Comparison of a Chronotherapeutically Administered β Blocker vs. a Traditionally Administered β Blocker in Patients With Hypertension

Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of β blockers during this period may decrease cardiac workload, particularly in β-blocker sensitive patients. The impact of a new chronotherapeutic β blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (−9.01-6.9 mm Hg and −10.41-7.7 mm Hg, respectively). The top 25% of responders to highdose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were −8.0/-6.7 mm Hg and −7.61-5.8 mm Hg, respectively. Mean blood pressure reductions in the β-blocker sensitive patients (n=11) between 6 a.m. and noon were −15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was −14.1 bpm and double product reduction was −3319 in the INP patients between 6 a.m. and 12 noon compared with −10.5 and −2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day β blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in β-blocker sensitive patients than does traditionally dosed propranolol.     

Clinic dosing of beta blockers in chronic heart failure

Beta blockers improve survival and reduce morbidity of patients with chronic heart failure. Stringent dosing guidelines calling for a 1-hour observation period after initiation or up-titration of beta-blocker therapy might limit the use of beta blockers and increase the expense involved. This study was conducted to determine the usefulness of this observation period. Data were collected from 130 in-clinic postdosing observation periods for 34 stable chronic heart failure patients started on carvedilol. The mean left ventricular ejection fraction was 0.22±0.09, and the mean functional class was 2.5±0.6. No patient had greater than first-degree heart block. Carvedilol was started at 3.125 or 6.25 mg b.i.d., and the dose was doubled every 1-3 weeks. All patients were observed for 1-2 hours after initiation or dosage increase, and blood pressure and heart rate were measured hourly. The maximal daily dose was 50±31 mg. In none of the observation periods was there a decrease in the dose of beta blockers administered in the clinic. The predosing mean blood pressure was 110±15/71±10 mm Hg, and the mean heart rate was 78±13 bpm; the 1-hour postdosing mean blood pressure was 101±14/67±10 mm Hg (p is less than 0.001), and the heart rate was 78±13 bpm. The dose was decreased in six patients and medication was discontinued in three, all consequent to symptoms reported several days after dosage increase. Beta blockers can be safely initiated and up-titrated at home in properly selected and evaluated stable patients with chronic heart failure and severe left ventricular dysfunction resulting in mild or moderate impairment of functional capacity. (c)2001 by CHF, Inc.     

Cigarette smoking interferes with treatment of hypertension

We retrospectively analyzed two studies to determine whether smoking affected the treatment of hypertension. In a study of the effects of propranolol hydrochloride (a hepatically metabolized beta-blocker) vs hydrochlorothiazide, 108 smokers and 232 nonsmokers were randomized to the propranolol treatment group. The propranolol-treated smokers tended to be younger, taller, thinner, and wre more likely to be black. This group also had an initial blood pressure reduction (+/- SD) of -7.9 +/- 12.9/-8.7 +/- 8.4 mm Hg compared with -10.7 +/- 13.0/-10.9 +/- 7.1 mm Hg for the nonsmokers. Blood pressure increased less during the one-year maintenance period for the nonsmokers. However, when analyzed by race, this effect was seen in blacks, but not in whites. Diastolic blood pressure tended to be reduced more in nonsmokers (vs smokers) receiving hydrochlorothiazide (-12.1 +/- 6.7 vs -10.7 +/- 6.7 mm Hg, respectively). The second study compared the effects of nadolol (a renally excreted beta-blocker) with bendroflumethiazide. There were no significant effects on blood pressure for either of these drugs. In both studies, there was a greater tendency for smokers to be terminated from the study irrespective of drug group. We conclude that cigarette smoking does interfere with the treatment of hypertension in general, and especially with reduction of blood pressure by propranolol in black patients.     

Clinical responses to oxprenolol in the elderly

Data from 6 controlled clinical trials of oxprenolol carried out in the United States were reviewed to determine the efficacy and tolerability of oxprenolol in patients aged greater than or equal to 55 years. All study designs but 1 called for dosage to be increased to a maximum of 480 mg/day. In a 10-week trial of oxprenolol versus placebo given twice daily, oxprenolol reduced diastolic pressure by 8 mm Hg, while placebo reduced it by 3 mm Hg. A comparison of once-daily with twice-daily dosing showed similar results for both groups: -12/-6 mm Hg for once-daily and -9/-8 mm Hg for twice-daily. There were 2 short-term studies comparing oxprenolol and placebo, both given in addition to hydrochlorothiazide. In the first, the change in blood pressure with oxprenolol was -18/-14 mm Hg and with placebo was +6/-3 mm Hg; only 3 of 14 patients receiving oxprenolol received a maximal dosage. In the follow-up study, most of the dosages were titrated to maximum; reductions were -9/-9 mm Hg with oxprenolol treatment and 0/-12 mm Hg with placebo. Two long-term studies compared oxprenolol and propranolol, also as combination therapy with hydrochlorothiazide. In the 14-week study, the reduction in blood pressure was slightly better with oxprenolol: -15/-15 versus -12/-11 mm Hg. In the 27-week study, almost half of the patients in the oxprenolol group received the maximal dosage. Blood pressure was reduced 2 or 3 mm Hg less with oxprenolol than with propranolol. Oxprenolol was well tolerated in the elderly; it produced a low incidence of typical beta-blocker side effects even when given in a once-daily regimen.     

Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.     

Treatment with metoprolol succinate, a selective beta adrenergic blocker, lowers blood pressure without altering insulin sensitivity in diabetic patients

Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity, especially among high-risk patients such as diabetics. This study examined the effect of the beta1-selective adrenergic receptor-blocking agent extended-release metoprolol succinate (ER metoprolol) on insulin sensitivity in type 2 diabetic patients with suboptimal blood pressure control. Diabetic patients with average blood pressure levels >130/85 mm Hg despite antihypertensive therapy had insulin sensitivity quantified by insulin clamp. ER metoprolol was then added to their ongoing therapy. Following 12 weeks of ER metoprolol plus other therapy, the insulin clamp study was repeated. There were no significant changes in measures of insulin sensitivity, plasma lipids, or hemoglobin A1c with use of ER metoprolol. When beta-blocker therapy is considered, it appears that this agent can be used to treat hypertension without adverse effects on insulin sensitivity in patients with type 2 diabetes, at least over the period of time treated.     

国产比索洛尔对高血压2型糖尿病患者糖代谢的影响

目的观察国产比索洛尔对高血压合并2型糖尿病患者糖代谢及血压的影响情况。方法将符合纳入标准的高血压合并2型糖尿病患者随机分组。观察治疗前后患者糖化血红蛋白(HbA1c)、空腹血糖、糖耐量和血压等的变化。结果共有92例患者完成研究,其中比索洛尔组47例,卡托普利组45例。治疗前和经12周治疗后两组HbA1c、空腹血糖、餐后2h血糖、收缩压和舒张压差异均无统计学意义(P=0.05)。结论本研究表明比索洛尔作为高选择性β1受体阻滞剂,对于原发性高血压合并2型糖尿病患者糖代谢无明显不良影响,同时具有良好的降压效果。     

Remission of mild to moderate hypertension after treatment with carteolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity

Previous studies have indicated that some hypertensive patients, following a period of effective treatment with certain antihypertensive drugs, may experience prolonged normotension after drug withdrawal. We have studied the ability of carteolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, to produce such remissions of hypertension. Thirty-four patients whose diastolic blood pressure was controlled at 90 mm Hg or less with carteolol monotherapy (2.5 to 5.0 mg/d for an average of 328 days) were randomized to a nine-month, double-blind, placebo-controlled drug-withdrawal trial. Those patients randomized to continue carteolol therapy had initially responded to carteolol treatment with reduction in blood pressure from 151 +/- 4/99 +/- 2 to 132 +/- 4/80 +/- 2 mm Hg. Those randomized to treatment with placebo had initially responded with blood pressure reductions from 154 +/- 4/97 +/- 2 to 137 +/- 4/81 +/- 2 mm Hg. Changes in mean systolic and diastolic blood pressure (mm Hg +/- SEM) from baseline during carteolol therapy to the final visit at nine months were not different for patients receiving placebo (13 +/- 5/6 +/- 4 mm Hg, recumbent; 11 +/- 6/4 mm Hg, standing) or carteolol (11 +/- 5/7 +/- 3 mm Hg, recumbent; 12 +/- 6/7 +/- 3 mm Hg, standing). The final mean recumbent diastolic blood pressure (86.9 mm Hg) was the same in both groups. Prolonged normotension may follow a period of carteolol treatment, again suggesting the potential importance of periodic withdrawal of antihypertensive medication.     

Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis.

Only some patients show a substantial hepatic venous pressure gradient (HVPG) reduction after propranolol, which makes it desirable to investigate drugs with greater portal hypotensive effect. The aim of this study was to investigate whether carvedilol, a nonselective beta-blocker with anti-alpha1-adrenergic activity, may cause a greater HVPG reduction than propranolol. Thirty-five cirrhotic patients had hemodynamic measurements before and after the random administration of carvedilol (n = 14), propranolol (n = 14), or placebo (n = 7). Carvedilol markedly reduced HVPG, from 19.5 +/- 1.3 to 15.4 +/- 1 mm Hg (P <.0001). This HVPG reduction was greater than after propranolol (-20.4 +/- 2 vs. -12.7 +/- 2%, P <.05). Moreover, carvedilol decreased HVPG greater than 20% of baseline values or to 相似文献   

The foundation role of beta blockers across the cardiovascular disease spectrum: a year 2009 update

Hypertension is a risk factor for myocardial infarction (MI), stroke, and heart failure and precedes heart failure in 91% of cases. This becomes even more important considering that the number of Americans with hypertension increased from 65 million in 2005 to 72 million in 2007. If blood pressure is effectively controlled this risk can be minimized-blood pressure reductions as small as 2 mm Hg have been shown to reduce the risk of cardiovascular events by up to 10%. There is also strong evidence that blood pressure targets for populations at high risk of cardiovascular disease, including those with diabetes, coronary artery disease, and chronic kidney disease, should be lower than 140/90 mm Hg. The number and type of antihypertensive drugs have increased dramatically from 28 diuretics in 1972 to over 125 agents today, including fixed dose combination dosage forms. Beta blockers have been available for the treatment of hypertension since the 1960s. However, there has been resistance to using these agents in patients with diabetes and renal failure because of metabolic side effects, and in other patients because of tolerability concerns such as depression, weight gain, and impotence. Two newer beta blockers with vasodilatory effects (carvedilol and nebivolol) have proven efficacy and tolerability in patients with hypertension and appear to lack the adverse effects associated with older beta blockers. Carvedilol causes vasodilation by alpha blockade, and nebivolol via nitric oxide mechanisms. Both of these agents reduce peripheral vascular resistance and maintain cardiac output. Clinical trial evidence to date leads to the conclusion that beta blockers are strongly indicated post-MI and in all patients with left ventricular dysfunction regardless of symptoms. Their beneficial abilities include improvement of oxygen supply and demand (which can reduce myocardial ischemia), anti-arrhythmic properties, and beneficial effects on cardiac remodeling.     

Superiority of nonpharmacologic therapy compared to propranolol and placebo in men with mild hypertension: a randomized, prospective trial.

We compared the effects of nonpharmacologic therapy, propranolol monotherapy, and placebo on blood pressure, metabolic, exercise, and quality of life variables in a 12-week, randomized, placebo-controlled trial of 79 male patients with hypertension. A significant reduction in diastolic blood pressure was observed with both nondrug therapy (-8.0 +/- 1.08 mm Hg) and propranolol (-9.5 +/- 1.46 mm Hg) compared to placebo (-0.1 +/- 2.01 mm Hg). However, only patients receiving nonpharmacologic therapy showed a reduced body mass index, lower total and low-density lipoprotein serum cholesterol levels, and increased exercise tolerance compared to both propranolol and placebo. Patients receiving propranolol felt less anxious and unsure but showed a significant decrement in nocturnal penile tumescence compared to both placebo and nondrug therapy. Patients receiving nondrug therapy felt more energetic and reported improved sexual arousal and greater sexual satisfaction after treatment. Reductions in blood pressure in the nondrug treatment group were related to both weight reduction and improved fitness. We conclude that nondrug therapy is effective in controlling blood pressure in men with mild hypertension and is associated with improvements in weight, lipoprotein levels, and exercise tolerance compared to both propranolol and placebo. Quality of life assessments further support the use of nondrug therapy in this context.     

Efficacy and safety of the selective aldosterone blocker eplerenone in Japanese patients with hypertension: a randomized, double-blind, placebo-controlled, dose-ranging study

Approximately 40% of Japanese patients with essential hypertension, including low-renin hypertension, are inadequately managed. Low-renin hypertension generally responds poorly to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, but may respond more optimally to diuretics, calcium channel blockers, and aldosterone blockers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluated the efficacy and safety of the selective aldosterone blocker eplerenone in 193 Japanese patients with essential hypertension. Although not a study inclusion criterion, baseline active plasma renin levels were consistently low (5.7-10.1 mU/L); most patients met the criteria for low-renin hypertension (< or =42.5 mU/L; normal range, 7-76 mU/L). Patients received placebo or eplerenone 50, 100, or 200 mg once daily for 8 weeks. Systolic blood pressure decreased significantly (-6.8 to -10.6 mm Hg vs. -2.1 mm Hg; p< or =0.0022 vs. placebo). Eplerenone offers significant blood pressure reduction with good tolerability in Japanese patients with hypertension, including those with low-renin hypertension.     

Is beta 1-antagonism essential for the antihypertensive action of beta-blockers?

Both nonselective beta-blockers and beta 1-selective blockers are effective antihypertensive agents. beta 1-Blockade generally is considered to be responsible for their antihypertensive action, whereas beta 2-blockade is regarded as undesirable. These common assumptions notwithstanding, the mechanism by which beta-blockers lower blood pressure remains unknown. To examine the possibility that beta 2-blockade may contribute to the antihypertensive action of beta-blocker therapy, we studied the cardiovascular effects of compound ICI 118551, a beta 2-selective blocker. First, we showed that 50 mg t.i.d. orally is a beta 2-selective dose. In contrast to propranolol, 80 mg t.i.d., or atenolol, 100 mg once a day, 50 mg of ICI 118551 t.i.d. failed to block beta 1-mediated inotropic stimulation and stimulation of renin by isoproterenol. We then performed a double-blind, placebo-controlled trial in patients with mild essential hypertension to compare this compound with propranolol, 80 mg t.i.d., and showed that ICI 118551 significantly decreased systolic and diastolic blood pressure. This antihypertensive effect was demonstrated by direct as well as by indirect blood pressure measurements. Thus, contrary to prevailing thought, beta 2-blockade has an antihypertensive effect independent of, and distinct from, beta 1-blockade.     

Novel use of a short-acting intravenous beta blocker in combination with inotropic therapy as a bridge to chronic oral beta blockade in patients with advanced heart failure

The role for beta blockers in advanced heart failure (New York Heart Association class IV) remains undefined because of concerns about tolerability and uncertainty about efficacy. We report the use of a short-acting intravenous beta blocker in combination with inotropic therapy as a means to bridge five patients with advanced heart failure to chronic oral beta blockade; two of these patients had been chronically managed with intravenous inotrope. At 4 months' follow-up, all patients remained on beta-blocker therapy and none was hospitalized for heart failure or had received intravenous diuretics. Given the early separation of survival curves in the randomized clinical trials of beta blockers in heart failure, it is possible that these patients will accrue a survival benefit. We conclude that some patients with advanced heart failure can be offered oral beta-blocker therapy by bridging with a combination of intravenous inotrope and short-acting intravenous beta blocker.     

Combination Therapy Versus Monotherapy in Reducing Blood Pressure: Meta-analysis on 11,000 Participants from 42 Trials

Objective

To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose.

Methods

Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo.

Results

We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]).

Conclusion

Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.     

Acute effect of propranolol on splanchnic circulation in normal and portal hypertensive rats

Propranolol decreases portal venous pressure in patients with cirrhosis but no method is available in man to study the effect of this beta-blocker on splanchnic organ blood flow. Because in rats, the microsphere method allows evaluation of regional blood flow, the acute effect of propranolol on both splanchnic and systemic circulations was studied in normal rats and in rats with portal hypertension due to portal vein stenosis. Portal venous pressure significantly decreased during propranolol administration in normal (5.6 +/- 1.0-4.7 +/- 1.1 mm Hg; mean +/- SD) as well as in portal hypertensive rats (11.7 +/- 2.3-10.3 +/- 1.8 mm Hg). Propranolol slightly decreased cardiac output and arterial pressure in all rats. Portal tributary blood flow was significantly reduced by propranolol in normal rats (17.4 +/- 3.0-11.3 +/- 2.2 ml/min) and in portal hypertensive rats (23.7 +/- 5.0-16.6 +/- 3.3 ml/min). Accordingly vascular resistance of the different organs in the portal venous territory increased in these rats receiving propranolol. The percentage of the decrease in portal tributary blood flow was significantly more marked than the percentage of reduction in cardiac output in portal hypertensive rats but, in normal rats, these percentages were parallel. Hepatic arterial blood flow did not change or slightly increased and, consequently, hepatic arterial vascular resistance decreased. These findings further clarify the marked effects of propranolol on splanchnic circulation.     

Effect of selective blockade of beta 2-adrenergic receptors on portal and systemic hemodynamics in a portal hypertensive rat model

Propranolol, a nonselective beta-adrenergic blocker, appears to reduce portal pressures in portal hypertension by reducing portal blood flow. The aim of this study was to investigate the relative role of selective beta 1- and beta 2-blocking properties of propranolol participating in portal blood flow reduction. Portal hypertensive rats receiving placebo exhibited elevated portal blood flow of 1.31 +/- 0.4 ml/min per g splanchnic tissue and portal pressure of 15.4 +/- 0.43 mmHg, with elevated cardiac index of 358 +/- 20 ml/min per kg. Portal hypertensive rats were divided into groups receiving propranolol nonspecific beta-blockade, atenolol selective beta 1-blockade, and ICI 118551 selective beta 2-blockade. Significant (p less than 0.05) reductions in portal blood flow of 32%, 27%, and 21% were achieved in all three groups, respectively, accompanied by significant (p less than 0.05) reductions in portal pressure of 1.7 +/- 0.3, 0.9 +/- 0.2, and 0.8 +/- 0.2 mmHg, respectively. Cardiac index was significantly reduced in the propranolol-treated (25%) and atenolol-treated (20%) groups, but remained unchanged in the ICI 118551-treated group. We conclude that propranolol appears to achieve its therapeutic reduction in portal blood flow and portal pressure through combined participation of beta 1- and beta 2-adrenergic blockade. Furthermore, ICI 118551 selective beta 2-adrenergic blockade offers portal blood flow and portal pressure reduction independent of reduction in cardiac output, which could be uniquely advantageous in situations where impairment of cardiac compensatory mechanisms might prove deleterious.     

Beta-adrenergic blocker withdrawal

Abrupt withdrawal of long-term beta-blocker therapy in patients with angina may be associated with unstable angina and myocardial infarction. It appears that an "overshoot" in heart rate from pretreatment values occurs, which increases myocardial oxygen demand. This increase in heart rate may be secondary to increased beta receptor numbers or increased receptor sensitivity. Another possible mechanism for the increased risk of myocardial infarction after beta-blocker withdrawal is increased platelet aggregability. Withdrawal reactions may be less severe with beta blockers that have partial agonist activity. In patients undergoing coronary artery bypass surgery, beta-blocker withdrawal reactions have also been observed. Maintenance of beta-blocker therapy on the morning of surgery appears to reduce this risk. Gradual withdrawal regimens in outpatients with angina may be associated with lower risk for a beta-blocker withdrawal reaction. The gradual withdrawal of beta blockers in hypertensive patients requires further study.     

Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study

OBJECTIVE: To investigate whether isosorbide-5-mononitrate (Is-5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. DESIGN: A randomized controlled trial. PATIENTS: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. INTERVENTION: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. MEASUREMENTS: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. MAIN RESULTS: At 3 months, the hepatic venous pressure gradient decreased more (P less than 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 +/- 3.9 to 14.9 +/- 3.8 mm Hg; 95% CI, -2.4 to -4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 +/- 3.5 to 16.3 +/- 3.1 mm Hg; CI, -1.1 to -2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P less than 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. CONCLUSIONS: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.     

Clinical and hemodynamic effects of nesiritide (B-type natriuretic peptide) in patients with decompensated heart failure receiving beta blockers

The use of beta blockers in congestive heart failure presents a therapeutic challenge for patients with acute episodes of decompensation. Such patients may be less responsive to positive inotropic agents, whereas the beneficial effects of nesiritide, which are not dependent on the beta-adrenergic receptor signal-transduction pathway, may be preserved. This analysis of the Vasodilation in the Management of Acute CHF trial evaluated the safety and efficacy of nesiritide in decompensated congestive heart failure patients receiving beta blockers. The Vasodilation in the Management of Acute CHF trial was a multicenter, randomized, controlled evaluation of nesiritide in 489 hospitalized patients with decompensated congestive heart failure. One hundred twenty-three patients were on chronic beta-blocker therapy at enrollment (31 randomized to placebo, 50 to nesiritide, and 42 to nitroglycerin). Primary end points included pulmonary capillary wedge pressure and dyspnea evaluation at 3 hours. Patients receiving nesiritide, but not IV nitroglycerin, had significantly reduced pulmonary capillary wedge pressure vs. placebo at 3 hours regardless of beta-blocker use. The use of beta blockers did not alter the beneficial effects of nesiritide on systemic blood pressure, heart rate, or dyspnea evaluation. In nesiritide-treated subjects, safety profiles were similar regardless of beta-blocker use. Thus, the clinical and hemodynamic benefits and safety of nesiritide are preserved in decompensated congestive heart failure patients receiving chronic beta blockade.