Treatment Effects In Subgroups Research Articles

Pharmacologic Management of Chronic Low Back Pain

Systematic review of the literature with subgroup analysis for heterogeneous treatment effects. The objectives of this systematic review were to summarize prior Cochrane reports regarding the safety and effectiveness of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antidepressants for treatment of chronic low back pain (LBP) and to evaluate whether certain subpopulations respond more favorably to pharmacological management. While medications are a mainstay of LBP management, there is uncertainty as to the optimal use of commonly prescribed medications such as opioids, antidepressants, and NSAIDS. To summarize the overall treatment effect and safety for each of the three pharmacological drug classes (opioids, NSAIDs, or antidepressants), we summarized existing Cochrane reviews. To evaluate whether the effects of treatment varied by specific subgroups of patients, we sought randomized controlled trials (RCTs) evaluating one of the three pharmacological drug classes versus an alternative management for chronic LBP. Based on the Cochrane reviews, opioids are more effective than placebo with respect to pain and disability, with a much greater effect size for pain than disability. When compared with NSAIDs, opioids did not confer a greater benefit with regard to pain and disability. The rate of side effects from opioids is significantly greater than placebo with differences ranging between 2% and 9%. The systematic review of RCTs showed that antidepressants are not more effective than placebo with respect to pain, functional status, or depression. Certain subgroup treatment effects were identified, supporting our hypothesis that chronic LBP should be considered a heterogeneous set of disorders. As such, chronic LBP subgroups should be considered both when making clinical treatment decisions and when designing future research trials. Opioids and NSAIDs are effective for chronic LBP, while antidepressants have no meaningful clinical benefit. Based on the significant rate of side effects with opioids and the lack of convincing superiority over NSAIDs, opioids are not recommended as a treatment for chronic LBP. Attention to subgroups of patients will likely help guide treatment, and will likely help increase the clinical impact of future research. Recommendation 1: NSAIDs should be considered as a treatment of chronic LBP (Strength: Strong). There is evidence demonstrating favorable effectiveness, but also significant side effects that may have meaningful clinical consequences. Recommendation 2: Opioids may be considered in the treatment of chronic LBP but should be avoided if possible (Strength: Weak). There is evidence demonstrating favorable effectiveness compared to placebo, similar effectiveness compared to NSAIDs, and with significant side effects including decreasing effectiveness related to habituation when used long-term. Recommendation 3: Antidepressants should not be routinely used for the treatment of chronic LBP (Strength: Strong). There is evidence that they are not more effective than placebo with respect to pain, functional status, or depression. Based on the hypothesis that chronic LBP is a symptom reflective of a heterogeneous group of disorders, categorization of certain patient specific subgroups may be helpful in guiding future treatment decision making. It is likely that inclusion of subgroup factors in future RCTs will provide information needed to improve the strength and specificity of future clinical recommendations.

Research methods for subgrouping low back pain

BackgroundThere is considerable clinician and researcher interest in whether the outcomes for patients with low back pain, and the efficiency of the health systems that treat them, can be improved by 'subgrouping research'. Subgrouping research seeks to identify subgroups of people who have clinically important distinctions in their treatment needs or prognoses. Due to a proliferation of research methods and variability in how subgrouping results are interpreted, it is timely to open discussion regarding a conceptual framework for the research designs and statistical methods available for subgrouping studies (a method framework). The aims of this debate article are: (1) to present a method framework to inform the design and evaluation of subgrouping research in low back pain, (2) to describe method options when investigating prognostic effects or subgroup treatment effects, and (3) to discuss the strengths and limitations of research methods suitable for the hypothesis-setting phase of subgroup studies.DiscussionThe proposed method framework proposes six phases for studies of subgroups: studies of assessment methods, hypothesis-setting studies, hypothesis-testing studies, narrow validation studies, broad validation studies, and impact analysis studies. This framework extends and relabels a classification system previously proposed by McGinn et al (2000) as suitable for studies of clinical prediction rules. This extended classification, and its descriptive terms, explicitly anchor research findings to the type of evidence each provides. The inclusive nature of the framework invites appropriate consideration of the results of diverse research designs. Method pathways are described for studies designed to test and quantify prognostic effects or subgroup treatment effects, and examples are discussed. The proposed method framework is presented as a roadmap for conversation amongst researchers and clinicians who plan, stage and perform subgrouping research.SummaryThis article proposes a research method framework for studies of subgroups in low back pain. Research designs and statistical methods appropriate for sequential phases in this research are discussed, with an emphasis on those suitable for hypothesis-setting studies of subgroups of people seeking care.

AS-57: Comparison of High-Dose (600 mg) versus Moderate-Dose (300 mg) Clopidogrel Loading in Patients Receiving Drug-Eluting Stents: A Subanalysis of a Randomized Trial

Whether high-dose clopidogrel may improve early clinical outcome has been debated. We compared the efficacy and safety of high-dose (600 mg) vs moderate-dose (300 mg) clopidogrel loading in patients with non-ST-elevation acute coronary syndrome (ACS) or stable angina who received drug-eluting stents and clarified treatment effects in several clinical and anatomic subgroups.

Measuring disease progression in frontotemporal lobar degeneration

There is currently much interest in biomarkers of disease activity in frontotemporal lobar degeneration (FTLD). We assessed MRI and behavioral measures of progression in a longitudinal FTLD cohort. Thirty-two patients with FTLD (11 behavioral variant frontotemporal dementia [bvFTD], 11 semantic dementia [SemD], 10 progressive nonfluent aphasia [PNFA]) and 24 age-matched healthy controls were assessed using volumetric brain MRI and standard behavioral measures (Mini-Mental State Examination, Frontal Assessment Battery, Clinical Dementia Rating Scale, Neuropsychiatric Inventory with Caregiver Distress scale) at baseline and 1 year later. A semi-automated image registration protocol was used to calculate annualized rates of brain atrophy (brain boundary shift integral [BBSI]) and ventricular expansion (ventricular boundary shift integral [VBSI]). Associations between these rates and changes in behavioral indices were investigated. Rates of whole brain atrophy were greater in the entire FTLD cohort and in each subgroup compared with controls (all p < or = 0.004). Rates of ventricular expansion were greater in the entire cohort (p < 0.001) and the SemD (p = 0.002) and PNFA (p = 0.05) subgroups compared with controls. Changes in Mini-Mental State Examination, Frontal Assessment Battery, and Clinical Dementia Rating Scale scores were associated with MRI measures of progression, though not uniformly across FTLD subgroups. Both BBSI and VBSI yielded feasible sample size estimates for detecting meaningful treatment effects in SemD and PNFA language subgroups. Sample sizes were substantially larger using MRI biomarkers for the bvFTD subgroup, and using behavioral biomarkers in general. Semi-automated MRI atrophy measures are potentially useful objective biomarkers of progression in frontotemporal lobar degeneration (FTLD); however, careful stratification of FTLD subtypes will be important in future clinical trials of disease-modifying therapies.

The Importance of “Shrinkage” in Subgroup Analyses

Subgroup analyses examine associations (eg, between treatment and outcome) within subsets of a larger study sample. The traditional approach evaluates the data in each of the subgroups independently. More accurate answers, however, may be expected when the rest of the data are considered in the analysis of each subgroup, provided there are 3 or more subgroups. We present a conceptual introduction to subgroup analysis that makes use of all the available data and then illustrate the technique by applying it to a previously published study of pediatric airway management. Using WinBUGS, freely available computer software, we perform an empirical Bayesian analysis of the treatment effect in each of the subgroups. This approach corrects the original subgroup treatment estimates toward a weighted average treatment effect across all subjects. The revised estimates of the subgroup treatment effects demonstrate markedly less variability than the original estimates. Further, using these estimates will reduce our total expected error in parameter estimation compared with using the original, independent subgroup estimates. Although any particular estimate may be adjusted inappropriately, adopting this strategy will, on average, lead to results that are more accurate. When multiple subgroups are considered, it is often inadvisable to ignore the rest of the study data. Authors or readers who wish to examine associations within subgroups are encouraged to use techniques that reduce the total expected error.

The clinical effectiveness of aspirin for in-vitro fertilisation (IVF): results from an individual patient data meta-analysis (IPD MA). For the IPD Maria group

OBJECTIVE: Aspirin, a simple, safe and inexpensive drug, might improve the effectiveness of IVF. Previous systematic reviews for aspirin in IVF have shown conflicting results. Performing a meta-analysis on individual patient data from each trial permits us to adjust for important variables, such as female age, and allows an analysis of differential treatment effects in patient subgroups. The aim of this IPD MA was to compare the effectiveness of aspirin versus placebo in IVF. DESIGN: Individual patient data meta-analysis. MATERIALS AND METHODS: A systematic search of the literature was conducted to identify randomised controlled trials examining aspirin in IVF. Authors of these trials were requested to send their original data. Treatment effect of aspirin was estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression, based on the intention to treat principle. The analysis was stratified for centre. We controlled for female age as well as interaction between age and treatment effect. RESULTS: Ten studies fulfilled the inclusion criteria. Three authors were not able to share data. We are currently waiting for two datasets. Therefore, five trials comparing aspirin with placebo in a total of 1060 patients could be analysed. Data on outcome or allocation were missing in 54 patients, leaving data of 1006 patients for analysis. Mean female ages in the aspirin and placebo groups were 31.1 years and 31.9 years, respectively. The number of clinical pregnancies was 174 (34.5%) versus 168 (33.5%) in the placebo group (OR 1.04, 95% CI (0.80 to 1.4). Addition of female age to the model did not alter treatment effect (OR 1.03, 95% CI (0.79 to 1.3). This point estimate of 1.03 was lower than the 1.09 reported in conventional meta-analysis published in Cochrane. CONCLUSIONS: Previous conventional meta-analyses have overestimated the treatment effect of aspirin. According to our meta-analysis, low dose aspirin does not improve pregnancy rates after IVF.

What Is the Evidence on Efficacy of Spinal Cord Stimulation in (Subgroups of) Patients With Critical Limb Ischemia?

The use of spinal cord stimulation (SCS) has been advocated for the management of ischemic pain and the prevention of amputations in patients with inoperable critical limb ischemia (CLI), although data on benefit are conflicting. Several reports described apparently differential treatment effects in subgroups. The purpose of this study was to analyze the data on the efficacy of SCS and to clarify preselection issues. Five randomized trials have been performed with a total number of 332 patients. Primary outcome measures were mortality and limb survival. In the largest multicenter randomized trial (n = 120), which compared SCS treatment and best medical treatment alone in patients with inoperable CLI, we determined the incidence of amputation and its relation to various predefined risk factors. We used Kaplan-Meier and Cox regression analyses to quantify prognostic effects and differential treatment effects. Meta-analysis yielded a relative risk for amputation of 0.79 and a risk difference of -0.07 (p = 0.15). The risk factor analysis clearly showed that patients with ischemic skin lesions (ulcerations or gangrene) had a worse prognosis (i.e., higher risk of amputation) (relative risk 2.30, p = 0.01). We did not observe significant interactions between this prognostic factor (or any other) and the effect of SCS. The analysis did not indicate a subgroup of patients who might specifically be helped by SCS. Meta-analysis including all randomized data shows insufficient evidence for higher efficacy of SCS treatment compared with best medical treatment alone. Although some factors provide prognostic information as to the risk of amputation in patients with CLI, there are no data supporting a more favorable treatment effect in any group.

The Rationale and Design of the Perindopril Genetic Association Study (PERGENE): A Pharmacogenetic Analysis of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients with Stable Coronary Artery Disease

Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40 degrees C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACE-inhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05). The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease.

Genomic Aberrations, VH Mutation Status and Outcome after Fludarabine and Cyclophosphamide (FC) or FC Plus Rituximab (FCR) in the CLL8 Trial

The international multicenter randomized CLL8 trial evaluated 1st line treatment with FC or FCR in 817 CLL patients. Analyses of genomic aberrations by FISH and VH mutation status by DNA sequencing were scheduled for a subset of countries in a central reference laboratory. Samples were available for 648 (79%) patients and this cohort was representative of the full trial population regarding other baseline prognostic factors and demographics.The incidences of the most common genomic aberrations were 13q- 56.7%, 13q- single 36.4%, 11q- 24.6%, +12 12.0%, and 17p- 8.2%. No aberration was found for these regions in 22.4%. VH was unmutated in 63.4% and V3-21 was rearranged in 4.9%. Distributions of genetic parameters were not significantly different between treatment arms. Outcome was analyzed for subgroups defined by genetic parameters in univariate analyses. Genomic aberrations according to the hierarchical model were correlated with differences in CR, CR+PR, PFS and OS in both treatment arms combined and individually (all p<.001). Particularly poor outcome was observed for 17p- in both arms (FC and FCR): CR (4.5% and 19.0%), CR+PR (45.5% and 71.4%), PFS (at 24 months: 0.0% and 29.6%), and OS (at 24 months: 41.0% and 53.3%). Unmutated VH status was correlated with shorter PFS in both arms combined and individually (all p<.001), shorter OS in the FC arm (p=.006), and a trend towards shorter OS in the FCR arm (p=.092).Treatment results of FCR and FC were compared in subgroups defined by genetic parameters to identify prognostic and predictive markers. While FCR in general improved outcome, this effect was different in specific genetic subgroups (Table).Table: Treatment effect of FCR (odds ratio (OR) and hazard ratio (HR) with respective significance level for improvement of outcome in genetic subgroups)VH mutVH unmut17p-11q-+12normal13q-singleCROR3.1963.360494110.0009.0001542.386p-value<.001<.001<.185<.001<.001.274.003CR+PPOR3.5372.7303.0001.3701.7741.03814,884p-value.083.008.124.7231.0001.000.001PFSHR.476.599.495.405.544.962.372p-value.008.001.032.001251.890.001OSHR.877.625.715.328.3701.678387p-value.800.073.420.047.373.339.104Multivariate analysis was performed by Cox regression with backward selection including age, sex, stage, treatment arms, VH status and genomic aberrations as parameters. Regarding PFS, independent prognostic factors were 17p- (HR 6.76, p<.001), unmutated VH (HR 1.97, p<.001), FCR (HR 0.51, p<.001) and +12 (HR 0.58, p=.020). Regarding OS, only 17p- (HR 7.47, p<.001) and unmutated VH (HR 2.09, p=.018) were identified as significant independent factors, while a trend was observed for FCR (HR 0.66, p=.085). In conclusion, genetic parameters remain powerful prognostic markers after 1st line FC and FCR treatment in CLL. The overall improvements by FCR result from specific treatment effects in distinct genetic subgroups and 11q- appears to benefit particularly. However, 17p- and unmutated VH status remain predictors for shorter PFS and OS independently of the overall improvement by FCR.

Biologic and Clinical Markers for Outcome after Fludarabine (F) or F Plus Cyclophosphamide (FC) - Comprehensive Analysis of the CLL4 Trial of the GCLLSG.

The CLL4 trial evaluated 1st line treatment with F or FC among 375 CLL patients up to 65 years (Eichhorst et al., Blood, 2006). Updated follow-up (median 52.8 months (mo) for alive patients) revealed 50.4% events for progression-free survival (PFS) and 24.5% for overall survival (OS). Comparing the treatment arms, significant differences were observed in favor of FC for CR (19.9% vs 5.9%, p<.001), CR+PR (94.7% vs 82.4%, p<.001), and PFS (median 67.8 vs 43.7 mo, p=.002) but not for OS (median n.r. vs 84.6 mo, p=.191).The incidences of genomic aberrations by FISH (n=321) were 13q- 50.5%, 13q- single 36.0%, 11q- 21.1%, +12 13.6%, and 17p- 5.0%. No aberration was found in 25.9%. TP53 mutations (n=340) were observed in 8.8%. VH status (n=340) was unmutated in 64.3% and V3–21 was rearranged in 5.9%. ZAP70 (n=236) was >20% in 37.7% and CD38 (n=259) was >7% in 47.9%. β2-MG and TK (both n=261) were >5 mg/L in 13.8% and > 10U/L in 73.0%, respectively. The distributions of these biologic markers and the major clinical characteristics (age: median 59 (42–65) years, sex: 73.1% male, stage: Binet A 9.2%, B 55.4%, C 35.4%, LDH > 250U/L: 39.2%, lymphocytes > 50/nl: 57.1%, comorbidities >1: 21.4%, and creatinine clearance were not significantly different between treatment arms. Outcome was analyzed for subgroups defined by the clinical and biologic parameters in univariate analyses for the entire population (i.e. both treatment arms combined). PFS was significantly shorter for 11q-, 17p- (Fig.1), TP53 mutation, elevated TK and LDH. OS was significantly shorter for the same parameters and unmutated VH, elevated β2-MG, and >1 comorbidities.All except 2 patients with 17p- had TP53 mutations. There were 13 additional cases with TP53 mutation without 17p-. OS was similarly poor for TP53 mutation without 17p- as compared to 17p- and all other cases (OS at 48 mo: 25.9%, 21.4%, and 84.6%, respectively, p<.001) (Fig. 2). To investigate specific treatment effects, the efficacy of F and FC was compared in subgroups defined by biologic markers. PFS was longer after FC only for the subgroups with unmutated VH (p=.005), no aberration (p=.010), 11q- (p=.017), unmutated TP53 (p=.001), CD38 >7% (p=.011), and β2MG <5mg/L (p=.009). OS was significantly longer after FC only in the subgroups with 11q- (p=.037), +12 (p=.044), and unmutated TP53 (p=.029).Multivariate analysis was performed by Cox regression with backward selection including all clinical and biologic parameters in addition to the treatment arms. Regarding PFS, independent prognostic factors were FC (HR 0.68, p=.047), TK (HR 1.62, p=.051), 11q- (HR 1.66, p=.015), and TP53 mutation (HR 4.16, p<.001). Similarly, for OS independent factors were FC (HR 0.56, p=.033), TK (HR 2.79, p=.009), 11q- (HR 1.98, p=.015), and TP53 mutation (HR 11.61, p<.001). If TP53 mutation was not included in the analyses, 17p- entered the model as significant factor (PFS: HR 3.60, p=.003, OS: HR 12.64, p<.001).In summary, biologic parameters are the major determinants of outcome after 1st line treatment with F and FC in CLL. The overall improvement after FC as compared to F appears to result from specific treatment effects in distinct biologic subgroups. However, in comprehensive multivariate analysis, TP53 mutation, 11q-, and TK > 10 remain predictors for PFS and OS independently of the improvement by FC. TP53 mutation and 17p-, although largely overlapping, deserve further evaluation for their independent impact. [Display omitted] [Display omitted]

A flexible strategy for testing subgroups and overall population

Subgroup analyses in addition to the total study population analysis are common in clinical trials. However, it is well recognized that findings from subgroup analyses do not provide confirmatory evidence for subgroup treatment effects without placing a priori criteria for ensuring that their findings are scientifically sound. In this paper we address some of the common pitfalls of subgroup analyses. Subgroups analyses inherently have low power for detecting treatment effects. We investigate the power interplay for a subgroup analysis and that for the total study population and list factors that impact the power of a subgroup analysis. Then we introduce a flexible statistical strategy for testing a pre-specified sequence of hypotheses for both the overall and a subgroup. The proposed method strongly controls the familywise Type I error rate and enjoys higher power than other traditional methods. This testing strategy allows testing for a subgroup once a pre-specified degree of consistency in the efficacy findings between the subgroup and the overall study population is met. In addition, it accounts for the dependency between test statistics for the subgroup and the overall study population. We discuss the power performance of this new method and provide significance levels for subgroup analysis. Finally, we illustrate its application through retrospective analysis of data from three published clinical trials.

Long-Term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Multivessel Coronary Artery Disease

Randomized trials that studied clinical outcomes after percutaneous coronary intervention (PCI) with bare metal stenting versus coronary artery bypass grafting (CABG) are underpowered to properly assess safety end points like death, stroke, and myocardial infarction. Pooling data from randomized controlled trials increases the statistical power and allows better assessment of the treatment effect in high-risk subgroups. We performed a pooled analysis of 3051 patients in 4 randomized trials evaluating the relative safety and efficacy of PCI with stenting and CABG at 5 years for the treatment of multivessel coronary artery disease. The primary end point was the composite end point of death, stroke, or myocardial infarction. The secondary end point was the occurrence of major adverse cardiac and cerebrovascular accidents, death, stroke, myocardial infarction, and repeat revascularization. We tested for heterogeneities in treatment effect in patient subgroups. At 5 years, the cumulative incidence of death, myocardial infarction, and stroke was similar in patients randomized to PCI with stenting versus CABG (16.7% versus 16.9%, respectively; hazard ratio, 1.04, 95% confidence interval, 0.86 to 1.27; P=0.69). Repeat revascularization, however, occurred significantly more frequently after PCI than CABG (29.0% versus 7.9%, respectively; hazard ratio, 0.23; 95% confidence interval, 0.18 to 0.29; P<0.001). Major adverse cardiac and cerebrovascular events were significantly higher in the PCI than the CABG group (39.2% versus 23.0%, respectively; hazard ratio, 0.53; 95% confidence interval, 0.45 to 0.61; P<0.001). No heterogeneity of treatment effect was found in the subgroups, including diabetic patients and those presenting with 3-vessel disease. In this pooled analysis of 4 randomized trials, PCI with stenting was associated with a long-term safety profile similar to that of CABG. However, as a result of persistently lower repeat revascularization rates in the CABG patients, overall major adverse cardiac and cerebrovascular event rates were significantly lower in the CABG group at 5 years.

Bayesian designs to account for patient heterogeneity in phase II clinical trials.

Between-patient heterogeneity is very common in clinical trials. This complicates treatment evaluation, due to known prognostic subgroup effects or potential treatment-subgroup interactions. We review two Bayesian phase II clinical trial designs that account explicitly for patient heterogeneity. The first design uses analysis of covariance to assess treatment effects in subgroups known to have different prognoses. The second design uses a hierarchical model for settings where, a priori, the experimental treatment effects in the subgroups are assumed to be exchangeable. Compared with simpler designs that ignore patient heterogeneity, each design provides substantial improvements by reducing both false positive and false negative rates and focusing resources on subgroups where an experimental treatment is more likely to provide an advance over standard therapy. In either case, accounting for potential treatment-subgroup interactions is extremely important. Due to the rapidly increasing number of potential new treatments to be evaluated clinically, increasing costs and limited resources, it is critically important to perform early phase clinical trials efficiently. The new Bayesian methods described here and other related methods provide efficient, broadly applicable tools to address these problems.

Interactions Between Treatment and Continuous Covariates: A Step Toward Individualizing Therapy

Interactions Between Treatment and Continuous Covariates: A Step Toward Individualizing Therapy

Response to Letter by Marossezky et al

Response: The letter by Marossezky et al takes issue with the design of our recent randomized trial of splinting early after stroke,1 suggesting that our findings failed to show that “routine splinting soon after stroke should be discontinued.” They believe that we did not define “contracture.” We take this opportunity to clarify that we use the term contracture to refer to a reduction in the slack length or compliance of the relaxed muscle.2 Clinically, contracture manifests as a loss of range of motion or an increased resistance to passive movement.3 Much of our article refers to muscle extensibility to make clear …

Consistent Venous Thromboembolism Risk Reduction by Extended- Versus Standard-Duration Enoxaparin Prophylaxis in Subgroups of Acutely Ill Medical Patients in the EXCLAIM Study.

Introduction In the EXCLAIM study, extended-duration enoxaparin prophylaxis reduced the relative risk of VTE in acutely ill medical patients by 44% compared with placebo, following standard-duration prophylaxis (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the benefits of extended-duration enoxaparin prophylaxis in subgroups of acutely ill medical patients with the most prominent primary diagnoses enrolled in EXCLAIM.Methods Patients enrolled in EXCLAIM had: recent reduced mobility (≤3 days) due to a medical illness, age ≥40 years, and anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days, and were then double-blind randomized and received enoxaparin 40mg SC once-daily (n=2013) or placebo (n=2027) for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Univariate logistic regressions were conducted to estimate treatment effects in patient subgroups. The primary safety endpoint was major bleeding.Results Baseline characteristics were similar between treatments within each primary diagnosis subgroup, and the considered primary diagnoses accounted for >80% of the enrolled population. The reduced VTE incidence associated with extended-duration enoxaparin prophylaxis was consistent across subgroups of patients with different primary diagnoses (Table). The incidence of major bleeding was generally higher in patients receiving extended-duration prophylaxis (Table).Table:VTE and major bleeding in patient subgroups receiving extended-duration vs standard-duration prophylaxis/placeboPrimary diagnosisIncidence of VTE (%)*Odds Ratio [95% CI]**Incidence of Major Bleeding (%)***Odds Ratio [95% CI]Extended EnoxStandard Enox/PlaceboExtended EnoxStandard Enox/PlaceboHeart failure, NYHA class III or IV3.14.70.64 [0.29–1.39]0.00.2N/AAcute respiratory insufficiency2.23.70.60 [0.27–1.34]0.60.23.15 [0.33–30.4]Post ischemic stroke2.18.30.24 [0.06–0.91]0.60.0N/AAcute infection without septic shock3.65.30.66 [0.36–1.22]0.80.25.16 [0.60–44.3]*N=3347 evaluable patients; **Alpha adjustment for an interim analysis; ***N=4040 treated patientsConclusion Extended enoxaparin prophylaxis consistently reduced VTE risk in acutely ill medical patients with the most prominent primary diagnoses compared with placebo following standard-duration prophylaxis. Major bleeding was generally higher in the extended-duration enoxaparin arm, but rates of bleeding were low. These findings are consistent with the primary findings of the EXCLAIM study which demonstrated the clinical benefit of the extended-duration enoxaparin regimen.

Secondary Evaluations of MTA 36-Month Outcomes: Propensity Score and Growth Mixture Model Analyses

To evaluate two hypotheses: that self-selection bias contributed to lack of medication advantage at the 36-month assessment of the Multimodal Treatment Study of Children With ADHD (MTA) and that overall improvement over time obscured treatment effects in subgroups with different outcome trajectories. Propensity score analyses, using baseline characteristics and severity of attention-deficit/hyperactivity disorder symptoms at follow-up, established five subgroups (quintiles) based on tendency to take medication at the 36-month assessment. Growth mixture model (GMM) analyses were performed to identify subgroups (classes) with different patterns of outcome over time. All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment. GMM analyses identified heterogeneity of trajectories over time and three classes: class 1 (34% of the MTA sample) with initial small improvement followed by gradual improvement that produced significant medication effects; class 2 (52%) with initial large improvement maintained for 3 years and overrepresentation of cases treated with the MTA Medication Algorithm; and class 3 (14%) with initial large improvement followed by deterioration. We failed to confirm the self-selection hypothesis. We found suggestive evidence of residual but not current benefits of assigned medication in class 2 and small current benefits of actual treatment with medication in class 1.

A model of the natural history of screen-detected prostate cancer

A model of the natural history of screen-detected prostate cancer

A meta-analysis of safety and effectiveness of perioperative beta-blocker use for the prevention of cardiac events in different types of noncardiac surgery

Perioperative beta-blocker therapy has been proposed to improve outcome. Most of the trials conducted, however, lacked statistical power to evaluate the incidence of hard cardiac events and the relationship to the type of surgery. Therefore, we conducted a meta-analysis of all randomized controlled trials in which beta-blocker therapy was evaluated. An electronic search of published reports on Medline was undertaken to identify studies published between January 1980 and November 2004 in English language journals. All studies reported on at least one of three endpoints: perioperative myocardial ischemia, perioperative nonfatal myocardial infarction, and cardiac mortality. Type of surgery, defined as low, intermediate, and high risk according to the American College of Cardiology/American Heart Association guidelines, was noted. In total, 15 studies were identified, which enrolled 1,077 patient. No significant differences were observed in baseline clinical characteristics between patients randomized to beta-blocker therapy and control/placebo. Beta-blocker therapy was associated with a 65% reduction in perioperative myocardial ischemia (11.0% vs. 25.6%; odds ratio 0.35, 95% confidence interval 0.23-0.54; P<0.001). Furthermore, a 56% reduction in myocardial infarction (0.5% vs. 3.9%, odds ratio 0.44, 95% confidence interval 0.20-0.97; P=0.04) and a 67% reduction (1.1% vs. 6.1%, odds ratio 0.33, 95% confidence interval 0.17-0.67; P=0.002) in the composite endpoint of cardiac death and nonfatal myocardial infarction were observed. No statistical evidence was observed for heterogeneity in the treatment effect in subgroups according to type of surgery (P for heterogeneity 0.2). This meta-analysis shows that beta-blocker use in noncardiac surgical procedures is associated with a significant reduction of perioperative cardiac adverse events.

Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.

The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.