Current Medical Research and Opinion (1996), 13, No. 7, 409-415
Double-blind parallel study of a combination of chlorthalidone 50 mg and triamterene 50 mg in patients with mild and moderate hypertension	D. R. Spiers, MB, ChB, MRCGP* and R. C. Wade, BSc† *Medical Advisor, Dominion Pharma Ltd †Technical Manager, Dominion Pharma Ltd Accepted: 1st April 1996

Summary

Key Words

Introduction

Chlorthalidone, an oral, monosulphamyl diuretic with prolonged action, has been used widely and effectively in the treatment of mild to moderate hypertension for many years. However, as with the thiazide diuretics, treatment with chlorthalidone has been associated in some patients with disturbance of electrolyte balance, especially with decreases in serum potassium concentrations.^1-6 Several studies have indicated that normal serum potassium concentrations are maintained with the combination of chlorthalidone and triamterene.^7-9

A Phase III clinical study was initiated in six locations in the United States in order to compare combination chlorthalidone and triamterene versus chlorthalidone alone. The multicentre trial evaluated the relative safety, efficacy, tolerance, and maintenance of serum potassium concentration in the two protocols.

Patients and methods

Study population

141 hypertensive patients were enrolled into the double-blind phase of the study. The mean age was 50 (ranging from 28 to 68 years), and mean weight was 79 kg (range 48 to 122 kg). Twenty patients were black, 119 were white, 2 were of other races. The race, age and sex ratios were comparable in the two study groups.

Most patients (73%) had mild hypertension (defined as standing phase V diastolic pressure 95 through 104 mmHg), and most had been diagnosed as hypertensive more than a year prior to the start of the study. Concomitant disease was reported in 23% of patients, the most common being osteoarthritis, diabetes and hypothyroidism.

Exclusion criteria included medication other than the study drugs, including oral contraceptives or other hormonal agents. Patients with hypertension requiring surgical intervention, clinically significant hyperkalemia or hypokalemia, oedema requiring treatment, and severe non-hypertensive diseases, were excluded from the study, as were excessively obese individuals and pregnant or nursing women.

Patients were to restrict their dietary intake of salt throughout the study.

Medication

All study medications and placebo were in the form of identical white tablets. Treatment was administered in once-daily doses of the combination of chlorthalidone 50 mg and triamterene 50 mg with placebo, or chlorthalidone 50 mg with placebo, to make a total of two tablets per day.

Study schedule

The study was divided into two parts. Part 1 consisted of a four-week placebo run-in period (visits 1 to 3) and an active-treatment period of ten weeks (visits 3A to 8). Following a partial cross-over of the two study groups, patients entered Part 2 of the study. This involved a further six weeks of active treatment (visits 8A to 11), and a two-week placebo follow-up period (visit 12). As a result of the partial cross-over, Part 2 consisted of four study groups: one set of patients who had only ever received chlorthalidone alone, one set that switched from chlorthalidone to combination treatment, one set that switched from combination treatment to chlorthalidone, and one set that had only ever received combination treatment.

Clinical efficacy and safety assessments

Candidates for the study were screened with a physical examination which included measurement of blood pressure and pulse rate, haematology, urinalysis, blood chemistry, an electrocardiogram, and x-rays. Those admitted to the study, with informed consent, entered the four-week placebo run-in period, during which time they were to visit their investigator twice. At each visit, body weight, blood pressure and pulse rate were to be determined, and haematology, urinalysis and blood chemistry tests performed.

At the end of the placebo period, patients whose overall average standing phase V diastolic blood pressure was 95-114 mmHg, with BUN within normal limits and a serum potassium concentration between 3.5 and 5.0 mEq/l, were to be admitted to the double-blind, active treatment phase of the study.

Most (80%) of the 140 patients included in the evaluation of efficacy completed Part 1 of the study (10 weeks of active treatment), and a total of 111 patients were admitted to Part 2 of the study. Most (83%) of the 111 patients entering Part 2 completed the six-week treatment period. The duration of active treatment was similar for both treatment groups.

All adverse reactions were to be recorded by date, time of occurrence, type, severity, and duration. Any patient might be withdrawn from the study if severe or accelerated hypertension, clinically significant hyperkalemia or hypokalemia, or any other adverse reaction of sufficient severity or duration (in the judgement of the investigator) developed during treatment.

Results

Therapeutic efficacy

Therapeutic success was defined as a reduction of standing phase V diastolic blood pressure by at least 10 mmHg, or to less than 90 mmHg.

Part 1

Both groups of patients started the study with comparable mean baseline values for blood pressure and pulse rate. Statistically significant decreases from baseline levels occurred with both treatments with no statistically significant difference between the two study treatments. In both groups, standing phase V diastolic blood pressure decreased by approximately 11 mmHg, and standing systolic blood pressure decreased by approximately 16 mmHg within four weeks of active treatment. These therapeutic levels of blood pressure were maintained through Part 1 of the study. At ten weeks of active treatment, successful therapeutic responses occurred in 43% of patients receiving chlorthalidone alone compared with 60% of patients receiving chlorthalidone/triamterene combination therapy: these figures did not reach statistical significance.

*Includes only patients who continued in active treatment at least through visit 3A (before completing approximately 1 week).

For standing and supine diastolic blood pressure, the maximal reduction was reached within four weeks in both treatment groups and was sustained through Part 1 of the study. Some statistically significant differences were seen between the groups with regard to standing and supine systolic blood pressure: the maximal reduction was complete by two weeks of active treatment for those patients receiving the combination treatment, compared with four weeks for those receiving chlorthalidone alone ( p < 0.05). All other endpoints were similar in the two groups.

Part 2

In all treatment groups, the therapeutic reduction of blood pressure observed in Part 1 was maintained through Part 2, with slight additional decreases from values at the end of Part 1. The antihypertensive effect for patients who received combination chlorthalidone/triamterene treatment during both parts of the study was slightly greater at most visits than for those patients in the other treatment groups. However, these figures did not reach statistical significance. The exception was a greater decrease in standing systolic blood pressure for those patients who had been maintained on chlorthalidone alone during both parts of the study, when compared with patients who had been switched from chlorthalidone to combination treatment in Part 2.

Drug safety

Potassium

Although mean serum potassium concentration decreased over the entire active treatment period with both treatments, the decrease with the combination treatment was less at every visit than with chlorthalidone alone. During the first ten weeks of active treatment, the mean change from baseline ranged from -0.45 to -0.61  mEq/lwith the chlorthalidone/triamterene combination, and -0.81 to -0.88  mEq/l with chlorthalidone alone. These figures reached statistical significance at weeks 2 and 10, and also for endpoint and overall values. In addition, the incidence of biochemical hypokalemia (below 3.5 mEq/l at least once during active treatment) was significantly less with the combination (69%) than with chlorthalidone alone (91%).

During Part 2 of the study, serum potassium concentration decreased significantly in patients changed over from the combination treatment to chlorthalidone alone (-0.25 mEq/l, p < 0.05). In these patients, the decrease at week 6 (-0.33 mEq/l) was significantly different from the change in those patients who remained on the chlorthalidone/triamterene combination treatment through Part 2 of the study (0.06 mEq/l, p < 0.05) (see Figure 1).

Patients who had received chlorthalidone alone in Part 1, but were switched to combination treatment in Part 2, demonstrated a consistent (but not statistically significant) increase in serum potassium concentration starting from the visit 8 baseline. For those patients who had received chlorthalidone alone during both Part 1 and Part 2 of the study, serum potassium concentrations remained similar to baseline throughout the active-treatment period.

Other laboratory tests

Slight decreases were also observed in the other serum electrolytes - sodium and chloride - and slight increases in the other serum chemistry tests - urea nitrogen, creatinine, glucose and uric acid. However, there was no clinically significant pattern of differences between the two treatments in their effects on any of these tests.

Adverse reactions

In Part 1 of the study, the nature, frequency, and severity of adverse reactions were similar for chlorthalidone alone (49%) and the combination treatment (59%), as were the incidences of adverse events considered to be drug related (11% and 10%, respectively). Comparable results were obtained for the four treatment groups in Part 2 of the study. The number of patients withdrawn from Part 1 of the study for drug-related adverse reactions was higher among those receiving chlorthalidone alone (8%) than those receiving combination therapy (4%). Only one patient was withdrawn from Part 2 of the study due to a drug-related adverse reaction (hyperglycaemia in a patient who received chlorthalidone 50 mg alone through both parts of the study).

Discussion and conclusions

Combination treatment with chlorthalidone 50 mg/triamterene 50 mg in once-daily oral doses was found to be as effective in reducing blood pressure as chlorthalidone 50 mg alone. As might be expected, the decrease in serum potassium concentration was significantly less with the combination treatment than with chlorthalidone alone. There were no notable differences between the treatments in any other measure of laboratory safety or adverse reactions. These findings were consistent throughout both parts of the study.

References

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