Income level and inequality as complement to geographical differences in cardiovascular trials.

BACKGROUND: Analyses of country or regional differences in cardiovascular (CV) trials are based on geographical subgroup analyses. However, apart from map location and related racial, ethnic, and genetic variations, identified differences may also depend on social structure and provision and access to health care, for which country income and income inequality are indicators. The aim of the study was to examine the association between country per capita income and income inequality and prognosis in patients with heart failure or an acute coronary syndrome in 3 international trials (EMPHASIS-HF, EPHESUS, and EXAMINE). METHODS: Countries were classified into high income or low-middle income (LMICs) and into low, middle, or high inequality using the Gini index. The main outcome measures were all-cause and CV death. RESULTS: Patients from LMICs and countries with higher inequality were younger, were less often white, had fewer comorbid conditions, and were less often treated with guideline-recommended therapies, including devices. These patients had higher adjusted mortality rates (+15% to +70%) compared with patients from high-income countries and countries with less inequality. Patients from countries with the combination of greater inequality and low-middle income had particularly high mortality rates (+80% to +190%) compared with those that did not have both characteristics. Living in a country that is poor and has inequality had more impact on death rates than any comorbidity. These findings were reproduced in 3 trials. CONCLUSIONS: Patients from LMICs and countries with greater inequality had the highest mortality rates. The prognostic impact of income and inequality is substantial and should be considered when looking into subgroup differences in CV trials.

Nocturnal blood pressure measured by home devices: evidence and perspective for clinical application.

: Studies using ambulatory blood pressure (BP) monitoring have shown that BP during night-time sleep is a stronger predictor of cardiovascular outcomes than daytime ambulatory or conventional office BP. However, night-time ambulatory BP recordings may interfere with sleep quality because of the device cuff inflation and frequency of measurements. Hence, there is an unmet need for obtaining high quality BP values during sleep. In the last two decades, technological development of home BP devices enabled automated BP measurements during night-time. Preliminary data suggest that nocturnal home BP measurements yield similar BP values and show good agreement in detecting nondippers when compared with ambulatory BP monitoring. Thus, nocturnal home BP measurements might be a reliable and practical alternative to ambulatory BP monitoring to evaluate BP during sleep. As the use of home BP devices is widespread, well accepted by users and has relatively low cost, it may prove to be more feasible and widely available for routine clinical assessment of nocturnal BP. At present, however, data on the prognostic relevance of nocturnal BP measured by home devices, the optimal measurement schedule, and other methodological issues are lacking and await further investigation. This article offers a systematic review of the current evidence on nocturnal home BP, highlights the remaining research questions, and provides preliminary recommendations for application of this novel approach in BP management.

Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

Reinforcing adherence to antihypertensive medications.

This pilot study evaluated a reinforcement intervention to improve adherence to antihypertensive therapy. Twenty-nine participants were randomized to standard care or standard care plus financial reinforcement for 12 weeks. Participants in the reinforcement group received a cell phone to self-record videos of adherence, for which they earned rewards. These participants sent videos demonstrating on-time adherence 97.8% of the time. Pill count adherence differed significantly between the groups during treatment, with 98.8%±1.5% of pills taken during treatment in the reinforcement condition vs 92.6%±9.2% in standard care (P<.002). Benefits persisted throughout a 3-month follow-up, with 93.8%±9.3% vs 78.0%±18.5% of pills taken (P<.001). Pill counts correlated significantly (P<.001) with self-reports of adherence, which also differed between groups over time (P<.01). Systolic blood pressure decreased modestly over time in participants overall (P<.01) but without significant time-by-group effects. These results suggest that reinforcing medication adherence via cellular phone technology and financial reinforcement holds potential to improve adherence.

Rationale for establishing a mechanism to increase reimbursement to hypertension specialists.

Hypertension is an important public health problem both in the United States and worldwide, contributing to many forms of cardiovascular and renal diseases. Although great strides have been made in the proportion of the US population that achieves recommended blood pressure targets, many Americans still have undertreated and uncontrolled blood pressure that increases the risk of expensive strokes, heart attacks, heart failure, and dialysis. Because hypertension is a common but heterogeneous and sometimes complex condition, the American Society of Hypertension (ASH) has, since 1999, designated physicians as "ASH Hypertension Specialists." Such Hypertension Specialists (as defined by ASH's Specialist Program) are fully licensed physicians with a primary board certification who are competent in all aspects of the diagnosis and treatment of hypertension, as evidenced by passing a specific examination on these topics offered by ASH's Specialist Program. These physicians have a proven track record of controlling blood pressure in "resistant hypertensive" patients, the general population whom they serve, and educating other physicians to help them achieve higher blood pressure control rates among their patient populations. This report sets out a rationale for increased reimbursement for care of hypertensive patients by ASH-Designated Hypertension Specialists.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

Financial reinforcers for improving medication adherence: findings from a meta-analysis.

BACKGROUND: Increasingly, financial reinforcement interventions based on behavioral economic principles are being applied in health care settings, and this study examined the use of financial reinforcers for enhancing adherence to medications. METHODS: Electronic databases and bibliographies of relevant references were searched, and a meta-analysis of identified trials was conducted. The variability in effect size and the impact of potential moderators (study design, duration of intervention, magnitude of reinforcement, and frequency of reinforcement) on effect size were examined. RESULTS: Fifteen randomized studies and 6 nonrandomized studies examined the efficacy of financial reinforcement interventions for medication adherence. Financial reinforcers were applied for adherence to medications for tuberculosis, substance abuse, human immunodeficiency virus, hepatitis, schizophrenia, and stroke prevention. Reinforcement interventions significantly improved adherence relative to control conditions with an overall effect size of 0.77 (95% confidence interval, 0.70-0.84; P<.001). Nonrandomized studies had a larger average effect size than randomized studies, but the effect size of randomized studies remained significant at 0.44 (95% confidence interval, 0.35-0.53; P<.001). Interventions that were longer in duration, provided an average reinforcement of $50 or more per week, and reinforced patients at least weekly resulted in larger effect sizes than those that were shorter, provided lower reinforcers, and reinforced patients less frequently. CONCLUSION: These results demonstrate the efficacy of medication adherence interventions and underscore principles that should be considered in designing future adherence interventions. Financial reinforcement interventions hold potential for improving medication adherence and may lead to benefits for both patients and society.

A low-cost reinforcement procedure improves short-term weight loss outcomes.

OBJECTIVE: Reinforcement-based treatments, based on behavioral economics models, can improve outcomes of medical conditions with behavioral components. This study evaluated the efficacy of a low-cost reinforcement intervention to produce initial weight loss. METHODS: Overweight individuals (n=56) were randomized to one of two 12-week treatments: Lifestyle, Exercise, Attitudes, Relationships, Nutrition manual with supportive counseling or that same treatment with opportunities to win $1 to $100 prizes for losing weight and completing weight-loss activities. RESULTS: Patients receiving reinforcement lost significantly more weight (6.0% ± 4.9% baseline bodyweight) than patients in the non-reinforcement condition (3.5% ± 4.1%; P=.04). Moreover, 64.3% of patients receiving reinforcement achieved weight loss of ≥ 5% baseline bodyweight versus 25.0% of those in the non-reinforcement condition (P=.003). Proportional weight loss was significantly related to reductions in total cholesterol and 24-hour ambulatory heart rate. CONCLUSION: This reinforcement-based intervention substantially enhances short-term weight loss, and reductions in weight are associated with important changes in clinical biomarkers. Larger-scale evaluation of reinforcement-based treatments for weight loss is warranted.

Early morning hypertension: what does it contribute to overall cardiovascular risk assessment?

The early morning surge in blood pressure (BP) in patients with hypertension is associated with an increased risk of cardiovascular events, such as myocardial infarction and stroke, especially in the presence of comorbidities of diabetes, cardiac and renal disease. A variety of nonhemodynamic factors contribute to the early morning prothrombotic state, including increased atherothrombotic plaque vulnerability and endovascular shear stress, increased coagulability, platelet aggregation, and blood viscosity, and reduced fibrinolysis. In addition, there is a strong association between morning hypertension and vascular damage throughout the circulation, which may involve the myocardium, large arteries, and other target organs. Because morning hypertension is often unrecognized, the resultant target-organ damage may progress relentlessly. With recent advances in ambulatory BP monitoring and BP self-measurement and the inclusion of antihypertensive agents that target the underlying pathophysiological mechanisms related to the morning BP surge (ie, the sympathetic nervous system and the renin-angiotensin-aldosterone system), control of morning hypertension is clinically feasible and should be an important therapeutic target.

Clinical assessment of early morning blood pressure in patients with hypertension.

In most individuals with hypertension, blood pressure (BP) shows a moderate to marked increase around the time of awakening, which has been linked to increases in cardiovascular complications occurring at this time of day. Many antihypertensive agents do not adequately control early morning BP, particularly when administered once daily in the morning. Points to consider in selecting an effective antihypertensive drug include pharmacokinetics and formulation of the agent and timing of administration. Agents with long pharmacologic half-lives, such as the angiotensin II receptor blocker telmisartan, the calcium antagonist amlodipine, and the beta-blocker bisoprolol, are examples of antihypertensive drugs with demonstrated efficacy in controlling early morning BP. Bedtime administration of chronotherapeutic preparations is also effective for controlling early morning BP. Given the association between early morning BP and cardiovascular risk, future clinical trials should focus on the efficacy of antihypertensive drugs during this important period of risk.

Ambulatory blood pressure monitoring in the primary care setting: assessment of therapy on the circadian variation of blood pressure from the MICCAT-2 Trial.

BACKGROUND: We conducted a large-scale, practice-based trial (MICCAT-2) to evaluate the effects of telmisartan alone and in combination with a diuretic on 24-h blood pressure (BP) profiles, including the early morning period, a time when cardiovascular risk is excessive. METHODS: Patients with hypertension, either untreated or currently on treatment, were started on, or switched to, the angiotensin receptor blocker telmisartan 40 mg daily; after 2 weeks, if office blood pressure (BP) remained > or =140/85 mmHg, the dose was increased to 80 mg; and if necessary, hydrochlorothiazide 12.5 mg was added after a further 4 weeks and continued for a final 4-week period. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed at baseline and at the end of the treatment period. Baseline and treatment ABPM measurements were completed in 1619 patients. RESULTS: There were highly significant reductions in both the daytime (-11.8/-7.2 mmHg) and night-time (-9.6/-5.7 mmHg) mean BP following telmisartan alone or in combination with the diuretic. Evaluation of the 24-h profiles showed evidence for sustained pharmacodynamic effects of telmisartan over the entire dosing period. Ninety-five (6%) patients had a marked surge in early morning BP defined as >30 mmHg post-awakening change in systolic BP. The average reduction of in the early morning (post-awakening) BP in the entire cohort was -11.5/-7.0 mmHg (P<0.001; reductions were similar for monotherapy and combination therapy groups. The early morning post-awakening BPs fell by an average of -17.2/-10.1 mmHg in patients with large morning BP surges (P<0.05 versus non-surge patients). CONCLUSIONS: In a community based study using ambulatory BP monitoring, telmisartan-based therapy induced highly significant reductions in systolic and diastolic BP over 24 h and was particularly effective in reducing BP during the early morning period.

Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension.

Eplerenone is a highly selective aldosterone blocking agent, which was recently approved for the treatment of hypertension and has also been shown to reduce mortality in post-myocardial infarction patients with heart failure. To assess its usefulness in patients with essential hypertension, we performed a 12-week, double-blind, placebo-controlled, parallel-arm, fixed-dose study over a range of doses using clinic and ambulatory blood pressure (BP). After single-blind placebo therapy for 3 to 4 weeks to obtain baseline measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg once daily). In addition, changes from baseline in serum potassium, active renin activity, and serum aldosterone were assessed. After 12 weeks of therapy, reductions in clinic BP showed a significant dose response in which 25 mg of eplerenone achieved statistical significance compared with placebo for systolic BP; maximum clinic BP reduction was achieved with the 100 mg dose. Ambulatory BP monitoring showed that all doses of eplerenone (25 to 200 mg/day) lowered BP significantly greater than placebo with a significant dose response. The 24-hour mean BP reductions ranged from 6.4/4.4 to 10.3/5.7 mm Hg on eplerenone compared with 1.3/0.8 mm Hg on placebo. One patient on placebo and 1 patient on 200 mg of eplerenone had episodes of elevated serum potassium levels (>5.5 mEq/L). Increases in serum aldosterone were related to dose but not to reductions in 24-hour BP. Side effects and withdrawal rates attributed to eplerenone were similar to those of placebo. These data show that eplerenone is an effective antihypertensive agent at doses as low as 25 mg/day. The top effective dose in stage 1 to 3 hypertension based on clinic and ambulatory BP was 100 mg once daily. The incidence of elevated serum potassium levels was not increased across doses of eplerenone in this study.

Clinical utility of ambulatory blood pressure: perspectives for national insurance coverage.

During 2001, the Center for Medicare and Medicaid Services (CMS, formally known as HCFA) independently evaluated the US national insurance coverage policy for ambulatory blood pressure monitoring. Diagnostic uses evaluated included screening for white-coat hypertension, assessment for possible antihypertensive drug resistance, evaluation of hypotensive symptoms, episodic hypertension, and autonomic dysfunction. In their analysis, the committee presented and analyzed the relevant scientific and clinical literature on the use of ABPM in certain patient populations and delineated the reason for a limited national coverage decision for patients with suspected white-coat hypertension.