Losartan for Total Knee Replacement Complications

Overseen By Luz Thede

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Steadman Philippon Research Institute

Must not be taking: Losartan, Anticoagulants, Opioids, others

Disqualifiers: Pregnancy, Autoimmune arthritis, Hypotension, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: 4 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether Losartan (also known as Cozaar or Hyzaar) can reduce complications after knee replacement surgery, specifically arthrofibrosis, which hinders movement. Participants will receive either Losartan or a placebo (a non-active substance) for four weeks post-surgery to assess its impact on recovery. The trial seeks individuals scheduled for a single knee replacement who have not previously undergone the procedure on the same knee, are not experiencing other serious knee issues, and are not taking certain medications. As a Phase 1, Phase 2 trial, this research aims to understand how Losartan works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

If you are currently taking Losartan, similar medications, Warfarin, or related anticoagulants, you will need to stop these before joining the study. Also, if you've taken opioid painkillers in the last 8 weeks, you must be willing to stop them during the study, except right after surgery as needed.

Is there any evidence suggesting that Losartan is likely to be safe for humans?

Research has shown that Losartan, a medication tested for use after total knee replacement surgery, may help reduce complications. Specifically, studies found that patients taking Losartan after surgery were less likely to return to the hospital within 90 days and had a lower chance of needing additional procedures like manipulation under anesthesia (MUA) to improve knee movement.

Regarding safety, the FDA has already approved Losartan for treating high blood pressure, indicating its safety for that use is well-established. While this doesn't directly guarantee safety for use after knee surgery, it suggests the drug is generally well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for complications following total knee replacement, which often focus on managing symptoms like pain and inflammation with NSAIDs or corticosteroids, Losartan offers a unique approach. This drug is primarily known as a blood pressure medication but has promising potential due to its ability to influence the body's inflammatory response and promote tissue healing. Researchers are excited because Losartan could reduce swelling and improve recovery outcomes by targeting the underlying biological processes rather than just alleviating symptoms. This innovative angle could lead to faster recovery times and better overall results for patients undergoing knee replacement surgery.

What evidence suggests that Losartan might be an effective treatment for knee replacement complications?

This trial will compare Losartan with a placebo to assess its effects after knee replacement surgery. Research has shown that Losartan may reduce stiffness and aid recovery. Studies indicate that patients taking Losartan are less likely to return to the hospital within 90 days and have a lower chance of needing a procedure called MUA, which improves knee movement. Losartan blocks certain chemicals in the body that cause scarring and stiffness, potentially leading to better recovery outcomes for those who have had surgery. ^{1 2 3 6 7}

Who Is on the Research Team?

Johnny Huard, PhD

Principal Investigator

Steadman Philippon Research Institute

Scott Tashman, PhD

Principal Investigator

Steadman Philippon Research Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 who are planning to have a knee replacement surgery on one knee and can consent to the study. They should not be hypotensive, pregnant, or planning pregnancy; nor should they have had previous knee replacements or surgeries planned during the study. They must not take opioids recently or certain medications like Losartan.

Inclusion Criteria

I can make my own medical decisions and agree to follow the study's requirements.

I am scheduled for a total knee replacement on one knee.

Exclusion Criteria

You are allergic to any of the ingredients in Losartan.

My knee arthritis is due to an autoimmune disease.

I am not planning any leg surgery other than knee replacement in the study leg.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Losartan or placebo for four weeks post-TKA surgery

4 weeks

Visits on day of surgery, 10-17 days post-op

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Visits at 6 weeks post-op and 3 months post-op

What Are the Treatments Tested in This Trial?

Interventions

• Losartan

Trial Overview The trial is testing if taking Losartan before and after knee replacement surgery can prevent arthrofibrosis (stiffness) and improve outcomes. Participants will either receive Losartan or a placebo without knowing which one they're getting.

How Is the Trial Designed?

Group I: Losartan (investigational) Experimental Treatment 1 Intervention

Losartan 12.5 mg, PO, BID, for four weeks post-TKA surgery (on Days 1 through 28, starting the day after surgery).

Group II: Placebo (control) Placebo Group 1 Intervention

Losartan Placebo 12.5 mg, PO, BID, for four weeks post-TKA surgery (on Days 1 through 28, starting the day after surgery).

Losartan is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Stroke prevention in hypertension and left ventricular hypertrophy

Approved in European Union as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Approved in Canada as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Who Is Running the Clinical Trial?

Steadman Philippon Research Institute

Lead Sponsor

Trials

11

Recruited

700+

Published Research Related to This Trial

In a study of 2,974 patients who underwent primary total knee arthroplasty, the overall complication rate was 6.8%, with severe complications occurring in 2.5% of cases.

Key risk factors for severe complications included being male, over 75 years old, having arrhythmia, and having a history of cerebrovascular disease, indicating that these patients may require closer monitoring post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible Risk Factors for Severe Complications Occurring after Primary Total Knee Arthroplasty. Ma, LL., Yu, XR., Weng, XS., et al.[2023]

Outpatient revision knee arthroplasty is safe for carefully selected patients, with 88% of the 102 patients discharged the same day without complications, and no major complications reported within the first 48 hours post-surgery.

The presence of medical comorbidities did not increase the risk of complications, suggesting that with proper patient education and medical optimization, outpatient procedures can be effectively managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Feasibility of Outpatient Revision Total Knee Arthroplasty in Selected Case Scenarios. Law, JI., Adams, JB., Berend, KR., et al.[2022]

In a study of 159 rheumatoid arthritis (RA) patients undergoing total knee arthroplasty (TKA), no increase in postoperative adverse events (AEs) was observed compared to 318 patients with osteoarthritis (OA), despite RA patients having worse preoperative function and higher medication use.

The study found no significant differences in rates of infections or other complications between RA and OA patients, suggesting that with experienced surgeons, TKA can be safely performed in RA patients without increased risk of postoperative AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rheumatoid Arthritis Does Not Increase Risk of Short-term Adverse Events after Total Knee Arthroplasty: A Retrospective Case-control Study. LoVerde, ZJ., Mandl, LA., Johnson, BK., et al.[2022]

In a review of 162 patients with 224 total knee replacements, early complications included deep vein thrombosis (3%) and motion limitations requiring manipulation (7%).

Late complications were more prevalent, with patellofemoral arthritis (11%) being the most common and disabling issue, followed by heterotopic bone formation (10%) and loosening (7%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications of total knee replacement. Lovelock, JE., Griffiths, HJ., Silverstein, AM., et al.[2016]

In a study of 812 patients who underwent total knee replacement, the all-polyethylene tibial components (APT) showed a higher survival rate (97.1%) compared to metal-backed components (MBT) (93.2%), although the difference was not statistically significant.

Younger patients experienced significantly better functional outcomes with APT components compared to MBT, suggesting that all-polyethylene components may be a superior choice for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes and survival comparison between NexGen all-poly and its metal-backed equivalent in total knee arthroplasty. Apostolopoulos, V., Nachtnebl, L., Mahdal, M., et al.[2023]

Infection remains the leading cause of failure in revision total knee arthroplasty (TKA), accounting for 51% of cases, but there has been a notable increase in revisions due to mechanical loosening (from 19.1% to 31.9%) and instability (from 11.2% to 13.5%) over the past 17 years.

The study indicates a significant decrease in revisions due to polyethylene wear (from 9.0% to 2.9%) and a relative decrease in infection rates in later revisions, suggesting changing trends in the causes of TKA failures that orthopedic surgeons should be aware of.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trend Shift in the Cause of Revision Total Knee Arthroplasty over 17 Years. Na, BR., Kwak, WK., Lee, NH., et al.[2023]

In a study of 2033 total knee arthroplasty patients, the annual rate of adverse events decreased from 9.2% in 2002 to 5.8% in 2004, indicating improved safety over time.

Patients with congestive heart failure and chronic obstructive pulmonary disease had a significantly higher risk of adverse events during hospitalization, and experiencing an adverse event was linked to increased length of hospital stay and higher 30-day postprocedure mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events after total knee arthroplasty: a national Medicare study. Huddleston, JI., Maloney, WJ., Wang, Y., et al.[2009]

A case report highlights a potential link between the use of angiotensin-converting enzyme (ACE) inhibitors and the development of acute kidney injury after total knee arthroplasty (TKA), suggesting a need for caution in patients taking these medications during joint replacement surgery.

This relationship, previously studied in cardiac and gastric bypass patients, has not been explored in the context of joint replacement, indicating a gap in current research that could impact patient safety and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute kidney injury in the setting of knee arthroplasty: a case report and discussion investigating Angiotensin-converting enzyme inhibitors as the culprit. Rosenbaum, AJ., Luciano, JA., Marburger, R., et al.[2021]

A systematic review of 40 studies found that the rate of amputation following total knee replacement (TKR) ranges from 0.1% to 10%, highlighting the importance of discussing this risk with patients before surgery.

Deep infection was identified as the leading cause of amputation after TKR, with a notable 5.1% amputation rate in cases of infected TKR, emphasizing the need for careful monitoring and management of infections post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amputation as a Complication after Total Knee Replacement, is it a Real Concern to be Discussed?: A Systematic Review. Mousavian, A., Sabzevari, S., Ghiasi, S., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38428487/

The association between losartan potassium prescription ... Losartan, an angiotensin receptor blocker (ARB), has the potential to improve TKA outcomes by inhibiting TGF-β and decreasing fibrosis.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1877056824000598

The association between losartan potassium prescription ... This study found that losartan TKA patients demonstrated a significantly lower likelihood of readmission within 90 days and a lower likelihood of undergoing MUA ...

3. withpower.com withpower.com/trial/phase-2-total-knee-arthroplasty-tka-10-2023-771a7

Losartan for Total Knee Replacement Complications Trial Overview The trial is testing if taking Losartan before and after knee replacement surgery can prevent arthrofibrosis (stiffness) and improve outcomes.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12414002/

Patients on Losartan Have Similar Rates of Manipulation ... Patients taking losartan had longer lengths of stay compared to patients not taking losartan (1.34 days vs 1.28 days; p < 0.001). There was no ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06933706

Losartan to Improve Outcomes After Multi-ligament Knee ... Objectives: The purpose of this study is to determine if a 30-day course of oral losartan will improve a person's ability to return to duty or sport within 12 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06108063

Mitigation of Arthrofibrosis After Total Knee Arthroplasty ... The purpose of this study is to evaluate the efficacy of Losartan use post-operatively for reducing or preventing the development of arthrofibrosis.

7. researchgate.net researchgate.net/publication/365782463_The_effect_of_losartan_on_range_of_motion_and_rates_of_manipulation_in_total_knee_arthroplasty_a_retrospective_matched_cohort_study

The effect of losartan on range of motion and rates ... Conclusion Angiotensin receptor blocker use throughout the 90 days after TKA is associated with a decreased risk of MUA, arthroscopy/LOA, ...