Allan I. Goldberg

Effects of Losartan on a Background of Hydrochlorothiazide in Patients With Hypertension

The purpose of this multicenter trial was to compare the antihypertensive efficacy and safety of losartan potassium (losartan), a selective angiotensin II receptor antagonist, when added to hydrochlorothiazide in hypertensive patients whose blood pressure was not adequately controlled by 25 mg hydrochlorothiazide monotherapy. After a 4-week monotherapy period of 25 mg hydrochlorothiazide, 304 patients with trough (22 to 26 hours postdose) sitting diastolic pressure between 93 and 120 mm Hg were maintained on 25 mg hydrochlorothiazide and randomized double-blind into treatment arms consisting of either 25, 50, or 100 mg losartan or placebo once daily for 12 weeks. The reductions in sitting diastolic pressure for patients treated with 25, 50, or 100 mg losartan concomitantly administered with 25 mg hydrochlorothiazide were significantly greater (P < or = .05) than the reductions observed in the 25 mg hydrochlorothiazide plus placebo group beginning 1 week after randomization. The antihypertensive response in all groups was greater at week 3 than week 1, with some additional decrease in blood pressure in some groups at later times. Sitting systolic pressures were also significantly reduced in each group over time. Standing blood pressures at week 12 were similar to sitting blood pressures. A dose-response relationship to losartan was observed in this patient population. The percentages of the total drug-related clinical adverse experiences as assessed by the investigator were generally similar in the 25, 50, and 100 mg losartan plus 25 mg hydrochlorothiazide groups (10.3%, 24.4%, and 20.0%, respectively) compared with the placebo plus 25 mg hydrochlorothiazide group (24.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension

The objective of this study was to compare the antihypertensive efficacy and tolerability of losartan potassium (losartan) and atenolol in patients with mild-to-moderate essential hypertension. This was a multinational, prospective, randomized, 12-week double-blind parallel study with a follow-up of 4 to 10 days posttreatment to assess any adverse effects of abrupt therapy withdrawal. Two hundred two patients were randomized (2:1) to treatment with losartan or atenolol, 50 mg once daily. Patients were titrated after 6 weeks to 100 mg once daily if their blood pressure was uncontrolled (sitting diastolic blood pressure > or = 90 mm Hg). Trough sitting diastolic blood pressure reductions at weeks 6 and 12 were similar in both the losartan (-9.2 mm Hg and -8.3 mm Hg) and atenolol (-10.8 mm Hg and -10.1 mm Hg) groups and a similar percentage of patients responded to each drug. Both agents were generally well tolerated, although eight patients (two patients taking losartan, and six taking atenolol) were withdrawn because of clinical adverse events (P < or = .05). Reduction in pulse rate from baseline averaged 10 beats/min in the atenolol group with no pulse rate reduction observed in the losartan group (P < .01). No evidence of rebound hypertension was observed in either group. In conclusion, losartan was as efficacious as atenolol in blood pressure reduction, and was at least as well tolerated.

Pilot study of combined blockade of the renin–angiotensin system in essential hypertensive patients

Background Additive hemodynamic effects of combined blockade of the renin–angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure. Objective To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach. Design Multicenter, randomized, double-blind, parallel-group, pilot study. Patients 177 patients with mild-to-moderate hypertension [diastolic blood pressure (DBP): 95–115 mmHg after a 4-week placebo run-in period] were included in the study. Intervention Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks. The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily Main outcome measures 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment. Results 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more. The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [confidence interval (95%, CI) 0.7–5.7 mmHg, P = 0.012], and more effective than enalapril by 4.0 mmHg (95% CI, 1.5–6.4 mmHg, P = 0.002). In a subgroup of 28 patients, higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed. This finding confirmed that the combination of the two agents inhibited the renin–angiotensin system to a greater extent than did either agent alone. Conclusion A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary, although modest, fall in clinic DBP in patients with mild-to-moderate essential hypertension.

Controlled Trial of Losartan Given Concomitantly with Different Doses of Hydrochlorothiazide in Hypertensive Patients

The purpose of this trial was to evaluate the antihypertensive efficacy of the concomitant administration of selected doses of hydrochlorothiazide (HCTZ) on a background of losartan potassium (losartan) 50 mg, a selective angiotensin II receptor antagonist. Patients with essential hypertension ( > or = 95 mmHg inclusion criteria) with a mean sitting diastolic blood pressure (SiDBP) of 105 +/- 0.4 (S.E.) mmHg entered a 4-week, single-blind monotherapy period of losartan 50 mg once daily. At the end of the monotherapy period, patients whose blood pressure was adequately controlled were discontinued. Patients whose blood pressure was partially controlled based on a SiDBP > 92 mmHg entered a 12 week double-blind period and were randomly assigned to either receive placebo (n = 80), HCTZ 6.25 mg (n = 80), HCTZ 12.5 mg (n = 72) or HCTZ 25 mg (n = 80) in addition to losartan 50 mg. During the losartan monotherapy period, there was a 4 mmHg fall in SiDBP with a further fall of 5 mmHg after 12 weeks of double-blind therapy in the losartan/placebo control group. Based on the between group differences in BP change from the end of the losartan monotherapy period (baseline) to end of 12 weeks of double-blind, the concomitant administration of a very low dose of HCTZ (6.25 mg) with losartan did not significantly decrease SiDBP compared with the fall in blood pressure in the losartan/placebo control group (diff. between groups = -2 (95% C.I.[-4.1, +0.9] mmHg)). However, the concomitant administration of HCTZ 12.5 or 25 mg with losartan 50 mg resulted in significantly different (p < or = 0.05) reductions in diastolic blood pressure compared to the losartan/placebo group (diff. between groups = -4 (95% C.I. [-6.3, -1.1] mmHg) for 12.5mg combination group; -6 (95% C.I. [-8.3, -3.3]) mmHg for the HCTZ 25 mg combination group). The proportions of patients treated with losartan plus HCTZ 12.5 mg or 25 mg that achieved a trough SiDBP < 88 mmHg or a trough SiDBP > or = 88 mmHg but with a decrease of at least 5 mmHg were 71% and 83%, respectively. The percentage of clinical adverse experiences that were considered drug-related as assessed by the investigator were generally similar across all treatment groups. There were no reports of orthostatic hypotension in any of the treatment groups. Changes in serum glucose, potassium and uric acid were not appreciably different amongst the treatment groups. In summary, in patients with predominantly moderate to severe essential hypertension, the addition of HCTZ 12.5 mg or 25 mg to losartan 50 mg produced effective control of blood pressure in a substantial majority of patients who only partially responded to losartan monotherapy. There were no differences amongst the treatment groups with respect to drug-related adverse experiences in this trial.

Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension.

BACKGROUND African Americans with hypertension, particularly those with more severe blood pressure elevations, are generally less responsive to monotherapy from any antihypertensive class. These patients usually require treatment with drugs from > or = 2 antihypertensive classes to achieve adequate blood pressure control. OBJECTIVE The purpose of this study was to assess the antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide (HCTZ) in African American adults with mild to moderate hypertension. METHODS In this 12-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled study, African American patients were randomized in a 3:3:1 ratio to I of 3 treatment groups: placebo, losartan monotherapy (50 to 150 mg), or losartan plus HCTZ (50/0 to 50/12.5 to 100/25 mg). Doses were titrated at weeks 4 and 8 if sitting diastolic blood pressure (SiDBP) was > or = 90 mm Hg. Safety was assessed by determining the incidence of clinical and laboratory Adverse events and evaluating mean changes in pulse, body weight, electrocardiographic parameters, and laboratory test results. RESULTS A total of 440 patients were randomized-188 to placebo, 193 to losartan monotherapy, and 59 to losartan/HCTZ; 391 completed the study. At week 12, the response rate with losartan monotherapy was 45.8%, with a significant (P < or = 0.01) lowering in mean SiDBP by 6.6 mm Hg compared with placebo; the response rate with placebo was 27.2%, with a mean SiDBP reduction of 3.9 mm Hg. Sitting systolic blood pressure (SiSBP) was significantly lowered with losartan monotherapy, by 6.4 mm Hg, compared with placebo (reduction of 2.3 mm Hg). The response rate with losartan/ HCTZ was 62.7%, with reductions in SiSBP and SiDBP of 16.8 mm Hg and 10.8 mm Hg, respectively (P < or = 0.01 vs placebo and losartan monotherapy). The incidence of clinical adverse events was comparable in the 3 treatment groups. CONCLUSIONS The results of this study suggest that in African American patients, losartan monotherapy was significantly more effective than placebo in lowering SiSBP and SiDBP. Moreover, the losartan/ HCTZ combination regimen resulted in significant and clinically meaningful additional reductions in SiSBP and SiDBP compared with losartan monotherapy or placebo. Losartan monotherapy and the losartan/HCTZ regimens were generally as well tolerated as placebo.

Comparative Antihypertensive Effects of Losartan 50 mg and Losartan 50 mg Titrated to 100 mg in Patients with Essential Hypertension

The antihypertensive activity of losartan potassium (losartan, Cozaar), an angiotensin II receptor antagonist, was evaluated in a parallel 12-week, double-blind, placebo-controlled trial in hypertensive patients with mild-to-moderate hypertension. After a 4-week, single-blind, placebo lead-in period, which included monitoring of baseline variables, 366 patients with a group mean sitting diastolic blood pressure of 101 +/- 5 (s.d.) mmHg were assigned randomly to one of three treatment groups: placebo, losartan 50 mg, or losartan 50 mg with the option to titrate to 100 mg after the first 6 weeks if the target sitting diastolic blood pressure (< 90 mmHg) was not reached. To assess the potential blood pressure response associated with the act of titration, patients in the placebo and losartan 50 mg treatment groups with a sitting diastolic blood pressure of > or = 90 mmHg at week 6 were mock titrated (changed to a new tablet containing the same study medication and dose). Sitting diastolic blood pressure was also evaluated at the end of the trial during a 1-week off-drug period to assess for rebound hypertension. At week 6, patients in the active-drug-treatment arms experienced significantly greater peak (6 h post-dose) and trough (24 h post-dose) reduction in systolic and diastolic sitting blood pressures compared with placebo (p < or = 0.01). Based on trough blood pressures at week 12, active drug (both arms) was more effective than placebo in lowering sitting diastolic blood pressure, with a very small additional benefit associated with increasing the dose of losartan to 100 mg in patients who did not reach the target blood pressure after the first 6 weeks on losartan 50 mg. There was no evidence of rebound hypertension during 1 week after withdrawal of losartan. The correlation between baseline plasma renin activity and reduction in peak and trough blood pressure at week 12, although statistically significant, was generally poor in the active treatment groups. In this trial, losartan was efficacious and well tolerated, and was similar to placebo with regard to adverse-experience profile. Adverse experiences that could reasonably be related to excessive lowering of blood pressure were not common and there was no evidence of rebound hypertension.

Antihypertensive efficacy and tolerability of once daily losartan potassium compared with captopril in patients with mild to moderate essential hypertension.

Introduction: Losartan potassium, an orally active, highly selective AT1 angiotensin II receptor inhibitor, effectively reduces blood pressure by direct receptor blockade, thereby lessening the likelihood of angiotensin converting enzyme (ACE) inhibitorassociated side effects such as dry cough or possibly angioedema Study design: In this multinational, double-blind, randomized, parallel study, the efficacy and tolerability of once-daily losartan (50 mg) versus once-daily ACE inhibitor (captopril; 50 mg) was evaluated in 163 patients with mild to moderate hypertension. Non-responders after a 6-week treatment period had the dosage doubled for both study drugs until the end of study (week 12) Results: Mean reductions in trough sitting diastolic blood pressure were significantly greater in the losartan group at week 6 (7.8 mmHg) and week 12 (9.1 mmHg) than in the captopril group (5.2 and 5.7 mmHg, respectively). Losartan and captopril were well tolerated. Headache was the most common adverse event reported in both groups Conclusions: It was concluded that a once-daily administration of losartan was significantly more effective in this study in lowering sitting diastolic blood pressure than once-daily administration of captopril in patients with mild to moderate essential hypertension. Both losartan and captopril regimes were well tolerated

Comparative effects of combination drug therapy regimens commencing with either losartan potassium, an angiotensin II receptor antagonist, or enalapril maleate for the treatment of severe hypertension.

OBJECTIVE To compare the efficacy and safety of a regimen of losartan potassium (losartan) and a regimen of enalapril maleate (enalapril) in a randomized trial of patients with severe hypertension in which the initial treatments were blinded. DESIGN AND METHODS Seventy-five patients, 23-74 years of age, with sitting diastolic blood pressure of 115-130mmHg, were enrolled in a 12-site multicenter study. The primary efficacy parameters were the change in trough systolic and diastolic blood pressure, as well as response to treatment in terms of categories of hypertensive response. RESULTS A gradual reduction in mean sitting diastolic blood pressure was observed in all patients treated from week 1 to 12 (10-29mmHg for the losartan regimen and 14-32 mmHg for the enalapril regimen). At week 4, a substantial number of patients remained on monotherapy at either the initial dose or double the dose of losartan (52%) or enalapril (72%). The blood pressure curves for each treatment were parallel over time. The enalapril-based regimen elicited a statistically significantly greater reduction in blood pressure than the losartan-based regimen, although the mean differences in the blood pressure response between the two treatment groups was small. Based on sitting diastolic blood pressure < 90 mmHg or a reduction in blood pressure of at least 10 mmHg, 98% of the patients assigned to the losartan regimen and 100% of the patients assigned to the enalapril regimen had a satisfactory response with a regimen of one to three antihypertensive drugs. Headache was the most common adverse experience in both treatment groups (occurring in 22% of patients assigned to the losartan regimen and 20% of patients assigned to the enalapril regimen). CONCLUSIONS In this study, the losartan-based regimen effectively lowered blood pressure, was generally well tolerated, and was generally similar to the enalapril-based regimen in the treatment of patients with severe hypertension.

Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors

The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in the United States were included in this double-masked, randomized, parallel-group, active- and placebo-controlled study, with stratification according to sex. After a challenge phase with lisinopril and a placebo washout phase, patients were randomly allocated to receive losartan 50 mg once daily, lisinopril 20 mg once daily, or placebo for a maximum of 8 weeks. The primary efficacy end point of the study was the presence or absence of dry cough during the double-masked period, as rated by the patient at each visit using a validated symptom assessment questionnaire. A secondary end point was the frequency of dry cough, as measured at each visit using a visual analogue scale (VAS). The incidence of dry cough was significantly higher in the lisinopril group than in the losartan and placebo groups (87.5% vs 36.7% and 31.4%, respectively) at the end of the double-masked treatment period; there was no statistically significant difference between the losartan and placebo groups. Mean VAS scores showed that patients treated with lisinopril rated themselves as having a significantly higher frequency of cough than did patients treated with losartan or placebo (4.0 vs 1.2 and 1.5, respectively). Again, the difference between the losartan and placebo groups was not statistically significant. All treatments were otherwise well tolerated, and no serious clinical or laboratory adverse events were reported during the double-masked phase of the study. These results demonstrate that the incidence, severity, and frequency of dry cough in patients with a history of ACE inhibitor-induced dry cough are significantly lower in those treated with losartan than in those treated with lisinopril and are similar to the incidence, severity, and frequency of dry cough in those receiving placebo.

A randomized, double-masked comparison of the antihypertensive efficacy and safety of combination therapy with losartan and hydrochlorothiazide versus captopril and hydrochlorothiazide in elderly and younger patients

Abstract A multinational, randomized trial was conducted to compare the antihypertensive efficacy and safety of the combination therapy of the angiotensin II receptor antagonist losartan with hydrochlorothiazide (HCTZ) (fixed-dose tablet) with that of the angiotensin-converting enzyme inhibitor captopril with HCTZ (fixed-dose tablet) in elderly and younger patients with mild-to-moderate essential hypertension. The study consisted of a 4-week single-masked placebo baseline period followed by a 12-week double-masked, parallel comparison of once-daily administration of losartan 50 mg/HCTZ 12.5 mg or captopril 50 mg/HCTZ 25 mg (2:1 randomization ratio). Patients with a mean trough sitting diastolic blood pressure (SiDBP) of 95 to 115 mm Hg after the placebo baseline period were randomly assigned to receive losartan/HCTZ (n = 216) or captopril/HCTZ (n = 109). At each center, patients were stratified according to age (