(Hypertension. 1996;27:1325-1328.)
© 1996 American Heart Association, Inc.
Articles |
A Diuretic Is More Effective Than a ß-Blocker in Hypertensive Patients Not Controlled on Amlodipine and Lisinopril
From the Blood Pressure Unit, Department of Medicine, St George's Hospital Medical School, London, UK.
Correspondence to Prof Graham A. MacGregor, Blood Pressure Unit, Department of Medicine, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
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Abstract |
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Abstract The combination of an angiotensin-converting enzyme inhibitor and a calcium antagonist has a synergistic effect in patients with more severe hypertension. However, when this combination fails to control blood pressure, it is not clear which drug is then additive. The aim of this work was to study in a double-blind, randomized, crossover design the effect on blood pressure of the addition of either a thiazide diuretic (bendrofluazide, 5 mg once daily) or a ß-blocker (atenolol, 100 mg once daily) or placebo each for a month in hypertensive patients who are not adequately controlled on the combined treatment of amlodipine 5 mg once daily and lisinopril 5 mg twice daily. Eighteen patients with a supine diastolic pressure of more than 90 mm Hg after at least 1 month on the combined treatment of amlodipine and lisinopril were enrolled in the study. The results show that in patients whose blood pressures are not controlled by the combination of amlodipine and lisinopril, the addition of bendrofluazide 5 mg once daily causes a significant fall in blood pressure compared with placebo and a significantly greater fall than 100 mg atenolol once daily.
Key Words: hypertension, essential • angiotensin-converting enzyme inhibitors • diuretics • ß-blockers • clinical trials • calcium channel blockers
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Introduction |
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The combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker is known to have an additive effect in the treatment of hypertension, and this combination is increasingly used in the treatment of patients with more severe hypertension.1 2 When this combination fails to lower blood pressure (BP) to the normal or desired range, it is unclear which other drugs can be usefully added to this combination to lower BP further.
Diuretics are known to be additive to ACE inhibitors alone3 4 but in general do not have an additive effect on BP in patients who are already on dihydropyridine calcium antagonists.5 6 7 8 By contrast, ß-blockers are known to be additive to dihydropyridine calcium antagonists when given alone,9 10 11 12 but the majority of studies have shown no additive effect to ACE inhibitors.3 13 14
We therefore conducted a double-blind, randomized, crossover study to investigate the effect on BP of the addition of either a thiazide diuretic or ß-blocker compared with placebo in hypertensive patients who are not adequately controlled by the combined treatment of amlodipine and lisinopril.
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Methods |
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Patients with well-documented essential hypertension referred to the Blood Pressure Unit by local general practitioners were included in the study if no underlying cause for their high BP had been found. Only those patients treated with amlodipine (Istin, Pfizer) 5 mg once daily (OD) and lisinopril (Zestril, ICI) 5 mg twice daily (BD), both for at least 4 weeks, were included in the study if their supine diastolic BP was more than 90 mm Hg on two different occasions. Patients with renal failure (plasma creatinine level >140 µmol/L), ischemic heart disease, cerebrovascular disease, and diabetes mellitus as well as premenopausal women were excluded from the study. The protocol was approved by the local ethics committee. Informed consent was obtained from each patient. Initially, 19 patients were recruited but 1 patient was then excluded because during the trial he was put on nitrates by his general practitioner. There were 11 men and 7 women; 5 were white and 13 were black. The mean age was 52 years (range, 40 to 61 years). After a 4-week run-in period, patients were entered into a double-blind, randomized, crossover study receiving either atenolol 100 mg OD in the morning for a month or bendrofluazide 5 mg OD in the morning for a month or a matching placebo OD in the morning for a month while continuing their treatment with amlodipine and lisinopril as above. No dietary advice was given, and patients were studied on their usual diets.
Patients were seen in the Blood Pressure Unit every 2 weeks in the morning before taking the morning dose (ie, 24 hours after treatment with amlodipine and either atenolol or bendrofluazide and 12 hours after treatment with lisinopril). Compliance was checked at every visit by counting the number of remaining tablets.
For each patient, BP readings were made at the same time of day, by the same nurse, in the same room. BP was measured in the same arm with a semiautomatic ultrasound sphygmomanometer (Arteriosonde, Roche)15 with an attached recorder and appropriately sized cuff. The measurements were therefore free from observer bias. Supine and standing BPs were taken as the mean of five readings obtained at 1- to 2-minute intervals with the patient in the corresponding position. Supine BP was measured before standing BP. Pulse rate was measured in both supine and standing positions. Body weight was recorded in the morning, after patients had voided, with the patients wearing indoor clothing and no shoes.
At the end of each treatment period (ie, every month), venous blood was taken without stasis after the patient had been sitting upright for 10 minutes. Variables measured were serum electrolytes, urea, creatinine, uric acid, glucose, total cholesterol, triglycerides, and full blood count. Plasma renin activity (PRA),16 aldosterone,17 and atrial natriuretic peptide18 were measured by radioimmunoassay.
All results are given as mean±SE. One-way ANOVA with repeated measurements was used to test for the overall treatment effect, and when appropriate, Student's t test was used for paired observations. The statistical analysis was carried out with the Statistical Package for the Social Sciences (SPSS Inc) and StatView 4.0 (Abacus Concepts, Inc).
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Results |
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Blood Pressures
All 18 patients completed the study. After a 1-month run-in observation period while patients were on both lisinopril 5 mg BD and amlodipine 5 mg OD, the average supine BP was 154±3/99±2 mm Hg. The average standing BP was 153±3/106±2 mm Hg. At the end of 1 month of double-blind placebo tablets, the average supine BP 24 hours after drug administration was 152±4/95±2 mm Hg. After 4 weeks of treatment with atenolol 100 mg OD, mean supine BP was 150±4/92±2 mm Hg (P=.59), and after 1 month of bendrofluazide 5 mg OD treatment, there was a statistically significant (overall P=.005 by one-way ANOVA with repeated measurements) reduction in supine BP to 141±4/91±2 mm Hg compared with both placebo and atenolol (P<.005 and P<.05, respectively) (Table 1
, Fig 1). Changes in standing BP
were similar to those in supine BP (Table 1).
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Individual falls in systolic BP for bendrofluazide and atenolol
compared with placebo are shown in Fig 2. Responses did
not differ between men and women or between whites and blacks.
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) vs blacks (
). A similar
pattern was observed for supine diastolic pressures.
Pulse Rates and Body Weights
At the end of the run-in observation period, the supine pulse
rate was 74±2 beats per minute; after 1 month of placebo tablets, it
was 76±2 beats per minute. As expected, after 1 month of atenolol
treatment, pulse rate fell significantly to 64±2 beats per minute
compared with placebo and bendrofluazide (P<.001 and
P<.0001, respectively). After 1 month of bendrofluazide
tablets, body weight decreased by 0.7 kg (P=NS) (Table 1
).
Plasma Biochemistry
After 1 month of treatment with bendrofluazide tablets,
plasma potassium levels decreased significantly from 4.2±0.1 to
3.9±0.1 mmol/L compared with placebo and atenolol tablets
(P<.003 and P<.005, respectively). Plasma
levels of uric acid also increased significantly, from 0.30±0.01 to
0.39±0.01 mmol/L (P<.003) (Table 2).
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PRA, Atrial Natriuretic Peptide, and
Aldosterone
After 1 month of placebo tablets, PRA was 1.6±0.4 ng
angiotensin I (Ang I)/mL per hour, atrial
natriuretic peptide was 14.2±4.0 pg/mL, and
aldosterone was 482±49 pmol/L.
With atenolol treatment, PRA fell by 0.9 ng Ang I/mL per hour
(P<.05), whereas during bendrofluazide treatment, PRA
increased by 1.1 ng Ang I/mL per hour (P<.05), as expected.
At the end of 4 weeks of atenolol treatment, ANP increased
significantly compared with placebo and bendrofluazide tablets
(P<.05 and P<.05, respectively) (Table 3). Plasma aldosterone did not change
significantly (overall P=.17 by one-way ANOVA).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This double-blind, randomized, placebo-controlled study demonstrates that in hypertensive patients who are not adequately controlled on the combination of the long-acting dihydropyridine calcium antagonist amlodipine and the ACE inhibitor lisinopril, the addition of a thiazide diuretic has an additive beneficial effect on BP compared with placebo. In contrast, when atenolol was added to the combination of amlodipine and lisinopril, BP did not fall significantly. White patients had, if anything, a slightly larger but nonsignificant fall in BP with the diuretic than black patients.
The majority of studies in which a thiazide diuretic has been added to a dihydropyridine calcium antagonist alone have shown little or no additional effect.5 6 7 8 Our results now show that a thiazide diuretic does have an additive effect when added to the combination of a dihydropyridine calcium antagonist and an ACE inhibitor. In other words, the lack of additive effect of a thiazide in the face of a dihydropyridine calcium antagonist alone is likely to be due to a compensatory reaction of the renin-angiotensin system, in many ways analogous to that which occurs when diuretics are given to normotensive subjects.6 19 Both salt restriction and thiazide diuretics in the short term have little effect on BP in normotensive subjects,20 21 and this has been shown to be due to a compensatory rise in renin release and thereby Ang II formation that blocks the fall in BP. However, in patients with essential hypertension who tend to have a suppressed renin-angiotensin system, short-term salt restriction and thiazide diuretics on their own do lower BP.22 23 The major mechanism for this appears to be through a lesser rise in renin and thereby Ang II, which allows the BP to fall.24 Studies with amlodipine and other dihydropyridine derivatives have shown that in hypertensive subjects, there is a rise in PRA25 and when a thiazide diuretic is added there is a greater increase in renin than there would have been if the thiazide diuretic had been given alone.5 This compensatory rise in Ang II with the addition of a diuretic cannot occur in the presence of an ACE inhibitor and therefore, BP falls. Although thiazides and ACE inhibitors are additive,26 27 the majority of studies have shown that the addition of a ß-blocker to an ACE inhibitor or vice versa produces little or no additional hypotensive effect,4 5 28 29 30 31 32 illustrating that the BP-lowering action of a ß-blocker is related in part to the suppression of renin.33 This is likely to explain our findings that atenolol has little or no additive effect on the combination of an ACE inhibitor and a dihydropyridine calcium antagonist.
In conclusion, in view of the increasing use of a combination of a calcium antagonist and an ACE inhibitor in the treatment of the more severe or resistant forms of hypertension, our results are of some importance as they clearly demonstrate that a diuretic does have an additive effect to this combination and that it is more effective than the addition of a ß-blocker. It is of course possible that by increasing the dose of the calcium antagonist, this might also have resulted in a further fall of BP. However, it was not the purpose of our study to look at this but merely to see whether a diuretic or a ß-blocker was additive to the usual dose of drugs that are currently used and which of these two drugs was more effective.
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Acknowledgments |
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The authors thank the nurses of the Blood Pressure Unit (Christine Carney, Frances Whitcher, and Maxine Crane) for their dedication and hard work with the patients.
Received January 23, 1996; first decision February 13, 1996; accepted February 13, 1996.
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References |
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