Effects of Losartan on a Background of Hydrochlorothiazide in Patients With Hypertension
Abstract 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≤.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%). In addition, the anticipated hydrochlorothiazide-associated decrease in serum potassium and the increase in serum uric acid appeared to be somewhat blunted in the losartan plus hydrochlorothiazide groups relative to the hydrochlorothiazide plus placebo group. These results demonstrate that the addition of 25, 50, and 100 mg losartan to 25 mg hydrochlorothiazide produced a significant and dose-related reduction in blood pressure at trough after 12 weeks compared with the 25 mg hydrochlorothiazide plus placebo group. In addition, losartan given concomitantly with hydrochlorothiazide was generally well tolerated in this study.
Losartan potassium (losartan, DuP 753) is an orally active and highly selective antagonist of angiotensin II (Ang II) at the type 1 (AT1) receptor.1 2 3 4 Clinical pharmacology studies have confirmed that losartan blocks the Ang II receptor.5 6 Clinical trials have demonstrated that losartan potassium given alone lowers blood pressure (BP) and is well tolerated in long-term trials in patients with essential hypertension.7 8
Despite the efficacy of losartan potassium or other monotherapy agents such as hydrochlorothiazide (HCTZ), some patients with more resistant forms of hypertension may require concomitant antihypertensive therapy to control their BP.9 In previous studies, combination therapy with agents that interfere with the renin system, such as the converting enzyme inhibitors and β-adrenergic blockers, have been shown to enhance the antihypertensive efficacy of HCTZ.10 Concomitant administration of antihypertensive drugs with different modes of action will often allow small doses of drugs to be used to achieve BP control, thereby minimizing the potential for dose-dependent side effects.
In a preliminary report, 25 mg losartan did not significantly reduce BP at 24 hours compared with placebo, whereas doses of 50 and 100 mg decreased BP over 24 hours in patients with mild to moderate essential hypertension.11
The purpose of this 12-week trial was to evaluate the antihypertensive activity of a relatively ineffective dose (25 mg) compared with effective doses (50 and 100 mg) of losartan on a background of 25 mg hydrochlorothiazide in patients with mild to severe essential hypertension.
Twenty-five study sites participated in this trial after protocol review and Investigational Review Board approval. Patients with essential hypertension entered the trial.
All patients underwent a 2-week placebo period after documentation of a mean trough (22 to 26 hours postdose) sitting diastolic BP (SiDBP) of 90 to 120 mm Hg. As a safety precaution, early entry to the HCTZ monotherapy period was permitted for those patients whose SiDBP was 110 to 120 mm Hg after 3 days in the placebo period. On completion of 2 weeks of placebo, patients with mean SiDBP of 95 to 120 mm Hg entered a 4-week monotherapy period during which 25 mg HCTZ was administered once daily. Clinic visits were performed at 2-week intervals to obtain two consecutive SiDBP values that were 93 to 120 mm Hg and also did not vary by more than 7 mm Hg. Early entry into the double-blind period was permitted in those patients whose SiDBP was 106 to 120 mm Hg on two visits each separated by at least 3 days. Patients with BP controlled on HCTZ monotherapy defined as SiDBP less than 93 mm Hg were considered to have reached target BP and were discontinued from the trial. Patients who did not reach target BP (n=304) were randomized to one of four treatment groups for the 12-week double-blind period. They were treated with 25 mg HCTZ once daily plus placebo, or 25 mg HCTZ plus 25, 50, or 100 mg losartan once daily (Fig 1⇓). Patients were seen in the clinic after 1, 3, 6, 9, and 12 weeks of double-blind therapy.
Trough sitting and standing BP and heart rate were measured at the beginning of every clinic visit. The time of the clinic visit was approximately 22 to 26 hours after the previous day’s dose of study medication, which was taken between 6:30 and 10 am. Three sitting BP measurements were obtained after patients had sat for 5 minutes, and standing BP measurements were taken after patients had stood for 2 minutes. All BP measurements were made with a standard mercury sphygmomanometer according to the American Heart Association guidelines, and the disappearance of Korotkoff phase V sounds was used to determine DBP. Heart rates were measured for 30 seconds with patients in the sitting and standing positions before the respective BP measurement at each visit.
Changes in SiDBP and sitting systolic BP (SiSBP) after 12 weeks of treatment were analyzed as continuous data by ANOVA with baseline (end of monotherapy period) BP included in the model as a covariant and investigator as a blocking factor. Adjusted mean changes were used to indicate which results may have been in a completely balanced experiment. All comparisons of BP change were based on the change from the end of the HCTZ monotherapy period, not the end of the placebo period. Standing BP values were summarized but not analyzed for statistical significance.
Spontaneously reported or observed adverse experiences were recorded on case report forms, as was the degree of severity and duration. Drug-relationship was determined by the investigator based on clinical judgment. Laboratory safety evaluations included routine hematology, blood chemistry, and urinalysis and were performed before the study, at the end of the HCTZ monotherapy phase, and after 3 and 12 weeks of double-blind therapy. Electrocardiograms were performed before the study, at the end of the HCTZ monotherapy phase, and at the end of double-blind therapy.
Three hundred and ninety-nine patients entered the HCTZ monotherapy period with a SiDBP of 95 to 120 mm Hg. Ninety-five patients in this group reached the target BP on HCTZ as defined as a decrease in SiDBP of less than 93 mm Hg and were discontinued from the trial. The group mean SiDBP of the remaining patients at entry into the HCTZ monotherapy period was 104 mm Hg.
The demographic characteristics of the patients randomized to enter double-blind treatment after HCTZ monotherapy were generally similar with respect to sex, age, race, and duration of essential hypertension (Table 1⇓). The mean DBP at the end of the HCTZ monotherapy was essentially identical in all groups, averaging 101 mm Hg.
Time Course of BP Change by Week of Treatment
Fig 2⇓ summarizes the change in SiDBP by week from the end of the HCTZ monotherapy period (baseline=week 0) in the various treatment groups. The HCTZ plus placebo control group had a modest and statistically significant fall in SiDBP (−4.7 mm Hg, P<.05) that was evident as early as 1 week after initiation of double-blind placebo therapy. The BP response in this group persisted essentially unchanged over 12 weeks. There were numerically greater SiDBP responses in all of the combination groups as early as week 1. The antihypertensive response began to plateau at 3 to 6 weeks after randomization. At week 12, there were greater reductions in trough SiDBP for all the losartan plus HCTZ groups, and these changes were significantly greater than the reductions for the HCTZ plus placebo control group.
SBP averaged 147 to 150 mm Hg for the four treatment groups at the end of the HCTZ monotherapy period. As summarized in Fig 3⇓, most of the fall in SBP in the 25 and 50 mg losartan combination groups occurred in the first 3 weeks of double-blind therapy, although there were some slight additional decreases in SBP at some later time points. In the 100 mg losartan plus HCTZ group, the largest fall in BP occurred by week 6, with some modest additional decreases at later times.
Table 2⇓ displays the baseline and end-of-treatment (week 12) absolute BP values as well as the changes in BP by treatment group. The largest DBP responses among the losartan groups were observed with the 100 mg losartan plus HCTZ group (−13.3 mm Hg), in which DBP fell to an average of 88.8 mm Hg. This reduction was significantly different from the 25 mg losartan plus HCTZ group and HCTZ plus placebo control group (P<.01). The DBP reductions observed for the 25 and 50 mg losartan plus HCTZ groups were also significantly different (−9.6 and −12.0 mm Hg, respectively) from the HCTZ plus placebo group and from each other.
Reductions in SiSBP at week 12 followed the same pattern as that observed for SiDBP with 100 mg losartan plus 25 mg HCTZ, demonstrating the greatest reduction (−16.2 mm Hg) with a resultant mean SBP of 133.9 mm Hg at week 12 (P≤.01). Losartan at 25 and 50 mg plus HCTZ produced marked reductions (−10 and −12.6 mm Hg) in SiSBP compared with the control group; these changes were both clinically and statistically significant (P≤.01).
Table 3⇓ summarizes the changes in standing BP after 1 and 12 weeks of double-blind therapy. The magnitude of the BP changes was slightly less than that observed with sitting BP. No formal statistics were performed on this data.
Despite these changes in BP, sitting and standing heart rate did not change significantly (data not shown).
Hydrochlorothiazide increased serum uric acid concentrations. As shown in Table 4⇓, before the HCTZ monotherapy serum uric acid concentrations ranged from 378 to 395 μmol/L in the four treatment groups. As predicted, uric acid levels increased to a range from 435 to 463 μmol/L in the four treatment groups at the end of the HCTZ monotherapy period. After 12 weeks of double-blind therapy, serum uric acid fell modestly although significantly in a dose-dependent fashion in the three groups that received losartan plus HCTZ compared with the increase in the HCTZ plus placebo group.
A fall in serum potassium from the prestudy period was observed during HCTZ administration in all groups (Table 4⇑). During the 12 weeks of double-blind treatment, serum potassium remained essentially unchanged in the HCTZ plus placebo group. In contrast, there was a modest and statistically significant reversal of the HCTZ-induced fall in serum potassium in the three groups treated with HCTZ plus losartan (Table 4⇑).
Adverse Experience Profile
The percentage of patients with one or more adverse experiences ranged from 47.4% to 53.4% and was similar among all treatment groups (Table 5⇓). Furthermore, the percentage of drug-related side effects as assessed by the investigator was generally similar across all treatment groups (range, 10.3% to 24.7%). Finally, there were no dose-related trends in adverse experiences for losartan on a background of HCTZ.
The most common clinical adverse experiences in the trial were upper respiratory tract infections (range, 7.7% to 12.8%), dizziness (range, 5.1% to 9.0%), asthenia/fatigue (range, 2.6% to 6.8%), and headache (range, 2.7% to 8.2%) (Table 6⇓). These side effects did not appear to cluster in any treatment group. There was no dose response for these adverse experiences except there was a dose-related decrease in headaches (8.2% to 2.7%) with increasing doses of losartan.
The direct addition of fixed doses of losartan to patients stabilized on 25 mg HCTZ was a potential concern with respect to symptomatic hypotension and related symptoms. In general, there were no treatment-related increases in the percentage of patients with orthostatic hypotension after the addition of losartan. Two patients withdrew, one for severe hypotension/severe dizziness (50 mg losartan plus HCTZ group, described below) and one for mild dizziness (100 mg losartan plus HCTZ). These patients withdrew after several doses of study medication.
Ten patients had serious adverse experiences, two of which were considered to be related to therapy by the investigators. One patient developed a severe ischemic heart disorder in the HCTZ plus placebo monotherapy group that was categorized as possibly drug related. A second patient was discontinued from the study after experiencing a hypotensive episode (SiDBP=71/61 mm Hg) 1 week into double-blind therapy in the 50 mg losartan plus HCTZ group.
The most common laboratory adverse experiences were the expected thiazide-induced small increases in serum uric acid (incidence range, 5.1% to 12.3%) and a modest decrease in serum potassium (incidence range, 2.7% to 12.3%). These abnormalities tended to occur less frequently with higher doses of losartan. Renal function parameters such as blood urea nitrogen and serum creatinine did not change significantly during the study for any of the doses of losartan with HCTZ or for HCTZ plus placebo. Serum glucose was not altered by concomitant administration of losartan. Overall, no serious laboratory adverse experiences were reported in this study.
Diuretics are among the most frequently prescribed class of antihypertensive drug.9 In patients who respond poorly to a thiazide diuretic, physicians have the flexibility to switch to another class or to add another antihypertensive agent that has complementary pharmacological actions. The primary purpose of the present trial was to assess the effectiveness of adding a new class of antihypertensive drug, eg, the Ang II receptor antagonists, to treat patients with mild to severe hypertension who do not respond adequately to HCTZ.
As early as 1 week into the double-blind phase, all losartan treatment groups showed an antihypertensive response that was significantly greater than that in the HCTZ plus placebo group. This additive effect can be understood in terms of blockade of Ang II receptors after single and multiple doses5 12 of losartan and would be expected as a consequence of addition of an Ang II receptor antagonist on a background of a diuretic, particularly because diuretics are well known to stimulate the renin-angiotensin-aldosterone system.9 10
At week 12, the magnitude of SBP and DBP responses in the combination groups was significantly greater than the placebo plus HCTZ group. In terms of SBP and DBP, there was a clear dose-response relationship between 25 and 50 mg losartan on a background of HCTZ. Doses of 100 mg losartan given concomitantly with 25 mg HCTZ produced a small further incremental decrease in BP.
In patients treated with HCTZ plus placebo, BP was reduced 5 mm Hg at the end of the 12-week double-blind phase. It is conceivable that a 4-week monotherapy period was not long enough for the patients to fully express the maximal antihypertensive effects of HCTZ, and the placebo effect may reflect in part an additional BP response to the diuretic. A placebo response is a fairly common observation in large hypertension trials and may in part reflect an inherent weakness in the methodology used in large clinical trials. The reason for placebo responses in clinical trials has been attributed to regression to the mean or abolition of the orienting reflex with time.13 In a guanfacine dose-response trial of somewhat comparable design to the present study, a 7 mm Hg placebo response was observed in patients who had first stabilized on 5 weeks of monotherapy with chlorthalidone followed by placebo.14 Despite the placebo response in the present study, it was still possible to distinguish the additional antihypertensive effect of losartan.
The clinical safety of losartan given concomitantly with HCTZ was extensively evaluated in this study. The clinical adverse experiences related to study drug therapy were generally similar in the losartan plus HCTZ treatment groups and the HCTZ plus placebo treatment group. Overall, the losartan plus HCTZ combination therapy was found to be well tolerated.
Of particular importance, there was no pattern of orthostatic symptoms during the first week of double-blind treatment (Table 3⇑), indicating that on a background of a modest dose of HCTZ, interruption of the renin system by Ang II receptor blockade is well tolerated.
As would be expected based on its pharmacology, HCTZ can elevate uric acid and may provoke gout in sensitive individuals.9 15 Based on a short-term study in healthy volunteers, losartan decreased serum uric acid and increased urinary uric acid excretion. No studies have demonstrated a long-term increase in urinary uric acid excretion after losartan.16 In the present trial, serum uric acid increased during the HCTZ monotherapy period; however, by the end of the 12 weeks of double-blind concomitant therapy, hyperuricemia in those patients treated with losartan plus HCTZ appeared to lessen. This observation suggests that the modest uricosuric effect of losartan was sustained over 12 weeks, which may represent a potential advantage of the losartan plus HCTZ combination.
In summary, once-daily concomitant administration of 25, 50, or 100 mg losartan with 25 mg HCTZ in patients with mild to severe hypertension significantly reduced SBP and DBP 24 hours postdose after 12 weeks of treatment compared with HCTZ alone. A dose-response relationship was observed when losartan was added to a background of HCTZ in this patient population. Concomitant administration of losartan with HCTZ was well tolerated, as evidenced by the good clinical and laboratory safety profiles in this study.
We thank the HCTZ/Losartan Filter Study Group for their clinical research support: Drs J. Angelo (New Orleans, La), T. Bjornsson, A. Besarab (Philadelphia, Pa), S. Chrysant (Oklahoma City, Okla), N. Cutler (Beverly Hills, Calif), J. Fillingim (Savannah, Ga), H. Gavras (Boston, Mass), D. Ginsberg (Harleysville, Pa), D. Gremillion (Nashville, Tenn), B. Harris (Lexington, Ky), A. Jain (New Orleans, La), K. Lasseter (Miami, Fla), A. Lovell (Springfield, Mass), J. Mersey (Baltimore, Md), J. Robert Morray (San Diego, Calif), A. Niederman (Fort Lauderdale, Fla), M. Peveler (Louisville, Ky), Dennis Ruff (San Antonio, Tex), D. Sugimoto (Chicago, Ill), P. Toth (Indianapolis, Ind), J. David Wallin (New Orleans, La), Michael Weber (Long Beach, Calif), A. Whelton (Baltimore, Md), and T. Woehler (Houston, Tex).
- Received November 21, 1994.
- Revision received January 13, 1995.
- Accepted March 21, 1995.
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