Issues in extrapolating from clinical trials to clinical practice and outcomes

Extrapolation of clinical trial results to clinical practice requires consideration of whether the trial patients were representative of clinical practice, whether the trial therapy studied was optimal, whether the sample size was adequate, and the impact of adjunctive treatments.
In thrombolytic trials in particular, regional variations in attitudes to coronary angiography may have affected outcomes. Clinical trial results need to be interpreted in the light of the cost effectiveness of the application.
The assessment of clinical outcomes depends on interplay between the structure and process of care, patient factors and chance. Large standardised databases are necessary to assess clinical practice and outcomes.     

Ethical aspects of clinical trials: the attitudes of the public and out-patients

OBJECTIVES: To investigate attitudes to clinical research amongst potential research participants. DESIGN: Questionnaire-survey. SETTING: Two medical out-patient clinics and the background population. SUBJECTS: A total of 508 randomly selected citizens in Copenhagen County (64% responded) and 200 consecutive patients attending the out-patient clinics (64% responded). OUTCOME MEASURES: Attitudes toward different aspects of clinical research. RESULTS: Positive attitudes toward medical research were disclosed. The majority found scientific testing necessary, although only a minority considered participation a moral obligation. Both personal benefits and altruistic motives for participation were highly rated, whereas former positive experiences from trial participation had only minor impact on decisions. Several respondents stated former trial participation had changed their attitudes negatively. Lack of feedback of results was of major importance for this change. Attitudes are significantly influenced by the presence of independent research ethics committees, whereas trial technicalities such as drawing lots and blinding was found problematic by only a few respondents. Altruistic motives of physicians to conduct trials were highly rated by a majority of respondents, but the motive of promoting doctors' careers was also judged important. Respondents rated nondiscomforting procedures as acceptable or having only a small impact or strain on their lives. CONCLUSION: Attitudes toward medical research are positive amongst out-patients and the general public. Altruistic and nonaltruistic motives both concerning trial participation and concerning the motives of physicians to conduct medical research were rated highly. Lack of feedback concerning results of trials to participants was important for a negative change in attitude toward participation.     

The importance of randomized clinical trials and evidence-based medicine: A clinician's perspective

Clinical evaluation of therapies for patient care has evolved during the twentieth century from a variety of scientific methods. As a result of medical, political, and economic changes that occurred in the 1990s, randomized clinical trials and evidence-based methods are presently in the forefront of the physician's thinking in the decision-making process for therapeutic interventions. A new standard of patient care has emerged during this process. This report provides a clinician's viewpoint of the importance and interpretation of evidence-based methods and suggests a strategy when such evidence does not exist.     

Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials

Background  Recombinant factor VIIa (rFVIIa) is used for haemophilic patients with inhibitors against coagulation factor VIII or IX, but there is also an off-label use of rFVIIa for patients with massive bleeding. The aim of the present study was to review the randomized clinical trials (RCT) for evidence of such an approach.
Methods  In October 2007, a review of RCT involving rFVIIa for non-haemophilic indications was performed. The effect of rFVIIa on blood loss and transfusion requirements was recorded.
Results  Seventeen RCTs were identified concerning different bleeding conditions, for example, secondary to surgery, infection and stem cell transplantation. Three pilot studies reported a significant reduction in transfusion requirements and/or blood loss in the rFVIIa-treated groups, but these have not been confirmed in large randomized trials. No difference in thromboembolic complications between rFVIIa and placebotreated patients were found, except for a study in patients with intracranial haemorrhage. In the intracranial haemorrhage study, 16 out of 16 arterial thrombotic events and 19 out of 21 combined arterial and venous thromboembolic events were found in the rFVIIa-treated patients.
Conclusion  There is little evidence to support routine use of rFVIIa for patients with massive bleeding based on the results of the randomized trials performed. In patients with a normal haemostatic system, administration of rFVIIa may be associated with an increased risk of thromboembolic events.     

Clinical trials and the real world: selection bias and generalisability of trial results

The clinical effectiveness movement underpins a major health professional culture change which is occurring worldwide. Clinical practice guidelines are an important component of this movement and seek to promote evidence-based care, and combine quality and efficiency with equity of access in a patient centred approach. However some areas of practice are more amenable to guidelines than others and may thus be advantaged in terms of resource allocation. While high grade evidence from randomised controlled trials forms the basis for many cardiovascular guidelines, selection bias may considerably limit the generalisability of such data. This is particularly exemplified by clinical trials in heart failure which are not necessarily relevant to the majority of older patients with heart failure in the community. Future research in heart failure should be oriented towards the community and realigned in the context of health care priorities for the more elderly who have yet to benefit from previous advances.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: II. Participant samples and assessment

PURPOSE: This paper is the second in a series that describes strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the first paper focused on treatment implementation and research design, here we address issues pertaining to participant samples and assessment methods. SCOPE: With respect to participant samples, sections focus on the definition of study populations; informed consent; sample size and statistical power; recruitment and enrollment; sample retention; and participant tracking systems. Assessment topics include eligibility screening and baseline assessment; treatment-related variables; outcome measures; the frequency of follow-up evaluation; and assessment process. A final section highlights the importance of pilot testing. CONCLUSIONS: Sample recruitment and retention strategies are needed that safeguard both internal and external validity. Daily estimation assessment procedures are recommended because of their versatility for creating a range of outcome measures. Assessment batteries should include measures that permit the investigation of treatment processes and mechanisms of action.     

Effects of orlistat on blood pressure: a systematic review and meta-analysis of 27 randomized controlled clinical trials

Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta-analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (?1.15 mmHg [?2.11, ?0.19]) and diastolic BP (?1.07 mmHg [?1.69, ?0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: III. Data processing and statistical analysis

PURPOSE: This is the third paper in a series that reviews strategies for optimizing the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. Whereas the two previous papers focused on design and implementation, here we address issues pertaining to data processing and statistical analysis. SCOPE: Recommendations for enhancing data quality and utility are offered in sections on data coding and entry; and data format, structure and management. We discuss the need for preliminary data analyses that examine statistical power; patterns of attrition; between-group equivalence; and treatment integrity and discriminability. We discuss tests of treatment efficacy, as well as ancillary analyses aimed at explicating treatment processes. CONCLUSIONS: Safeguards are necessary to protect data quality, and advance planning is needed to ensure that data formats are compatible with statistical objectives. In addition to treatment efficacy, statistical analyses should evaluate study internal and external validity, and investigate the change mechanisms that underlie treatment effects.     

Enhancing the validity and utility of randomized clinical trials in addictions treatment research: I. Treatment implementation and research design

PURPOSE: This paper is the first in a series that examines methods for improving the validity and utility of randomized clinical trials (RCTs) in addictions treatment research. The specific foci of this article are treatment implementation and research design. SCOPE: We begin by considering the conditions under which the RCT provides an appropriate design choice. Sections that follow discuss methodological issues with respect to RCT structure and collaborative arrangements; treatment specification, delivery and cost; experimental design; and randomization/blinding procedures. We emphasize the importance of advance planning; treatment integrity and discriminability; treatment standardization; staff training and supervision; client compliance; maintenance of between-group equivalence across study conditions; and inclusion of appropriate comparison groups in study designs. CONCLUSIONS: Investigators are encouraged to maximize the internal validity of RCTs, but also to consider methods for enhancing external validity. The utility of addictions RCTs for advancing theory and improving clinical practice can be enhanced by investigating underlying mechanisms of action.     

The effect of renal denervation on resistant hypertension: Meta-analysis of randomized controlled clinical trials

Background: This meta-analysis was conducted to evaluate the efficiency of renal denervation (RDN) on resistant hypertension. Methods: PubMed, EMBASE, and the Cochrane Central database were searched for eligible randomized controlled clinical trials (RCTs). Changes from the baseline of the office blood pressure and the 24-h ambulatory blood pressure were extracted. Results: Nine RCTs were included. RDN reduced the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) by ?8.23 mm Hg (95%CI: ?16.86, 0.39) and ?3.77 mm Hg (95%CI: ?7.21, ?0.32), respectively, compared with the control. In the population with a baseline SBP more than 170 mm Hg, the RDN reduced SBP by ?17.77 mm Hg (95%CI: ?33.73, ?1.82) and DBP by ?7.51 mm Hg (95%CI: ?12.58, ?2.44). In the subgroup with no medication adjustment, the RDN reduced SBP by ?15.56 mm Hg (95%CI: ?26.33, ?4.80) and DBP by ?6.89 mm Hg (95%CI: ?9.99, ?3.79). The proportion of patients with SBP decrease of 10 mm Hg or more and the controlled office BP were not different between two groups. RDN reduced 24-h mean SBP and DBP by ?3.34 mm Hg (95%CI: ?5.30, ?1.38) and ?1.56 mm Hg (95%CI: ?2.71, ?0.41), respectively. The SBPs in the subgroups with higher baseline SBP and with no medication adjustment were significantly decreased after the HTN-3 was omitted. Conclusion: Radiofrequency RDN in a randomized manner did not have superiority compared with medical treatment at 6-month follow-up in general population. Current evidence provides insufficient evidence to support the use of such RDN strategy in the treatment of resistant hypertension. The result could not be used to extrapolate other strategies’ effect.     

Randomized clinical trials of osteoarthritis: a review

Aim: The objective of this study was to review published randomized clinical trials (RCTs) of osteoarthritis (OA) in three time periods to determine the characteristics of RCTs and the types of outcome measures used and whether any changes have occurred. Methods: We identified RCTs assessing clinical efficacy of treatments for osteoarthritis published in English in 1987/1988, 1997/1998 and 2001/2002, using MEDLINE. RCTs were then assessed for baseline disease characteristics, treatment type and outcome measures utilized. We classified outcome measures into 10 broad subgroups. Results: The number of RCTs increased with each time period (31 in 1987/1988; 36 in 1997/1998; 91 in 2001/2002). The majority of RCTs were of knee, hip or both (94% in 1987/1988, 69% in 1997/1998, 71% in 2001/2002). The median duration of RCTs for all three time periods was ≤ 3 months. In 1987/1988, nonsteroidal anit‐inflammatory drugs (NSAIDs) accounted for 65% of RCTs. In 1997/1998, NSAID/COX‐2 trials accounted for 41.7%, with glucosamine (14%) and hyaluronan (11%). In 2001/2002, 28% of RCTs were related to NSAID/COX‐2 inhibitors and 25% to complementary therapies. The median number of participants was unchanged over the three time periods. The median number of outcome measures used at all three time periods was four (range 1–8). The most commonly used outcome measures were: (i) symptoms (pain, stiffness); (ii) function; (iii) global assessment (patient, physician); and (iv) composite scores (such as Western Ontario and McMaster [WOMAC] Osteoarthritis index) in order of use. There has been significant increase in use of function and composite score as outcome measures. Conclusion: There has been a recent increase in both the number and variety of therapeutic interventions for OA. This study shows that currently a wide variety of outcome measures are used. This reinforces the importance of using standardized responder criteria, such as the OMERACT‐OARSI set of responder criteria, which incorporate pain, function and patient's global assessment.     

Conduct of clinical trials in developing countries

Research subjects in developing countries may be especially vulnerable to exploitation. Scrupulous care should be taken to maintain the basic principles of ethical trial conduct: the right of participants to make their own informed decisions, a favorable balance of benefit to risk, good trial design, candour about results, and, above all, use of honourable investigators. Involvement of local participants in planning a trial helps ensure both culturally-sensitive protocols and consents and also maximum benefit to patients and to local research infrastructure.     

Association of run‐in periods with weight loss in obesity randomized controlled trials

Study‐level design characteristics that inform the optimal design of obesity randomized controlled trials (RCTs) have been examined in few studies. A pre‐randomization run‐in period is one such design element that may influence weight loss. We examined 311 obesity RCTs published between 1 January 2007 and 1 July 2009 that examine d weight loss or weight gain prevention as a primary or secondary end‐point. Variables included run‐in period, pre‐post intervention weight loss, study duration (time), intervention type, percent female and degree of obesity. Linear regression was used to estimate weight loss as a function of (i) run‐in (yes/no) and (ii) run‐in, time, percent female, body mass index and intervention type. Interaction terms were also examined. Approximately 19% (18.6%) of the studies included a run‐in period, with pharmaceutical studies having the highest frequency. Although all intervention types were associated with weight loss (Mean = 2.80 kg, SD = 3.52), the inclusion of a pre‐randomization run‐in was associated with less weight loss (P = 0.0017) compared with studies that did not include a run‐in period. However, this association was not consistent across intervention types. Our results imply that in trials primarily targeting weight loss in adults, run‐in periods may not be beneficial for improving weight loss outcomes in interventions.     

Verapamil use in patients with cardiovascular disease: An overview of randomized trials

Background: Several reports have questioned the lack of safety data on calcium antagonists as a drug class. Because this drug class is heterogeneous, unique features of certain calcium antagonists may set them apart in terms of safety and efficacy. Hypothesis: With in excess of 7,000 person-years of observation from randomized clinical trials, verapamil was selected to evaluate whether there was evidence of harm in patients with cardiovascular disease. Methods: MEDLINE search of English-language articles, Science Citation Index, Current Contents, manual review of cited references, pharmaceutical files, and investigator correspondence was performed. Independent review of 66 articles identified 14 randomized, parallel-group studies for inclusion. Independent, duplicate assessments were made of patient outcomes and trial characteristics (including study design, treatment dosage and schedule, duration of treatment, inclusion criteria, and sample size). Standard meta-analytic techniques were employed for analysis and interpretation of results. Results: Based on over 4,000 person-years of observation, patients with acute myocardial infarction (MI) treated with verapamil had a decreased risk of nonfatal reinfarction compared with placebo (relative risk 0.79; 2-sided 95% confidence interval 0.65, 0.97; p = 0.024). Verapamil had no significant effect on overall mortality compared with placebo (relative risk ranged from 0.93; 2-sided 95% confidence interval 0.78, 1.10; p = 0.40 to 0.86; 2-sided 95% confidence interval 0.71, 1.04; p = 0.13) depending on rules used to include or exclude patients from the pooling process. For the combined outcome of death or reinfarction, verapamil use was associated with a decreased risk compared with placebo (relative risk 0.82; 2-sided 95% confidence interval 0.70, 0.97; p = 0.016). In patients with angina involving a wide spectrum of disease severity, data were limited to 2,900 person-years of observation, and verapamil use did not appear to be associated with an apparent effect on mortality or MI. Data available from randomized studies of verapamil in patients with hypertension were too limited to reach conclusions (50 person-years of observation, with no deaths or MIs reported). Subgroups of hypertensive patients in two of the largest post-MI studies and the largest angina study, involving over 600 patients, yielded little useful added information. Conclusions: In patients with MI, the risks of both nonfatal reinfarction and the combined outcome of death or nonfatal MI were reduced over intermediate-term follow-up among patients treated with verapamil compared with controls (p = 0.024 and p = 0.016, respectively). In patients with angina, no evidence for harm was noted, but in hypertension the data were too limited to draw conclusions. These findings support the need to distinguish among different calcium antagonist compounds and to emphasize the need for more data in patients with hypertension.     

A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease

BACKGROUND & AIMS: Placebo-controlled, randomized clinical trials (PC-RCTs) are commonly used to assess therapies for Crohn's disease (CD). Knowledge of the placebo rates of remission and response and understanding of design factors that influence these rates is important for designing future clinical trials evaluating pharmacotherapy of CD. The aims of this study were to estimate rates of remission and response in patients with active CD receiving placebo and to identify factors influencing these rates. METHODS: We performed a systematic review and meta-analysis of PC-RCTs evaluating therapies for active CD identified from MEDLINE from 1966 to 2001. RESULTS: The pooled estimates of the placebo rates of remission and response were 18% (95% confidence interval, 14%-24%; range, 0%-50%) and 19% (95% confidence interval, 13%-28%; range, 0%-46%), respectively, both with significant heterogeneity among studies (P < 0.01 for remission, P < 0.03 for response). In multivariate models, study duration, number of study visits, and entry Crohn's Disease Activity Index score were important predictors of the placebo remission rate, with study duration the most important. However, no single factor could account for all of the heterogeneity. Factors that influence the placebo response rates were similar to those affecting the placebo remission rates. The absolute benefit of active treatment beyond placebo was generally larger when outcome was measured by response than remission. CONCLUSIONS: Placebo remission and response rates in PC-RCTs for active CD are variable. Study duration, number of study visits, and disease severity at entry have a large influence on placebo remission rates.     

Efficacy and safety of sacubitril-valsartan in patients with heart failure: a systematic review and meta-analysis of randomized clinical trials: A PRISMA-compliant article

Background:To investigate the efficacy and safety of sacubitril-valsartan in patients with heart failure, relevant randomized clinical trials (RCTs) were analyzed.Methods:We used Cochrane Library, PubMed web of science, CNKI, VIP, Medline, ISI Web of Science, CBMdisc, and Wanfang database to conduct a systematic literature research. A fixed-effects model was used to evaluate the standardized mean differences (SMDs) with 95% confidence intervals. We conducted sensitivity analysis and analyzed publication bias to comprehensively estimate the efficacy and safety of sacubitril-valsartan in patients with heart failure.Results:Among 132 retrieved studies, 5 relevant RCTs were included in the meta-analysis. The result showed that left ventricular ejection fraction (LVEF) was improved after sacubitril-valsartan in patients with heart failure, with an SMD (95% CI of 1.1 [1.01, 1.19] and P < .00001 fixed-effects model). Combined outcome indicators showed that, combined outcome indicators showed that, compared with control group, the left ventricular volume index (LAVI) (WMD = −2.18, 95% CI [−3.63, −0.74], P = .003), the E/e’ (WMD = −1.01, 95% CI [−1.89, −0.12], P = .03), the cardiovascular death (RR = 0.89, 95% CI [0.83, 0.96], P = .003], and the rehospitalization rate of heart failure (RR = 0.83, 95% CI [0.78, 0.88], P < .01) decreased more significantly, but it had no effect on renal function (WMD = 0.74, 95% CI [0.54, 1.01], P = .06).Conclusions:The present meta-analysis suggested that sacubitril-valsartan may improve the cardiac function of heart failure. Given the limited number of included studies, additional large sample-size RCTs are required to determine the long-term effect of cardiac function of sacubitril-valsartan in patients with heart failure.     

Ethical aspects of clinical trials: the attitudes of participants in two non-cancer trials

OBJECTIVES: To investigate attitudes to clinical trials in non-cancer trial participants. DESIGN: Questionnaires at entry, during, and after participation in a clinical study. SETTING: Participants in: (i) ROC: a clinical study comparing systemic interferon-alpha-2A treatment vs. prednisolone enemas in ulcerative colitis; and (ii) MRCRUC: a clinical study investigating low-field magnetic resonance imaging as a new modality for the evaluation of patients with inflammatory bowel disease. SUBJECTS: Thirty-two patients in ROC and 47 patients in MRCRUC. OUTCOME MEASURES: Attitudes towards different aspects of clinical research. RESULTS: The majority found scientific testing of clinical methods necessary, having positive attitudes towards both participation by themselves and others. The creation of a personal moral problem by denying participation was rejected by a large majority, and still both personal and altruistic motives for participation were highly rated. An important motive for accepting inclusion was the expectation of being 'a special patient' during the trial. The presence of research ethics committees controlling clinical research had a significant positive impact on decisions to participate, and drawing lots and blinding were found problematic by only a minority. Patients valued their satisfaction with participation in the trials highly, and would almost all accept a request to participate in future trials. The most important reason for this was a feeling of receiving better care and information than expected outside a trial setting, primarily determined by the patients seeing only one physician during the trials. A pronounced wish to obtain follow-up information was expressed. CONCLUSION: Attitudes towards medical research are positive with both altruistic and nonaltruistic motives for participation. Expectations of being treated as 'a special patient' in the trial were important in accepting to participate. Seeing the same physician at control visits was an important factor for satisfaction with participation.