A novel method for interpreting survival analysis data: description and test on three major clinical trials on cardiovascular prevention.
ABSTRACT: BACKGROUND:Major results of randomized clinical trials on cardiovascular prevention are currently provided in terms of relative or absolute risk reductions, including also the number needed to treat (NNT), incorrectly implying that a treatment might prevent the occurrence of the outcome/s under investigation. Provided that these results are based on survival analysis, the primary measure of which is time-to-the outcome and not the outcome itself, we sought an alternative method to describe, analyse and interpret clinical trial results consistent with this assumption, so as to better define qualitative and quantitative heterogeneity of various therapeutic strategies in terms of their effects and costs. METHODS:The original Kaplan-Meier graphs of three major positive cardiovascular prevention trials (PROVE-IT, LIFE and HOPE) were captured from the PDF images of the article and then digitalized. We calculated the difference between the placebo and active treatment curves and plotted it as a function of time to describe the event-free time gain (Time-Gain) produced by the active treatment. By calculating the exposure to the active treatment in terms of months (MoT) as a function of time and dividing it for the corresponding time-dependent number of event-free years gained (i.e. months/12), we described the kinetics of the pharmaco-economic index MoT/y+. The same procedure was repeated replacing MoT with the actual number of patients being treated at each time point as a function of time to obtain the NNT to gain 1 event-free year (NNT/y+) curve. RESULTS:The Time-Gain curves depict the kinetics of the treatment-related effect over time and possess the peculiar feature of being smooth and accurately fitted by second-order polynomial functions (a*time2 +?b*time); similarly, also the MoT/y+ and NNT/y+ curves can be accurately fitted by power functions (a*timeb). These curves and indices allow to fully appreciate the quantitative and qualitative heterogeneity, both in terms of effects and costs, of the different therapeutic strategies adopted in the three trials. CONCLUSIONS:With our novel method, by exploiting original Kaplan-Meier curves from three major clinical trials on cardiovascular prevention, we generate new information on the actual consequences of choosing a therapeutic strategy vs another, thus ultimately providing the clinical gain in terms of time-dependent functions. Accurately assessing clinically and economic meaningful results from any intervention trial reporting positive results through this approach, facilitates objective comparisons and increases reliability in predicting survival among the various therapeutic options provided. TRIAL REGISTRATION:PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy (TIMI22), Clinical trial registration number: NCT00382460, date of registration: September 29, 2006, study start date: November 2000). LIFE (Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study, Clinical trial registration number: NCT00338260, date of registration: June 20, 2006, study start date: June 1995). HOPE (Heart Outcomes Prevention Evaluation; we could not find Clinical trial registration number and date of registration).
Project description:To investigate the issues of the NNT based on the absolute risk reduction (ARR), namely NNTARR; and to propose an alternative definition and an estimation procedure based on the restricted mean survival time (RMST), namely NNTRMST, for RCTs. Three recent clinical trials with survival endpoints, representing different scenarios, were selected to compare the performance of the NNTARR and NNTRMST. For each trial, both versions of NNT were estimated using the reconstructed individual-level data, and the average life gain (ALG) was derived to show the differences between the NNTARR and NNTRMST. Four hypothetical scenarios were constructed to further explore the advantages and disadvantages of each definition of the NNT for survival endpoints. For the illustrative trial examples, the NNTARR failed to capture the profile of the treatment effect over time as it is calculated at a specific time point. Sometimes it may even result in misinterpretations of the treatment benefit. In particular, when either the observed event rates are low, the two survival curves cross, or a mixture of survival patterns exist. In contrast, the NNTRMST based on the average survival (or event-free) time can quantify the treatment effect more accurately and its interpretation is more intuitive and clinically meaningful. The NNTRMST can be used as an alternative measure for quantifying treatment effect in RCTs, especially so in the case of the ALG, which helps practitioners to better understand the magnitude of the benefit conferred by treatment.
Project description:Clinicians are expected to select a therapy based on their appraisal of evidence on benefit-to-risk profiles of therapies. In the management of relapsing-remitting multiple sclerosis (RRMS), evidence is typically expressed in terms of risk (proportion) of event, risk reduction, relative and hazard rate reduction, or relative reduction in the mean number of magnetic resonance imaging lesions. Interpreting treatment effect using these measures from a RRMS clinical trial is fairly reliable; however, this might not be the case when treatment effect is expressed in terms of the number needed to treat (NNT). The objective of this review is to discuss the utility of NNT in RRMS trials. This article presents an overview of the methodological definition and characteristics of NNT as well as the relative merit of NNT use in RRMS controlled clinical trials, where endpoints are typically time-to-event and frequency of recurrent events. The authors caution against using NNT in multiple sclerosis, a clinically heterogeneous disease that can change course and severity unpredictably. The authors also caution against the use of NNT to interpret results in comparative trials where the absolute risk difference is not statistically significant, computing NNT using the time-to-event endpoint at intermediate time points, computing NNT using the annualized relapse rate, and comparing NNT across trials.
Project description:BACKGROUND:The number needed to treat (NNT) for one participant to benefit is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. Analysis of continuous data from our randomized controlled trial has previously demonstrated a significant and clinically important difference favoring spinal manipulation over a light massage control. METHODS:Eighty participants were randomized to receive spinal manipulation or a light massage control (n = 40/group). Improvements in cervicogenic headache pain (primary outcome), disability, and number in prior four weeks were dichotomized into binary outcomes at two thresholds: 30% representing minimal clinically important change and 50% representing clinical success. Groups were compared at 12 and 24-week follow-up using binomial regression (generalized linear models) to compute the adjusted risk difference (RD) between groups and number needed to treat (NNT) after adjusting for baseline differences between groups. Results were compared to logistic regression results. RESULTS:For headache pain, clinically important improvement (30% or 50%) was more likely for spinal manipulation: adjusted RD = 17% to 27% and NNT = 3.8 to 5.8 (p = .005 to .028). Some statistically significant results favoring manipulation were found for headache disability and number. CONCLUSION:Spinal manipulation demonstrated a benefit in terms of a clinically important improvement of cervicogenic headache pain. The use of adjusted NNT is recommended; however, adjusted RD may be easier to interpret than NNT. The study demonstrated how results may depend on the threshold for dichotomizing variables into binary outcomes. TRIAL REGISTRATION:ClinicalTrials.gov NLM identifier NCT00246350.
Project description:BACKGROUND:Dementia is a progressive disease that decreases quality of life of persons with dementia and is associated with high societal costs. The burden of caring for persons with dementia also decreases the quality of life of family caregivers. The objective of this study was to assess the societal cost-effectiveness of Namaste Care Family program in comparison with usual care in nursing home residents with advanced dementia. METHODS:Nursing homes were randomized to either Namaste Care Family program or usual care. Outcome measures of the cluster-randomized trial in 231 residents included Quality of Life in Late-Stage Dementia (QUALID) and the Gain in Alzheimer Care Instrument (GAIN) for family caregivers over 12?months of follow-up. Health states were measured using the EQ-5D-3L questionnaire which were translated into utilities. QALYs were calculated by multiplying the amount of time a participant spent in a specific health state with the utility score associated with that health state. Healthcare utilization costs were estimated using standard unit costs, while intervention costs were estimated using a bottom-up approach. Missing cost and effect data were imputed using multiple imputation. Bootstrapped multilevel models were used after multiple imputation. Cost-effectiveness acceptability curves were estimated. RESULTS:The Namaste Care Family program was more effective than usual care in terms of QUALID (-?0.062, 95%CI: -?0.40 to 0.28), QALY (0.0017, 95%CI: -?0.059 to 0.063) and GAIN (0.075, 95%CI: -?0.20 to 0.35). Total societal costs were lower for the Namaste Care Family program as compared to usual care (-?552 €, 95%CI: -?2920 to 1903). However, these differences were not statistically significant. The probability of cost-effectiveness at a ceiling ratio of 0 €/unit of effect extra was 0.70 for the QUALID, QALY and GAIN. CONCLUSIONS:The Namaste Care Family program is dominant over usual care and, thus, cost-effective, although statistical uncertainty was considerable. TRIAL REGISTRATION:Netherlands Trial Register ( http://www.trialregister.nl/trialreg/index.asp , identifier: NL5570, date of registration: 2016/03/23).
Project description:Background:Recent randomized controlled trials (RCTs) support using physiotherapeutic scoliosis-specific exercises (PSSE) for adolescents with idiopathic scoliosis (AIS). All RCTs reported statistically significant results favouring PSSE but none reported on clinical significance. The number needed to treat (NNT) helps determine if RCT results are clinically meaningful. The NNT is the number of patients that need to be treated to prevent one bad outcome in a given period. A low NNT suggests that a therapy has positive outcomes in most patients offered the therapy. The objective was to determine how many patients require Schroth PSSE added to standard care (observation or brace treatment) to prevent one progression (NNT) of the Largest Curve (LC) or Sum of Curves (SOC) beyond 5° and 10°, respectively over a 6-month interval. Methods:This was a secondary analysis of a RCT. Fifty consecutive participants from a scoliosis clinic were randomized to the Schroth PSSE + standard of care group (n = 25) or the standard of care group (n = 25).We included males and females with AIS, age 10-18 years, all curve types, with curves 10°- 45°, with or without brace, and all maturity levels. We excluded patients awaiting surgery, having had surgery, having completed brace treatment and with other scoliosis diagnoses. The local ethics review board approved the study (Pro00011552).The Schroth intervention consisted of weekly 1-h supervised Schroth PSSE sessions and a daily home program delivered over six months in addition to the standard of care. A prescription algorithm was used to determine which exercises patients were to perform. Controls received only standard of care.Cobb angles were measured using a semi-automatic system from posterior-anterior standing radiographs at baseline and 6 months.We calculated absolute risk reduction (ARR) and relative risk reduction (RRR). The NTT was calculated as: NNT = 1/ARR. Patients with missing values (PSSE group; n = 2 and controls; n = 4) were assumed to have had curve progression (worst case scenario). The RRR is calculated as RRR = ARR/CER. Results:For LC, NNT = 3.6 (95% CI 2.0-28.2), and for SOC, NNT = 3.1 (95% CI 1.9-14.2). The corresponding ARR was 28% for LC and 32% for the SOC. The RRR was 70% for LC and 73% for the SOC. Patients with complete follow-up attended 85% of prescribed visits and completed 82.5% of the home program. Assuming zero compliance after dropout, 76% of visits were attended and 73% of the prescribed home exercises were completed. Conclusions:The short term of Schroth PSSE intervention added to standard care provided a large benefit as compared to standard care alone. Four (LC and SOC) patients require treatment for the additional benefit of a 6-month long Schroth intervention to be observed beyond the standard of care in at least one patient. Trial registration:NCT01610908 April 2, 2012.
Project description:OBJECTIVE:Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient's own brain activity to self-regulate brain networks which in turn could lead to a change in behavior and clinical symptoms. The objective was to determine the effect of NF and motor training (MOT) alone on motor and non-motor functions in Parkinson's Disease (PD) in a 10-week small Phase I randomized controlled trial. METHODS:Thirty patients with Parkinson's disease (PD; Hoehn and Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with MOT. Group 2 (MOT: 15 patients) received MOT alone. The primary outcome measure was the Movement Disorder Society-Unified PD Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention "off-medication". The secondary outcome measures were the "on-medication" MDS-UPDRS, the PD Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. RESULTS:Patients in the NF group were able to upregulate activity in the supplementary motor area (SMA) by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the "off-medication" state (95% confidence interval: -2.5 to -6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to -6.8). The improvement in the intervention group meets the minimal clinically important difference which is also on par with other non-invasive therapies such as repetitive Transcranial Magnetic Stimulation (rTMS). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. INTERPRETATION:This Phase I study suggests that NF combined with MOT is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions.
Project description:Background:Atrial fibrillation (AF) is the most common arrhythmia worldwide. Despite effective treatment, it is characterized by frequent recurrences. Optimal therapeutic management of AF requires active participation and self-management from patients. Two major components of self-management are self-monitoring and sign-and-symptom management. Pulse self-palpation (PSP) is a method of self-monitoring; however, not all AF patients are capable of successfully performing PSP. Due to a lack of interventions on this topic, a nurse-led intervention for patients with AF (PSPAF intervention) was developed to foster self-monitoring and to enhance self-management through PSP. The purpose of this pilot study was to test the acceptability, feasibility, and potential effects of this intervention on the capability of patients' PSP and sign-and-symptom management. Moreover, we aimed at gathering data on the feasibility of applied research methods to aid in the design of future studies. Methods:The pilot trial involved 20 adult patients with AF, randomized to an intervention or usual care group. At baseline and during a home visit 3-5?weeks later, we collected data using questionnaires, checklists, field notes, a mobile ECG device, and a diary. Acceptability and feasibility measures were validated through predefined cut-off points. Effect size estimates were expressed as relative risks (RR) and the number needed to treat (NNT). Results:The PSPAF intervention seemed feasible, but only partly acceptable. There were limitations in terms of potential effectiveness, suitability, addressing participants' willingness to implement its content in daily life, and adherence. Estimations of effect sizes suggest a large effect of the intervention on patients' PSP capability (RR = 6.0; 95% CI = [0.83, 43.3]; NNT = 2.4), but almost no effect on sign-and-symptom management (RR = 1.5; 95% CI = [0.7, 3.1]; NNT = 4.0). The feasibility of applied research methods showed minor limitations on recruitment and participant burden. Conclusions:Despite some limitations, the intervention seemed to be applicable and promising. Taking into account the suggestions and amendments we have made, we recommend conducting a full-scale trial to examine the efficacy of the PSPAF intervention. Trial registration:This pilot study was registered in the German Clinical Trials Register at September 4, 2017 (Main ID: DRKS00012808).
Project description:BACKGROUND:Aged long-term care receivers are affected by various adverse skin conditions like pressure ulcers, incontinence-associated dermatitis, dryness, intertrigo, and many more. Prevention of these skin problems and the provision of general hygiene and skin care activities are key areas of nursing practice. Numerous condition-specific guidelines are available and are implemented separately. On the other hand, there is huge overlap in terms of etiology, pathogenesis, and prevention of the skin conditions mentioned above. This leads to fragmented practice neglecting shared etiologies and prevention and treatment principles. METHODS:The overall aims of this trial are to test the feasibility and to estimate possible effects of the implementation of a comprehensive skin care and prevention strategy targeting main nursing-relevant skin problems at the same time. A two-arm cluster-randomized controlled trial will be performed in 20 nursing homes randomly selected from the population of nursing homes of the state of Berlin, comparing skin care according to the skin care and prevention strategy with standard skin care. DISCUSSION:It is expected that the implementation of this evidence-based skin care and prevention strategy will reduce the incidence of pressure ulcers, incontinence dermatitis, and other skin problems frequently related to care dependency. This trial will benefit individual patients and aged nursing home residents in general given the high prevalence and incidence of the addressed skin conditions. Findings of this exploratory trial may lay the foundation for a change in the development and evaluation of clinical standards and practices in general as it moves the perspective from individual conditions to a more comprehensive view on overlapping or coexisting health problems, in this case common skin conditions, in old-age long-term care receivers. TRIAL REGISTRATION:The study is registered at the German Clinical Trials Register https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015680 (Deutsches Register Klinischer Studien, or DRKS; registration number: DRKS00015680 , date of registration: January 29, 2019) and ClincialTrials.gov (registration number: NCT03824886 , date of registration: January 31, 2019).
Project description:Background:To research 1) how many acupuncture clinical trials are registered with the WHO International Clinical Trial Registry Platform (ICTRP) and what patterns they demonstrate, 2) publication of the articles of acupuncture clinical trials which were registered with ICTRP. Methods:The search strategy using the ICTRP: Intervention: acupuncture; Recruitment status: All; Date of registration; from 1 Jan 1990 to 31 Dec 2018. We searched the indexed articles in PubMed using trial IDs on 25 Feb 2019. When the paper was published, we indicated the number of weeks from the date of registration with ICTRP to the date of publication in order to define time till the publication. We divided the whole period we analyzed into 6 periods of every 3 years and measured the proportion of publication and the time from the date of registration of each trial till its publication in each period by the Kaplan-Meier method. Results:Forty-three countries/areas conducted at least one acupuncture clinical trial. The total number of registrations was 1758. China, the USA, and the Republic of Korea accounted for 61% of those registrations. The proportion of publication was 178/1758 10% for the fully published papers and 141/1758 8% for the protocol papers. Conclusions:The substantial increase of registrations by China, the Republic of Korea, Iran, Brazil, Japan was observed which may be attributed to improved awareness of the CONSORT statement. However, the fully published papers rate is low at 10%. The publication of results of acupuncture clinical trials should also be rigorously mandated.
Project description:BACKGROUND:Urethrocutaneous fistulae (UCFs) represent one of the most frequent causes of morbidity after urethroplasty. Hypospadias can be repaired using different surgical techniques, but-regardless of technique-the incidence of UCF ranges between 10% and 40%. Surgical repair of UCF remains the treatment of choice, even if some patients need further surgery because of recurrences. Cyanoacrylates have been used as skin suture substitutes, and some evidence suggests a beneficial effect when these adhesives are used as an adjuvant in the management of UCF. Here we describe the results of management of UCF using 2-octyl cyanoacrylate (OCA) compared with surgical repair. METHODS:A randomized clinical trial conducted from January 2008 to December 2012 included 42 children with UCF complications after urethroplasty for hypospadias. Twenty-one children were assigned to receive OCA as ambulatory patients and 21 were treated surgically. The main outcome variable was closure of the UCF. The estimated costs of both treatments were also calculated, as were absolute risk reduction (ARR), relative risk reduction (RRR) and number needed to treat (NNT) to prevent a surgical intervention. RESULTS:The mean numbers of UCF were 1.3 in the OCA group (n = 28) and 1.1 in the surgical group (n = 25) with no statistically significant difference. The external orifices measured were 2.96 ± 1.0 mm and 3.8 ± 0.89 mm, respectively (NS). Sixty per cent of the UCFs treated with cyanoacrylate were completely closed and 68% of the surgical group healed completely (NS). More than one reoperation to improve complications was needed in the surgical group (3.5 ± 1.2). The clinical significance of the therapeutic usefulness of OCA was demonstrated by an ARR of 0.08, RRR of 0.25 and NNT of 12 to avoid further surgical treatment. The total costs of adhesive applications and reoperations were $US 14,809.00 and $US 158,538.50, respectively. CONCLUSIONS:The results showed a similar success rate for both treatments. However, sealant use should be considered before surgical treatment because this is a simple outpatient procedure with a reasonable success rate. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02115191. Date: April 13, 2014.