Enabling patient-reported outcome measures in clinical trials, exemplified by cardiovascular trials.

Objectives: There has been limited success in achieving integration of patient-reported outcomes (PROs) in clinical trials. We describe how stakeholders envision a solution to this challenge.

Methods: Stakeholders from academia, industry, non-profits, insurers, clinicians, and the Food and Drug Administration convened at a Think Tank meeting funded by the Duke Clinical Research Institute to discuss the challenges of incorporating PROs into clinical trials and how to address those challenges.

Lessons learned from a survey of the diagnosis and treatment journeys of postmenopausal women with hypertension.

In this qualitative, experiential study, 300 members of the database of WomenHeart: The National Coalition for Women With Heart Disease completed an online survey about hypertension diagnosis and treatment, patient education, and perceptions of this and related conditions. Based on the findings from the survey, characteristics of the prototypical journey were identified. To the extent to which the surveyed WomenHeart members represent typical experiences, this survey provides insights into common hurdles women encounter in their journey throughout the hypertension diagnosis and treatment process.

Progression to type 2 diabetes, healthcare utilization, and cost among pre-diabetic patients with or without comorbid hypertension.

Objective: This study examined progression to type 2 diabetes and compared healthcare utilization and costs among patients with pre-diabetes, with or without comorbid hypertension.

Research Design And Methods: This study drew from a large national claims database (2003-2008). Patients were ≥18 years of age with a medical claim or lab value indicating the presence of pre-diabetes.

Combination therapy for managing difficult-to-treat patients with stage 2 hypertension: focus on valsartan-based combinations.

Blood pressure (BP) control rates in the United States remain low despite the availability of a wide array of treatment options. High-risk populations, including women, black individuals, and obese patients are even less likely to achieve BP targets than the general population. Uncontrolled BP can lead to serious consequences.

Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes.

Background And Purpose: The SPARCL trial showed that atorvastatin 80 mg/d reduces the risk of stroke and other cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). We tested the hypothesis that the benefit of treatment varies according to index event stroke subtype.

Methods: Subjects with stroke or TIA without known coronary heart disease were randomized to atorvastatin 80 mg/d or placebo.

Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

Objective: To explore the relative contributions of baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and lipoproteins on the risk of recurrent stroke or first major cardiovascular event (MCVE) and their potential impact on the benefit of statin treatment.

Methods And Results: The SPARCL trial randomized 4731 patients with recent stroke or transient ischemic attack (TIA) and no known coronary heart disease and LDL-C between 100 and 190 mg/dL to either atorvastatin 80 mg/d or placebo. Baseline assessment included SBP, DBP and measurements of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and triglyceride levels.

Persistence of atorvastatin and simvastatin among patients with and without prior cardiovascular diseases: a US managed care study.

Background: In clinical practice, persistence with statin therapy is poor. While little is known about relative persistence to specific statins, previous studies have observed greater persistence in patients who achieve greater degrees of lipid lowering. Identification of statin therapies which improve patient persistence has the potential to improve the quality of patient care and clinical outcomes.

Cardiovascular outcomes among patients newly initiating atorvastatin or simvastatin therapy: a large database analysis of managed care plans in the United States.

Background: While the results of randomized clinical trials have indicated that statins improve outcomes in patients without cardiovascular disease (CVD), it remains uncertain whether there are differences in efficacy between statins, particularly in clinical practice, where the public health implications could be substantial.

Objective: We assessed cardiovascular (CV) outcomes among primary-prevention patients newly initiating therapy with atorvastatin or simvastatin.

Methods: Using claims data from 92 US managed care plans, we identified new statin users without CVD who initiated atorvastatin (10 or 20 mg) or simvastatin (20 or 40 mg) from January 2003 to September 2005 and were continuously enrolled in a covered plan for > or = 12 months before and > or = 1 month after the initiation of statin therapy.

Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

Background And Purpose: The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a >or=50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline.

High-dose atorvastatin after stroke or transient ischemic attack.

Background: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established.

Methods: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.

Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone.

Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRA), a selective aldosterone blocker, in the treatment of hypertension and heart failure.

Emerging therapies for heart failure.

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death.

Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction.

Background: Mitogen-activated protein kinases (MAPKs) have emerged as an important pathophysiologic regulator during the development of heart failure (HF). p38 MAPK activity is elevated in cardiac hypertrophy and HF. We used a mouse model of myocardial infarction (MI) to test the hypotheses that (1) inhibition of p38 MAPK activity may improve cardiac function and remodeling after myocardial infarction (MI) and (2) coadministration of a p38 inhibitor (p38i) and an angiotensin-converting enzyme inhibitor (ACEI) may provide only limited further cardioprotection in this model.

Eplerenone, a selective aldosterone blocker, improves diastolic function in aged rats with small-to-moderate myocardial infarction.

Background: The incidence of cardiovascular diseases increases rapidly with age, and the elderly suffer higher morbidity and mortality. Aldosterone blockers have shown benefits in patients with left ventricular (LV) dysfunction and heart failure after myocardial infarction (MI). However, aldosterone blockade efficacy has not been explored in aged animals with MI.

Aldosterone target organ protection by eplerenone.

The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant effect of this hormone. However, there is convincing evidence for additional extrarenal actions of aldosterone that are mediated via activation of mineralocorticoid receptors (MRs) in the heart, vasculature and brain. It is now postulated that many of the detrimental effects of aldosterone are mediated through MR activation in these nonclassical target organs.

Role of a selective aldosterone blocker in mice with chronic heart failure.

Background: Spironolactone, a nonselective aldosterone blocker, has a cardioprotective effect; however, significant endocrine side effects limit its use. Eplerenone is a new selective aldosterone blocker. We investigated whether eplerenone attenuates cardiac remodeling and improves function in a mouse model of heart failure and whether coadministration of eplerenone and an angiotensin-converting enzyme inhibitor (ACEi) provides better cardioprotection than either agent alone.

Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter.

Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.

Background: We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker, eplerenone.

Methods: Unnephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and randomized to receive treatment for 28 days: vehicle infusion (control); 0.75 microg/hour aldosterone subcutaneous infusion; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone.

Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure.

Background: In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF.

The role of the factor X activation peptide: a deletion mutagenesis approach.

To understand the role of the factor X (fX) activation peptide (AP), a deletion mutagenesis approach was employed. Two single-chain, variant enzymes were generated in which 41 residues were deleted from the AP: fX (des-137-183) and fX(des-137-183;N191A), which lacks a carbohydrate moiety at Asn191 due to an alanine substitution. Deletion of the fX AP did not impact fXa catalytic activity.

Aldosterone induces a vascular inflammatory phenotype in the rat heart.

Vascular inflammation was examined as a potential mechanism of aldosterone-mediated myocardial injury in uninephrectomized rats receiving 1% NaCl-0.3% KCl to drink for 1, 2, or 4 wk and 1) vehicle, 2) aldosterone infusion (0.75 microg/h), or 3) aldosterone infusion (0.

Structural, functional, and molecular characterization of the SHHF model of heart failure.

Heart failure is a complex multifactorial disease resulting in a myriad of progressive changes at the molecular, cellular, and physiological level. To better understand the mechanisms associated with the development of congestive heart failure, a comprehensive examination of the aging lean male spontaneously hypertensive, heart failure-prone rat (SHHF) was conducted. Myocardial function and structural integrity progressively diminished as evidenced by decreased ejection fraction and increased left ventricular volume measured using echocardiography.

Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector.

Transmission by flea bite is a relatively recent adaptation that distinguishes Yersinia pestis, the plague bacillus, from closely related enteric bacteria. Here, a plasmid-encoded phospholipase D (PLD), previously characterized as Yersinia murine toxin (Ymt), was shown to be required for survival of Y. pestis in the midgut of its principal vector, the rat flea Xenopsylla cheopis.