Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients

The efficacy and tolerability of eplerenone, a selective aldosterone blocker, was assessed when added to existing antihypertensive therapy with an ACE inhibitor or an angiotensin II receptor blocker (ARB). Hypertensive patients (n=341) whose blood pressure (BP) was not controlled despite ACE inhibitor or ARB were randomized (double-blind) to receive 50 mg eplerenone (increasing to 100 mg if required) once daily or placebo for 8 weeks. Diastolic and systolic BP and adverse events were recorded. By study end (week 8), mean seated diastolic BP was significantly reduced from week 0 among patients receiving eplerenone/ARB (-12.7+/-0.81 mm Hg) compared with those receiving placebo/ARB (-9.3+/-0.83 mm Hg). The change in mean seated diastolic BP was -9.9+/-0.88 mm Hg in eplerenone/ACE inhibitor patients and -8.0+/-0.86 mm Hg in placebo/ACE inhibitor patients (P=NS). Systolic BP levels were also significantly lower at week 8 for eplerenone/ACE inhibitor (-13.4+/-1.35 mm Hg) and eplerenone/ARB (-16.0+/-1.37 mm Hg) patients, respectively, compared with placebo/ACE inhibitor (-7.5+/-1.31 mm Hg) and placebo/ARB patients (-9.2+/-1.41 mm Hg). Adverse events were generally nonsevere and not significantly different between eplerenone and placebo. This study demonstrated that in patients whose BP was not controlled with an ACE inhibitor or ARB, the addition of eplerenone over an 8-week period significantly lowered systolic BP in both groups and diastolic BP in ARB patients. Selective aldosterone blockade with eplerenone, therefore, may be useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or ARB alone.     

Atenolol plus nifedipine for mild to moderate systemic hypertension after fixed doses of either agent alone

Three therapies were used to treat 35 patients with mild to moderate systemic hypertension: (1) the cardioselective beta-adrenoceptor blocker atenolol, (2) the calcium antagonist nifedipine and (3) combination therapy for those who failed to reach the target diastolic blood pressure (BP) of less than 90 mm Hg with monotherapy. After an initial run-in placebo period, when the mean supine diastolic BP was 102 +/- 1 mm Hg (mean +/- standard error of the mean), patients were randomized (double-blind) to atenolol, 100 mg as a single daily dose or nifedipine (slow-release form), 20 mg twice daily, then to a washout dummy placebo period before crossover. Each period lasted 4 weeks. Supine, erect and exercise BP were recorded. Atenolol and nifedipine, in the same fixed doses but in combination, were given to 20 patients in whom either supine or erect diastolic BP exceeded 90 mm Hg after the period of monotherapy. Atenolol monotherapy reduced the erect diastolic BP to less than 90 mm Hg in 14 patients (40%); of the remainder, 1 patient responded only to fixed-dose nifedipine and 11 to combination therapy, yielding a total success rate of 74%. The combination gave enhanced control, as shown by a further decrease in supine and erect BP and by better control of exercise BP; these effects were achieved without an increased incidence of adverse effects. The mean reductions in supine diastolic BP were: atenolol, 9 +/- 2 mm Hg; nifedipine, 6 +/- 2 mm Hg; and combination therapy, 16 +/- 2 mm Hg (p less than 0.05 vs atenolol or nifedipine).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effect of lercanidipine,felodipine, and nifedipine GITS on blood pressure and heart rate in patients with mild to moderate arterial hypertension: the Lercanidipine in Adults (LEAD) Study

This multicenter, double-blind, parallel-group study compared the effects of three dihydropyridine calcium channel blockers (lercanidipine, felodipine, and nifedipine gastrointestinal therapeutic system) on blood pressure and heart rate in 250 patients with mild to moderate hypertension (diastolic blood pressure 95 and 109 mm Hg). Patients were randomized to 4 weeks of treatment with once-daily doses of lercanidipine 10 mg, felodipine 10 mg, or nifedipine gastrointestinal therapeutic system 30 mg. After 4 weeks of treatment, the dose was doubled in nonresponding patients. At 8 weeks, no significant differences in blood pressure were observed among the three groups. Increases in heart rate in all three groups induced by stressful conditions before and after treatment were not exacerbated during active treatment. The incidence of adverse drug reactions was lower in the lercanidipine and nifedipine groups than in the felodipine group ( p <0.05); in particular, the incidence of edema for lercanidipine was 5.5% vs. 13% for felodipine and 6.6% for nifedipine.     

Felodipine–metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/β-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine–metoprolol treatment controlled blood pressure (diastolic ≤90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine–metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients’ well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.     

Comparison of acebutolol with and without hydrochlorothiazide versus carvedilol with and without hydrochlorothiazide in black patients with mild to moderate systemic hypertension.

In the present study, we assessed the antihypertensive efficacy of acebutolol 200 mg versus carvedilol 25 mg once daily, given as monotherapy for 3 months to 40 black patients (20 patients in each group, mean age 53+/-10 years, 24 women) with mean blood pressure (BP) during the day >90 and <110 mm Hg. Patients in whom blood pressure could not be controlled took medication, which was increased at 3-month intervals as follows: step 2, acebutolol 200 mg or carvedilol 25 mg plus hydrochlorothiazide 12.5 mg once daily; step 3, acebutolol 400 mg or carvedilol 50 mg plus hydrochlorothiazide 25 mg once daily. Overall, significant but modest BP reduction was achieved with both beta blockers at 3 months. In the acebutolol group, 24-hour BP decreased from 142+/-15/94+/-7 mm Hg to 138+/-16/89+/-8 mm Hg (p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP decreased from 145+/-15/98+/-5 mm Hg to 140+/-14/93+/-7 mm Hg (p<0.05 for systolic BP and p<0.0005 for diastolic BP at 3 months vs. baseline). In the carvedilol group, 24-hour BP decreased from 145+/-11/93+/-6 to 138+/-16/87+/-9 mm Hg (p<0.05 for systolic BP and p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP decreased from 149+/-10/99+/-5 to 141+/-16/91+/-87 mm Hg (p<0.05 for systolic BP and p<0.0005 for diastolic BP at 3 months vs baseline). At 12 months, most patients required combination therapy to achieve BP control. The control (mean day diastolic BP <90 mm Hg) and response (mean day diastolic BP decrease > or =10 mm Hg) rates at 12 months were 59% and 82% in the acebutolol and 78% and 78% in the carvedilol groups, respectively. In conclusion, acebutolol or carvedilol in combination with hydrochlorothiazide, rather than acebutolol or carvedilol alone, should be considered as first-line antihypertensive therapy in black patients with mild to moderate hypertension.     

Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients

AIM: To compare candesartan cilexetil and lisinopril in fixed combination with hydrochlorothiazide with respect to antihypertensive efficacy and tolerability. METHODS: This was a double-blind (double-dummy), randomised, parallel group comparison in patients with a mean sitting diastolic blood pressure 95-115 mm Hg on prior antihypertensive monotherapy. Treatments were candesartan cilexetil/hydrochlorothiazide 8/12.5 mg once daily (n = 237) and lisinopril/hydrochlorothiazide 10/12.5 mg once daily (n = 116) for 26 weeks. The primary efficacy variable was change in trough sitting diastolic blood pressure. RESULTS: Changes in mean sitting diastolic blood pressure did not differ significantly between the groups (mean difference 0.5 mm Hg; 95% confidence interval -1.6, 2.7, P = 0.20). No significant differences between the groups was found for other haemodynamic variables (sitting systolic blood pressure, standing blood pressure, sitting/erect heart rate, and proportion of responders and controlled patients). Both drugs were well tolerated but the proportion of patients with at least one adverse event was significantly greater in the lisinopril group (80% vs 69%, P = 0.020). The proportion of patients spontaneously reporting cough (23.1% vs 4.6%) and discontinuing therapy due to adverse events (12.0% vs 5.9%) was also higher in the lisinopril group compared with the candesartan cilexetil group. CONCLUSIONS: The fixed combinations of candesartan cilexetil and hydrochlorothiazide 8/12.5 mg and lisinopril and hydrochlorothiazide 10/12.5 mg once daily are equally effective as antihypertensive agents. The fixed combination containing candesartan cilexetil is better tolerated than that containing lisinopril.     

Effect of enalapril and nifedipine on orthostatic hypotension in older hypertensive patients

OBJECTIVE: To compare the effect of enalapril with long-acting nifedipine on orthostatic hypotension in older patients. DESIGN: A prospective, double blinded, cross-over study. SETTING: The outpatient clinic of a university hospital. PARTICIPANTS: Thirty-nine patients aged 65 years or older with systolic blood pressure (SBP) of 140-190 mm Hg and diastolic blood pressure (DBP) of 90-110 mm Hg. INTERVENTION: Enalapril 5-20 mg od or nifedipine 30-90 mg od for 8 weeks, followed by 4 weeks washout and cross-over for a second 8-week period. MEASUREMENTS: Supine and standing 0-, 1-, and 5-minutes blood pressure was recorded before and at the end of each treatment period. RESULTS: At baseline, SBP was 158.8 +/- 8.7 mm Hg, and DBP was 97.1 +/- 5.9 mm Hg. There was a decline in SBP of 6.1 +/- 2.7 mm Hg and 8.4 +/- 4.1 mm Hg after 1 and 5 minutes of standing, respectively. Both agents caused a significant decline in supine blood pressure. Enalapril: supine SBP 158.8 +/- 8.7 to 143 +/- 7.3 mm Hg; supine DBP 97.1 +/- 5.9 to 85.1 +/- 5.1 mm Hg (P = .0001). The drop in SBP after standing for 5 minutes was only 2.4 +/- 1.6 mm Hg with no change in diastolic values. A > or = 10 mm Hg drop in SBP was observed in only three patients, and no patient experienced a decline of 20 mm Hg or more. Nifedipine: supine SBP: 160.3 +/- 9 to 145.3 +/- 8.1 mm Hg; supine DBP: 96.3 +/- 5.7 to 86.3 +/- 5.8 (P = .0001). Nifedipine induced an orthostatic decline in SBP values; there was an 8.7 +/- 4.8 mm Hg difference between supine and 5 minutes standing values (P = .0005) without change in diastolic values. An orthostatic decline in SBP of > or = 10 mm Hg occurred in 13 patients, and there was a drop of > or = 20 mm Hg in six patients. The cross-over of enalapril and nifedipine reproduced the hypotensive effect and reversed the postural effect. (P = .0002 nifedipine vs enalapril) CONCLUSIONS: Enalapril and nifedipine were equipotent in reducing supine blood pressure levels. Enalapril also reduced the number of orthostatic episodes significantly, whereas nifedipine aggravated this phenomenon.     

Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension

In a randomized, double-blind, placebo-controlled crossover trial, diltiazem and nifedipine were compared in 10 patients with stable angina pectoris and mild to moderate hypertension (supine diastolic blood pressure greater than or equal to 90 mm Hg). Patients received placebo for 2 weeks, then increasing doses of diltiazem (90 to 360 mg/day) or nifedipine (30 to 120 mg/day) in 3 daily divided doses over 2 weeks, followed by 1 week of therapy at the maximal dose, a 1-week placebo "washout," then crossover to the other drug. Heart rate and blood pressure at rest and during exercise, anginal frequency, nitroglycerin consumption and treadmill exercise tolerance were assessed. Compared with placebo, anginal frequency and nitroglycerin consumption were reduced with both diltiazem and nifedipine (p less than 0.01) and exercise tolerance was increased with both drugs (p less than 0.01). Standing blood pressure at rest was reduced by diltiazem and nifedipine (146.6 +/- 11.4/97.7 +/- 5.3 mm Hg at placebo, baseline reduced to 129.6 +/- 15.2/79.5 +/- 13.7 mm Hg with diltiazem, and to 122.2 +/- 9.9/82.0 +/- 7.1 with nifedipine, p less than 0.01 for both). Compared with placebo, diltiazem and nifedipine also reduced exercise diastolic blood pressure (p less than 0.01), but not systolic blood pressure. Diltiazem lowered the heart rate at rest from 88.5 +/- 14.4 beats/min at placebo baseline to 79.7 +/- 17.9 beats/min (p less than 0.01); the heart rate with diltiazem was 11 beats/min lower than that with nifedipine (p less than 0.05). Both diltiazem and nifedipine had similar effects on the heart rate-blood pressure product at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of two strategies for intensifying antihypertensive treatment: low-dose combination (enalapril + felodipine ER) versus increased dose of monotherapy (enalapril). LEVEL (Lexxel vs Enalapril) Study Group.

To compare two popular strategies for intensifying treatment for hypertension, a double-blind, randomized, prospective, parallel-group, and partial crossover study was done. After 2 weeks of placebo run-in (baseline) and 3 weeks of 5 mg enalapril once daily, 217 patients were randomized to 6 weeks of treatment with either a low-dose combination therapy (5 mg enalapril + 5 mg felodipine ER once daily, Lexxel, Astra Merck, Inc.), or a higher dose of monotherapy (10 mg enalapril once daily, Vasotec, Merck & Co., Inc.). The group randomized to the combination had significantly greater reductions in sitting systolic/diastolic blood pressure (BP)--14.2/10.6 mm Hg compared with baseline versus 9.6/7.4 mm Hg (P < .05/.01)--as well as a greater percentage of patients having achieved either diastolic BP < 90 mm Hg or a decline of at least 10 mm Hg (responders), 59% v 41% (P < .01). When patients originally taking 10 mg enalapril were crossed over to the combination therapy for a further 6 weeks, there was a further BP reduction and increase in response rate, with loss of significant differences compared with those treated continuously with the combination for the entire 12 weeks. The greater BP-lowering efficacy of the combination was independent of age, gender, and race. There were no significant differences in tolerability between the regimens. These data support the hypothesis that in patients who do not achieve goal BP reduction with a low dose of an antihypertensive agent, a combination of two drugs with complementary mechanisms of action is more effective than increasing the dose of the first agent.     

Comparative trial of nifedipine retard and atenolol in the treatment of elderly patients with mild to moderate hypertension

Forty-one elderly patients with mild to moderate hypertension (resting diastolic blood pressure 100-130 mmHg after an eight week placebo run-in phase) were randomised to a double-blind parallel group comparison of nifedipine retard 10 mg twice daily or atenolol 50 mg once daily. If the resting diastolic pressure exceeded 95 mmHg after four weeks of treatment the dose(s) were doubled for a further four weeks. Initial sitting blood pressures were 187 +/- 21/105 +/- 5 mmHg in the nifedipine group and 181 +/- 19/106 +/- 6 in the atenolol group. At four weeks, eight patients given nifedipine and nine given atenolol had their doses doubled. At eight weeks sitting blood pressures were 159 +/- 19/85 +/- 7 and 162 +/- 21/87 +/- 8 respectively, with 18/20 patients given nifedipine and 16/21 given atenolol having a sitting diastolic pressure equal to or less than 95 mmHg. One patient given nifedipine was withdrawn because of unacceptable ankle oedema and one given atenolol withdrawn because of worsening angina. Both drugs were equally acceptable to the patients and neither caused a change in their sense of well-being.     

Combination therapy with felodipine and metoprolol compared with captopril and hydrochlorothiazide. German MC Study Group.

This study compared the antihypertensive efficacy and tolerability of a combination tablet containing the vascular-selective calcium antagonist felodipine and the beta1-selective adrenergic antagonist metoprolol, with a combination tablet of captopril-hydrochlorothiazide in a randomized, double-blind trial involving 109 patients with mild to moderate hypertension. After 2 weeks on placebo, patients with a supine diastolic blood pressure of 95-115 mm Hg were randomized to felodipine-metoprolol, 5/50 mg o.d. (Logimax) or captopril-hydrochlorothiazide, 25/25 mg o.d. (Capozide). After a further 4 weeks, there was a mandatory dose increase to felodipine-metoprolol 10/100 mg o.d., and captopril-hydrochlorothiazide, 50/25 mg o.d., and treatment then continued for a another 4 weeks. At the end of the study, felodipine-metoprolol reduced supine blood pressure significantly more than captopril-hydrochlorothiazide. The mean differences in change in supine systolic and diastolic blood pressure between treatments after 8 weeks were 5.2 and 3.4 mm Hg, respectively, in favour of felodipine-metoprolol (p<0.05). Standing blood pressure also showed trends in favour of felodipine-metoprolol. The proportion of responders was similar in both groups. Both treatments were well tolerated. Two patients treated with felodipine-metoprolol and 5 with captopril-hydrochlorothiazide discontinued treatment due to adverse events. Felodipine-metoprolol combination reduced supine blood pressure significantly more than captopril-hydrochlorothiazide with maintained tolerability.     

Clinical efficacy and tolerability of candesartan cilexetil. Candesartan Study Groups in Japan

Clinical trials of candesartan cilexetil conducted in Japan are reviewed. Candesartan cilexetil inhibited the pressor response to intravenous angiotensin II in healthy volunteers, with peak effects observed at 4 or 8 h after oral dosing; suppressing effects persisted up to 24 h. In 14 multicentre studies with 928 hypertensive patients treated for 8 to 12 weeks, candesartan cilexetil had an efficacy rate (reduction of systolic/diastolic blood pressure > or = 20/10 mm Hg and/or mean blood pressure > or = 13 mm Hg) of 72% and 63%, and an adverse effect rate of 9.9% and 7.3%, in patients with mild-to-moderate essential hypertension and those with impaired renal function, respectively. When data for elderly patients were analysed, there was no difference in efficacy and tolerability compared to non-elderly patients. In a double-blind comparative study, candesartan cilexetil was superior to enalapril in hypertensive patients: efficacy rate, 74% vs 66% (NS); adverse symptom rate, 10.4% vs 27.3% (P < 0.01); incidence of cough, 1.5% vs 14.8% (P < 0.01). Treatment with 2-8 mg of candesartan cilexetil once daily for 8 to 12 weeks reduced the left ventricular mass index without deterioration of cardiac function. In conclusion, 4-12 mg of candesartan cilexetil once daily is effective and well tolerated in patients with essential hypertension, including elderly patients, those with severe hypertension, and hypertensive patients with renal insufficiency. Its improved tolerability profile over angiotensin-converting enzyme inhibitors, as well as its end-organ protective effects, suggest that candesartan cilexetil is useful as a first-line antihypertensive drug.     

Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.     

Calcium antagonists,a useful additional therapy in treatment resistant hypertension: Comparison of felodipine ER and nifedipine Retard by 24-h ambulatory blood pressure monitoring

Objective: To compare the efficacy and tolerability of felodipine extended release (ER) 2.5 mg (F2.5) and 5 mg (F5) once daily with nifedipine Retard 10 mg (N20) and 20 mg (N40) twice daily as additional therapy in patients who remained hypertensive despite treatment with an ACE-inhibitor, β-blocker or diuretic.Design and methods: In a multicentre, double-blind parallel study, 61 men and 54 women, aged 35–75, with a supine diastolic blood pressure between 95 and 115 mmHg were randomised to treatment with F2.5, F5, N20 or N40 for 8 weeks, with optional doubling of the dose after 4 weeks. Blood pressure was measured at the office after 0, 4 and 8 weeks and by 24-h ambulatory monitoring (ABPM) after 0 and 4 weeks. Spontaneously reported adverse events and a subjective symptom assessment questionnaire were used for side-effect profiling.Results: Mean office systolic; diastolic blood pressure was clinically relevantly reduced in all treatment groups after 4 weeks by 8/7, 12/9, 11/9 and 18/11 mmHg for F2.5, F5, N20 and N40, respectively, and after 8 weeks (F2.5–5: 17/11 mmHg; F5–10: 18/14 mmHg; N20–40: 19/14 mmHg; N40–80: 25/14 mmHg) with no statistically significant differences between these groups. The lowest dose of felodipine (F2.5) was the least effective. After 4 weeks the ABPM showed consistent 24-h reductions in blood pressure (4/2; 8/5; 7/5; 10/6 mmHg, respectively) over 24 h for the felodipine ER 5 mg group only and for both nifedipine groups. No statistically significant difference between these groups was found. An office responder does not appear to be identical to an ambulatory one and vice versa. The adverse events, mostly oedema, flushing and headache, were dose-related.Conclusions: Both felodipine ER and nifedipine Retard are effective ‘add-on’ drugs in patients with monotherapy-resistant hypertension. The blood-pressure-lowering effect is dose-dependent and tolerability is inversely related to efficacy. The results emphasize the benefits of combining two agents with low doses.     

Oral metoprolol therapy in dilated cardiomyopathy: hemodynamic evidence for improved diastolic function accompanying amelioration of symptoms

Twenty patients with dilated cardiomyopathy (11 males and 9 females) aged from 14 to 54 (37.3 +/- 10.5) years were treated orally with metoprolol (dose 37.5 mg-100 mg/day, mean 91 +/- 18.6 mg/day) after a baseline hemodynamic study. On follow-up, all patients showed improvement in symptomatic status by at least one NYHA class within 2 to 4 weeks of the initiation of therapy. Repeat right heart study and left ventricular angiography (venous digital subtraction angiography) afer 3 to 6 months of treatment in 10 patients showed a fall in the mean pulmonary arterial wedge pressure from 24.4 +/- 9.6 to 12.8 +/- 7.7 mm Hg (P = 0.025), right ventricular end-diastolic pressure from 8.8 +/- 4.7 mm Hg to 4.5 +/- 1.9 mm Hg (P = 0.025) and mean pulmonary arterial pressure from 34.2 +/- 12.4 mm Hg to 25.9 +/- 10.9 mm Hg (P less than 0.01). There was no significant change in the left ventricular ejection fraction (18.7 +/- 1.6% vs. 22 +/- 0.48%, P = NS) or cardiac index (2.2 +/- 0.48 l/m/m2 to 2.12 +/- 0.68 l/m/m2, P = NS). These hemodynamic results indicate that the improvement in symptoms and congestive cardiac failure produced by treatment with metoprolol in patients having dilated cardiomyopathy is related to improvement in diastolic function of the myocardium.     

Is sublingual nifedipine administration superior to oral administration in the active treatment of hypertension?

Nifedipine, a calcium-channel-blocking agent, was administered orally to 44 untreated patients (Group A) and sublingually to 51 untreated patients (Group B) who had a diastolic blood pressure more than 90 mm Hg and systolic blood pressure more than 140 mm Hg. The mean pretreatment systolic and diastolic blood pressure values were 185.3 +/- 26.0 and 115.1 +/- 13.4 mm Hg in Group A patients and 193.6 +/- 23.1 and 118.1 +/- 14.1 mm Hg in Group B patients respectively (p greater than 0.05). The hypotensive activity of nifedipine was observed at the tenth minute in both groups. Mean systolic and diastolic pressures were 168.9 +/- 23.7 and 101.9 +/- 14.2 mm Hg in Group A and 170.6 +/- 26.2 and 103.0 +/- 15.8 mm Hg in Group B, (p less than 0.001) Diastolic blood pressures dropped under 100 mm Hg at the twentieth minute in both groups. Maximal reduction of blood pressure was observed at the fortieth minute in both groups and the degree of reduction in blood pressure was also the same (mean systolic and diastolic blood pressures: 143.7 +/- 22.1 and 86.9 +/- 11.7 in Group A and 148.7 +/- 21.4 and 91.7 +/- 17.0 in Group B (p less than 0.05). The authors conclude that sublingual nifedipine administration is not superior to oral nifedipine administration (in capsular form) in the acute treatment of hypertension.     

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist.

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients with mild to moderate uncomplicated essential hypertension. After a 3-6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9, 9.3, 9.2, 11.1, and 13.2 mm Hg in the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p less than 0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p less than 0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p less than 0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.     

A comparison of felodipine and nifedipine as monotherapies for the treatment of mild to moderate hypertension

We conducted a randomised double-blind crossover comparison of felodipine, 10 mg once daily, nifedipine 20 mg twice daily, each treatment being given as a monotherapy for four weeks. Active treatment was preceded by a two-week placebo run-in. Both systolic (SBP) and diastolic (DBP) blood pressures (supine and erect) fell significantly (all P less than 0.001) following both drug treatments. Nifedipine produced a greater orthostatic effect, and hence a significantly greater fall in erect SBP than felodipine (P less than 0.05). There was no significant difference between the effects of the drugs on DBP. Achieved DBP was 90 mmHg or less in 18/22 patients on felodipine and 18/22 patients on nifedipine. Both drugs were well-tolerated. Felodipine given once daily was effective as a monotherapy for the control of mild to moderate hypertension and compared favourably with twice daily nifedipine.     

Management of perioperative hypertension using sublingual nifedipine. Experience in elderly patients undergoing eye surgery

Sublingual nifedipine was administered perioperatively to 19 elderly (age, greater than or equal to 60 years) patients undergoing ophthalmologic surgery. All of the patients had blood pressures exceeding 200 mm Hg systolic or 110 mm Hg diastolic, and 18 of the patients had both. Average (mean +/- SD) systolic blood pressure fell from 224.9 +/- 13.9 mm Hg to 154.6 +/- 19.0 mm Hg, while average diastolic blood pressure was reduced from 121.5 +/- 12.2 mm Hg to 78.1 +/- 10.6 mm Hg. Mean time to onset of response to nifedipine was 9.47 +/- 3.9 minutes, while the maximum antihypertensive response occurred in 35.3 +/- 10.2 minutes. A prompt antihypertensive response was obtained without any serious side effects. To our knowledge, this is the first reported study demonstrating the efficacy and safety of using sublingual nifedipine for the management of perioperative hypertension.     

Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.