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Biomedical subjects

Jay N Cohn

Publications and source records attributed to Jay N Cohn.

At least 73 records · Page 4Linked to original sources
PubMed2003

Interaction of beta-blockers and angiotensin receptor blockers/ACE inhibitors in heart failure.

The renin-angiotensin-aldosterone system contributes to the progression of heart failure and its inhibition slows ventricular remodelling and favourably affects morbidity and mortality. beta-blockers exert a remarkably favourable effect on progression that may be mediated at least in part by renin inhibition. Although earlier trials suggested a possible adverse interaction when an angiotensin receptor blocker was added to an angiotensin-converting enzyme inhibitor and a beta-blocker, a recent study and newly analysed mechanistic data indicate that the triple combination provides modest additional inhibition of angiotensin that can further slow progression of disease.

Adrenergic beta-Antagonists↗
PubMed2002

Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT).

BACKGROUND: Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. METHODS AND RESULTS: Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or beta-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (+/-SEM) BNP increased from baseline by 23+/-5 pg/mL in the placebo group (n=1979) but decreased by 21+/-5 pg/mL (n=1940) in the valsartan group (P<0.0001). NE increased by 41+/-6 pg/mL (n=1979) and 12+/-6 pg/mL (n=1941) for placebo and valsartan, respectively (P=0.0003). Concomitant therapy with both ACE inhibitors and beta-blockers significantly reduced the effect of valsartan on BNP but not on NE (P for interaction=0.0223 and 0.2289, respectively). CONCLUSIONS: In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.

Adrenergic beta-Antagonists↗
PubMed2002

Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors.

OBJECTIVES: A subgroup analysis of the Valsartan Heart Failure Trial (Val-HeFT) was performed to evaluate the effects of the angiotensin II receptor blocker, valsartan, in the patients with chronic heart failure (HF) not receiving angiotensin-converting enzyme (ACE) inhibitors. BACKGROUND: The ACE inhibitors reduce mortality and morbidity in patients with HF. Nonetheless, nearly 20% of potentially eligible patients may not be prescribed ACE inhibitors. RESULTS: Val-HeFT was an international, randomized, double-blinded trial that compared valsartan with placebo when added to the prescribed treatment of patients with HF. The two primary end points of the study were all-cause mortality and the composite of all-cause mortality and morbidity (sudden death with resuscitation, hospital admission for HF, or administration of intravenous inotropic or vasodilator drugs for >or=4 h without hospital admission). Of the 5,010 patients enrolled in the trial, 366 (7.3%) were not treated with ACE inhibitors at baseline. The effects of valsartan on the primary and secondary end points of the study were assessed in this subgroup of patients. RESULTS: Both all-cause mortality and combined mortality and morbidity for patients not treated with ACE inhibitors were significantly reduced in the valsartan treatment group compared with the placebo group (17.3% vs. 27.1%, p = 0.017 and 24.9% vs. 42.5%, p < 0.001, respectively). Consistent with the data on clinical events, patients randomized to valsartan showed improvements in physiologic variables, such as ejection fraction, left ventricular internal diameter in diastole, and plasma neurohormone levels. Permanent discontinuation of study treatment because of adverse experiences was comparable between the two groups. CONCLUSIONS: Val-HeFT has provided the first placebo-controlled outcome data demonstrating a favorable effect of an angiotensin receptor blocker on mortality and morbidity in patients with HF not treated with ACE inhibitors. Based on these results, valsartan appears to be an effective therapy in ACE inhibitor-intolerant patients.

Aged↗
PubMed2002

Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study.

OBJECTIVES: The objective of the study was to evaluate the effect of an angiotensin receptor blocker on left ventricular (LV) structure and function when added to prescribed heart failure therapy. BACKGROUND: The clinical benefit derived from heart failure therapy is attributed to the regression of LV remodeling. METHODS: At 302 multinational sites, 5,010 patients in New York Heart Association (NYHA) classification II to IV heart failure taking angiotensin-converting enzyme inhibitor (ACEI) and/or beta-blocker (BB) were randomized into valsartan and placebo groups and followed for a mean of 22.4 months. Serial echocardiographic measurements of left ventricular internal diastolic diameter (LVIDd) and ejection fraction (EF) were recorded. Total study reproducibility calculated to 90% power at 5% significance defined detectable differences of 0.09 cm for LVIDd and 0.86% for EF. RESULTS: Baseline LVIDd and EF for valsartan and placebo groups were similar: 3.6 +/- 0.5 versus 3.7 +/- 0.5 (cm/m(2)) and 26.6 +/- 7.3 versus 26.9 +/- 7.0 (%). Mean group changes from baseline over time were compared. Significant decrease in LVIDd and increase in EF began by four months, reached plateau by one year, and persisted to two years in valsartan compared with placebo patients, irrespective of age, gender, race, etiology, NYHA classification, and co-treatment therapy. Changes at 18 months were -0.12 +/- 0.4 versus -0.05 +/- 0.4 (cm/m(2)), p < 0.00001 for LVIDd, and +4.5 +/- 8.9 versus +3.2 +/- 8.6 (%), p < 0.00001 for EF. The exception occurred in patients taking both ACEI and BB as co-treatment, in whom the decrease in LVIDd and increase in EF were no different between valsartan and placebo groups. CONCLUSIONS: The Val-HeFT echocardiographic substudy of 5,010 patients with moderate heart failure demonstrated that valsartan therapy taken with either ACEI or BB reversed LV remodeling.

Adrenergic beta-Antagonists↗
PubMed2002

Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure.

BACKGROUND: In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. METHODS AND RESULTS: A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. CONCLUSIONS: Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.

Blood Pressure↗
PubMed2002

Contemporary treatment of heart failure: is there adequate evidence to support a unique strategy for African-Americans? Pro position.

Clinical trials provide average effects of interventions but are not powered to identify differences in subgroup responses. African-Americans have been under-represented in most previous trials in patients with heart failure. Furthermore, physiologic differences have been demonstrated between African-Americans and whites in the mechanisms and response to therapy in hypertension. Review of previous heart failure trials reveals that African-Americans exhibit less benefit than whites from ACE inhibitors, angiotensin receptor blockers, and at least one b-blocker. In contrast, black patients experienced a greater benefit than white patients from the combination of nitrate and hydralazine. These data emphasize the need for trials in black patients to identify effective therapy. The first such trial, African-American Heart Failure Trial, is currently underway.

Adrenergic beta-Antagonists↗
PubMed2002

Prognostic application of arterial stiffness: task forces.

Epidemiologic and clinical studies have shown that increased pulse pressure is an independent cardiovascular risk factor in general population. Pulse pressure is determined by combined effects of cardiac factors (stroke volume) and the arterial stiffness. Arterial stiffness can be more directly evaluated by several measurements including the measure of pulse wave velocity (PWV). Aortic PWV, a marker of aortic stiffness, has been shown to be a strong independent predictor of cardiovascular and all cause mortality in patients with end-stage renal disease (ESRD) on hemodialysis as well as in patients with essential hypertension and older subjects over 80 years. Local arterial stiffness assessment, namely carotid distensibility was also shown to predict cardiovascular risk, both in ESRD patients and in renal transplant recipients. Furthermore, it has been shown in a therapeutic trial that the lack of aortic PWV attenuation despite significant drug-induced reduction in mean blood pressure was a significant predictor of cardiovascular death in subjects with ESRD. These results support the hypothesis that measurement of aortic PWV could then help, not only in risk assessment strategies, but also in risk reduction strategies by monitoring arterial stiffness under different pharmacologic regimens. The drug-related reduction of aortic PWV could then give prognostic information, additionally to blood pressure reduction. Aortic stiffness measurements could serve as an important tool in identifying ESRD patients at higher risk of cardiovascular disease. The ability to identify these patients would lead to better risk stratification and earlier and more cost-effective preventive therapy.

Arteries↗
PubMed2002

African-American Heart Failure Trial (A-HeFT): rationale, design, and methodology.

BACKGROUND: Hydralazine and isosorbide dinitrate combination (H+ISDN), angiotensin-converting enzyme inhibitors, and beta-blockers have improved outcomes in heart failure (HF). Analysis of previous trials has shown that H+ISDN appears especially beneficial in African American patients. METHODS AND RESULTS: The African-American Heart Failure Trial (A-HeFT) is double-blind, placebo-controlled, and includes African American patients with stable New York Heart Association Class III-IV HF on standard therapy. Patients must have prior HF-related events and left ventricular ejection fraction (LVEF) < or = 35% or LVEF <45% with left ventricular internal diastolic dimension >2.9 cm/m(2). Randomization to addition of placebo or BiDil (Nitro Med, Inc., Bedford, MA), a fixed combination of H+ISDN, is stratified for beta-blocker usage. All patients are treated and followed until the last patient entered completes 6 months of follow-up. The primary efficacy endpoint is a composite score including quality of life, death, and hospitalization for HF. At least 600 patients will be randomized; the first was randomized in June 2001. CONCLUSIONS: In addition to providing additional information on BiDil efficacy in HF, A-HeFT is the first HF trial aimed at a selected subgroup of patients and the first to use a new composite HF score as its primary efficacy endpoint.

Adolescent↗
PubMed2002

The African-American Heart Failure Trial: background, rationale and significance.

New treatments have improved outcomes in heart failure (HF), but applicability of these advances may be limited in African Americans. Analysis of previous trials has shown that a combination of hydralazine (H) plus isosorbide dinitrate (ISDN) may be especially beneficial in African Americans with HF. The African American Heart Failure Trial (A-HeFT) is a double-blind, randomized, and placebo-controlled trial in African American patients with stable NYHA Class III-IV HF while on standard therapy. Randomization to addition of BiDil, a fixed combination of H+ISDN, or placebo, will be stratified for beta-blocker usage, and all patients will be treated and followed until the last patient entered has completed six months of follow-up. The primary efficacy endpoint will be a composite score including quality of life, deaths, and hospitalizations for HF. At least 600 patients will be randomized. The first patient was randomized in June, 2001. Besides additional testing of H+ISDN in HF, A-HeFT will be the first HF trial aimed at a subgroup of African American patients, as well as the first to use a new composite HF score as its primary efficacy endpoint.

Black or African American↗
PubMed1991

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.

BACKGROUND: Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35. METHODS: Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months. RESULTS: There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001). CONCLUSIONS: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.

Blood Pressure↗
PubMedDate not supplied

Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.

BACKGROUND: Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. METHODS: 642 patients with chronic heart failure were assigned the oral endothelin(A)-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. FINDINGS: Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1.27 mL [95% CI -9.9 to 12.4] with 10 mg dose, -1.84 mL [-13.0 to 9.3] with 25 mg, -5.68 mL [-16.9 to 5.6] with 50 mg, -4.05 mL [-15.5 to 7.4] with 100 mg, and -4.34 mL [-15.7 to 7.0] with 300 mg). Heart failure worsened in 71 (11.1%) patients, and 30 (4.7%) died during the study with no difference between groups. INTERPRETATION: Endothelin(A) blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.

Dose-Response Relationship, Drug↗