthroscopic shoulder procedures were evaluated. Non–rotator cuff repair arthroscopic shoulder procedures queried were arthroscopic capsulorrhaphy, superior labral anterior to posterior lesion repair, loose body removal, partial or complete synovectomy, débridement, Mumford procedure, lysis of adhesions, subacromial decompression, or biceps tenodesis. Supplementary Appendix SB describes all the CPT and ICD-10 codes used to identify postoperative outcomes.
Three separate analyses were performed in this study. One analysis was non–sex-specific, while two were performed by selectively querying TriNetX for only male or only female patients. The male ARB cohort was propensity matched with a male control cohort, and the female ARB cohort was propensity matched with a female control cohort. Control groups were not prescribed postoperative ARBs. Secondary surgery rates within 2 years of surgery were subsequently evaluated in each analysis.
Statistical analysis
All analyses were performed utilizing the TriNetX platform. Descriptive metrics were documented as mean ± standard deviation or number (%). Mann–Whitney U tests were used to evaluate continuous variables while chi-square tests were used to evaluate categorical variables. The propensity match analysis was performed using 1:1 matching with a nearest-neighbor greedy matching algorithm and a caliper of 0.25. Comparative analyses between cohorts were performed using odds ratios with a 95% confidence interval (CI) and P value. Statistical significance was defined as P < .05. All P values are reported as unadjusted, without statistical correction for multiple comparisons, consistent with practices used in comparable large-scale database orthopedic studies.19,23
Results
Patient demographics: non–sex-specific analysis
Demographics prior to and after propensity match are documented in Table I. The initial TriNetX query yielded 83,262 patients that underwent arthroscopic rotator cuff repairs between October 1, 2015, and August 1, 2022. After 1:1 propensity matching, 2,883 patients were assigned into the ARB and control cohorts. The mean age at the time of surgery in each cohort was 62.5 years. Each cohort consisted of 42% females, with 86.2% of patients with hypertension, 42.8% with overweight or obese status, and 38.5% with diabetes. The postoperative ARB cohort exhibited significantly higher prior usage rates of losartan (70.1% vs. 13.0%, P < .001), valsartan (19.3% vs. 5.3%, P < .001), and olmesartan (9.5% vs. 2.1%, P < .001) at any point prior to surgery. Descriptive, baseline statistics as well as chi-square analyses and Mann–Whitney U test analysis after propensity matching are reported in Table I.
Table I.
Non–sex-specific: demographics, comorbidities and medications.
| Demographics & comorbidities | Before propensity match |
After propensity match |
||||
|---|---|---|---|---|---|---|
| RTC repair w/o ARB (n = 80,379) | RTC repair w/ARB (n = 2,883) | P value | RTC repair w/o ARB (n = 2,883) | RTC repair w/ARB (n = 2,883) | P value | |
| Age at index (Mean ± SD) | 58.2 ± 10.5 | 62.5 ± 8.9 | <.001 | 62.5 ± 8.9 | 62.5 ± 8.9 | .988 |
| Female (%) | 31,918 (39.71%) | 1,228 (42.60%) | .002 | 1,217 (42.21%) | 1,228 (42.60%) | .770 |
| Diagnoses | ||||||
| Essential hypertension (I10) | 29,601 (36.83%) | 2,486 (86.23%) | <.001 | 2,486 (86.23%) | 2,486 (86.23%) | 1.000 |
| Overweight & obesity (E66) | 16,005 (19.91%) | 1,234 (42.80%) | <.001 | 1,234 (42.80%) | 1,234 (42.80%) | 1.000 |
| Diabetes (E08-E13) | 13,112 (16.31%) | 1,110 (38.50%) | <.001 | 1,111 (38.54%) | 1,110 (38.50%) | .978 |
| Medications | ||||||
| Losartan (RxNorm 52175) | 4,994 (6.21%) | 2,022 (70.14%) | <.001 | 375 (13.01%) | 2,022 (70.14%) | <.001 |
| Valsartan (RxNorm 69749) | 1,877 (2.34%) | 555 (19.51%) | <.001 | 153 (5.31%) | 555 (19.25%) | <.001 |
| Olmesartan (RxNorm 321064) | 699 (0.87%) | 274 (9.50%) | <.001 | 61 (2.12%) | 274 (9.50%) | <.001 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SD, standard deviation.
P < .05 indicates statistical significance.
Values are presented as mean ± SD, or n (%).
Patient demographics: sex-specific analyses
Demographics after propensity matching female-only cohorts are listed in Table II. One control group and one ARB group of 1,228 females were matched, with an average age of 63.2. The rates of hypertension in the female cohorts were 87.9%, with rates of overweight/obesity and diabetes at 48.0% and 41.2%, respectively. Demographics for the male-only cohorts after propensity matching are listed in Table III. Each cohort consisted of 1,562 male patients, with an average age of 62 years. The rates of hypertension, overweight/obesity, and diabetes were 84.7%, 39.0%, and 36.3%, respectively. In both the male- and female-specific analyses, patients prescribed with postoperative ARB reported significantly higher rates of ARB prescription at any time point prior to their surgery.
Table II.
Females: demographics, comorbidities and medications.
| Demographics & comorbidities | Before matching |
After matching |
||||
|---|---|---|---|---|---|---|
| RTC repair w/o ARB (n = 31,918) | RTC repair w/ARB (n = 1,228) | P value | RTC repair w/o ARB (n = 1,228) | RTC repair w/ARB (n = 1,228) | P value | |
| Age at index (Mean ± SD) | 58.8 ± 10.1 | 63.2 ± 8.83 | <.001 | 63.2 ± 8.83 | 63.2 ± 8.83 | 1.000 |
| Diagnoses | ||||||
| Essential hypertension (I10) | 12,109 (37.94%) | 1,079 (87.87%) | <.001 | 1,079 (87.87%) | 1,079 (87.87%) | 1.000 |
| Overweight & obesity (E66) | 7,99 (25.04%) | 589 (47.96%) | <.001 | 589 (47.96%) | 589 (47.96%) | 1.000 |
| Diabetes (E08-E13) | 5,713 (17.90%) | 506 (41.21%) | <.001 | 506 (41.21%) | 506 (41.21%) | 1.000 |
| Medications | ||||||
| Losartan (RxNorm 52175) | 2,165 (6.78%) | 890 (72.48%) | <.001 | 171 (13.93%) | 890 (72.48%) | <.001 |
| Valsartan (RxNorm 69749) | 792 (2.48%) | 236 (19.22%) | <.001 | 47 (3.83%) | 236 (19.22%) | <.001 |
| Olmesartan (RxNorm 321064) | 289 (0.91%) | 125 (10.18%) | <.001 | 26 (2.12%) | 125 (10.18%) | <.001 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SD, standard deviation.
P < .05 indicates statistical significance.
Values are presented as n (%).
Table III.
Males: demographics, comorbidities and medications.
| Demographics & comorbidities | Before matching |
After matching |
||||
|---|---|---|---|---|---|---|
| RTC repair w/o ARB (n = 42,869) | RTC repair w/ARB (n = 1,562) | P value | RTC repair w/o ARB (n = 1,562) | RTC repair w/ARB (n = 1,562) | P value | |
| Age at index (Mean ± SD) | 57.7 ± 10.8 | 62 ± 8.97 | <.001 | 62 ± 8.98 | 62 ± 8.97 | .984 |
| Diagnoses | ||||||
| Essential hypertension (I10) | 15,564 (36.31%) | 1,323 (84.70%) | <.001 | 1,323 (84.70%) | 1,323 (84.70%) | 1.000 |
| Overweight & obesity (E66) | 7,118 (16.60%) | 609 (38.99%) | <.001 | 609 (38.99%) | 609 (38.99%) | 1.000 |
| Diabetes (E08-E13) | 6,619 (15.44%) | 566 (36.24%) | <.001 | 567 (36.30%) | 566 (36.24%) | .970 |
| Medications | ||||||
| Losartan (RxNorm 52175) | 2,618 (6.11%) | 1,085 (69.46%) | <.001 | 195 (12.48%) | 1,085 (69.46%) | <.001 |
| Valsartan (RxNorm 69749) | 930 (2.17%) | 296 (18.95%) | <.001 | 68 (4.35%) | 296 (18.95%) | <.001 |
| Olmesartan (RxNorm 321064) | 367 (0.86%) | 141 (9.03%) | <.001 | 38 (2.43%) | 141 (9.03%) | <.001 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SD, standard deviation.
P < .05 indicates statistical significance.
Values are presented as n (%).
Secondary surgeries
Postoperative secondary surgery rates within 2 years of rotator cuff repair are reported in Table IV for the non–sex-specific analysis, Table V for the female-specific analysis, and Table VI for the male-specific analysis.
Table IV.
Non-sex specific: odds of secondary surgery within 2 years after surgery.
| Outcomes | RTC repair w/o ARB (n = 2,883) | RTC repair w/ARB (n = 2,883) | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| MUA | 12 (0.42%) | 19 (0.66%) | 0.63 (0.31, 1.30) | .207 |
| Revision | 220 (7.63%) | 183 (6.35%) | 1.22 (1.00, 1.49) | .056 |
| Total shoulder arthroplasty | 46 (1.60%) | 54 (1.87%) | 0.85 (0.57, 1.26) | .420 |
| Non–rotator cuff repair arthroscopic procedures | ||||
| Lysis of adhesions | 28 (0.97%) | 18 (0.62%) | 1.56 (0.86, 2.83) | .139 |
| Capsulorrhaphy | ≤10 (0.35%) | ≤10 (0.35%) | 1 (0.42, 2.41) | 1.000 |
| SLAP repair | ≤10 (0.35%) | ≤10 (0.35%) | 1 (0.42, 2.41) | 1.000 |
| LBR | ≤10 (0.35%) | ≤10 (0.35%) | 1 (0.42, 2.41) | 1.000 |
| Partial synovectomy | ≤10 (0.35%) | ≤10 (0.35%) | 1 (0.42, 2.41) | 1.000 |
| Complete synovectomy | ≤10 (0.35%) | ≤10 (0.35%) | 1 (0.42, 2.41) | 1.000 |
| Débridement limited | 26 (0.90%) | 19 (0.66%) | 1.37 (0.76, 2.48) | .295 |
| Débridement extensive | 133 (4.61%) | 127 (4.41%) | 1.05 (0.82, 1.35) | .703 |
| Mumford | 52 (1.80%) | 44 (1.53%) | 1.19 (0.79, 1.78) | .410 |
| SAD | 173 (6.00%) | 127 (4.41%) | 1.39 (1.10, 1.75) | .006 |
| Biceps tenodesis | 56 (1.94%) | 31 (1.08%) | 1.82 (1.17, 2.83) | .007 |
| Non–rotator cuff repair arthroscopic shoulder procedure total | 236 (8.19%) | 203 (7.04%) | 1.18 (0.97, 1.43) | .101 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SLAP, superior labrum anterior to posterior; LBR, loose body removal; SAD, subacromial decompression; CI, confidence interval; MUA, manipulation under anesthesia.
P < .05 indicates statistical significance.
Values are presented as n (%).
Table V.
Females: odds of secondary surgery within 2 years after surgery.
| Outcomes | RTC repair w/o ARB (n = 1,228) | RTC repair w/ARB (n = 1,228) | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| MUA | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| Revision | 78 (6.35%) | 78 (6.35%) | 1 (0.72, 1.38) | 1.000 |
| Total shoulder arthroplasty | 36 (2.93%) | 25 (2.04%) | 1.45 (0.87, 2.44) | .154 |
| Non–rotator cuff repair arthroscopic procedures | ||||
| Lysis of adhesions | 14 (1.14%) | ≤10 (0.81%) | 1.41 (0.62, 3.18) | .412 |
| Capsulorrhaphy | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| SLAP repair | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| LBR | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| Partial synovectomy | ≤10 (0.81%) | 0 | N/A | .002 |
| Complete synovectomy | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| Débridement limited | 12 (0.98%) | ≤10 (0.81%) | 1.20 (0.52, 2.79) | .668 |
| Débridement extensive | 56 (4.56%) | 48 (3.91%) | 1.18 (0.79, 1.74) | .423 |
| Mumford | 28 (2.28%) | 18 (1.47%) | 1.57 (0.86, 2.85) | .137 |
| SAD | 62 (5.05%) | 51 (4.15%) | 1.23 (0.84, 1.79) | .289 |
| Biceps tenodesis | ≤10 (0.81%) | ≤10 (0.81%) | 1 (0.42, 2.41) | 1.000 |
| Non–rotator cuff repair arthroscopic shoulder procedure total | 96 (7.82%) | 85 (6.92%) | 1.14 (0.84, 1.54) | .396 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SLAP, superior labrum anterior to posterior; LBR, loose body removal; SAD, subacromial decompression; CI, confidence interval; MUA, manipulation under anesthesia.
P < .05 indicates statistical significance.
Values are presented as n (%).
Table VI.
Males: odds of secondary surgery within 2 years after surgery.
| Outcomes | RTC repair w/o ARB (n = 1,562) | RTC repair w/ARB (n = 1,562) | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| MUA | ≤10 (0.64%) | 12 (0.77%) | 0.83 (0.36, 1.92) | .669 |
| Revision | 129 (8.26%) | 99 (6.34%) | 1.33 (1.01, 1.75) | .039 |
| Total shoulder arthroplasty | 18 (1.15%) | 25 (1.60%) | 0.72 (0.39, 1.32) | .284 |
| Non–rotator cuff repair arthroscopic procedures | ||||
| Lysis of adhesions | 12 (0.77%) | 13 (0.83%) | 0.92 (0.42, 2.03) | .841 |
| Capsulorrhaphy | ≤10 (0.64%) | ≤10 (0.64%) | 1.00 (0.42, 2.41) | 1.000 |
| SLAP repair | ≤10 (0.64%) | ≤10 (0.64%) | 1.00 (0.42, 2.41) | 1.000 |
| LBR | ≤10 (0.64%) | ≤10 (0.64%) | 1.00 (0.42, 2.41) | 1.000 |
| Arthroscopic partial synovectomy | ≤10 (0.64%) | ≤10 (0.64%) | 1.00 (0.42, 2.41) | 1.000 |
| Arthroscopic complete synovectomy | ≤10 (0.64%) | ≤10 (0.64%) | 1.00 (0.42, 2.41) | 1.000 |
| Arthroscopic limited débridement | 12 (0.77%) | 13 (0.83%) | 0.92 (0.42, 2.03) | .841 |
| Arthroscopic extensive débridement | 79 (5.06%) | 70 (4.48%) | 1.14 (0.87, 1.58) | .450 |
| Arthroscopic Mumford | 49 (3.14%) | 26 (1.67%) | 1.913 (1.18, 3.10) | .007 |
| Arthroscopic SAD | 107 (6.85%) | 73 (4.67%) | 1.5 (1.10, 2.04) | .009 |
| Arthroscopic biceps tenodesis | 32 (2.05%) | 22 (1.41%) | 1.46 (0.85, 2.53) | .170 |
| Shoulder arthroscopy non–rotator cuff repair total | 142 (9.09%) | 108 (6.91%) | 1.35 (1.04, 1.75) | .025 |
ARB, angiotensin II receptor blocker; RTC, rotator cuff; SLAP, superior labrum anterior to posterior; LBR, loose body removal; SAD, subacromial decompression; CI, confidence interval; MUA, manipulation under anesthesia.
P < .05 indicates statistical significance.
Values are presented as n (%).
In the non–sex-specific analysis, within 2 years after arthroscopic rotator cuff repair, no significant differences in rates of revision rotator cuff repair or total non–rotator cuff repair arthroscopic procedures were found between the ARB cohort and control. The ARB group, however, demonstrated a significant reduction in arthroscopic subacromial decompressions (6.0% vs. 4.4%, P = .006) and biceps tenodesis (1.9% vs. 1.1%, P = .007), specifically. Conversion to TSA occurred at similar rates in both cohorts (1.6% vs. 1.9%, P = .420).
In the female-specific analysis, similar rates of revision rotator cuff repair, non–rotator cuff repair arthroscopic shoulder procedures, or conversion to TSA were observed between the ARB group and control.
Lastly, in the male-specific analysis, postoperative ARB use was associated with decreased rates of revision rotator cuff repair (6.3% vs. 8.3%, P = .039) within 2 years after rotator cuff repair. Conversion to TSA was similar between the male ARB and control group (1.2% vs. 1.6%, P = .2842). ARB use was also associated with decreased rates of total non–rotator cuff repair arthroscopic shoulder procedures (6.9% vs. 9.1%, P = .025). Specifically, ARB use was associated with decreased rates of arthroscopic Mumford procedures (1.7% vs. 3.1%, P = .007) and arthroscopic subacromial decompressions (4.7% vs. 6.9%, P = .009).
Discussion
The main findings of this study were that receiving an ARB prescription within 3 months after arthroscopic rotator cuff repair was associated with decreased rates of revision arthroscopic rotator cuff repair and non–rotator cuff repair arthroscopic shoulder surgeries within 2 years of surgery in male patients but not in female patients. Further, in the non–sex-specific analysis, postoperative ARB prescription was associated with similar rates of revision arthroscopic rotator cuff repair, decreased rates of arthroscopic subacromial decompression and biceps tenodesis, but no difference in total non–rotator cuff repair arthroscopic shoulder procedures. Lastly, no differences in rates of MUA or conversion to TSA were found between patients with and without postoperative ARB prescriptions in all three analyses.
The most notable finding of the present study was that ARB prescription within 3 months after arthroscopic rotator cuff repair was associated with decreased revision rotator cuff repair rates and total non–rotator cuff repair arthroscopic procedures within 2 years postoperatively in males only. There have been numerous studies demonstrating increased benefit with ARB use in males specifically. In their systematic review and meta-analysis of nine prospective studies, Wu et al found that ARB usage offered protective benefit against total fracture risk in males (Relative Risk = 0.65, 95% CI: 0.49-0.89) but not females.35 Numerous studies also substantiate sex-based differences in both RAS function and response to ARB.30,36 In their study of hospitalized patients with COVID-19, Rochelau et al found that males operate at an increased level of RAS dysregulation at baseline and, consequently, benefit more from inhibition of this pathway, resulting in their observed improved clinical outcomes with ARB use in males but not females.29 Sex-based differences in response to ARBs have been largely unexplored in orthopedic literature, however, and the findings of this study may suggest discrepancies in RAS pathway inhibition and their effects on musculotendinous recovery between sexes.
There are several possible mechanisms for why the observed secondary surgery rates were lower with postoperative ARB use in the male-specific analysis. While this study examined postoperative ARB use, it is important to note that patients in both ARB and non-ARB cohorts may have been on preexisting medical management for hypertension. A history of hypertension was documented in 86.23% of the ARB cohort and 36.8% of the non-ARB cohort. In addition, 69% and 19% of patients in the postoperative ARB cohort had been prescribed losartan or valsartan, respectively, at some point prior to surgery (compared to 6.2% and 2.2%, respectively, in the non-ARB cohort). In the context of mouse studies on rotator cuff injury demonstrating decreased muscle fibrosis and fatty infiltration with TGF-β1 inhibition, it is conceivable that long-term preoperative ARB use, through its inhibition of the TGF-β1 pathway, may reduce preoperative rotator cuff fibrosis and fatty infiltration.8,16 Consequently, this would enhance compliance and vascularity of the rotator cuff tendons and musculature.8,16,34 This is particularly relevant as a meta-analysis by Raman et al reported that, of all variables, increased fatty infiltration (odds ratio 9.3; 95% CI: 4.22-20.70) had the single greatest effect on prognosis after rotator cuff repair, more so than tear size, muscle strength, number of tendons involved.14,28 These findings suggest that improved preoperative tissue quality, potentially achieved through long-term ARB use, may be associated with decreased failure rates found in this study. Further studies examining the effects of ARB use over longer preoperative periods, including sex-specific sub-analyses, may provide further clarity on the impact of ARB on postoperative outcomes and help clarify why the effects may be more pronounced in males compared to females.
Another finding of this study was that in the non–sex-specific analysis, postoperative ARB prescriptions were not associated with a reduction in risk for total arthroscopic nonvrotator cuff repair or rotator cuff repair procedures. However, postoperative ARB administration was associated specifically with decreased rates of arthroscopic subacromial decompression and biceps tenodesis. Although ARB use did not reduce the incidence of clinical arthrofibrosis in this study(ie, requiring MUA), it is possible that ARB administration was associated with less subclinical arthrofibrosis. Such a reduction may help reduce fibrotic thickening of the subacromial bursa. In addition, this may reflect a more favorable postoperative state in the ARB group, reducing the need for secondary procedures such as Mumford procedures for residual AC joint symptoms, as observed in the male ARB cohort. Interestingly in the non–sex-specific analysis, the observed reduction in secondary surgery risk was not evident for revision rotator cuff repairs or other arthroscopic shoulder procedures, including synovectomies and débridement. Additional studies utilizing a different database or longitudinal observation may validate these findings and clarify the potential underlying mechanisms driving the varying effects of postoperative ARB administration on secondary arthroscopic shoulder procedures.
Lastly, existing literature is equivocal as to whether postoperative ARB use can improve incidence of MUA after arthroscopic rotator cuff repair. Testa et al, conducted a retrospective cohort study using a large database and found that ARB use was associated with a protective effect against new onset adhesive capsulitis.32 On the other hand, in a single-center study examining perioperative use of ARBs or ACE inhibitors in shoulder arthroscopy, Bi et al reported no significant differences in the incidence of postoperative adhesive capsulitis or MUA compared to the control group at minimum 2-year follow-up.5 Similarly, Miltenberg et al found that perioperative use of losartan was not associated with a significant difference in rates of lysis of adhesions or MUA within 1-2 years following arthroscopic rotator cuff repair.22 This was consistent with the findings of the current study, which similarly reported no significant differences in the rates of MUA. Further, Bi et al attributed their results to the potential inadequacy of the sample size and the considerable impact of other key inflammatory cytokine mediators of arthrofibrosis in the shoulder, such as those in the cyclooxygenase or tissue inhibitor of metalloproteinase pathways, which may overshadow the effects of TGF-β1 inhibition.5,17,18 The findings of this current study reaffirmed the possibility of such explanations and any confirmation would likely require studies with substantially larger power.
Limitations
There were several limitations to this study. First, due to the nature of ICD-10 and CPT codes, the results of this study does not account for differences in coding by hospitals or physician practices. Second, the deidentified data provided by TriNetX cannot be confirmed clinically, which may increase the margin for error. Third, the laterality of the procedures could not be verified on TriNetX, which may further confound the findings of this study and warrants cautious interpretation of data. Fourth, the 3-month postoperative timeframe may be a limitation of this study, as the effect of ARB use could influence postoperative healing and complications differently at various time points within the 3-month period. Fifth, we were not able to evaluate for chronicity or severity of rotator cuff tear, number of tendons involved, or degree of fatty atrophy present, which all influence postoperative outcomes after rotator cuff repair. Sixth, reported P values were unadjusted and should be interpreted cautiously in the context of multiple testing. Seventh, while our cohorts were matched on key covariates relevant to both ARB prescription and tendon healing, residual confounding may still exist, as our matching model may not have captured all clinically relevant factors. Eighth, due to the limitations of CPT coding, we were unable to distinguish between anatomic and reverse total shoulder arthroplasties, as both are coded using CPT 23472. As such, cases classified as conversion to TSA may have included either anatomic or reverse shoulder arthroplasty. Ninth, we cannot confirm that all index surgeries were primary repairs, as some may represent revision procedures for surgeries performed prior to 2015. Finally, this study only examined short-term outcomes, precluding any assessment of long-term results with postoperative ARB use.
Conclusion
The findings of this study suggest that postoperative ARB use may be associated with protection against secondary shoulder surgeries in patients undergoing rotator cuff repair, with the effects predominantly observed in male patients.
Disclaimers:
Funding: No funding was disclosed by the authors.
Conflicts of interest: The authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.
Footnotes
Institutional review board approval was not required for this study. This study was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki.
This study was performed at the Department of Orthopaedics and Rehabilitation, Yale School of Medicine.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jseint.2025.05.007.
Supplementary Data
References
- 1.Abtahi A.M. Factors affecting healing after arthroscopic rotator cuff repair. World J Orthop. 2015;6:211. doi: 10.5312/wjo.v6.i2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Albright J.A., Testa E.J., Ibrahim Z., Quinn M.S., Chang K., Alsoof D., et al. Postoperative angiotensin receptor blocker use is associated with decreased rates of manipulation under anesthesia, arthroscopic lysis of adhesions, and prosthesis-related complications in patients undergoing total knee arthroplasty. J Arthroplasty. 2024;39:954–959.e1. doi: 10.1016/j.arth.2023.10.015. [DOI] [PubMed] [Google Scholar]
- 3.Arraut J., Lygrisse K.A., Singh V., Fiedler B., Schwarzkopf R., Rozell J.C. The effect of losartan on range of motion and rates of manipulation in total knee arthroplasty: a retrospective matched cohort study. Arch Orthop Trauma Surg. 2022;143:4043–4048. doi: 10.1007/s00402-022-04696-8. [DOI] [PubMed] [Google Scholar]
- 4.Azar M., Van Der Meijden O., Pireau N., Chelli M., Gonzalez J.-F., Boileau P. Arthroscopic revision cuff repair: do tendons have a second chance to heal? J Shoulder Elbow Surg. 2022;31:2521–2531. doi: 10.1016/j.jse.2022.04.024. [DOI] [PubMed] [Google Scholar]
- 5.Bi A.S., Li Z.I., Triana J., Fisher N.D., Morgan A.M., Garra S., et al. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors have no significant relationship with postoperative arthrofibrosis after shoulder arthroscopy. Arthrosc Sports Med Rehabil. 2023;5 doi: 10.1016/j.asmr.2023.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Campistol J.M., Iñigo P., Jimenez W., Lario S., Clesca P.H., Oppenheimer F., et al. Losartan decreases plasma levels of TGF-β1 in transplant patients with chronic allograft nephropathy. Kidney Int. 1999;56:714–719. doi: 10.1046/j.1523-1755.1999.00597.x. [DOI] [PubMed] [Google Scholar]
- 7.Davey M.S., Hurley E.T., Carroll P.J., Galbraith J.G., Shannon F., Kaar K., et al. Arthroscopic rotator cuff repair results in improved clinical outcomes and low revision rates at 10-year follow-up: a systematic review. Arthroscopy. 2023;39:452–458. doi: 10.1016/j.arthro.2022.11.002. [DOI] [PubMed] [Google Scholar]
- 8.Davies M.R., Liu X., Lee L., Laron D., Ning A.Y., Kim H.T., et al. TGF-Β small molecule inhibitor SB431542 reduces rotator cuff muscle fibrosis and fatty infiltration by promoting fibro/adipogenic progenitor apoptosis. PLoS One. 2016;11 doi: 10.1371/journal.pone.0155486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fang Q.-Q., Wang X.-F., Zhao W.-Y., Ding S.-L., Shi B.-H., Xia Y., et al. Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways. Sci Rep. 2018;8:3332. doi: 10.1038/s41598-018-21600-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Green C.K., Scanaliato J.P., Dunn J.C., Rosner R.S., Parnes N. Rates of return to manual labor after arthroscopic rotator cuff repair. Am J Sports Med. 2022;50:2227–2233. doi: 10.1177/03635465221097102. [DOI] [PubMed] [Google Scholar]
- 11.Guo Z., Qiu M. [Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat] Zhonghua Nei Ke Za Zhi. 2003;42:403–408. [PubMed] [Google Scholar]
- 12.Hudson M., Rahme E., Behlouli H., Sheppard R., Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — a population study. Eur J Heart Fail. 2007;9:602–609. doi: 10.1016/j.ejheart.2007.02.001. [DOI] [PubMed] [Google Scholar]
- 13.Jain N.B., Higgins L.D., Losina E., Collins J., Blazar P.E., Katz J.N. Epidemiology of musculoskeletal upper extremity ambulatory surgery in the United States. BMC Musculoskelet Disord. 2014;15:4. doi: 10.1186/1471-2474-15-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jensen A.R., Taylor A.J., Sanchez-Sotelo J. Factors influencing the reparability and healing rates of rotator cuff tears. Curr Rev Musculoskelet Med. 2020;13:572–583. doi: 10.1007/s12178-020-09660-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Khodaei B., Nasimi M., Nassireslami E., Seyedpour S., Rahmati J., Haddady Abianeh S., et al. Efficacy of topical losartan in management of mammoplasty and abdominoplasty scars: a randomized, double-blind clinical trial. Aesthetic Plast Surg. 2022;46:2580–2587. doi: 10.1007/s00266-022-02935-2. [DOI] [PubMed] [Google Scholar]
- 16.Lacheta L., Gao X., Miles J.W., Murata Y., Fukase N., Utsunomiya H., et al. Losartan in combination with bone marrow stimulation showed synergistic effects on load to failure and tendon matrix organization in a rabbit model. Arthroscopy. 2023;39:2408–2419. doi: 10.1016/j.arthro.2023.05.020. [DOI] [PubMed] [Google Scholar]
- 17.Lho Y.-M., Ha E., Cho C.-H., Song K.-S., Min B.-W., Bae K.-C., et al. Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder. J Shoulder Elbow Surg. 2013;22:666–672. doi: 10.1016/j.jse.2012.06.014. [DOI] [PubMed] [Google Scholar]
- 18.Lubis A.M.T., Lubis V.K. Matrix metalloproteinase, tissue inhibitor of metalloproteinase and transforming growth factor-beta 1 in frozen shoulder, and their changes as response to intensive stretching and supervised neglect exercise. J Orthop Sci. 2013;18:519–527. doi: 10.1007/s00776-013-0387-0. [DOI] [PubMed] [Google Scholar]
- 19.Mahmoud Y., Ramtin S., Quindlen C.E., Chung J., Kellish A.S., Ilyas A.M., et al. The role of medical comorbidities in rotator cuff retear after arthroscopic repair: a TriNetX database review of 98,844 patients. JSES Int. 2025;9:678–682. doi: 10.1016/j.jseint.2024.11.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Manning C.N., Kim H.M., Sakiyama-Elbert S., Galatz L.M., Havlioglu N., Thomopoulos S. Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model. J Orthop Res. 2011;29:1099–1105. doi: 10.1002/jor.21301. [DOI] [PubMed] [Google Scholar]
- 21.Miller J.A., Cherney D.Z., Duncan J.A., Lai V., Burns K.D., Kennedy C.R.J., et al. Gender differences in the renal response to renin-angiotensin system blockade. J Am Soc Nephrol. 2006;17:2554–2560. doi: 10.1681/ASN.2005101095. [DOI] [PubMed] [Google Scholar]
- 22.Miltenberg B., Martinazzi B.J., Monahan P.F., Johns W.L., Onor G., Faasuamalie P.E., et al. Perioperative losartan is associated with similar rates of additional surgical procedures for postoperative shoulder stiffness after primary arthroscopic rotator cuff repair but lower rates of secondary debridement and repair. Arthroscopy. 2024;40:512–520. doi: 10.1016/j.arthro.2024.11.084. [DOI] [PubMed] [Google Scholar]
- 23.Monahan P.F., Surucu S., Pahapill N.K., Jimenez A.E., Taylor K.F. Prior diagnosis of opioid-related disorder is associated with higher medical resource utilization following primary hip arthroscopy: a national database study. Arthroscopy. 2024;40:2021–2028.e1. doi: 10.1016/j.arthro.2023.12.008. [DOI] [PubMed] [Google Scholar]
- 24.Nazari S.E., Naimi H., Sayyed-Hosseinian S.-H., Vahedi E., Daghiani M., Asgharzadeh F., et al. Effect of angiotensin II pathway inhibitors on post-surgical adhesion band formation: a potential repurposing of old drugs. Injury. 2022;53:3642–3649. doi: 10.1016/j.injury.2022.08.046. [DOI] [PubMed] [Google Scholar]
- 25.Philippon M.J., Ryan M., Martin M.B., Huard J. Capsulolabral adhesions after hip arthroscopy for the treatment of femoroacetabular impingement: strategies during rehabilitation and return to sport to reduce the risk of revision. Arthrosc Sports Med Rehabil. 2022;4:e255–e262. doi: 10.1016/j.asmr.2021.10.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Premkumar A., Anatone A., Illescas A., Memtsoudis S., Cross M.B., Sculco P.K., et al. Perioperative use of antifibrotic medications associated with lower rate of manipulation after primary TKA: an analysis of 101,366 patients. J Arthroplasty. 2022;37:S1010–S1015.e1. doi: 10.1016/j.arth.2022.03.026. [DOI] [PubMed] [Google Scholar]
- 27.Rabi D.M., Khan N., Vallee M., Hladunewich M.A., Tobe S.W., Pilote L. Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy. Can J Cardiol. 2008;24:491–496. doi: 10.1016/S0828-282X(08)70624-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Raman J., Walton D., MacDermid J.C., Athwal G.S. Predictors of outcomes after rotator cuff repair—a meta-analysis. J Hand Ther. 2017;30:276–292. doi: 10.1016/j.jht.2016.11.002. [DOI] [PubMed] [Google Scholar]
- 29.Rocheleau G.L.Y., Lee T., Mohammed Y., Goodlett D., Burns K., Cheng M.P., et al. Renin-angiotensin system pathway therapeutics associated with improved outcomes in males hospitalized with COVID-19∗. Crit Care Med. 2022;50:1306–1317. doi: 10.1097/CCM.0000000000005589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Rogers S.C., Ko Y.-A., Quyyumi A.A., Hajjar I. Differential sex-specific effects of angiotensin-converting enzyme inhibition and angiotensin receptor blocker therapy on arterial function in hypertension: CALIBREX trial. Hypertension. 2022;79:2316–2327. doi: 10.1161/HYPERTENSIONAHA.122.19105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Santema B.T., Ouwerkerk W., Tromp J., Sama I.E., Ravera A., Regitz-Zagrosek V., et al. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet. 2019;394:1254–1263. doi: 10.1016/S0140-6736(19)31792-1. [DOI] [PubMed] [Google Scholar]
- 32.Testa E.J., Callanan T.C., Albright J.A., Quinn M., O’Donnell R., Daniels A.H., et al. Decreased prevalence of new-onset adhesive capsulitis in patients prescribed angiotensin receptor blockers. J Shoulder Elbow Surg. 2024;33:2427–2432. doi: 10.1016/j.jse.2024.02.035. [DOI] [PubMed] [Google Scholar]
- 33.Testa E.J., Schmitt P., Callanan T.C., Milner J.D., Penvose I.R., Owens B.D. Angiotensin II receptor blockers and their applications in orthopaedic surgery and musculoskeletal medicine. Ann Jt. 2024;9:39. doi: 10.21037/aoj-24-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Trasolini N.A., Waterman B.R. Editorial commentary: rotator cuff repairs fail at an alarmingly high rate during long-term follow-up: graft augmentation and biologics may improve future outcomes. Arthroscopy. 2022;38:2413–2416. doi: 10.1016/j.arthro.2022.04.002. [DOI] [PubMed] [Google Scholar]
- 35.Wu J., Wang M., Guo M., Du X.-Y., Tan X.-Z., Teng F.-Y., et al. Angiotensin receptor blocker is associated with a lower fracture risk: an updated systematic review and meta-analysis. Int J Clin Pract. 2022;2022:1–9. doi: 10.1155/2022/7581110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Yoshida H., Rosano G., Shimizu M., Mochizuki S., Yoshimura M. Gender differences in the effects of angiotensin receptor blockers on cardiovascular Disease. Curr Pharm Des. 2011;17:1090–1094. doi: 10.2174/138161211795656909. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.