Redefining Blood Pressure Assessment - The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety.

According to models developed from large epidemiological studies, mean increases in systolic blood pressure of 2-3 mmHg can increase the risk of cardiovascular (CV) adverse events, especially in patients with a high risk for CV disease. There are new regulatory recommendations for the use of a safety ambulatory blood pressure monitoring (ABPM) study to assess the blood pressure (BP) effects of drugs used chronically. The ABPM study collects BP measurements over 24 hours at baseline and during treatment in patients with underlying CV risk. Our evaluation of ABPM studies submitted to the US Food and Drug Administration (FDA) shows these studies can provide precise estimates of BP changes and lack a pronounced placebo response. With the assessment of BP effects in development programs, opportunities exist for developing quantitative safety models to predict CV risk, support dose selection, identify patients with increased BP response, and provide insight into underlying mechanisms.

Correction to: FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

The author name that previously read.

FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.

Relationship between International Normalized Ratio and Outcomes in Modern Trials with Warfarin Controls.

INTRODUCTION: A target international normalized ratio (INR) of 2-3 has been recommended for patients with atrial fibrillation (AF) and risk factors for thromboembolism. This recommendation is largely based on evidence from observational studies a decade ago. This study utilized collective data from modern trials with warfarin controls to examine the relationship of warfarin anticoagulation, as assessed by INR, on the clinical outcome events of interest. METHODS: Data on warfarin-treated patients from three clinical studies supporting the approval of dabigatran (Pradaxa), apixaban (Eliquis), and edoxaban (Savaysa) were pooled. Ischemic stroke, intracranial hemorrhage (ICH), and all-cause death were selected as the outcome events of interest. Multivariate Cox regression modeling was performed to examine the association between time-dependent INR and each outcome event. Benefit-risk assessment was evaluated by summing the estimated annual event rate for ischemic stroke and ICH. RESULTS: A total of 21,883 patients representing 322 ischemic strokes, 288 ICHs, and 657 all-cause deaths were included in the analysis. The models used suggest that the risk of ischemic stroke is greatly reduced when INR exceeds 2; in contrast, the risk of ICH increases monotonically as INR increases. When combining ischemic stroke and ICH events, the lowest estimated annual event rate was observed between INR of 2 and 2.5; the risk only slightly increased between INR of 1.8 and 3.0. Similarly, a U-shaped relationship between INR and the risk of all-cause death was found. CONCLUSIONS: This study using collective warfarin data from recent large prospective trials indicates that INR between 2 and 2.5 provides the best balance between ischemic stroke and ICH, as well as optimal protection against death in patients with AF.

Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis.

BACKGROUND: Early life events have been suggested to influence multiple sclerosis (MS) susceptibility, and to potentially modulate its clinical course. We assessed vitamin D-related exposures from childhood to disease onset and their associations with MS progression. METHODS: Among veterans in the Multiple Sclerosis Surveillance Registry, 219 reported having the progressive form and met the inclusion criteria. Participants reported their past sun exposure, vitamin D-related intake and age at disability milestones using the Patient-Determined Disease Steps (PDDS). The Cox proportional hazards model was used to examine the association between vitamin D-related exposures and time (years) to disability. RESULTS: Low average sun exposure in the fall/winter before disease onset was associated with an increased risk of progressing to a PDDS score of 8 (hazard ratio, HR: 2.13, 95% confidence interval, CI: 1.20-3.78), whereas use of cod liver oil during childhood and adolescence was associated with a reduced risk (HR: 0.44, 95% CI: 0.20-0.96). CONCLUSIONS: These results suggest that exposure to vitamin D before MS onset might slow disease-related neurodegeneration and thus delay progression to disability among patients with the progressive subtype.

Sun exposure, vitamin D and age at disease onset in relapsing multiple sclerosis.

BACKGROUND: Current evidence suggests that sun exposure and vitamin D intake, during childhood and adolescence, are associated with a reduced risk of multiple sclerosis (MS). However, the role of these environmental agents in the timing of disease symptom onset remains to be investigated. METHODS: Using a cross-sectional study design, we recruited participants from the Veterans Health Administration-Multiple Sclerosis Surveillance Registry. Self-reported histories of residential locations, sun exposure and intake of vitamin D were used to estimate vitamin-D-related exposures. Multivariable linear regression analysis was used to examine the associations between these variables and age at MS onset. RESULTS: Among veterans with relapsing MS who resided in low-to-medium solar radiation areas (n = 540), low sun exposure in the fall/winter during the ages of 6-15 years was significantly associated with earlier symptom onset by 2.1 years (p = 0.02). Intake of cod liver oil during the same age period was associated with later onset of MS symptoms by 4 years (p = 0.02). CONCLUSIONS: The current study provides evidence for an association between vitamin-D-related exposures during childhood and early adolescence and the timing of MS symptom onset, and supports vitamin D as a potential modulator of the clinical course of this disease.

Using geographic information system tools to improve access to MS specialty care in Veterans Health Administration.

Access to appropriate and timely healthcare is critical to the overall health and well-being of patients with chronic diseases. In this study, we used geographic information system (GIS) tools to map Veterans Health Administration (VHA) patients with multiple sclerosis (MS) and their access to MS specialty care. We created six travel-time bands around VHA facilities with MS specialty care and calculated the number of VHA patients with MS who resided in each time band and the number of patients who lived more than 2 hours from the nearest specialty clinic in fiscal year 2007. We demonstrate the utility of using GIS tools in decision-making by providing three examples of how patients' access to care is affected when additional specialty clinics are added. The mapping technique used in this study provides a powerful and valuable tool for policy and planning personnel who are evaluating how to address underserved populations and areas within the VHA healthcare system.

Time of birth, residential solar radiation and age at onset of multiple sclerosis.

UNLABELLED: BACKGROUNDS/AIM: Gestational and early life events have been suggested to contribute to multiple sclerosis (MS) susceptibility. We assessed the effects of time and place of birth on the age at onset of MS symptoms. METHODS: We selected a national cohort of 967 veterans from the Multiple Sclerosis Surveillance Registry for whom month and season (time) of birth, and birthplace (city and state) were available. Multiple linear regression analyses were used to examine the association between time of birth, birthplace latitude and solar radiation, and the age at onset of MS symptoms among the study sample. RESULTS: Patients with a relapsing form of the disease (R-MS), who were born in winter and whose birthplace was in low solar radiation areas, had disease symptom onset on average 2.8 years earlier than those born in seasons other than winter and in medium- and high-solar radiation areas (p = 0.02). CONCLUSIONS: These results suggest that exposure early in life to geographical and seasonal factors, possibly related to the protective effect of sunlight, and thus vitamin D, is associated with a delay in MS symptom onset. Other larger studies are required to examine the period-specific (from conception to adulthood) environmental factors that are associated with MS susceptibility.