Treatment-emergent Hypertension Research Articles

Blood pressure increases are associated with weight gain and not antiretroviral regimen or kidney function: a secondary analysis from the ADVANCE trial in South Africa.

Recent evidence has raised questions about whether newer HIV treatment regimens, including dolutegravir (DTG) and tenofovir alafenamide (TAF),are associated with increases in blood pressure (BP). Weassessed changes in BP by treatment regimen andevaluated the relative contribution of kidney function and weight gain to these changes among participants in the ADVANCE phase-3 trial clinical trial in South Africa (study dates: January 2017-February 2022). Our primary outcome of interest was a change in systolic BP (SBP) at 96 and 192 weeks, among those not receiving antihypertensive medication. The secondary outcome was treatment-emergent hypertension at these same time points, defined as BP ≥140/90 mmHg on two occasions, or initiation of antihypertensive medication after week 4 among individuals without hypertension at enrolment. We used linear regression to evaluate the relationship between change in estimated glomerular filtration rate (eGFR) and change in SBP; and Poisson regression to evaluate the relationship between change in eGFR and treatment-emergent hypertension at each time point. All models were adjusted for age, sex, treatment group and change in body mass index (BMI). Over 96 weeks, the average changes in SBP were 1.7 mmHg (95% CI: 0.0-3.4), -0.5 mmHg (95% CI: -2.2 to 1.7) and -2.1 mmHg (95% CI: -3.8 to 0.4) in the TAF/emtricitabine (FTC)/DTG, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV) groups, respectively. This difference was significant for the TAF/FTC/DTG compared to the TDF/FTC/EFV group (p = 0.002). Over 96 weeks, 18.2% (95% CI: 13.4-22.9), 15.4% (95% CI: 11.0-19.9) and 13.3% (95% CI: 8.9-17.6) of participants developed treatment-emergent hypertension, respectively. In adjusted models, there was no significant relationship between change in eGFR and either outcome. Change in BMI was significantly associated with an increase in SBP, while age was associated with an increased risk of treatment-emergent hypertension. Adjustment for BMI also mitigated the unadjusted relationship between HIV treatment regimen and SBP where present. In the ADVANCE cohort, weight gain and age accounted for increases in BP and risk of treatment-emergent hypertension. HIV treatment programmes may need to integrate the management of obesity and hypertension into routine care. NCT03122262.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. ClinicalTrials.gov Identifier: NCT03096834.

Final 192-Week Efficacy and Safety Results of the ADVANCE Trial, Comparing 3 First-line Antiretroviral Regimens.

ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive. This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks. Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm. High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes.

Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study.

Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. Patients from REFLECT who received lenvatinib (n=476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8weeks. A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7weeks (median); the worst grade CSTE-HTN occurred at 4.1weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4weeks: 16.3 vs. 11.6months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8weeks: 13.5 vs. 11.6months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4weeks: 6.6 vs. 6.4months; HR, 0.887; 95% CI, 0.680-1.157; at 8weeks: 5.7 vs. 6.4months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials.

Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials. Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated. Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit. Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.

69. Incidence of metabolic complications among treatment-naïve adults living with HIV-1 randomized to B/F/TAF, DTG/ABC/3TC or DTG+F/TAF after 144 Weeks

BackgroundMetabolic comorbidities including diabetes (DM) and dyslipidemia pose challenges to the long-term care of people with HIV (PWH). Incidence of cardiovascular disease and DM are reported at higher rates in PWH than the general population. Obesity is broadly prevalent in both the general population and PWH, and higher body mass index (BMI) can contribute to metabolic complications. Here we present longer-term follow up on incidence of DM, hypertension (HTN), BMI categorical shifts, and lipid changes over 144 weeks of blinded treatment from two trials of PWH initiating antiretroviral therapy.MethodsWe assessed incidence of metabolic complications in adult PWH in Study 1489: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir/abacavir/ lamivudine (DTG/ABC/3TC) and Study 1490: B/F/TAF vs DTG+F/TAF. Treatment-emergent (TE) metabolic comorbidities were defined by standard MedDRA search lists. CDC-defined BMI categories were compared from baseline (BL) to Week 144. Analyses by sex at birth and race were performed, as well as for lipid changes.ResultsAmong 1,274 total participants, median (range) age was 33 years (18-77), 90% men, 33% black. In study 1489, BL prevalence of DM and HTN was 4.5 and 12.1% with TE DM and HTN in B/F/TAF being 0.7% and 10%, and for DTG/ABC/3TC 1.3% and 6.9%, respectively. In study 1490, BL prevalence of DM and HTN was 6.8 and 18.8% with TE DM and HTN in B/F/TAF being 2.1 and 5.8%, and for DTG+F/TAF 2.3 and 6.5%, respectively. BMI shift from Normal to Obese: B/F/TAF 0%, DTG/ABC/3TC 3.2%, p=0.12 (1489) (Table 1); B/F/TAF 2.5%, DTG+F/TAF 2.9% p=1.00 (1490) (Table 2). Subgroup analyses by gender/race showed similar findings for TE DM, HTN, and BMI changes. Median changes from BL fasted lipids were small (Table 1).Table 1§. Studies 1489 and 1490: Metabolic Outcomes from Baseline to Week 144 Table 2±. Shift Table of BMI Category at Week 144 by Baseline BMI Category – Overall ConclusionThrough over 144 weeks of follow up, PWH randomized to initiate B/F/TAF, DTG/ABC/3TC or DTG+F/TAF had low rates of incident DM or HTN-related AEs, with no statistically significant differences by treatment group. BMI changes/categorical shifts from BL did not significantly differ by regimen, and no clinically significant change or difference by regimen in lipids were observed. While data are limited by three years of follow up, they are strengthened by randomized study design of three widely used initial ART regimens.Disclosures Eric Daar, MD, Bristol-Myers Squibb (Consultant)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)Janssen (Consultant, Advisor or Review Panel member, Research Grant or Support)Merck (Consultant, Advisor or Review Panel member, Research Grant or Support)Teva (Consultant, Advisor or Review Panel member)ViiV Healthcare (Consultant, Advisor or Review Panel member, Research Grant or Support) Chloe Orkin, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Other Financial or Material Support)Janssen (Research Grant or Support, Other Financial or Material Support)Merck (Research Grant or Support, Other Financial or Material Support)ViiV Healthcare (Research Grant or Support, Other Financial or Material Support) Paul Sax, MD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV (Consultant, Research Grant or Support) Jeffrey L. Stephens, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support) Ellen Koenig, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Amanda Clarke, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Conference attendance sponsorship)ViiV Healthcare (Consultant, Other Financial or Material Support, Conference travel sponsorship) Axel Baumgarten, MD, AbbVie (Advisor or Review Panel member, Speaker’s Bureau)Bristol-Myers Squibb (Advisor or Review Panel member, Speaker's Bureau)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker’s Bureau)Merck (Advisor or Review Panel member) Cynthia Brinson, MD, Abbvie (Scientific Research Study Investigator)BI (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau, Personal fees)GSK (Scientific Research Study Investigator)Novo Nordisk (Scientific Research Study Investigator)ViiV Healthcare (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Hailin Huang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Terry Farrow, MD, Gilead Sciences Inc. (Employee, Shareholder) Jared Baeten, MD, PHD, Gilead Sciences Inc. (Employee, Shareholder) Jason Hindman, PharmD, Gilead Sciences Inc. (Employee, Shareholder) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder) Kimberly Workowski, MD, Nothing to disclose

Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer-Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension.

Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.

Safety, Tolerability, and Real-World Effectiveness of Intravenous Ketamine in Older Adults With Treatment-Resistant Depression: A Case Series

To evaluate the safety, tolerability, and effectiveness of repeated doses of intravenous (IV) ketamine in older adults (i.e., ≥60 years of age) with treatment-resistant depression. In this case series, fifty-three older adults (Mage = 67, SD = 6; 57% female [n = 30]) received 4 IV ketamine infusions, administered over 1-2 weeks. Effectiveness of IV ketamine was measured using the Quick Inventory for Depressive Symptomatology-Self Report 16 (QIDS-SR16) approximately 2 days after infusions 1-3, and 1-2 weeks after infusion 4. Safety was measured as hemodynamic changes before, during, immediately after, and 20 minutes after each infusion. Tolerability was assessed via systematic reporting of treatment-emergent adverse events during and after each infusion, in addition to symptoms of dissociation measured using the Clinician Administered Dissociative States Scale. Partial response (25%-50% symptomatic improvement from baseline), response (≥50% symptomatic improvement from baseline), clinically significant improvements (≥25% symptomatic improvement from baseline), and remission rates (QIDS-SR16 ≤5) were also calculated. Participants reported significant decreases in depressive symptoms (i.e., as measured by the QIDS-SR16) with repeated ketamine infusions (F(4, 92) = 7.412, p <0.001). The mean QIDS-SR16 score was 17.12 (SD = 5.33) at baseline and decreased to 12.52 (SD = 5.79) following 4 infusions. After 4 infusions, 31% (n = 8) of participants partially responded to IV ketamine, 27% (n = 7) responded, 58% (n = 15) experienced clinically significant improvements, and 10% (n = 3) met remission criteria. Thirty-six participants (69%) experienced treatment-emergent hypertension during at least 1 infusion, and 10 (19%) required intervention with an antihypertensive. Drowsiness was the most commonly reported adverse event (50% of infusions; n = 73). Ketamine was associated with transient treatment-emergent hypertension. Response and remission rates were comparable to those reported in general adult samples. Findings are limited by the open-label, chart review nature of this study.

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

AbstractPatients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

CTNI-10. MAINTENANCE CHEMOTHERAPY USING BEVACIZUMAB FOR NEUROFIBROMATOSIS 2 PATIENTS WITH HEARING LOSS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY (NF104)

Abstract BACKGROUND Bevacizumab treatment at 2.5–5 mg/kg/week is associated with hearing improvement and tumor shrinkage in about 40% of patients with neurofibromatosis 2 (NF2) and progressive vestibular schwannomas (VS). Treatment-emergent hypertension and proteinuria are common with prolonged treatment, and data supporting strategies to maintain hearing and minimize toxicity are lacking. METHODS We conducted a multicenter, phase II, open-label study of bevacizumab for subjects (≥6 years old) with NF2, hearing loss, and progressive VS. After 6 months of induction therapy (10 mg/kg every 2 weeks), subjects received low dose bevacizumab at 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing decline was defined as a significant decrease in word recognition score below baseline. Progressive disease was defined as ≥20% increase in tumor volume from baseline. RESULTS Twenty of 22 subjects (median age=23 years) were treated with maintenance bevacizumab. The proportion of subjects free from hearing decline at 6, 12, and 18 months was 88%, 94%, and 85%, respectively; the proportion free from tumor progression at 6, 12, and 18 months from baseline was 88%, 94%, and 85%, respectively. Three subjects (15%) experienced hearing loss during maintenance and required dose escalation. Maintenance chemotherapy with bevacizumab was well tolerated: 1 subject discontinued due to perirectal abscess and 2 discontinued by choice. Grade 3 hypertension occurred in 2 subjects (10%). Adverse events of interest included hypertension (55%), proteinuria (20%), and irregular menstruation (6/13, 46%). CONCLUSIONS Maintenance chemotherapy with bevacizumab at 5 mg/kg every 3 weeks is associated with prolonged hearing and tumor stability that surpasses historical controls. A minority of subjects require dose escalation during low dose bevacizumab treatment.

Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence

ABSTRACT Objectives Rigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD). There is a paucity of data on the safety and tolerability of ketamine in community-based clinics treating patients with TRD. Methods Retrospective data was analyzed from 203 patients with TRD who received repeat-dose IV ketamine. Safety was operationalized as hemodynamic changes. Tolerability was evaluated through the reporting of adverse events and dissociation symptom severity, as measured by the Clinician-Administered Dissociative States Scale. Results Ketamine was well-tolerated, with less than 5% of patients withdrawing due to tolerability concerns. Blood pressure significantly increased during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (i.e., blood pressure ≥ 165/100 mmHg). 12% of patients exhibiting hypertension required pharmacological intervention. The most frequently reported adverse events included drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity significantly attenuated after the first infusion, but plateaued for subsequent infusions. Conclusion Intravenous ketamine was safe and well-tolerated. Hypertension was commonly observed and was often transient. Dissociation was most frequently reported after the first infusion but remained a consistent but not treatment-limiting adverse event thereafter. No patients exhibited psychosis, mania, or new onset suicidality with IV ketamine.

Combination Chemotherapy with Carfilzomib, Bendamustine and Dexamethasone Is Highly Active for Therapy of Newly Diagnosed Multiple Myeloma-Results of Single Center Phase I/II Study

Background: Carfilzomib and Bendamustine are currently FDA approved for therapy of relapsed refractory multiple myeloma (MM). Bendamustine, in addition to interference with DNA replication, it can induce inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of a p53-dependent DNA-damaging stress response leading to apoptosis of tumor cells (1). It has previously shown significant activity in relapsed myeloma (2). Carfilzomib is a second generation, irreversible proteasome inhibitor has demonstrated promising activity in first line therapy (3,4). we hypothesized that combining them will yield an effective induction regimen in the newly diagnosed MM. Study design: Inclusion criteria included newly diagnosed MM with measurable disease, age ≥18, ECOG PS 0-2, adequate renal (creatinine clearance &gt;30 mL/min), cardiac and hepatic function. Carfilzomib was given IV on days 1, 2, 8, 9, 15, 16. All patients received 20 mg/m2 on days 1 and 2 of cycle 1, after which their dose was escalated to one of the following levels: 27, 36, 45, or 56 mg/m2. Bendamustine IVPB on days 1, 2, at 70 (dose levels 1 and 2) or 90 mg/m2 (dose levels 3-5). Dexamethasone 20 mg PO or IV D 1, 2, 8, 9, 15, 16, 22, 23. Each cycle of therapy was 28 days, and a total of 8 cycles was given. Stem cell harvest was done after 4 cycles and eligible patients proceeded to ASCT after 8 cycles. Maintenance was recommended - either carfilzomib (36mg/m2 D 1,2, 15, 16 of a 28-day cycle for 2 years, or investigator's choice. Primary objective was to determine the recommended phase 2 dose (RP2D) and additional objectives assessed efficacy and safety. Results: Between February 2014 and May 2018, 20 patients with newly diagnosed MM pts were accrued onto study (5 pts in phase I and 15 in phase II). Median age was 65 (range 48-74), and 14 (70%) patients were male. 7 (35%) were of Hispanic ethnicity. 3 patients (15%) were R-ISS stage 3, and 1 (5%) had high-risk cytogenetics. We did not observe any DLTs with our study treatment and established the RP2D as: carfilzomib 56 mg/m2, bendamustine 90 mg/m2 and dexamethasone 20 mg on the dosing schedule given above. The most common and severe toxicities were hematologic. Grade 3/4 hematologic toxicities were lymphocytopenia in 90% of patients, neutropenia 40%, anemia 20% and thrombocytopenia 20%. Notable non-hematologic toxicities were grade 3/4 infection in 20% of patients (typically upper respiratory and pneumonia), grade 1/2 acute kidney injury in 45% of patients, and grade 1/2 diarrhea in 40% of patients. No treatment emergent hypertension or heart failure were noted. 1 patient died while on study, from septic shock due to pneumonia 7 weeks after completion of induction. The regimen was highly effective, with an ORR of 100%. Best responses were: 2 (11%) PR, 5 VGPR (26%), and 12 CR (63%) (Figure 2). Among the CRs, 4 were MRD-positive, 5 were MRD-negative, and 3 did not have MRD testing. With a median follow-up of 28 months (range 11-71), 2 patients have progressed - 1 with del(17p) at 19 months after diagnosis, and the other with standard cytogenetic risk disease at 56 months. 2 patients have died - the patient with del(17p) from refractory myeloma at 37 months after diagnosis, and the other from septic shock as discussed above. Median PFS was 56 months, and median OS has not been reached. Conclusion: Carfilzomib, Bendamustine and Dexamethasone is safe and highly effective for newly diagnosed transplant eligible MM and should be further explored in a larger prospective trial for this patient population.

Response to Erythropoiesis Stimulating Agents in Patients with WHO-Defined Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T)

Background: Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) was formally included as a unique WHO-defined entity in the 2016, iteration of the classification of hematological neoplasms (under MDS/MPN overlap syndromes). Patients with MDS/MPN-RS-T have features of MDS-RS-single lineage dysplasia (SLD), persistent thrombocytosis (platelet count ≥450x109/L), with proliferation of large atypical megakaryocytes. Anemia, including red blood cell transfusion dependency (RBC-TD) is a major problem. While extensive studies have documented erythroid response rates (ERR) to erythropoiesis stimulating agents (ESA) in MDS and MDS-RS-SLD, the data in MDS/MPN-RS-T is less clear. We carried out this study to asses ERR in ESA treated patients with MDS/MPN-RS-T. Methods: After approval by the IRB, patients with 2016, WHO-defined MDS/MPN-RS-T were included in the study. The bone marrow (BM) morphology, cytogenetics and BM RS% were retrospectively reviewed. All study patients underwent next generation sequencing for 29 myeloid-relevant genes, obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods (Patnaik et al., BCJ 2016). Treatment details, including the type of ESA used, dose administered, side effects and reason for discontinuation were retrospectively abstracted. Erythroid responses were assessed using the 2006, international working group (IWG) MDS and the 2015, IWG MDS/MPN response criteria. Results: Forty seven patients with MDS/MPN-RS-T were identified, of which 37 (79%) patients received ESA treatment at any time point during their disease course; median age 73 years (range, 52-93), 46% male.The hemoglobin at diagnosis (HB) and baseline erythropoietin (EPO) levels were 9.1 gm/dL (range, 6.6-12.1) and 39 IU/L (range, 8-500), respectively. Ten (29%) patients were RBC-TD at baseline. None of the 37, ESA-treated patients were on concomitant cyto-reductive therapy for thrombocytosis. Twenty (54%) patients were treated with erythropoietin-a, 13 (35%) with darbepoetin, and 4 (11%) with both sequentially. Median doses were 40,000 IU weekly (range, 20,000-80,000) for erythropoietin-a and 200 mcg every 2 weeks (range, 100-500), for darbepoetin. Median treatment duration was 14 months (range, 1-173) and causes for discontinuation included; ESA failure/loss of response in 20 (54%), sustained HB rise in 1 (3%) and other causes, including adverse events in 4 (11%) patients. With regards to safety, the following events were considered potentially ESA related; treatment emergent hypertension in 2 (5%), venous thromboembolism, ischemic stroke and splenic infarction in 1 (3%) patient each, respectively. All patients with thrombotic/ischemic events had been on low dose aspirin prophylaxis. Erythroid responses by the IWG MDS and MDS/MPN response criteria were assessable in 35 (95%) patients: with 16 (46%) meeting criteria for an erythroid response, by both assessment systems. The median duration of ER was 20 months (range, 2-172). In comparison to ESA non-responders, those that responded were more likely to have baseline EPO levels ≤44 IU/L (ROC analysis; median, 28 vs 112 IU/L; p=0.0080), while there was a trend for inferior responses associated with RBC-TD (p=0.0857). Age, gender, baseline white blood cell and platelet counts, type of ESA used, BM RS %, JAK2V617F, SF3B1, DNMT3A, TET2 and ASXL1 mutational status did not impact ESA response (Table 1). On a univariate survival analysis (OS), survival was not significantly different between ESA responders vs non-responder (median OS, 76 vs 45 months; p=0.2929). After ESA failure, 7 (19%) patients received hypomethylating agents (HMA), while 5 (14%) received lenalidomide. There were no erythroid responses to HMA, while 1 of 3 (33%) assessable lenalidomide treated patients achieved a morphological complete response. Conclusion: Erythropoiesis stimulating agents are effective first line therapies for the management of anemia in patients with MDS/MPN-RS-T, with 46% achieving an erythroid response (median duration of response of 20 months). Low baseline endogenous EPO level (&lt;44 IU/L) was the best predictor of response, with a trend towards an inferior response in the presence of RBC-TD. In the context of clonal thrombocytosis, potentially related thrombotic/ischemic events were documented in 8% of patients. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Systemic side effects after intravitreal administration of antivascular endothelial growth factors for neovascular age-related macular degeneration

Age-related macular degeneration is a chronic and progressive disease of the retina that occurs with increasing frequency with age, representing the leading cause of irreversible blindness in patients over 50 years of age. The loss of visual perception occurs due to neovascular proliferation. Antivascular endothelial growth factors revolutionized the treatment of exudative age-related macular degeneration. Our aim was to assess the systemic safety of intravitreal administration of ranibizumab, bevacizumab, or aflibercept in patients with neovascular age-related macular degeneration. The study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. The primary outcomes included: all-cause death and all serious systemic adverse events. We calculated the incidence of systemic adverse events, relative risk of the outcomes, and 95% confidence intervals. This review included representative outcome data on 12,292 participants from 24 trials, which included both men and women aged 50 years or older with neovascular age-related macular degeneration. In bevacizumab-treated patients, the most frequent systemic adverse event in our analysis was nonocular hemorrhage. In ranibizumab-treated patients, systemic adverse events were not dose-dependent. The number of systemic adverse events was similar in patients treated with ranibizumab (4.73%) or with aflibercept (4.76%). This meta-analysis did not find any statistically significant difference regarding the occurrence of death or other serious systemic adverse events such as treatment-emergent hypertension, myocardial infarction, stroke, or nonocular hemorrhage after intravitreal use of antivascular endothelial growth factors.

Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study

Recent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC. To explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not. 153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66-0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34-0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial. In this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB. NCT00703326.

Abstract P6-16-02: Beta-adrenergic receptor blockers (BB) and increased progression free survival (PFS) in patients with advanced triple negative breast cancer (TNBC): A retrospective analysis of the ROSE/TRIO012 study

Abstract Introduction: Recent retrospective studies suggest beta-adrenergic blocking drugs are associated with improved survival in patients with a wide range of cancers. Although limited and discordant data suggest that the use of BB may increase overall survival (OS) of patients with localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC, which may be a more appropriate clinical scenario to evaluate anti-cancer effects of new treatment strategies. We analyzed the relationship between BB use and clinical outcomes in the ROSE/TRIO012 study, a double-blinded multinational registration phase III trial that randomized 1,144 patients with HER2-negative advanced BC to receive first-line docetaxel in combination with ramucirumab (RAM) or placebo. Objective: To explore the association between BB use and BC outcomes in patients participating in the ROSE/TRIO-012 trial. Methodology: We retrospectively compared PFS,OS,Overall Response Rate (ORR) and Clinical Benefit Rate (CBR) using the ITT population, in patients who received BB during the trial with those who did not receive them. PFS and OS were estimated using the Kaplan-Meier method. PFS and OS of both treatment groups were compared using the Log-Rank test. Cox proportional models were fitted to determine the association between BB, PFS and OS. ORR and CBR in both groups were compared using the Fisher's Exact Test. Results: 153/1,144 (13%) patients received BB during the trial. Median PFS in patients treated with BB was 10.3 months, compared to 8.3 months in patients who did not receive them (HR 0.81; 95% CI 0.66-0.99; p=0.0379). In patients treated with BB only after enrolment (57/153, 37%) median PFS was 15.5 months vs. 8.3 months in patients with no BB (p=0.0005). In the subset of patients with TNBC, median PFS was 13 months if received BB compared to 5.2 months if no BB (HR 0.52; 95% CI 0.34-0.79; p=0.002). No difference in PFS was observed in patients with hormone receptor positive BC. The magnitude of PFS benefit in the RAM arm was similar as the whole ITT population (HR 0.73; 95% CI 0.57-0.94; p=0.014. If BB received only after enrolment HR 0.50; 95% CI 0.35-0.72; p=0.0003). The benefit of BB intake in PFS was independent of development of treatment-emergent hypertension (hypertension occurring within 42 days of first study drug administration; HR 0.92; 95% CI 0.73-1.15; p=0.476) but dependent on treatment arm (HR 0.86; 95% CI 0.74-0.99; p=0.037). The test for interactions between BB and treatment arm was not significant (p =0.276). No differences in OS, ORR or CBR were seen. Conclusions: In this exploratory post-hoc analysis of the ROSE/TRIO012 study, BB intake was associated with a significant improvement in PFS compared to patients who did not receive them, particularly in patients with TNBC and patients not previously exposed to these drugs. Further evaluation of the BB intake on BC outcomes warrants evaluation in a prospectively-designed clinical trial. Citation Format: Spera G, Fresco R, Fung H, Dyck JRB, Pituskin E, Patterson I, Aspeslet L, Mackey JR. Beta-adrenergic receptor blockers (BB) and increased progression free survival (PFS) in patients with advanced triple negative breast cancer (TNBC): A retrospective analysis of the ROSE/TRIO012 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-02.

Abstract P6-14-03: Genome wide association study (GWAS) to identify variants conferring ramucirumab-associated hypertension in the ROSE/TRIO-012 breast cancer trial

Abstract Background: In a candidate single nucleotide polymorphism (SNP) association study, we previously identified VEGFR-1 and VEGFR-2 SNPs strongly associated with treatment emergent hypertension (HT) in the ramucirumab (RAM) and docetaxel (Doc) arm in the ROSE/TRIO-012 study, a double-blinded multinational phase III trial that randomized 1,144 patients with advanced breast cancer to receive first-line Doc in combination with RAM or placebo (Mackey et al, JCO Jan 10, 2015:141-148; Mackey et al, JCO, Volume 33, Issue 15_suppl, May 20, 2015: 547). However, candidate SNP studies limit the number of genes for interrogation and a more comprehensive genome wide search may identify critical variants associated with the phenotype of HT. Preliminary analysis indicated that patients experiencing HT with RAM showed better overall survival (Mackey JR, et al (2015). Reply to H. Lee, et al. JCO; in press). These observations provide the potential to identify those patients with genetic variants for predisposition to RAM-associated HT to inform therapeutic decisions. Methods: Genotyping of samples is underway using Affymetrix SNP 6.0 arrays. Genotype data will be filtered for deviations from Hardy Weinberg Equilibrium and minor allele frequency of &amp;gt;0.05. Study subjects (n=792) provided ethics-committee approved prospective consent for this genetic study of whom 478 subjects were allocated RAM + Doc arm. Toxicity grades 0-1 (n= 394 controls; low toxicity) vs. grade &amp;gt;2 (n= 84 cases, high toxicity) is our binary outcome. Dominant genotypic model is assumed. Chi-square test, FDR and/or 10000 permutation tests will be employed (Golden Helix-SVS v8.3) and p&amp;lt;0.05 considered statistically significant. Population stratification will be identified (EIGENSTRAT) and association statistics will be corrected using Eigenvectors along with age as covariates. Fine mapping of loci showing significant associations will be attempted using imputation tools. Results and conclusions: We expect up to 700,000 SNPs to be retained after filtering based on our previous breast cancer GWAS analyses (Damaraju et al. Cancer Research (suppl); Vol 70 (24), page 258s, 2010 and Sehrawat et al Hum Genet. 2011 Oct;130(4):529-37) and 30,000 SNPs to show significance at a nominal p-value (0.05); these will be analysed for regions of high linkage disequilibrium to narrow down potential loci showing association with HT to serve as candidate markers in further independent validation studies. Cumulative dose to adverse events will be considered in the analysis. Identified loci will be interrogated for potential genes in the flanking regions with biological relevance based on pathway analysis. Identified variants from candidate SNP and GWAS may allow developing predictive tools to enable stratification of patients for therapies. The analysis is expected to be completed by mid- November, 2015. Citation Format: Mackey JR, Lipatov O, Martín M, Webster M, Hegg R, Verma S, Ramos-Vázquez M, Fresco R, Thireau F, Houé V, Press MF, Kumaran M, Damaraju S. Genome wide association study (GWAS) to identify variants conferring ramucirumab-associated hypertension in the ROSE/TRIO-012 breast cancer trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-14-03.

Treatment-Emergent Hypertension and Efficacy in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (Select)

ABSTRACT Aim: Hypertension (HTN), an on-target adverse event (AE) of VEGFR inhibition, is a biomarker for tyrosine kinase inhibitor efficacy in renal cell carcinoma treatment. In the phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT), the most frequent AE in patients (pts) on lenvatinib (LEN)—an inhibitor of VEGFR1–3, FGFR1–4, PDGFRa, RET, and KIT—was HTN. This analysis examines treatment-emergent HTN (TE-HTN) and efficacy in SELECT. Methods: In this multicenter, double-blind study, pts with documented progressive 131I-refractory differentiated thyroid cancer (RR-DTC) were randomized 2:1 to LEN or placebo (24mg/d; 28-d cycle). Primary endpoint was progression-free survival (PFS); secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. This analysis of investigator-assessed TE-HTN included increased blood pressure and prehypertension AEs. Results: Overall, 190/261 (73%) LEN-treated and 20/131 (15%) placebo-treated pts experienced TE-HTN. For LEN, percentages of pts with TE-HTN were: Grade 1, 7%; Grade 2, 22%; Grade 3, 44%; Grade 4, 0.4%. Median time to first onset of TE-HTN was 2.3 weeks (range, 1.4–5.0). Median PFS in LEN-treated pts with and without TE-HTN was 18.8 months (95% confidence interval [CI] 16.5–not estimable [NE]) and 12.9 months (95% CI 7.4–NE), respectively. Pts with TE-HTN had a 5.9-month median PFS advantage (hazard ratio 0.59 [95% CI 0.39–0.88]; P = 0.009). ORR for LEN-treated pts with TE-HTN was 69% vs 56% for those without (odds ratio 1.72 [95% CI 0.98–3.01]). Median change in tumor size for pts with and without TE-HTN was -45% and -40%, respectively (P = 0.2). Median OS had not been reached in pts with TE-HTN; in pts without TE-HTN: 21.7 months (95% CI 15.7–NE). LEN-HTN was managed concomitantly with antihypertensive agents (68%): calcium channel blockers (51%), ACE inhibitors (38%), and angiotensin II receptor antagonists (29%). TE-HTN led to LEN dose interruption in 34 (13%), dose reduction in 35 (13%), and drug discontinuation in 3 (1%) pts. Conclusions: Although HTN is a clinically significant AE that warrants careful monitoring and management, LEN-emergent HTN was significantly correlated with improved clinical outcome in pts with RR-DTC. Further studies will investigate HTN as a predictive indicator of LEN response. Disclosure: M. Tahara: Research Funding: Eisai, Boehringer-Ingelheim; B. Robinson: Advisory Role: AstraZeneca, Bayer, Eisai; M. Brose: Advisory Role: Eisai Research Funding: Eisai; N. Kiyota: Research Funding: Eisai C. Dutcus: Employee of Eisai Inc.; B.D.L. Heras: Employee of Eisai Ltd; J. Zhu: Employee of Eisai Inc. S. Sherman: Advisory Role: AstraZeneca, Amgen, Eisai, Exelixis, NovoNordisk, Eli Lilly Research Funding: Amgen; M. Schlumberger: Advisory Role/Expert Testimony: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi. Honoraria: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi, Sobi. Research Funding: AstraZeneca, Bayer, Eisai, Genzyme-Sanofi. All other authors have declared no conflicts of interest.

Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24

BackgroundHypertension (HTN), a recognized adverse effect of angiogenesis inhibitors, may be a potential biomarker of activity of these agents. We conducted a retrospective analysis to examine the incidence and predictors of the development of on-treatment HTN with the vascular endothelial growth factor receptor tyrosine kinase inhibitor cediranib, and the relationship of this adverse event with treatment outcomes. Patients and methodsBR24 was a double-blind placebo-controlled phase II trial of carboplatin/paclitaxel chemotherapy with either daily oral cediranib or placebo in patients (n = 296) with advanced non-small-cell lung cancer (NSCLC). Exploratory analyses characterized relationships between HTN, baseline variables, and efficacy outcomes. ResultsNew onset or worsening of preexisting HTN (treatment-emergent HTN) was more frequent in patients receiving cediranib (68 versus 45%, P < 0.0001). Factors associated with HTN in all randomized patients were good performance status and treatment with cediranib. In both arms, treatment-emergent HTN was associated with improved efficacy outcomes, but there was no evidence of a differential treatment effect, with nonsignificant interaction P values. ConclusionsIn advanced NSCLC, HTN is frequent in patients receiving chemotherapy, with or without cediranib. The development of HTN was favorably prognostic in these patients, but not predictive of a differential outcome with cediranib.

A Randomized, Double-Blind, Placebo-Controlled Study of the Effect of Sustained-Release Bupropion on Blood Pressure in Individuals With Mild Untreated Hypertension

The effects of bupropion on blood pressure and heart rate were evaluated in a double-blind, placebo-controlled study of community volunteers with untreated mild (stage 1) hypertension (systolic blood pressure [SBP], 140-159 mm Hg, and/or diastolic blood pressure, 90-99 mm Hg). Three hundred subjects were randomly assigned (1:1:1:1) to 4 weeks of placebo or bupropion sustained release (SR) 150, 300, or 400 mg/d. Mean clinical blood pressures decreased from baseline to the end of protocol in all groups (n = 296): -6.53, -6.46, -4.20, -4.87 mm Hg for SBP; and -2.36, -2.27, -1.95, -1.55 mm Hg for diastolic blood pressure, for each group, respectively. Although decreases in mean clinical blood pressure were observed in all groups, the reduction in SBP was less on bupropion SR 300 mg/d than on placebo (-4.20 vs -6.53 mm Hg, respectively; Delta = 2.33, P = 0.020). Neither mean 24-hour ambulatory blood pressure measurements nor the proportion of subjects with clinically significant increases in blood pressure differed between any bupropion SR dose and placebo. Mean heart rate increases were small but statistically significant at 400 mg/d versus placebo (2.28 vs -0.64 beats/min; Delta = 2.92, P = 0.004). Although only minor effects on blood pressure were observed in this trial, an infrequent association of bupropion therapy and treatment-emergent hypertension cannot be ruled out.