colchicine decreases hip and knee replacements

 An interesting analysis of the LoDoCo2 study (Low-Dose Colchicine 2), a non-drug company sponsored study, found that people randomized to colchicine 0.5mg/d had fewer total knee and hip replacement surgeries (see colchicine dec hip knee replacements AIM2023 in dropbox, or doi:10.7326/M23-0289)

Details:

-- 5478 people from Australia and the Netherlands with chronic coronary artery disease were randomized to colchicine 0.5mg/d vs placebo 

    -- this was a double-blind RCT finding significant benefit from colchicine on recurrent cardiovascular events in those with chronic coronary artery disease (see below)

    -- this current assessment of needing total knee or hip replacement (TKRs and THRs) is an exploratory analysis, since this was not a specific outcome of this study

-- mean age 66, 15% female, BMI 28

-- hypertension 51%, diabetes 18%, current smoker 12%, gout 8%

-- country: Australia 34%, the Netherlands 66% [note: the study started in Australia in 2014 with 13 centers;  2 years later (in 2016) 30 centers from the Dutch Network for Cardiovascular Research were added]

    --enrolment completed in 2018, last data collected in 2020

-- exclusion criteria: moderate to severe renal impairment (serum creatinine >1.5mg/mL or eGFR <50), systolic or diastolic heart failure NYHA class 3 or 4, not able to take colchicine for the 1 month long open-label run-in phase (intolerance or just nonadherence to protocol)

-- primary outcome: time to first TKR or THR since randomization, on an intention-to-treat basis

-- median follow-up 28.6 months

Results:

--TKR was performed in 39 patients and THR in 29 during the follow-up

    --incidence rate for the combination of TKR and THR, comparing those on colchicine vs not: 0.88 vs 1.30 surgeries per 100 person-years, incidence rate difference of -0.42 (-0.77 to -0.07), HR 0.68 (0.49-0.94)

-- sensitivity analyses    -- not much difference if one excludes either the first 3 or 6 months of the study (HRs 0.61 and 0.58 respectively, and the rate differences of -0.48 for each time period) 

    -- no difference if one excludes people with gout

    -- the results were similar for the whole group compared to just the Australia group, but not significant for the Netherlands group (but the follow-up was >2 years in 99% from Australia but only 55% from the Netherlands; follow-up was 97% in Australia by the 3 year mark, vs 2% in the Netherlands)

        -- and, per the graph above, there was not a statistically significant benefit for colchicine until the 2-3 year follow-up time

Commentary:

-- the initial LoDoCo2 study examined the effects of colchicine 0.5mg vs placebo in people with chronic CAD, finding a 31% decrease in cardiovascular events over 28.6 months: https://www.nejm.org/doi/full/10.1056/nejmoa2021372

-- this reduction in these orthopedic surgeries was likely associated with the anti-inflammatory effects of colchicine:

    -- colchicine is associated with a broad activation of caspase-1 activation, including IL-1b processing and release

    -- synovial fluid in patients with osteoarthritis has a broad range of inflammatory cytokines, including: IL-1b, TNF, IL-6, IL-15, IL-17, IL-18, IL-21 and IL-8

    -- colchicine also decreases high sensitivity C-reactive protein levels, a marker of systemic inflammation

    -- colchicine is effective in a variety of otherwise unrelated inflammatory conditions: gout, familial Mediterranean fever, pericarditis, pseudogout, cirrhosis

    -- this conclusion about the role of decreasing inflammation on TKRs and THRs was reinforced in the CANTOS study, which found that canakinumab (a specific inhibitor of the pro-inflammatory cytokine interleukin-1b) in those with MIs was associated with statistically significant decreases in the rates of TKR and THR during followup of 3.7 years

    -- other studies have found that colchicine plus acetaminophen stabilize levels of cartilage oligomeric matrix protein (which stabilizes the collagen network) in patients with symptomatic knee osteoarthritis, an effect not found with acetaminophen alone: https://pubmed.ncbi.nlm.nih.gov/28261974/

-- this study, though an exploratory post hoc analysis, did find a 31% lower likelihood of patients with chronic CAD to have TKRs or THRs done, consistent with the results of the CANTOS studied noted above, where they found a 40-47% reduction, depending on the canakinumab dose

-- a prior study found that colchicine given to patients with gout was associated with significantly fewer cardiac events: https://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html

-- there are also several studies on the potential cardiovascular benefit of allopurinol, which seems to be independent of its uric acid lowering: https://gmodestmedblogs.blogspot.com/2023/05/allopurinol-decreases-heart-disease.html 

    -- of note here, uric acid itself is associated with inflammation (Uric Acid Is Associated With Inflammatory Biomarkers and Induces Inflammation Via Activating the NF-κB Signaling Pathway in HepG2 Cells | Arteriosclerosis, Thrombosis, and Vascular Biology (ahajournals.org) ); and allopurinol has anti-inflammatory effects (Allopurinol for pain relief: more than just crystal clearance? - PMC (nih.gov))

-- as an aside, there was an interesting argument that aggressively treating acute pain with anti-inflammatories might increase the risk of chronic pain long-term: https://gmodestmedblogs.blogspot.com/2022/05/acute-pain-anti-inflammatories-lead-to.html 

    -- ie, perhaps acute pain is the body's normal response to acute inflammation, and decreasing this response is in fact counterproductive to the normal healing process and may lead to chronic pain  

       -- perhaps acute pain should be treated with non-anti-inflammatory meds, just with heat (not cold), acetaminophen (not NSAIDs, steroids, etc), physical therapy, and nonpharmacologic ways to prevent injury (decreasing recurrent trauma to joints etc, maintaining a good weight, doing stretching exercises/yoga/etc...) 

       -- a recent article found that very early introduction of PT for patients with acute sciatica was associated with less pain 1 year later: https://gmodestmedblogs.blogspot.com/2020/10/sciatica-early-pt-helps-longterm.html 

      -- and perhaps by avoiding the acute anti-inflammatory approach might have helped prevent the need for so many TKRs and THRs 

Limitations: 

-- the exclusion criteria in this study eliminated lots of our primary care patients, including those with even mild to moderate chronic kidney disease or those who do not take their medications regularly, as well as those with severe heart failure or were not in a stable condition 

-- there were too few women in this study to have meaningful conclusions

-- this was an exploratory analysis and not an RCT:

    -- we have minimal initial data that would have been reported if this were a specific study on colchicine on chronic knee or hip pain:

        -- what was the actual reason for the surgeries. Likely osteoarthritis, but were there lots of people in this cohort who fell and broke their hips? other knee pathologies?

        -- we do not know that the performance of the surgeries was consistent: did the surgeons have very differing thresholds to do surgery?? a good RCT would make sure there was consistency in criteria for those doing these surgeries

        -- were there important issues not reported here that could have influenced the development of these orthopedic conditions: trauma, other arthridities (RA, gout, pseudogout..), family history, meds (steroids), work- or leisure time-related activities that increase joint wear-and-tear, etc. These unknowns would have been controlled for in a good RCT

so, what does this all mean and what should we do???

-- this study adds to the impressive data that chronic inflammation is bad and that colchicine seems to decrease certain consequences:

    -- reasonably clear for the heart, less clear but possibly so for osteoarthritis

        -- and if so, probably best to start colchicine prior to getting too much heart disease or too much osteoarthritis??

        -- and perhaps for other diseases associated with chronic inflammation: diabetes, depression, hypertension, exposure to air pollution, stress??

            -- and perhaps using the broader assessment of cardiovascular risk factors in the decision-making process, since most of them are related to chronic inflammation:  https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html ??

               -- ie, chronic inflammation seems to be part and parcel of living in an industrial society. and it is not so good for one's health outcomes/quality of life

        -- which brings up the real issue: should we add colchicine to the drinking water??  it worked for fluoride in preventing tooth decay.....

 

geoff

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