David Espinoza

Changes in body weight and blood pressure: paradoxical outcome events in overweight and obese subjects with cardiovascular disease

Background/Objectives:The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in body weight and blood pressure, and the impact of these changes on subsequent cardiovascular outcome events.Subjects/Methods:A total of 9804 male and female subjects, aged 55 years or older, with a body mass index of 27–45 kg m–2 were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor (hypertension, dyslipidemia, current smoking or diabetic nephropathy) to assess cardiovascular outcomes. Post hoc subgroup analyses of weight change (categories) and blood pressure were performed overall and by treatment group (6-week sibutramine followed by randomized placebo or continued sibutramine). The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models with factors for treatment, subgroups and interactions.Results:During the initial 6-week sibutramine treatment period, systolic blood pressure decreased progressively with increasing weight loss in hypertensive subjects (−8.1±10.5 mm Hg with <5 kg weight loss to −10.8±11.0 mm Hg with ⩾5 kg weight loss). The highest POE incidence occurred mainly in groups with increases in both weight and blood pressure. However, with long-term sibutramine treatment, a markedly lower blood pressure tended to increase POEs.Conclusion:Modest weight loss and modest lower blood pressure each reduced the incidence of cardiovascular events, as expected. However, the combination of early marked weight loss and rapid blood pressure reduction seems to be harmful in this obese elderly cardiovascular diseased population.

A Pilot Randomized Controlled Trial of the Feasibility, Acceptability, and Impact of Giving Information on Personalized Genomic Risk of Melanoma to the Public

Background: Communication of personalized melanoma genomic risk information may improve melanoma prevention behaviors. Methods: We evaluated the feasibility and acceptability of communicating personalized genomic risk of melanoma to the public and its preliminary impact on behaviors and psychosocial outcomes. One hundred eighteen people aged 22 to 69 years provided a saliva sample and were randomized to the control (nonpersonalized educational materials) or intervention (personalized booklet presenting melanoma genomic risk as absolute and relative risks and a risk category based on variants in 21 genes, telephone-based genetic counseling, and nonpersonalized educational materials). Intention-to-treat analyses overall and by-risk category were conducted using ANCOVA adjusted for baseline values. Results: Consent to participate was 41%, 99% were successfully genotyped, and 92% completed 3-month follow-up. Intervention participants reported high satisfaction with the personalized booklet (mean = 8.6, SD = 1.6; on a 0–10 scale) and genetic counseling (mean = 8.1, SD = 2.2). No significant behavioral effects at 3-month follow-up were identified between intervention and control groups overall: objectively measured standard erythemal doses per day [−16%; 95% confidence interval (CI), −43% to 24%] and sun protection index (0.05; 95% CI, −0.07 to 0.18). There was increased confidence identifying melanoma at 3 months (0.40; 95% CI, 0.10–0.69). Stratified by risk category, effect sizes for intentional tanning and some individual sun protection items appeared stronger for the average-risk group. There were no appreciable group differences in skin cancer–related worry or psychologic distress. Conclusions: Our results demonstrate feasibility and acceptability of providing personalized genomic risk of melanoma to the public. Impact: Genomic risk information has potential as a melanoma prevention strategy. Cancer Epidemiol Biomarkers Prev; 26(2); 212–21. ©2016 AACR.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial

BACKGROUND We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

BACKGROUND We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY ACTRN12609000643279.

Does personalized melanoma genomic risk information trigger conversations about skin cancer prevention and skin examination with family, friends and health professionals?

Receiving information about genomic risk of melanoma might trigger conversations about skin cancer prevention and skin examinations.

Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial.

Background/Objectives:The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups.Subjects/Methods:9804 males and females, aged ⩾55 years, with a body mass index of 27–45 kg m−2 were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models.Results:During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9±7.7 beats per minute (bpm)  with weight increase; 1.4±7.3 bpm, 0–5 kg weight loss; 0.6±7.4 bpm, ⩾5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia.Conclusion:Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management.

Validation of Questionnaire and Diary Measures of Time Outdoors Against an Objective Measure of Personal Ultraviolet Radiation Exposure

Self‐reported sun exposure is commonly measured using questionnaires or diaries, but there are limited data on their validity, particularly for population subgroups. This research aimed to compare self‐reported sun exposure, measured as (1) habitual time outdoors over the past month on weekends and weekdays and (2) a 4‐day diary measure, against objective measurement of personal ultraviolet radiation using polysulfone film dosimeters. From November 2015 to January 2016, 94 people (22–69 years and living in New South Wales, Australia) completed a questionnaire, 4‐day diary and 4‐day dosimeter measures of overall, weekday and weekend sun exposure. Spearman correlations and Bland–Altman plots were used to measure agreement. The overall weekly correlation was 0.57 (95% confidence interval [CI] 0.44, 0.68) between standard erythemal doses (SEDs) measured by dosimeter and time spent outdoors measured by questionnaire, 0.74 (95% CI 0.66–0.81) between dosimeter and diary, and 0.59 (95% CI 0.48–0.68) between questionnaire and diary measures. Validity was lower for younger people and weekend sun exposure. There was strong correlation between dosimeter and sun diary measures and moderate correlation between dosimeter and questionnaire measures. Daily measurement over a longer period may be required to accurately capture weeklong sun exposure in all population subgroups.

Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial

BACKGROUND In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. METHODS In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6-12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. FINDINGS The adjusted average mean change from baseline over the first 12 months in TOI was -2·90 (95% CI -4·13 to -1·67) with olaparib and -2·87 (-4·64 to -1·10) with placebo (estimated difference -0·03; 95% CI -2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98-8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70-8·96) were significantly longer with olaparib than with placebo. INTERPRETATION Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. FUNDING AstraZeneca.

D-dimer Predicts Long-Term Cause-Specific Mortality, Cardiovascular Events and Cancer in Stable Coronary Heart Disease Patients: The LIPID Study

Background: D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors. Methods: LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. Results: Baseline D-dimer levels for 7863 patients were grouped by quartile (⩽112, 112–173, 173–273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (quartile 4 versus 1: hazard ratio [HR], 1.45; 95% confidence interval, 1.21–1.74), major cardiovascular disease (CVD) event (HR, 1.45; 95% confidence interval, 1.23–1.71) and venous thromboembolism (HR, 4.03; 95% confidence interval, 2.31–7.03; each P<0.001). During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR, 1.59), CVD mortality (HR, 1.61), cancer mortality (HR, 1.54), and non-CVD noncancer mortality (HR, 1.57; each P<0.001), remaining significant for deaths resulting from each cause occurring beyond 10 years of follow-up (each P⩽0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. Conclusions: D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years’ follow-up.

Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment

BACKGROUND Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women. METHOD Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms. FINDINGS Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue. CONCLUSION Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified.