The effects of antihypertensive class on gout in older adults: secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

OBJECTIVES: Gout is a common complication of blood pressure management and a frequently cited cause of medication nonadherence. Little trial evidence exists to inform antihypertensive selection with regard to gout risk. METHODS: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized clinical trial on the effects of first-step hypertension therapy with amlodipine, chlorthalidone, or lisinopril on fatal coronary heart disease or nonfatal myocardial infarction (1994-2002). Trial participants were linked to CMS and VA gout claims (ICD9 274.XX). We determined the effect of drug assignment on gout with Cox regression models. We also determined the adjusted association of self-reported atenolol use (ascertained at the 1-month visit for indications other than hypertension) with gout. RESULTS: Claims were linked to 23 964 participants (mean age 69.8 ±â€Š6.8 years, 45% women, 31% black). Atenolol use was reported by 928 participants at the 1-month visit. Over a mean follow-up of 4.9 years, we documented 597 gout claims. Amlodipine reduced the risk of gout by 37% (hazard ratio 0.63; 95% CI 0.51--0.78) compared with chlorthalidone and by 26% (hazard ratio 0.74; 95% CI 0.58--0.94) compared with lisinopril. Lisinopril nonsignificantly lowered gout risk compared with chlorthalidone (hazard ratio 0.85; 95% CI 0.70--1.03). Atenolol use was not associated with gout risk (adjusted hazard ratio 1.18; 95% CI 0.78--1.80). Gout risk reduction was primarily observed after 1 year of follow-up. CONCLUSION: Amlodipine lowered long-term gout risk compared with lisinopril or chlorthalidone. This finding may be useful in cases where gout risk is a principal concern among patients being treated for hypertension.This trial is registered at clinicaltrials.gov, number: NCT00000542.

Impact of Clinic-Based Blood Pressure Approaches on Blood Pressure Measurement.

BACKGROUND: Clinic-based blood pressure (BP) is a closely-tracked metric of health care quality, but is prone to inaccuracy and measurement imprecision. Recent guidelines have advocated for automated office blood pressure (AOBP) devices to improve clinic-based BP assessments. METHODS: Patients from a single hypertension clinic underwent a 3-day evaluation that included a 24-hour ambulatory blood pressure monitoring (ABPM), 2 manual clinic-based BP measurements (over 2 visits), and an unattended AOBP measurement (single visit). All measurements were compared to the average wake-time systolic BP (SBP) and diastolic BP (DBP) from ABPM. RESULTS: Among 103 patients (mean age 57.3 ± 14.8 years, 51% women, 29% black) the average wake-time SBP was 131.3 ± 12.3 mm Hg and DBP was 78.3 ± 9.2 mm Hg. The average of 2 manual BPs was significantly higher than wake-time ABPM with mean differences of 5.5 mm Hg (P < 0.001) for SBP and 2.7 mm Hg (P = 0.002) for DBP. In contrast, the averages of the last 2 AOBP measurements did not significantly differ from ABPM with mean differences of 1.6 mm Hg (P = 0.21) for SBP and -0.5 mm Hg (P = 0.62) for DBP. The estimated prevalence of SBP ≥ 140 or DBP ≥ 90 mm Hg based on wake-time ABPM was 27.2% vs. 49.5% based on the average of 2 manual measurements (difference 22.3%; P < 0.001) and 31.1% based on the average of the last 2 AOBP measurements (difference 3.9%; P = 0.57). CONCLUSIONS: A single visit, unattended AOBP more precisely estimated BP and the prevalence of stage 2 and uncontrolled hypertension than even the average of 2 manual clinic visits, supporting guideline recommendations to use AOBP for clinic-based BP measurements.

Effects of Antihypertensive Class on Falls, Syncope, and Orthostatic Hypotension in Older Adults: The ALLHAT Trial.

Hypertension treatment has been implicated in falls, syncope, and orthostatic hypotension (OH), common events among older adults. Whether the choice of antihypertensive agent influences the risk of falls, syncope, and OH in older adults is unknown. ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was a randomized clinical trial that compared the effects of hypertension first-step therapy on fatal coronary heart disease or nonfatal myocardial infarction (1994-2002). In a subpopulation of ALLHAT participants, age 65 years and older, we determined the relative risk of falls, syncope, OH, or a composite based on Centers for Medicare and Medicaid Services and Veterans Affairs claims, using Cox regression. We also determined the adjusted association of self-reported atenolol use (ascertained at the 1-month visit for indications other than hypertension) on outcomes in Cox models adjusted for age, sex, and race. Among 23 964 participants (mean age 69.8±6.8 years, 45% women, 31% non-Hispanic black) followed for a mean of 4.9 years, we identified 267 falls, 755 syncopes, 249 OH, and 1157 composite claims. There were no significant differences in the cumulative incidences of events across randomized drug assignments. However, amlodipine increased risk of falls during the first year of follow-up compared with chlorthalidone (hazard ratio [95% CI]: 2.24 [1.06-4.74]; P=0.03) or lisinopril (hazard ratio [95% CI]: 2.61 [1.03-6.72]; P=0.04). Atenolol use (N=928) was not associated with any of the 3 individual or composite claims. In older adults, the choice of antihypertensive agent had no effect on risk of fall, syncope, or OH long-term. However, amlodipine increased risk of falls within 1 year of initiation. These short-term findings require confirmation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Association of Orthostatic Hypotension Timing With Clinical Events in Adults With Diabetes and Hypertension: Results From the ACCORD Trial.

OBJECTIVE: To determine the effects of orthostatic hypotension (OH) measurement timing on its associations with dizziness, falls, fractures, cardiovascular disease (CVD), and mortality. METHODS: We analyzed OH measurements from the Action to Control Cardiovascular Risk in Diabetes BP trial, which evaluated two blood pressure (BP) goals (systolic BP [SBP] < 120 mm Hg vs. SBP < 140 mm Hg) and incident CVD among adults with diabetes and hypertension. Seated BP was measured after 5 minutes of rest at baseline and follow-up visits (12 months, 48 months, and exit). Standing BP was measured 3 consecutive times (M1-M3) after standing, starting at 1 minute with each measurement separated by 1 minute. Consensus OH was defined as a drop in SBP ≥ 20 mm Hg or diastolic BP (DBP) ≥ 10 mm Hg. Participants were asked about orthostatic dizziness, recent falls, and recent fractures, and underwent surveillance for CVD events and all-cause mortality. RESULTS: There were 4,268 participants with OH assessments over 8,450 visits (mean age 62.6 years [SD = 6.6]; 46.6% female; 22.3% black). Although all measures of consensus OH were significantly associated with dizziness, none were associated with falls, and only M2 (~3 minutes) was significantly associated with fractures. No measurements were associated with CVD events, but later measurements were significantly associated with mortality. BP treatment goal did not increase risk of OH regardless of timing. Associations were not consistently improved by the mean or minimum of M1-M3. CONCLUSION: In this population of adults with hypertension and diabetes, neither single time nor set of measurements were clearly superior with regard to outcomes. These findings support the use of a flexibly timed, single measurement to assess OH in clinical practice. CLINICAL TRIALS REGISTRATION: Trial Number NCT00000620.

What Should Be the Target Blood Pressure for This Older Patient With Hypertension?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Hypertension is prevalent and the most important risk factor for cardiovascular disease. Controversy exists regarding the optimum threshold above which to begin antihypertensive therapy and the optimum target blood pressure once medication is begun. This controversy is particularly true for older patients, who may be more likely to benefit from treatment because of their higher risk for cardiovascular events, but may also be more at risk for adverse effects of treatment. Two guidelines published in 2017 address this issue. The American College of Physicians/American Academy of Family Physicians guideline recommends initiating antihypertensive therapy for older patients (aged 60 years or older) if systolic blood pressure is 150 mm Hg or higher and to treat to the same target. They recommend a lower threshold for starting treatment and a lower target systolic blood pressure (140 mm Hg) for patients with cerebrovascular disease and potentially those at high risk for cardiovascular events. The American College of Cardiology/American Heart Association guideline, which is based primarily on SPRINT (Systolic Blood Pressure Intervention Trial), advises a target systolic blood pressure of 130 mm Hg for community-dwelling ambulatory patients aged 65 years or older. This article presents the case of a 79-year-old man who is contemplating antihypertensive therapy. Two experts discuss the optimal approach for the patient and suggest how to apply the 2 guidelines to his care.

The association between facility case volume and overall survival in patients with metastatic renal cell carcinoma in the targeted therapy era.

BACKGROUND: Improved overall survival of cancer patients treated by high-volume providers has been reported in surgical oncology and radiation oncology literature. Whether this volume-outcome association exists in medical oncology-managed metastatic solid tumors is uncertain. This study aimed to investigate the effect of facility case volume (FCV) on overall survival in patients with metastatic renal cell carcinoma (mRCC) diagnosed in the targeted therapy era. MATERIALS AND METHODS: Adult patients diagnosed with mRCC between 2006 and 2015 were identified in the National Cancer Database. The primary exposure was FCV, which was defined by mRCC case volume of each treating facility. The association between FCV and all-cause mortality in mRCC was investigated in multivariable Cox regression model and validated with inverse propensity-score weighting method. Logistic regression was used to identify independent predictors for treatment at high-volume facilities. Covariates adjusted for were sociodemographics, tumor characteristics and treatment modalities. RESULTS: There were 31,329 mRCC patients identified. The mean follow-up time was 14.3 months. When FCV was coded as a continuous variable, each increment of 10 mRCC cases/y was associated with reduced all-cause mortality after baseline covariates adjustment [adjusted hazard ratio: 0.93, 95% confidence interval: 0.90-0.96, P value:<0.0001]. In dichotomized models, improved all-cause mortality was observed at cutoffs of 85th (4.3 cases/y), 90th (5.4 cases/y) and 95th (7.4 cases/y) but not at 50th (2.2 cases/y) and 75th (3.4 cases/y) percentiles. For illustrative purpose, 95th percentile was chosen and inverse propensity-score weighting-adjusted Kaplan-Meier curve demonstrated improved overall survival for mRCC patients treated at high-volume facilities (adjusted hazard ratio: 0.90, 95% confidence interval: 0.88-0.94, P value <0.0001; the 1-, 2-, 3-year survival rates were 41%, 26%, and 19% vs. 36%, 22%, and 16% for patients treated at high and low-volume facilities, respectively). Patients without insurance or with Medicaid status, with shorter travel distance, living in nonmetropolitan area or in area with lower averaged education level were less likely to be treated at high-volume facilities. CONCLUSIONS: Patients diagnosed with mRCC in the targeted therapy era have improved overall survival when treated at high mRCC-volume facilities, suggesting a volume-outcome association in medical oncology-managed metastatic solid tumors.

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies.

BACKGROUND: Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. OBJECTIVES: The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. PATIENT AND METHODS: This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. RESULTS: Seventy-nine patients, median age 72 years (range 29-93), 71% men and 76% ECOG PS 0-1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8-3.6) and median PFS was 3.2 months (95%CI, 1.6-4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0-5.0) while 42% were referred to palliative care/hospice or died. CONCLUSIONS: Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma.

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, -2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

Clinical Effect of Dose Escalation After Disease Progression in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Given the variability in drug levels with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC), dose escalation at the occurrence of progressive disease (PD) might have antitumor effects. PATIENTS AND METHODS: The data from patients with mRCC who were treated at the Cleveland Clinic with TKIs and received a dose escalation after PD in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, were retrospectively reviewed. Patient- and disease-related data were collected and summarized as frequency counts and percentages or medians and ranges. The Kaplan-Meier method was used to summarize the treatment duration for the escalated doses. RESULTS: Twenty-two patients were identified. Most patients (82%) were men; the median age at diagnosis was 58 years (range, 40-71 years). The most common histologic type was clear cell (73%). Axitinib was the most frequently escalated agent after PD (17 patients), followed by sunitinib (3 patients), and pazopanib (2 patients). Before PD, the median treatment duration was 6.8 months (range, 1.6-50.6 months). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden. The median decrease in tumor burden after dose escalation was 14% (range, 2%-58%); 4 patients (22%) had decreases ≥10%, 2 (11%) ≥20%, and 4 (22%) >30% (RECIST partial response). At the last follow-up examination, 5 patients (23%) continued to be treated at escalated doses. The median duration of escalated therapy was estimated at 10.1 months (range, 0.6 to 37.9 months). CONCLUSION: Dose escalation of TKIs after PD for select patients with mRCC can lead to a reduction in tumor burden and extend the duration of therapy.

Iatrogenic hypercortisolism complicating triamcinolone acetonide injections in patients with HIV on ritonavir-boosted protease inhibitors.

Epidural corticosteroid injection is a commonly used approach for managing back pain of several etiologies. The risk of clinical complications from systemic absorption is felt to be rare. Ritonavir is a protease inhibitor whose potent cytochrome P450 3A4 inhibition is exploited for pharmacologic boosting in human immunodeficiency virus (HIV) infection. It has been associated with systemic hypercortisolism when used in combination with nasal and inhaled corticosteroids. This is a case series describing 2 patients with HIV on ritonavir-containing regimens who developed iatrogenic hypercortisolism following epidural injection of triamcinolone acetonide. The 2 patients developed cushingoid symptoms, with detectable serum triamcinolone acetonide levels weeks after their epidural injections. Their symptoms took several weeks to resolve, in one case necessitating a change to an HIV regimen that did not contain ritonavir. Iatrogenic hypercortisolism is a rarely reported, but potentially devastating complication of injectable corticosteroids. Individuals receiving ritonavir-based therapy appear to be at increased risk for this process due to pharmacologic boosting of the corticosteroid. The preponderance of reported cases of iatrogenic hypercortisolism following injectable corticosteroids has involved triamcinolone acetonide, which may be due to the relatively rapid absorption characteristics and high serum levels of this compound compared with other preparations. For individuals on ritonavir-containing HIV therapy, we recommend close coordination with the involved HIV clinicians prior to use of injectable corticosteroids, and avoidance of injections with triamcinolone acetonide whenever possible. Choosing an alternative corticosteroid preparation to triamcinolone acetonide may reduce the risk of systemic absorption, though more research is needed to confirm this hypothesis.

Prevalence and correlates of dietary supplement use in individuals with diabetes mellitus at an academic diabetes care clinic.

OBJECTIVES: This study sought to describe the prevalence of supplement use by those with diabetes mellitus receiving care at an academic outpatient diabetes care center and to identify any association of supplement use with glycemic control. METHODS: This study is based on a retrospective audit of provider-verified and patient-self-reported medication and supplement use by adults with diabetes at the University of Washington Diabetes Care Center during four 2-week periods from fall 2006 through summer 2007 (1 period per season). RESULTS: Verified medication and supplement histories for 459 adults demonstrated a per-person average use of 7 ± 4.1 prescription medicines and 0.4 ± 0.9 over-the-counter medicines daily, with 55% using some form of vitamin, mineral, or nonvitamin-nonmineral supplement on a daily basis. The rate of nonvitamin-nonmineral use was nearly twice that for type 2 diabetes mellitus as for type 1 diabetes mellitus (39.3% vs 20.3%), and A1c was lower in those using any supplement compared to those not using supplements. Vitamin use was associated with reduced A1c; however, this relationship did not hold at A1c < 7.0%. CONCLUSIONS: The findings highlight the prevalence of supplement use in diabetes mellitus and association of supplement use with improved glycemic control. Findings are limited by the retrospective design.

A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas.

BACKGROUND: The authors conducted a two-arm Phase II study of temozolomide to determine its efficacy and toxicity in patients with soft tissue sarcomas (STSs) who had received, had refused, or were not eligible for standard chemotherapy with doxorubicin and ifosfamide (Arm 1) and in patients with gastrointestinal stromal tumors (GISTs; Arm 2). Patients with GIST were eligible regardless of prior therapy before imatinib was available. METHODS: Sixty patients were enrolled in the current study, 19 of whom had GISTs and 41 of whom had other STSs. The patients received temozolomide at a dose of 85 mg/m2 orally for 21 days followed by 7 days without treatment. Standard radiographic imaging after every two cycles was used to assess the treatment response. RESULTS: Of the 39 patients in Arm 1, there was 1 complete response and 1 partial response of 39 evaluable patients, for a total response rate of 5% (95% confidence interval, 0-12%). The responses lasted 7 months and 8 months, respectively. In Arm 2, there was no response in 17 patients. The disease was stable in 22% of the patients with GISTs and 33% of the patients with other STSs. The median overall survival time was 26.4 months in patients with GISTs and 11 months in patients with other STSs. The median time to disease progression was 2.3 months in patients with GISTs and 3.3 months in patients with other STSs. Grade 3 and Grade 4 adverse effects (according to National Cancer Institute Common Toxicity Criteria) were rare and included fatigue (eight patients), anemia (six patients), constipation (four patients), neutropenia (four patients), and thrombocytopenia (four patients). CONCLUSIONS: The data from the current study suggest that temozolomide is well tolerated but has only minimal efficacy and a limited role in the treatment of patients with STSs.

Results of a 2-arm Phase II study of 9-nitrocamptothecin in patients with advanced soft-tissue sarcomas.

BACKGROUND: The authors conducted a 2-arm Phase II trial of 9-nitrocamptothecin (9-NC), an oral topoisomerase I inhibitor, to define response rates in patients with gastrointestinal (GI) leiomyosarcomas and other soft-tissue sarcomas (STS). METHODS: Patients were required to provide informed consent and have measurable disease, Zubrod performance status < or = 2, and adequate organ function. 9-NC was administered orally at 1.5 mg/m(2) per day x 5 days every week. Response evaluation was performed at 8 weeks, and those with stable or responding disease continued treatment until maximal response was achieved. A total of 56 patients (30 females and 26 males) with a median age of 55 years (range, 19-79 years) were enrolled on the study. Seventeen patients were enrolled on the GI leiomyosarcoma arm; only 1 minor response, lasting < 8 weeks in a patient with liver metastases, was noted, and so this arm was terminated. Thirty-nine patients were entered on the other STS arm. RESULTS: Three patients achieved a partial response (response rate, 8%) for durations of 4, 6, and 13 months, respectively. Fourteen patients had stable disease for a median of 4 months (range, 2-8 months). Two patients died of disease during the first 2 months. Four other patients required hospitalization for nausea, vomiting, and dehydration. Other toxicities included diarrhea (36 patients, 5 with Grade 3 toxicity); fatigue (42 patients, 11 with Grade 3 toxicity); anorexia (32 patients, 1 with Grade 3 toxicity); nausea (37 patients, 2 with Grade 3 toxicity); vomiting (24 patients, 3 with Grade 3 toxicity); neutropenia (14 patients, 5 with Grade 3 toxicity); and thrombocytopenia (16 patients, 5 with Grade 3 or 4 toxicity). CONCLUSIONS: 9-NC is well tolerated but inactive in GI leiomyosarcomas and has minimal activity in previously treated patients with STS.