Placebo Control and Blinding in Randomized Trials of Procedural Interventions: A Systematic Review and Meta-Regression.

Importance: Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed. Objective: To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm. Data Sources: Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison. Study Selection: Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity. Data Extraction and Synthesis: Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020. Main Outcomes and Measures: End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality. Results: Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88). Conclusions and Relevance: The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

Are return-to-play times longer in lower-limb muscle injuries involving the intramuscular tendon? A systematic review.

OBJECTIVES: To determine the influence of severity and direction (craniocaudal length vs cross-sectional area) of intramuscular tendon tears in the lower limb on return-to-play times, compared to muscle injuries without intramuscular tendon involvement. DESIGN: Systematic review with meta-analysis. METHODS: AMED, CINAHL, SPORTDiscus, ScienceDirect, PubMed (MEDLINE) and Web-of-Science were searched from inception to 31st July 2023, retrieving 666 records, of which nine were deemed eligible. A random-effects meta-analysis was performed on time to return-to-play for British Athletics Muscle Injury Classification 'b' vs 'c'. RESULTS: On the Quality in Prognosis Studies tool, one study had low risk of bias and eight had high risk. Using a best-evidence synthesis, no strong evidence emerged for a difference in time to return-to-play between injuries with or without intramuscular tendon involvement. Moderate evidence was found for an association between increased return-to-play time and the presence of "waviness" on magnetic resonance imaging and loss of tendon tension, but no association with longitudinal extent of tendon involvement. Pooled analysis revealed a medium effect-size difference between British Athletics Muscle Injury Classification 'b' and 'c' injuries, favouring classification 'b' (Hedges g = 0.67; 95% confidence interval 0.20 to 1.15; P = 0.002). CONCLUSIONS: It remains difficult to provide an accurate prognosis for muscle injuries involving the intramuscular tendon due to high risk of bias and moderate heterogeneity across studies. Moderate evidence favoured the prognosis for injuries at the musculotendinous junction (British Athletics Muscle Injury Classification 'b') over intratendinous injuries (British Athletics Muscle Injury Classification 'c').

Daily angina documentation versus subsequent recall: development of a symptom smartphone app.

Aims: The traditional approach to documenting angina outcomes in clinical trials is to ask the patient to recall their symptoms at the end of a month. With the ubiquitous availability of smartphones and tablets, daily contemporaneous documentation might be possible. Methods and results: The ORBITA-2 symptom smartphone app was developed with a user-centred iterative design and testing cycle involving a focus group of previous ORBITA participants. The feasibility and acceptability were assessed in an internal pilot of participants in the ongoing ORBITA-2 trial. Seven days of app entries by ORBITA-2 participants were compared with subsequent participant recall at the end of the 7-day period. The design focus group tested a prototype app. They reported that the final version captured their symptoms and was easy to use. In the completion assessment group, 141 of 142 (99%) completed the app in full and 47 of 141 (33%) without reminders. In the recall assessment group, 29 of 29 (100%) participants said they could recall the previous day's symptoms, and 82% of them recalled correctly. For 2 days previously, 88% said they could recall and of those, 87% recalled correctly. The proportion saying they could recall their symptoms fell progressively thereafter: 89, 67, 61, 50%, and at 7 days, 55% (P < 0.001 for trend). The proportion of recalling correctly also fell progressively to 55% at 7 days (P = 0.04 for trend). Conclusion: Episode counts of angina are difficult to recall after a few days. For trials such as ORBITA-2 focusing on angina, daily symptom collection via a smartphone app will increase the validity of the results.

The sensitivity of countermovement jump, creatine kinase and urine osmolality to 90-min of competitive match-play in elite English Championship football players 48-h post-match.

Purpose: Examine changes from 90-minutes of competitive match-play in countermovement jump (CMJ), creatine kinase (CK) and urine osmolality (Uosm) in elite football players over a season and their association to match external load.Methods: Eighteen footballers participated. CMJ, CK and Uosm were collected 24-h pre-match and 48-h post-match. Match-performance data was examined using Prozone®.Results: Post-match CK concentrations increased 49% (ES:0.66), while CMJ flight-time (FT), flight-time:contraction time ratio (FT:CT), take-off velocity (TV) and average power (AP) decreased 2.4-7.4% post-match (ES:0.39-0.63). CMJ height post-match reduced 4.2% (ES:0.35). CMJ FT and AP showed associations with high intensity distance covered (HID), high intensity number (HIN), explosive sprints (EXS) and medium intensity accelerations (r= -0.395 to -0.496). Changes in CMJ FT also displayed associations to total sprint distance (TSD), total sprint number (TSN) and medium intensity decelerations (r = -0.395-0.446). Increases in CMJ CT were associated with HIN (r=0.39), and CMJ AF with HIN, EXS and medium accelations/decelerations (r= -0.397 to 0.459) completed during the match.Conclusion: CMJ outputs from the push-off phase and countermovement phase were sensitive to change in neuromuscular fatigue. CK concentrations were sensitive to the match-play demands. This helps practitioners determine player readiness and has implications for individual recovery strategies.

Allopurinol initiation and change in blood pressure in older adults with hypertension.

Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mm Hg; 95% confidence interval, -0.6 to 4.8; and 1.7 mm Hg; 95% confidence interval, 0.4-3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed.