Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

The edge vascular response following implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold and the XIENCE V metallic everolimus-eluting stent. First serial follow-up assessment at six months and two years: insights from the first-in-man ABSORB Cohort B and SPIRIT II trials

AIMS To assess serially the edge vascular response (EVR) of a bioresorbable vascular scaffold (BVS) compared to a metallic everolimus-eluting stent (EES). METHODS AND RESULTS Non-serial evaluations of the Absorb BVS at one year have previously demonstrated proximal edge constrictive remodelling and distal edge changes in plaque composition with increase of the percent fibro-fatty (FF) tissue component. The 5 mm proximal and distal segments adjacent to the implanted devices were investigated serially with intravascular ultrasound (IVUS), post procedure, at six months and at two years, from the ABSORB Cohort B1 (n=45) and the SPIRIT II (n=113) trials. Twenty-two proximal and twenty-four distal edge segments were available for analysis in the ABSORB Cohort B1 trial. In the SPIRIT II trial, thirty-three proximal and forty-six distal edge segments were analysed. At the 5-mm proximal edge, the vessels treated with an Absorb BVS from post procedure to two years demonstrated a lumen loss (LL) of 6.68% (-17.33; 2.08) (p=0.027) with a trend toward plaque area increase of 7.55% (-4.68; 27.11) (p=0.06). At the 5-mm distal edge no major changes were evident at either time point. At the 5-mm proximal edge the vessels treated with a XIENCE V EES from post procedure to two years did not show any signs of LL, only plaque area decrease of 6.90% (-17.86; 4.23) (p=0.035). At the distal edge no major changes were evident with regard to either lumen area or vessel remodelling at the same time point. CONCLUSIONS The IVUS-based serial evaluation of the EVR up to two years following implantation of a bioresorbable everolimus-eluting scaffold shows a statistically significant proximal edge LL; however, this finding did not seem to have any clinical implications in the serial assessment. The upcoming imaging follow-up of the Absorb BVS at three years is anticipated to provide further information regarding the vessel wall behaviour at the edges.

Impact of overlapping newer generation drug-eluting stents on clinical and angiographic outcomes: pooled analysis of five trials from the international Global RESOLUTE Program

BACKGROUND Overlapping first generation sirolimus- and paclitaxel-eluting stents are associated with persistent inflammation, fibrin deposition and delayed endothelialisation in preclinical models, and adverse angiographic and clinical outcomes--including death and myocardial infarction (MI)--in clinical studies. OBJECTIVES To establish as to whether there are any safety concerns with newer generation drug-eluting stents (DES). DESIGN Propensity score adjustment of baseline anatomical and clinical characteristics were used to compare clinical outcomes (Kaplan-Meier estimates) between patients implanted with overlapping DES (Resolute zotarolimus-eluting stent (R-ZES) or R-ZES/other DES) against no overlapping DES. Additionally, angiographic outcomes for overlapping R-ZES and everolimus-eluting stents were evaluated in the randomised RESOLUTE All-Comers Trial. SETTING Patient level data from five controlled studies of the RESOLUTE Global Clinical Program evaluating the R-ZES were pooled. Enrollment criteria were generally unrestrictive. PATIENTS 5130 patients. MAIN OUTCOME MEASURES 2-year clinical outcomes and 13-month angiographic outcomes. RESULTS 644 of 5130 patients (12.6%) in the RESOLUTE Global Clinical Program underwent overlapping DES implantation. Implantation of overlapping DES was associated with an increased frequency of MI and more complex/calcified lesion types at baseline. Adjusted in-hospital, 30-day and 2-year clinical outcomes indicated comparable cardiac death (2-year overlap vs non-overlap: 3.0% vs 2.1%, p=0.36), major adverse cardiac events (13.3% vs 10.7%, p=0.19), target-vessel MI (3.9% vs 3.4%, p=0.40), clinically driven target vessel revascularisation (7.7% vs 6.5%, p=0.32), and definite/probable stent thrombosis (1.4% vs 0.9%, p=0.28). 13-month adjusted angiographic outcomes were comparable between overlapping and non-overlapping DES. CONCLUSIONS Overlapping newer generation DES are safe and effective, with comparable angiographic and clinical outcomes--including repeat revascularisation--to non-overlapping DES.

Comparing Haemophilus influenzae type b conjugate vaccine schedules: a systematic review and meta-analysis of vaccine trials

BACKGROUND The optimal schedule and the need for a booster dose are unclear for Haemophilus influenzae type b (Hib) conjugate vaccines. We systematically reviewed relative effects of Hib vaccine schedules. METHODS We searched 21 databases to May 2010 or June 2012 and selected randomized controlled trials or quasi-randomized controlled trials that compared different Hib schedules (3 primary doses with no booster dose [3p+0], 3p+1 and 2p+1) or different intervals in primary schedules and between primary and booster schedules. Outcomes were clinical efficacy, nasopharyngeal carriage and immunological response. Results were combined in random-effects meta-analysis. RESULTS Twenty trials from 15 countries were included; 16 used vaccines conjugated to tetanus toxoid (polyribosylribitol phosphate conjugated to tetanus toxoid). No trials assessed clinical or carriage outcomes. Twenty trials examined immunological outcomes and found few relevant differences. Comparing polyribosylribitol phosphate conjugated to tetanus toxoid 3p+0 with 2p+0, there was no difference in seropositivity at the 1.0 μg/mL threshold by 6 months after the last primary dose (combined risk difference -0.02; 95% confidence interval: -0.10, 0.06). Only small differences were seen between schedules starting at different ages, with different intervals between primary doses, or with different intervals between primary and booster doses. Individuals receiving a booster were more likely to be seropositive than those at the same age who did not. CONCLUSIONS There is no clear evidence from trials that any 2p+1, 3p+0 or 3p+1 schedule of Hib conjugate vaccine is likely to provide better protection against Hib disease than other schedules. Until more data become available, scheduling is likely to be determined by epidemiological and programmatic considerations in individual settings.

Actigraphic monitoring of physical activity in clinical trials in schizophrenia

Schizophrenia is still associated with poor outcome, which is mainly related to negative symptoms, reduced physical activity and low quality of life. Physical activity can be objectively measured without distress using wrist actigraphy. The activity levels during the wake periods of the day have been informative on psychopathology and antipsychotic medication. Several studies demonstrated prominent negative symptoms to be associated with reduced activity levels with strongest correlations in chronic patients. Particularly, the avolition score is correlated with reduced activity levels. Moreover, activity levels differ between DSM-IV schizophrenia spectrum disorders and subtypes as well as between patients treated with olanzapine or risperidone. The longitudinal course of activity levels during an psychotic episode demonstrates considerable variance between subjects. During a psychotic episode patients with low activity levels at baseline experience an amelioration of negative symptoms. In contrast, patients with high activity levels at baseline have stable low negative syndrome scores. Between psychotic episodes less variance is observed. Actigraphy is easily applied in schizophrenia and allows collecting large amounts of crosssectional or longitudinal data. With larger numbers of subjects in controlled trials, continuous recording of activity would foster the detection of different outcome trajectories, which may prove as useful groups to target interventions. In clinical trials, activity monitoring may supplement and validate measures of the negative syndrome and its avolition factor or serve as an outcome marker for physical activity, which is important for metabolic issues and quality of life.

Adjudication-related processes are underreported and lack standardization in clinical trials of venous thromboembolism: a systematic review

OBJECTIVES Although the use of an adjudication committee (AC) for outcomes is recommended in randomized controlled trials, there are limited data on the process of adjudication. We therefore aimed to assess whether the reporting of the adjudication process in venous thromboembolism (VTE) trials meets existing quality standards and which characteristics of trials influence the use of an AC. STUDY DESIGN AND SETTING We systematically searched MEDLINE and the Cochrane Library from January 1, 2003, to June 1, 2012, for randomized controlled trials on VTE. We abstracted information about characteristics and quality of trials and reporting of adjudication processes. We used stepwise backward logistic regression model to identify trial characteristics independently associated with the use of an AC. RESULTS We included 161 trials. Of these, 68.9% (111 of 161) reported the use of an AC. Overall, 99.1% (110 of 111) of trials with an AC used independent or blinded ACs, 14.4% (16 of 111) reported how the adjudication decision was reached within the AC, and 4.5% (5 of 111) reported on whether the reliability of adjudication was assessed. In multivariate analyses, multicenter trials [odds ratio (OR), 8.6; 95% confidence interval (CI): 2.7, 27.8], use of a data safety-monitoring board (OR, 3.7; 95% CI: 1.2, 11.6), and VTE as the primary outcome (OR, 5.7; 95% CI: 1.7, 19.4) were associated with the use of an AC. Trials without random allocation concealment (OR, 0.3; 95% CI: 0.1, 0.8) and open-label trials (OR, 0.3; 95% CI: 0.1, 1.0) were less likely to report an AC. CONCLUSION Recommended processes of adjudication are underreported and lack standardization in VTE-related clinical trials. The use of an AC varies substantially by trial characteristics.

Staging of osteoarthritis for clinical trials on femoroacetabular impingement

Future clinical trials investigating the natural history and treatment of femoroacetabular impingement (FAI) will require multimodal staging systems for hip osteoarthritis because the optimal system will differ based on the size of the study population, the specific objective in question, and the time frame in which the investigator expects to see the specified end point. Plain radiographs are readily available, low in cost, and of unquestioned validity, but they are relatively insensitive to early joint damage. MRI allows assessment of both bony and soft-tissue pathology within the joint, and it is much more sensitive for early joint damage because cartilage is visualized directly. Biochemical imaging techniques such as delayed gadolinium-enhanced MRI of cartilage, T2 mapping, and T1rho offer the potential to identify biochemical damage to cartilage before the onset of irreversible tissue loss. In the future, biomarkers may allow earlier detection of osteoarthritis before the development of radiographic evidence of disease.

Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials

OBJECTIVES In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? METHODS TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. RESULTS TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014. CONCLUSIONS We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer. Trial Registration TEXT: Clinicaltrials.govNCT00066703 SOFT: Clinicaltrials.govNCT00066690.

BENCHMARKING AND IMPLEMENTATION OF A NEW INDEPENDENT MONTE CARLO DOSE CALCULATION QUALITY ASSURANCE AUDIT TOOL FOR CLINICAL TRIALS

Introduction Commercial treatment planning systems employ a variety of dose calculation algorithms to plan and predict the dose distributions a patient receives during external beam radiation therapy. Traditionally, the Radiological Physics Center has relied on measurements to assure that institutions participating in the National Cancer Institute sponsored clinical trials administer radiation in doses that are clinically comparable to those of other participating institutions. To complement the effort of the RPC, an independent dose calculation tool needs to be developed that will enable a generic method to determine patient dose distributions in three dimensions and to perform retrospective analysis of radiation delivered to patients who enrolled in past clinical trials. Methods A multi-source model representing output for Varian 6 MV and 10 MV photon beams was developed and evaluated. The Monte Carlo algorithm, know as the Dose Planning Method (DPM), was used to perform the dose calculations. The dose calculations were compared to measurements made in a water phantom and in anthropomorphic phantoms. Intensity modulated radiation therapy and stereotactic body radiation therapy techniques were used with the anthropomorphic phantoms. Finally, past patient treatment plans were selected and recalculated using DPM and contrasted against a commercial dose calculation algorithm. Results The multi-source model was validated for the Varian 6 MV and 10 MV photon beams. The benchmark evaluations demonstrated the ability of the model to accurately calculate dose for the Varian 6 MV and the Varian 10 MV source models. The patient calculations proved that the model was reproducible in determining dose under similar conditions described by the benchmark tests. Conclusions The dose calculation tool that relied on a multi-source model approach and used the DPM code to calculate dose was developed, validated, and benchmarked for the Varian 6 MV and 10 MV photon beams. Several patient dose distributions were contrasted against a commercial algorithm to provide a proof of principal to use as an application in monitoring clinical trial activity.

Long-term outcomes of biodegradable versus durable polymer drug-eluting stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of individual patient data from three randomised trials

Aims: Arterial plaque rupture and thrombus characterise ST-elevation myocardial infarction (STEMI) and may aggravate delayed arterial healing following durable polymer drug-eluting stent (DP-DES) implantation. Biodegradable polymer (BP) may improve biocompatibility. We compared long-term outcomes in STEMI patients receiving BP-DES vs. durable polymer sirolimus-eluting stents (DP-SES). Methods and results: We pooled individual patient-level data from three randomised clinical trials (ISAR-TEST-3, ISAR-TEST-4 and LEADERS) comparing outcomes from BP-DES with DP-SES at four years. The primary endpoint (MACE) comprised cardiac death, MI, or target lesion revascularisation (TLR). Secondary endpoints were TLR, cardiac death or MI, and definite or probable stent thrombosis. Of 497 patients with STEMI, 291 received BP-DES and 206 DP-SES. At four years, MACE was significantly reduced following treatment with BP-DES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced TLR (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09). Conclusions: In STEMI, BP-DES demonstrated superior clinical outcomes to DP-SES at four years. Trends towards reduced cardiac death or myocardial infarction and reduced stent thrombosis require corroboration in specifically powered trials.

Initiation and continuation of randomized trials after the publication of a trial stopped early for benefit asking the same study question: STOPIT-3 study design

BACKGROUND Randomized control trials (RCTs) stopped early for benefit (truncated RCTs) are increasingly common and, on average, overestimate the relative magnitude of benefit by approximately 30%. Investigators stop trials early when they consider it is no longer ethical to enroll patients in a control group. The goal of this systematic review is to determine how investigators of ongoing or planned RCTs respond to the publication of a truncated RCT addressing a similar question. METHODS/DESIGN We will conduct systematic reviews to update the searches of 210 truncated RCTs to identify similar trials ongoing at the time of publication, or started subsequently, to the truncated trials ('subsequent RCTs'). Reviewers will determine in duplicate the similarity between the truncated and subsequent trials. We will analyze the epidemiology, distribution, and predictors of subsequent RCTs. We will also contact authors of subsequent trials to determine reasons for beginning, continuing, or prematurely discontinuing their own trials, and the extent to which they rely on the estimates from truncated trials. DISCUSSION To the extent that investigators begin or continue subsequent trials they implicitly disagree with the decision to stop the truncated RCT because of an ethical mandate to administer the experimental treatment. The results of this study will help guide future decisions about when to stop RCTs early for benefit.

Phase I clinical trials in 56 patients with thyroid cancer: the M. D. Anderson Cancer Center experience.

INTRODUCTION: Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. PATIENTS AND METHODS: We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). CONCLUSION: Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.