Preparation: TKR Pathway/Protocol Meeting

Total Knee Replacement: A Cursory Review of the Literature

As I have been anticipating some upcoming meetings where decisions will be made regarding the pathway for patient care status post total knee replacement (TKR), I have (for my own benefit) taken some time recently to review the current literature available concerning the rehabilitation of post-operative patients – it is a somewhat thorough (although with limited search engine resources) review of the materials that should help guide decision making when providing care and developing expectations of the progress and eventual outcomes post-operatively.

This is what I have discovered…

Predicting Outcomes

The are studies that have looked at a variety of factors to determine what does and doesn’t correlate to range of motion, strength, and functional outcomes. Some of the findings are very consistent, some remain inconsistent.

It seems that that the largest indicator of how a patient presents after surgery, is how they presented before. For instance, intraoperative range of motion (ROM) measures do not correlate with post-operative measures. However, pre-operative measures of ROM strongly correlate with post-operative measures throughout a multitude of studies (1,2,7,16,19,20,21,24,25,26,39,71). Some authors have come to the conclusion that the ROM the patient has before the surgery should be their expected ROM after surgery without the use of a manipulation under anesthesia (7). Interestingly – on average – patients who go into surgery with better ROM measures (i.e. >120 degrees) will have significantly greater motion than those with poor motion, but will (themselves likely have less motion 1 year after surgery than they did before (19). Higher complication rates (41% in one study) are likely in the severely debilitated population with knee flexion measures of less than 50 degrees (29).

Pre-operative strength may also be a strong predictor of post-operative outcomes. There is evidence that isometric quadriceps strength before surgery accounts for the bulk of variance in both Timed-Up-and-Go (TUG) and Stair Climb Test (SCT) at 1 year after surgery, while pre-op ROM did not correlate with long-term functional outcomes in one study (59). Contralateral limb strength has also been demonstrated to correlate with functional outcomes 1- and 2-years after surgery (70), so therapy should probably target both limbs (especially considering that nearly 40% of patients who have a TKR on one limb will have the same procedure on the other side within 10 years.*)

Functionally, there remains a strong correlation between baseline function, need for a walking device and walking distance pre- and post-operatively. (23)

Pain going into surgery also seems to impact how the patient moves and feels after surgery. For instance, severe pain with movement pre-operatively can increase the odds of severe post-operative pain almost 20-fold. Greater pre-operative pain correlates with increased post-operative pain (40,52) and greater utilization of home care services and MUA (40). It is important to note, however that predictors of pain are not necessarily the same as predictors of functional outcomes (1).

Some other factors that seem to have a correlation with poor/reduced post-operative outcomes include osteoarthritis (vs Rheumatoid, RA patients have better outcomes) (1), pre-operative anxiety, depression or poor mental health (1,2,41,52), Pulmonary diseases poorly affects outcomes (41). Diabetes is a significant predictor of a poor outcome (41) as is a history of previous surgery – combined they accounted for 85% of complicated patients in one study (33).

On the flip side of the same coin, general health after surgery strongly correlates with positive post-operative outcomes (3,27).

Neither age (27,28,40,41,57) nor gender (27,28,40,50) are correlated with positive/negative outcomes of patients who have had a TKR.

The evidence remains inconclusive on other matters. Socioeconomic status may, or may not, be a predictor of future post-surgical outcomes (1,3). BMI and body weight seems to correlate in some cases with a poor outcome (24,27,28,41,70), but there is conflicting evidence that BMI is not a predictor of functional outcomes (1,6) or the development of flexion contracture post-operatively (10).

*I read this in one of the articles cited, but cannot remember which one and forgot to make a note of it

Natural History

There is an 80-85% patient satisfaction rate following a TKR (5). Unfortunately, the views of surgeons and their patients do not correlate well when assessing the success of the surgical intervention – especially with respect to function and pain (5,32). This is consistent with data that reports 85% of patients will recover their function after surgery – regardless of what kind of protocol is used after surgery (31).

As experiential evidence would support, the greatest improvements after a TKR occur in the first 12 weeks with little (but some) improvement after 26 weeks (68). Maximal post-operative pain is typically reduced by ½, 3 months after surgery (40). With the exception of knee flexion range of motion, the majority of patients return to pre-operative levels including isometric quadriceps strength, 6-minute walk test (6MWT), SCT, TUG and single-limb stance time (69). Most of these measures remain reduced compared to the healthy population, however.

Stiffness (defined as <90 degrees of motion arc) effects 6-7% of patients after a TKR. A 17-year study across 5 different evolving systems/protheses demonstrated an average increase in motion arc of 8 degrees when comparing pre- and post-operative ROM with only 3 degrees of the motion obtained in flexion (26), consistent with the predictors as mentioned above. Flexion may continue to improve over time, with one study showing an average gain of 3 degrees between years 1 and 5 after surgery (11). Overall, average post-op ROM measures have improved from 99 to approx. 115 degrees, however, from 1993 to 2010 (5).

There is a flexion contracture incidence of 4% after TKR, but most patients who have a flexion contracture 3 months after surgery will have full extension 2 years after surgery, so long as the contracture is only 5 or 10 degrees with only 1/34 and 4/30 (respectively, in one study) not achieving full extension over 2 year’s time (13). Similar results were obtained in another study where 94% of patients with a flexion contracture ( (<15 degrees, no infection) resolved in less than 2 years (14).

Unexplained Pain

It is important to remember that 1 in 8 patients who have had a knee replacement report moderate to severe pain 1 year after surgery, despite an absence of significant clinical or radiographic abnormalities to account for the pain (40). In one study, 10 of 18 post-op TKR patients reported a 50% improvement in their painful complaints when comparing their short-term with their long-term (5-year) outcomes (18). Patients with unexplained pain (without recognized pathology) “should be treated conservatively since they may improve over a period of time and rarely do so after a revision operation” (42). Reassurance is therefore recommended to patient’s that the pain will/can improve in more than half with time (18).

Manipulation Under Anesthesia

I have heard from many therapists that ‘manipulations rarely work.’ I, personally, have only worked with one patient after a manipulation (4+ years after her initial surgery with 20 degrees gained). Was she an outlier?

The prevalence of MUA is 5 to 11% (39, 38). Those who have an MUA present with similar outcomes (3 degree difference in knee flexion ROM) to TKR patients who do not have/need an MUA after 1-year (38). Despite continued PT after MUA, the patient will not likely make ROM gains beyond those obtained with the MUA itself (15, 34).

Manipulations under anesthesia (MUA) works. There are multiple studies that demonstrate a 30+ degree improvement after MUA (15, 43, 44, 45, 17, 34, 38), with sustained gains 5 and 10 years after the MUA (45). There is conflicting evidence, however, as to when to perform an MUA. One study reports gains of >30 degrees if the procedure is completed in the first 90 days versus an average gain of 17 degrees after 90 days (37). There is a study that had 30+ degree gains in ROM with the MUA being performed 13 weeks after surgery, on average (34)

An MUA is likely to be less successful with the patient who has Diabetes or has a cruciate retaining prosthesis (34). Additionally, patients who had stiffness (110 degrees) pre-operatively (39) The results/outcomes after MUA are diminished if the patient has a history of multiple surgeries before their TKR.

Continuous Passive Motion (CPM)

There is conflicting evidence regarding short-term outcomes and the use of a CPM immediately after surgery (61), but there is no statistical long-term benefit (64). Rather than cite a series of references, I will instead provide the conclusions of a Cochrane Reviews’s author’s: “CPM does not have clinically important effects on active knee flexion ROM, pain, function or quality of life to justify its routine use. It may reduce the risk of manipulation under anaesthesia and risk of developing adverse events although the quality of evidence supporting these findings are very low and low, respectively. The effects of CPM on other outcomes are unclear.”

Transcutaneous Electrical Nerve Stimulation (TENS)

The use of TENS after a TKR has not been found to effective in improving outcomes after TKR (47, 48, 73)

NMES

There is much better evidence for the use of NMES than for TENS. In the short-term, there is improved knee extension ROM, knee extension/flexion strength and function with differences in strength and function persisting between the NMES and control groups 1 year after surgery (50). The intensity of NMES application is related to the recovery of quadriceps muscle strength early after TKR (53). A systematic review in 2013 discovered 4 RCTs on the effectiveness of NMES following TKR and found that NMES results “in overall improvements and function.” (78). In one of the studies referenced in the review – which I had access to – there was no significant benefit of outpatient PT compared to NMES and a home exercise program at 6 weeks or 6 months with mild ROM value differences favoring PT and functional outcome measures favoring the NMES/HEP group (77). A JOSPT clinical commentary recommends the early post-operative use of NMES, reporting that along with an exercise program, NMES demonstrated improved quadriceps strength and activation (66).

Dynasplint

Even a CPM applied aggressively for 6 hours per day has no significant benefit for ROM, pain, or function (76). I would therefore propose that the odds of passive motion/overpressure applied a few times per day by a clinician is unlikely to have significant benefit, either. I wondered, however, if progressive static stretching might be of benefit (i.e. Dynasplint). While there is some evidence to support it’s use to increase motion in a variety of joints under varying circumstances (go ahead, Google it), there is little information regarding the use of such devices after a TKR. I was only able to locate one study that used a Dynapslint-like device to treat arthrofibrosis; it’s use had positive results with an avg of 25 degrees gained in knee flexion after use of the device over an average of 7 weeks. 92% of the patients were satisfied with the results (36).

Cryotherapy

After a review of 11 randomised trials, the conclusion of authors of Cochrane Review stated: “Potential benefits of cryotherapy on blood loss, postoperative pain, and range of motion may be too small to justify its use, and the quality of the evidence was very low or low for all main outcomes. This needs to be balanced against potential inconveniences and expenses of using cryotherapy. Well designed randomised trials are required to improve the quality of the evidence.” (74). Admittedly, there is “little consensus with regard to treatment indicators, method of application and the management of cryotherapy after TKR. The results highlight a lack of consistency in the application of cryotherapy after TKR” (75), so even if it were of benefit if applied ‘correctly’ there is no evidence what the ‘correct’ way (e.g. frequency, duration, device, etc) might be or what it might benefit (e.g. pain, edema, ROM, etc).

Outcome Measures

There is no one perfect tool to assess the status of a patient and their progress after a TKR. Patient questionnaires are often thought to be best to assess patient outcomes (5), but (as mentioned earlier) the views of surgeons and their patients regarding the outcome of surgical interventions do not always correlate well—especially with respect to function and pain. (5, 32).

Recommendations from one presenter at a recent AAOS symposia included the use of the the KSS (Knee Society Scoring) (60)

The (Oxford Knee Score) OKS requires a license, but is noted for its simplicity and brevity (4).

The Knee Injury and Osteoarthritis Score (KOOS) is valuable for measuring outcomes in younger and/or more active patients with knee injury and knee osteoarthritis. The KOOS is also used to measure outcomes following a range of both surgical and conservative interventions of the knee, both surgical and conservative (4).

In the early stages of recovery, responsiveness is greatest (descending order) in Stair Climbing Test, 6MWT, TUG, then self reports (i.e. SF-36 PCS). There is poor correlation between self-reports and objective measures (56). The TUG is noted to have the earliest ceiling effect (56).

In the later stages of recovery, the KSS and WOMAC (both proprietary) were most sensitive at 2 months while the Forgotten Joint Score (FJS-12) was most sensitive at one-year post-op (58). The WOMAC is currently the only outcome measure that has validated responder definitions and cutoff points specifically for TKR (4). Interestingly, the WOMAC and the FJS-12 strongly correlate with the Pain Catastrophizing Scale, explaining 50% of variance of WOMAC and 30% of variance in FJS-12 (54).

Physical Therapy Care

Quadriceps strength post-operatively correlates more strongly with functional outcomes than ROM (30). Additionally, hip abduction strength has been found to correlate more strongly with functional outcomes than age, edema or quad strength (9).

In addition to the above study (see NMES) that showed no benefit of outpatient PT compared to NMES with HEP, there is additional evidence that 6-weeks of outpatient PT is not significantly better than HEP after inpatient PT (12). In 2011, there was a promising small study with 8 patients showed significant gains with high-intensity rehab (62), but a recent study in 2014 showed progressive strength training had no benefit with a larger sample of 82 patients (63).

There has also been a meta-analysis of the available data from RCTs regarding PT care after TKR, disappointingly, only 5 studies met quality standards (if you needed any evidence that PT needs to continue to work on developing statistically-strong data to support our provision of care). The review revealed, “Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit.” (79).

So, in light of the evidence, what does a clinical commentary on post-operative TKR physical therapy care recommend? You can read the paper here (66). The supplemental guidelines are outlined below:

 

REHABILITATION GUIDELINES FOLLOWING
A TOTAL KNEE ARTHROPLASTY

Meier W, Mizner R, Marcus R, Dibble L, Peters C, Lastayo. Total Knee Arthroplasty: Muscle Impairments, Functional Limitations, and Recommended Rehabilitation Approaches. JOSPT;38;246-256.

Phase I: Home or Outpatient (2-3x/wk, 2-3 wk)

Goals:
1. Increase range of motion (ROM)
2. Decrease edema and pain
3. Gait training
4. Independence with activities of daily living (ADLs)

Exercises:
1. Seated or supine knee active range of motion (AROM)
2. Alternated ankle dorsiflexion and plantar flexion
3. Quadriceps sets
4. Straight-leg raise
5. Hamstring sets
6. Standing leg curls
7. Seated knee extension
8. Supported single standing for balance
9. Repeated sit-to-stand transfer training
10. Ambulating with appropriate assistive device

Modalities:
1. Ice 2-3 times per d, with lower extremity elevated for 20-30 min

Criteria for progression to exclusively outpatient physical therapy:
a. AROM approaching 90° of knee flexion
b. Minimal pain/swelling
c. Independence in mobility in and out of the home

Phase II: Outpatient Physical Therapy (2-3x/wk, 4-6 weeks)

Warm-up (15-20 min):
1. Exercise bike (10-15 min), start with forward and backward pedaling with no
resistance until there’s enough knee ROM for a full revolution. Seat height may
be lowered for progression of ROM
2. Seated or supine knee AROM (flexion and extension)
3. Alternated ankle dorsiflexion and plantar flexion
4. Passive knee extension stretch
5. Patellar and knee mobilizations

Specific strengthening (10-15 min), 1-3 sets of 10 repetitions:
1. Neuromuscular electrical stimulation (NMES) to augment quadriceps muscle
activation. NMES parameters: 2500-Hz triangular-wave alternating current,
12-s on-time, 80-s of-time, 2- to 3-s ramp-up time, knee flexed to 60°, 10
isometric contractions, dose set to maximally tolerated by the patient, large
(7.6 12.7 cm) self-adhesive electrodes placed on the motor points of the
quadriceps femoris muscle
2. Quadriceps sets
3. Straight-leg raises (assistance as needed, goal to perform without a knee
extension lag)
4. Hip abduction (side lying)
5. Standing leg curls
6. Seated knee extension
7. Standing terminal knee extension from 45° to 0°

Functional exercises (10-15 min):
1. Step-ups, 5-15 cm, or climbing a flight of stairs
2. 45° wall slides or sit-to-stands
3. Walking backward, side step, march, or crossover steps
4. Walking through an obstacle course
5. Gait training emphasis on heel strike and push-of at toe-of

Endurance exercises (5-20 min):
1. Walking
2. Stationary cycle

Cool-down (10 min):
1. Ice and compression as needed
2. Gentle stretching and ROM

Criteria for progression:
a. Voluntary quadriceps muscle control or 0° knee extension lag
b. AROM 0° to greater than 105° of knee flexion
c. Minimal to no pain and swelling

Exercise progression:
a. Exercises are to be progressed once the patient can complete 3 sets of 10
reps of the exercise correctly and feels maximally fatigued
b. Add 0.2- to 1.5-kg weights to the exercises
c. Increase step height if showing good concentric/eccentric control
d. Increase wall slides to 60° and to 90°

Phase III: Semi-Independent (1-2x/wk, 4-6 weeks)

Exercises:
1. Continue all exercises in phase I as a home exercise program or a gym
membership

Warm-up (15-20 min):
1. Seated or supine knee AROM (flexion and extension)
2. Alternated ankle dorsiflexion and plantar flexion
3. Passive knee extension and hamstring stretch
4. Exercise bike or treadmill walking (perceived exertion should be light)

Strengthening (20 -30 min, 1-3 sets of 10-20 reps of any of the following):
1. Leg press varying working ROM*
2. Leg extension: ROM, 90°-0° or 90°-30° for extension*
3. Standing or sitting leg curls*
4. Standing heel raises*
5. 4-way hip machine or (rubber band or ankle weights for resisted hip ROM)*
6. Sit-to-stand free weights in hands
7. Weight-bearing exercises with emphasis on eccentric control
8. Upper extremity strength training optional
*Use a 5- or 10-repetition maximum to determine 60%-70% resistance of 1-repetition maximum
*Machine weights

Functional exercises (10-15 min):
1. Step-ups 5-15 cm or climbing a flight of stairs
2. 45° to 90° wall slides or sit-to-stands, hold 5-10 s
3. Walking backward, side step, march, or crossover steps

Endurance exercises (5-20 min, alternate between walking and biking):
1. Walking, change speed and incline
2. Biking

Criteria for progression:
Exercises are to be progressed once the patient can complete 3 sets of 10 reps
of the exercise correctly and feels maximally fatigued

Exercise progression:
a. Reassess 65%-70% of maximal efort biweekly to determine progression of
resistance
b. Increase step height if showing good concentric/eccentric control
c. Increase wall slides to 60° and to 90°

REFERENCES

(1) Predictors of Outcomes of Total Knee Replacement Surgery
(2) Predicting the outcome of total knee arthroplasty.
(3) Patient factors that influence the outcome of total knee replacement: a critical review of the literature
(4) The Utility of Outcome Measures in Total Knee Replacement Surgery
(5) Total knee arthroplasty: Techniques and results
(6) The Outcome of Total Knee Arthroplasty in Obese Patients
(7) Factors affecting postoperative range of motion after total knee arthroplasty.
(8) Range of motion correlates with patient perception of TKA outcome.
(9) Contribution of hip abductor strength to physical function in patients with total knee arthroplasty.
(10) Flexion contracture following primary total knee arthroplasty: risk factors and outcomes.
(11) Does flexion contracture continue to improve up to five years after total knee arthroplasty?
(12) DOES AN OUTPATIENT PHYSIOTHERAPY REGIME IMPROVE THE RANGE OF KNEE MOTION AFTER TOTAL KNEE ARTHROPLASTY: A PROSPECTIVE STUDY.
(13) Flexion contracture persists if the contracture is more than 15° at 3 months after total knee arthroplasty.
(14) Fixed flexion deformity following total knee arthroplasty. A prospective study of the natural history.
(15) Manipulation of total knee replacements. Is the flexion gained retained?
(16) Stiffness after total knee arthroplasty. Prevalence of the complication and outcomes of revision.
(17) Predictors of range of motion in patients undergoing manipulation after TKA.
(18) A conservative approach is feasible in unexplained pain after knee replacement: a selected cohort study.
(19) Range of motion after total knee arthroplasty
(20) Factors Influencing Range of Motion after Total Knee Arthroplasty
(21) Predicting range of motion after total knee arthroplasty. Clustering, log-linear regression, and regression tree analysis.
(22) MUA after TKR
(23) Determinants of Function After Total Knee Arthroplasty
(24) PREOPERATIVE FACTORS INFLUENCING THE RANGE OF MOVEMENT AFTER TOTAL KNEE ARTHROPLASTY FOR SEVERE OSTEOARTHRITIS
(25) Range of Motion after Total Knee Replacement for Osteoarthritis
(26) Total Knee Arthroplasty: Range of Motion across Five Systems.
(27) Factors Affecting Postoperative Range of Motion After Total Knee Arthroplasty
(28) Factors Influencing Range of Motion After Contemporary Total Knee Arthroplasty
(29) Outcome of Knee Arthroplasty in Patients With Poor Preoperative Range of Motion.
(30) Quadriceps Strength and the Time Course of Functional Recovery After Total Knee Arthroplasty
(31) Total knee arthroplasty rehabilitation protocol: What makes the difference?
(32) Patient satisfaction after total knee arthroplasty: A comparison between subjective and objective outcome assessments
(33) Management of knee pain and stiffness after total knee arthroplasty
(34) Manipulation Under Anaesthesia for Stiffness Following Knee Arthroplasty
(35) How to Treat the Stiff Total Knee Arthroplasty?: A Systematic Review
(36) Static progressive stretch improves range of motion in arthrofibrosis following total knee arthroplasty
(37) Early and Late Manipulation Improve Flexion After Total Knee Arthroplasty
(38) The stiff total knee arthroplasty: Evaluation and management
(39) The incidence and results of manipulation after primary total knee arthroplasty
(40) Ranawat Award Paper: Predicting Total Knee Replacement Pain: A Prospective, Observational Study.
(41) Looks Good But Feels Bad: Factors That Contribute to Poor Results After Total Knee Arthroplasty
(42) The management of patients with painful total knee replacement
(43) Stiffness after knee arthrotomy: Evaluation of prevalence and results after manipulation under anaesthesia
(44) Management of stiffness following total knee arthroplasty: A systematic review
(45) Long-Term Outcomes of MUA for Stiffness in Primary TKA
(46) Arthrofibrosis after TKA – Influence factors on the absolute flexion and gain in flexion after manipulation under anaesthesia
(47) Transcutaneous electrical nerve stimulation for postoperative pain relief after total knee arthroplasty
(48) A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty
(49) Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic consumption. A meta-analysis with assessment of optimal treatment parameters for postoperative pain
(50) Early Neuromuscular Electrical Stimulation to Improve Quadriceps Muscle Strength After Total Knee Arthroplasty: A Randomized Controlled Trial
(51) Manipulation under anaesthesia post total knee replacement: long term follow up.
(52) Predictors of postoperative movement and resting pain following total knee replacement
(53) Relationship Between Intensity of Quadriceps Muscle Neuromuscular Electrical Stimulation and Strength Recovery After Total Knee Arthroplasty
(54) Association of psychological status and patient-reported physical outcome measures in joint arthroplasty: a lack of divergent validity
(55) Measuring Tools for Functional Outcomes in Total Knee Arthroplasty
(56) Measuring Functional Improvement after Total Knee Arthroplasty Requires both Performance-Based and Patient-Report Assessments: A Longitudinal Analysis of Outcomes
(57) Health-related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature.
(58) Comparative responsiveness of outcome measures for total knee arthroplasty
(59) Preoperative Quadriceps Strength Predicts Functional Ability One Year After Total Knee Arthroplasty
(60) IMPROVING OUTCOMES WITH TOTAL KNEE ARTHROPLASTY
(61) Effect of CPM following total knee arthroplasty on knee ROM and function: a systematic review
(62) Early High-Intensity Rehabilitation Following Total Knee Arthroplasty Improves Outcomes
(63) Early progressive strength training to enhance recovery after fast-track total knee arthroplasty. A randomized controlled trial
(64) Effectiveness of Continuous Passive Motion and Conventional Physical Therapy After Total Knee Arthroplasty: A Randomized Clinical Trial
(65) Comparison of Clinic- and Home-Based Rehabilitation Programs After Total Knee Arthroplasty
(66) Total Knee Arthroplasty: Muscle Impairments, Functional Limitations, and Recommended Rehabilitation Approaches
(67) A Balance Exercise Program Appears to Improve Function for Patients With Total Knee Arthroplasty: A Randomized Clinical Trial
(68) Assessing Recovery and Establishing Prognosis Following Total Knee Arthroplasty
(69) Outcomes Before and After Total Knee Arthroplasty Compared to Healthy Adults
(70) Early Postoperative Measures Predict 1- and 2-Year Outcomes After Unilateral Total Knee Arthroplasty: Importance of Contralateral Limb Strength
(71) Predictive Risk Factors for Stiff Knees in Total Knee Arthroplasty
(72) Continuous passive motion after knee replacement surgery
(73) Use of Postoperative TENS and Continuous Passive Motion Following Total Knee Replacement
(74) Cryotherapy following total knee replacement.
(75) Cryotherapy after total knee replacement: a survey of current practice.
(76) Aggressive continuous passive motion exercise does not improve knee range of motion after total knee arthroplasty.
(77) Comparing conventional physical therapy rehabilitation with neuromuscular electrical stimulation after TKA.
(78) Neuromuscular electrical stimulation after total joint arthroplasty: a critical review of recent controlled studies.
(79) Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials

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