Summary

1. Introduction

Drugs 41 (Supp!. 3): 80-91, 1991

0012-6667/91/0300-0080/$6.00/0 © Adis International Limited All rights reserved.

DRSUP2155

Low Dose Loop Diuretics in Essential Hypertension Experience with Torasemide

I. Achhammer and P. M etz Clinical Development and Project Development, Boehringer Mannheim GmbH, Mannheim, Federal Republic of Germany

Diuretics belong to the class of antihypertensive drugs recommended for first-line therapy of essential hypertension. Although they are widely and effectively used for the treatment of hypertension, the question remains whether their possible negative influence on metabolic and electrolyte parameters could partly offset the benefit of blood pressure reduction with respect to reduction of coronary artery disease.

Recently published data demonstrate that much lower doses of thiazides exert the same antihypertensive effect as the higher doses used in the past and even prescribed today. These lower doses produce relatively little change in biochemical parameters. Thus, the postulated risks can be avoided by using the lowest effective dose. Traditionally, loop diuretics of the furosemide (frusemide) type are rarely used as first-line antihypertensive agents. They seem to display less efficacy coupled with an intense diuresis when used in standard available doses. However, there is evidence that newly. developed loop diuretics, in lower doses than used in congestive heart failure, are effective antihypertensive agents. For example, torasemide 2.5mg once daily, which does not exert a significant diuresis over 24 hours compared with placebo, lowers elevated blood pressure to a similar extent than thiazides or related compounds. This antihypertensive effect is accompanied by less, if any, changes in metabolic or electrolyte parameters compared with widely used stand­ard diuretics such as hydrochlorothiazide, indapamide or chlorthalidone. The influence on serum potassium and magnesium is similar to or even less than fixed combinations of hydrochlorothiazide and triamterene or amiloride.

Thus, low-dose torasemide constitutes an alternative to established thiazide anti­hypertensive therapy.

Continuously high blood pressure presents a persistent cardiovascular risk. As many as 10 to 20% of the adult population are found to have mild elevations in blood pressure. Antihypertensive treatment based on diuretics and iJ-blockers has improved the risks associated with high blood pressure in severe, moderate and mild hyperten-

sion. The beneficial effect seems to depend on the severity of hypertension, being less evident in mild hypertensives who are the majority. Even if there is agreement to treat patients with essential hyper­tension in order to prevent cardiovascular com­plications, large scale intervention trials clearly showed prevention of stroke, progression of hyper­tension and of cardiac failure, but failed to prove consistent significant ·effects on coronary artery

Torasemide in Essential Hypertension

disease. In fact, meta-analysis of several large scale intervention trials has indicated that the reduction of coronary heart disease mortality which occurs is less than half of that expected, based on epi­demiological data on the associaton between high blood pressure and coronary heart disease (Amery et al. 1990; Collins et al. 1990; McMahon et al. 1990). To date, there are no data on cardiovascular mortality and morbidity for the newer antihyper­tensive agents, e.g. angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers in the treatment of hypertensive patients. However, based on their possible potential advantages over thiazides and iJ-blockers with respect to metabolic effects, they are recommended as 'first-line' therapy together with diuretics and iJ-blockers (Joint Na­tional Committee 1988). This approach is not completely shared by others (Swales et al. 1989; Swales 1990) who more rigidly recommend di­uretics and iJ-blockers as first-line antihypertensive drugs and the other classes in case of contraindi­cations or ineffectiveness.

2. Diuretics in the Treatment of Mild Hypertension

The appearance of thiazide diuretics in the 1950s, with their improved tolerability profile over existing agents constituted a turning point in the pharmaceutical handling of essential hypertension.

Today, there is no doubt that diuretics induce a decrease in arterial blood pressure in hyperten­sive patients during long term therapy. However, the mode of antihypertensive action of diuretics has not been completely understood. The loss in intravascular volume can only explain the early phase of antihypertensive activity, but not the chronic phase.

Several mechanisms have been proposed for the antihypertensive action of diuretics: • intravascular volume contraction • reduced vascular responsiveness to naturally oc­curring vasoconstrictor substances and enhanced responsiveness to depressor substances • decreased sodium content of the arterial wall • altered transmembrane ionic exchange

81

• diminished baroreceptor activity • induction of local tissue dilators (e.g. kinins, prostacyclins) in the arterial wall • a direct vasodilating action on the arteriole (Bakris & Frohlich 1989).

Despite their obscure mechanism of action, di­uretics are an effective antihypertensive treatment and are widely used. They are usually well toler­ated and physicians can rely on a long history of experience in their use. Diuretics require less titra­tion to arrive at an effective dose compared with other antihypertensive drugs (Kau 1988), and are less expensive on a cost per day basis. Further­more, the development of tolerance has not been described.

Many of the disadvantages associated with di­uretic therapy result from their use as first-line treatment in the traditional stepped-care approach, with titration to high doses resulting in metabolic side effects. Adverse effects such as glucose intol­erance, decreased serum potassium, magnesium and sodium, and increased serum uric acid, cholesterol and triglycerides have been reported. Metabolic disturbances increase with higher diuretic doses, but antihypertensive efficacy does not increase in par­allel (Beermann & Groschinsky-Grind 1978; Carl­son et al. 1990; Materson et al. 1978; McVeigh et al. 1988).

It has been debated whether negative effects on metabolic parameters, or arrhythmia through po­tassium and magnesium depletion caused by di­uretics could, at least in part, offset the possible benefit of blood pressure reduction on coronary ar­tery disease. Hypercholesterolaemia, glucose intol­erance and hyperinsulinaemia are risk factors for coronary artery disease which may be aggravated by diuretics.

There is some evidence for a negative effect of diuretics, especially on glucose metabolism, over long term treatment but data available from pro­spective studies are inconclusive (Freis 1989; McMahon 1990; Morgan 1990; Skarfors et al. 1989; Thomson 1990). In addition, the data on the effect of diuretics on regression of left ventricular hyper­trophy are contradictory (Komajda et al. 1990; Mace et al. 1985; Shigematsu et al. 1990).

82

Today a more individualised approach is recommended, which also takes into consideration the risk: benefit ratio for the particular patient. Low doses of diuretics are recommended for initial monotherapy. Before titrating one compound to high levels, a second should be added or another drug with a different mechanism of action should be tried (Joint National Committee 1988). In the spectrum of antihypertensive drugs, diuretics have the advantage off ewer contraindications and a well­defined tolerability profile. The basic requirement for optimal therapy is knowledge of the dose-re­sponse curve in order to avoid unnecessarily high doses (Brunner et al. 1990).

3. Loop Diuretics in Mild Hypertension

Loop diuretics are often regarded as more po­tent natriuretics than thiazide diuretics due to their rapid onset of diuretic action after administration. This concept is questionable however, when the ef­fects of once-daily dosing on 24-hour excretion of water and solutes are evaluated (Reyes et al. 1988, 1990a; Leary & Reyes 1988).

Additionally, data available for furosemide sug­gested less antihypertensive efficacy than standard doses of thiazides (McMahon 1990). In conse­quence, the use of loop diuretics was recom­mended in cases with concomitant chronic renal failure and in the treatment of hypertensive crisis, but not as first-line therapy of mild hypertension. However, during the last few years well-controlled studies have been published indicating that newly developed loop diuretics such as torasemide, mu­zolimine and etozoline, which differ from furosem­ide by a longer duration of action, are efficacious antihypertensive agents when used as monother­apy compared with thiazides or other antihyper­tensives (Achhammer & Eberhard 1990; Cocchieri et al. 1985; Kirsten et al. 1985; Lucsko et al. 1985; Pagano et al. 1985; Reyes et al. 1990a; Romano et al. 1987; Russo et al. 1987; Spannbrucker et al. 1988).

Drugs 41 (Suppl. 3) 1991

4. Thiazide and Loop Diuretics, Establishing the Antihypertensive Dose Range

Loop diuretics have a striking diuretic effect within hours of administration of a standard dose (e.g. furosemide 40mg or torasemide 10mg) and a clear dose-response relationship over a wide dose range (Lambe et al. 1986). In contrast, thiazides show a fairly flat dose-response relationship; doses higher than hydrochlorothiazide 12.5 to 25mg do not provoke increased excretion of volume and sodium compared with the lower dose (Beermann & Groschinski-Grind 1977).

Doses as low as hydrochlorothiazide or chlor­thalidone 12.5mg have been used effectively to lower blood pressure in essential hypertension without the pronounced electrolyte and· metabolic disturbances of high doses (Beermann &. Gros­chinski-Grind 1978; Materson et al. 1978). Re­cently published placebo-controlled studies clearly establish that doses far below those commonly marketed display similar antihypertensive effects with little if any influence on electrolyte or meta­bolic parameters (Carlson et al. 1990; McVeigh et al. 1988). Cyclopenthiazide 125 and 500ILg pro­duced the same blood-pressure lowering effect, and bendroflumethiazide 1.25mg produced the same effect as bendroflumethiazide 10mg, the dose used in the MRC trial (Medical Research Council Working Party 1985). The use ofthiazides is open to challenge by newer agents because of the for­mers' negative biochemical effects and little impact on cardiovascular mortality in the large interven­tion trials. However, in the context of recent data the use of thiazides in lower doses might have a more favourable impact than already discussed.

There is comparable evidence available for torasemide that doses lower than those used for treatment of oedema are useful for antihyperten­sive treatment. Clinical pharmacological studies comparing placebo and torasemide 2.5 to 20mg show a dose-dependent increase in volume and sodium excretion in the early phase (0 to 6 hours) after administration, followed by a rebound phen­omenon at doses of 10mg and higher (Reyes et al.

Torasemide in Essential Hypertension

Ca++ Na+ 1 --0

-,- ~ -9

- r-r- -'-

r-- --r-

-'-r-I--

3

-~

2

o 8 o 8

-,-

OBP r--

,-

1---I"'"'

o 8

130

1

1

20 ~ E

10 S. t:' :>

1 00 ::l t:' Q.

9 o

8 o

7 o

60

83

Weeks

Fig. 1. Mean values of intracellular Ca++ and Na+ activity and diastolic blood pressure from all patients (n = 14) during antihypertensive treatment with torasemide (median dose 5mg) [H. Vetter, unpublished, with permissionj.

1990b). The increase after torasemide 2.5 or 5mg is small, with changes in maximal urinary flow and the peak effect being similar for torasemide 5mg and hydrochlorothiazide 25mg, demonstrating that .the striking diuretic effect of standard loop diuretic doses used in congestive heart failure (e.g. torasem­ide lOmg and furosemide 40mg) is not overt at lower doses (Reyes et al. 1988, 1 990b). The time course of the excretory effects oftorasemide on ur­inary fluid and electrolytes was also dose depend­ent. Compared with placebo, maximal urinary flow increased and time to maximum flow decreased as a function of dose. Low doses of a loop diuretic therefore mimic the excretory profile of a thiazide diuretic (e.g. hydrochlorothiazide 25mg), but the potency in terms of absolute urinary excretion is much lower (for review see Reyes, pp. 35-59 this issue). Torasemide 2.5 or 5mg once daily increased 24-hour volume and electrolyte excretion slightly

but non significantly compared with placebo, with­out a significant rebound effect.

Two open-<iose titration studies in a total of 34 patients addressed the question of whether these low doses would be effective antihypertensive treatment. Both studies started with ·· torasemide 2.5mg after a placebo washout and allowed incre­mental increases in dose after 2 or 4 weeks, re­spectively. In 1 study (n = 20), torasemide 2.5mg administered for 4 weeks lowered blood pressure significantly. When the dose was doubled a further decrease in blood pressure resulted with a total re­sponse rate after 6 weeks [diastolic blood pressure (DBP) ::E; 90mm Hg] of 75%. An increase to tora­semide lOmg did not result in an additive decrease in blood pressure (Mueller & Haecker 1985). In the second study (n = 14), the starting dose was to­rasemide 2.5mg doubled every 2 weeks · in nonre­sponders. Response was reached in the dose range of 2.S to Smg in 64% of patients, confirming the

84

results of the first study. No additional antihyper­tensive effect was seen in the remaining nonre­sponders using up to 15mg oftorasemide (H. Vet­ter, personal communication). In the latter study, the decrease in DBP from 112.4 + 13.4mm Hg to 88.2 + 11.4mm Hg was accompanied by a small increase in intracellular erythrocyte free-sodium activity and a significant decrease in intracellular free-calcium (fig. 1). This effect on intracellular electrolyte activity has also been demonstrated in a single-dose study (Spieker et ai. 1990), suggesting that intracellular free-calcium plays a dominant role in regulating vascular tone in essential hyperten­sion (Spieker et ai. 1988; Zidek et ai. 1982, 1984).

In a multicentre double-blind placebo-con­trolled parallel group study, patients with a DBP of 95 to 115mm Hg received torasemide 2.5 or 5mg for 12 weeks (table I; Achhammer et aI., unpub­lished data). 154 patients were enrolled and 147 qualified for efficacy analysis according to inten­tion-to-treat analysis. Blood pressure was reduced significantly (p < 0.05) in all 3 groups, but tora­semide significantly reduced sitting DBP com­pared with placebo at end-point without a signifi­cant difference between the 2 doses. Although the difference between torasemide and placebo was ev­ident 2 to 4 weeks after the start of treatment, max­imum and statistically significant differences were not observed until 8 weeks. No significant decrease

Drugs 41 (Suppl. 3) 1991

in bodyweight, which could serve as an indicator for increased diuresis, could be detected. Blood pressure response (defined as DBP ~ 90mm Hg or decrease in DBP of ~ 10%) was achieved in 28% of patients in the placebo group, 46% in the tora­semide 2.5mg group and 50% in the torasemide 5mg group. Eight of 50 patients receiving torasem­ide 2.5mg, 10 of 53 patients receiving torasemide 5mg and 13 of 51 patients receiving placebo with­drew from the study. The higher trend for placebo was caused by withdrawal due to nonresponse. The adverse event rate was similarly distributed over all 3 groups with 4 of 50, 5 of 53 and 5 of 51 patients receiving torasemide 2.5 and 5mg and placebo, re­spectively. Adverse events reported were mainly dizziness and headache. No significant difference in serum concentrations of potassium, uric acid, glucose, cholesterol and triglycerides was found after torasemide or placebo.

Two other single-centre trials compared tora­semide 2.5mg once-daily with placebo over 4 weeks (Dupont et ai. 1988), or over 8 weeks with chlor­thalidone 25mg as a positive control (Porcellati et ai. 1990).

Both studies revealed a significant blood pres­sure-lowering effect oftorasemide 2.5mg compared with placebo, which was similar to that achieved with chlorthalidone. Torasemide 2.5mg did not af­fect serum potassium, magnesium, glucose or chol-

Table I. Effect of once-daily placebo. torasemide 2.5 and5mg for 12 weeks on sitting systolic blood pressure (SBP). diastolic blood pressure (OBP) and serum biochemical parameters in patients with essential hypertension (OBP 95-115mm Hg at baseline) [all values

mean ± SO]

Parameter Placebo (n = 50) Torasemide 2.5mg (n = 47) Torasemide 5mg (n = 50)

start 12 weeks start 12 weeks start 12 weeks

SBP (mm Hg) 175.4 ± 19.0 168.8 ± 24.3 172.1 ± 16.1 158.2 ± 16.2* 169.6 ± 17.2 159.3 ± 13.4*

DBP (mm Hg) 102.4 ± 4.5 97.4 ± 9.2 101.2 ± 3.6 92.6 ± 9.0* 102.2 ± 4.0 92.4 ± 8.7*

Heart rate (beats/min) 76.4 ± 4.9 76.7 ± 9.8 75.7 ± 6.3 74.6 ± 5.1 75.3 ± 4.6 74.5 ± 5.8

K ' (mmol/L) 4.4 ± 0.4 4.4 ± 0.3 4.3 ± 0.4 4.5 ± 0.5 4.7 ± 0.5 4.4 ± 0.3

Uric acid (mol/L) 345 ± 105 348 ± 106 356 ± 75 312 ± 69* 368 ± 98 366 ± 97 Glucose (mmol/L) 5.5 ± 1.2 5.7 ± 1.3 5.1 ± 1.2 5.1 ± 2.3 4.8 ± 0.7 5.1 ± 0.7

Cholesterol (mmol/L) 6.7 ± 1.1 6.7 ± 1.3 6.9 ± 1.2 6.9 ± 1.2 6.6 ± 1.2 6.5 ± 1.2

Triglycerides (mmol/L) 1.7 ± 0.9 1.9 ± 1.1 1.7 ± 0.9 1.9 ± 1.1 1.8 ± 1.0 2.4 ± 2.0

* = P < 0.05 compared with placebo.

Torasemide in Essential Hypertension

esterol compared with placebo, whereas chlorthal­idone produced a significant increase in uric acid, glucose and cholesterol, and a significant decrease in serum potassium (table II).

Dupont et a1. (1988) also reported no increase in the activity of the renin-angiotensin system and no stimulation of plasma renin activity or haemo­globin Al with torasemide compared to placebo.

5. Torasemide Compared with Other Diuretics 5.1 Efficacy

Several studies compared torasemide 2.5mg once daily with other commonly used diuretics, using a double-blind parallel group design and lasting 8 to 24 weeks. Patients presenting with mild to mod­erate hypertension were included (table III).

Blood pressure showed a significant reduction within the first week after starting therapy and con­tinued to decrease up to weeks 8 to 12 for both torasemide and the comparator drugs. In some studies where dose-doubling was allowed in patients not responding to the initial dose, a similar num­ber of patients with torasemide or the comparison diuretic received the double dose according to pro­tocol (usually about 20 to 30% of patients) [Ach­hammer & Eberhard 1990; Boelke et a1. 1990b; Spannbrucker et a1. 1988]. Significant differences between treatments in the blood pressure-lowering effect were seen in only 2 studies during the course of treatment.

85

Torasemide 2.5mg lowered sitting DBP and sys­tolic blood pressure (SBP) significantly less than a fixed combination of hydrochlorothiazide 50mgand amiloride 5mg after 10 weeks of treatment, but not at end-point after 24 weeks (Boelke et a1. 1990b). Reyes et a1. (1990) reported a significantly more pronounced effect of hydrochlorothiazide 25mg compared with torasemide 2.5mg on SBP but not on DBP in patients aged> 65 years.

On average, SBP and DBP decreased in the range of 13-27/13-22mm Hg with torasemide com­pared with 15-42/14-23mm Hg with thiazides and related compounds. The overall response rate was defined as DBP ~ 90mm Hg with some studies also requiring a decrease in DBP of ~ lOmm Hg. 70 to 90% of patients responded irrespective of the di­uretic used (including dose-doubling) [table III]. The time course of the blood pressure lowering ef­fect was similar for thiazides and torasemide. Steady-state antihypertensive effect was reached between 8 to 12 weeks after initiating therapy. Ad­ditionally, it could be shown that torasemide 2.5mg lowered continuously monitored 24-hour ambula­tory blood pressure to a similar extent compared with the combination of hydrochlorothiazide 25mg/ triamterene 50mg, by preserving circadian rhythm over time (Boelke et a1. 1990a).

5.2 Safety

In accordance with the results of placebo-con­trolled studies, torasemide, in the dose range 2.5 to 5mg once daily, did not affect serum potassium

Table II. Effect of once-daily placebo. torasemide 2.5mg and chlorthalidone 25mg for 8 weeks on systolic blood pressure (SBP). diastolic blood pressure (DBP) and serum biochemical parameters in patients with essential hypertension (DBP > 95mm Hg) [adapted from Porcellati et al. 19901

Mean change from baseline

no. of SBP DBP potaSSium uric acid glucose cholesterol patients (mm Hg) (mm Hg) (mmoI/L) (mg/dl) (mg/dl) (mg/dl)

Placebo 9 -2.0 -1.0 +0.2 +0.1 ±O.O -8.0 Torasemide 2.5mg 9 -13.0* -14.0· ±O.O +0.2 -6.0 +6.0 Chlorthalidone 25mg 9 -15.0* -15.0* -0.7· +1.4* +15.0* +28.0*

• = p < 0.01 vs baseline (no significant changes were seen for serum concentrations of chloride. calcium. magnesium. or creatinine for either treatment).

86

or glucose significantly, whereas all monodiuretics used (indapamide, hydrochlorothiazide or chI or­thalidone) caused significant decreases in serum potassium and increases in blood glucose (Porcel­lati et al. 1990; Reyes et al. 1990a; Spannbrucker et al. 1988). Torasemide did not affect serum po­tassium and magnesium compared to a fixed com­bination of hydrochlorothiazide/triamterene 2S/ SOmg (fig. 2; Achhammer & Eberhard 1990). In this study, transient decreases in serum potassium below 3.S mmol/L were noted in 1 of 29 patients in the torasemide group and 3 of 29 patients in the com­bination group. Serum potassium was reduced more with the fixed combination of hydrochlorothiaz­ide/amiloride SO/Smg than with torasemide; the same applies for the number of hypokalaemic events comparing both drugs [serum potassium < 3.S mmol/L in 3 of7l patients and 6 of 72 patients with torasemide or the fixed combination, respec­tively (Boelke et al. 1990b)]. These data are in ac-

Drugs 41 (Suppl. 3) 1991

cordance with literature on this fixed combination, reporting more frequent hypokalaemic events than expected for a 'potassium sparing' combination.

A usual finding for all diuretics studied was the incremental increase in uric acid, achieving partial significance in some studies. The incremental in­crease in uric acid and glucose was found to be comparatively higher for hydrochlorothiazide/ami­loride SO/Smg than for torasemide 2.Smg, most likely as a result of the full diuretic dose of the thiazide being used (Boelke et al. 1990b).

Torasemide had a favourable tolerability profile when the cumulative rate of subjective adverse events was evaluated. About 20% of patients re­ceiving torasemide experienced at least 1 adverse event, compared with about 40% of those receiving thiazides, or thiazide/amiloride or triamterene combination therapy. The most common adverse events with torasemide were headache, dizziness, nausea, asthenia and muscle cramps. The pattern

Table III. Comparison of antihypertensive effects of torasemide (TS) with indapamide (IND), hydrochlorothiazide (HCT), chlorthalidone

(CHL) and the fixed combinations of hydrochlorothiazide with triamterene (HCT/T) or amiloride (HCT/A) in a double-blind randomised

group comparison design

Study drug and dose (mg)

TS 2.5-5 IND 2.5-5

TS 2.5 HCT 25

TS 2.5

CHL 25 Placebo

TS 2.5-5

HCT /T 25/50-50/1 00

TS 2.5

HCT/T 25/50

TS 2.5-5

HCT/A 50/5-100/0

No. of patients

32

34

13 11

9 9 9

29

29

41

43

72

71

Duration

(weeks)

12

19

8

24

12

24

Initial BP/DBP

(mmHg)

166/107 164/106

175/105 177/103

157/106 162/106

162/103

165/1 01

168/1 02

167/100

171/102

168/103

170/103

Decrease in SBP/ DBP (mm Hg)

before dose

doubling (weeks)

-17/-15 (4) -16/-15 (4)

-18/-14 (12)

-19/-15 (12)

-17/-13 (10)

-25*/-16* (10)

Decrease in SBP / DBP at end-point

(mmHg)

-25/-22 -28/-22

-27/-21

-42*/-23

-13/-14 -15/-15 -2/-1

-17/-14

-23/-17

-17/-13

-21/-14

-25/-17

-31/-19

Reference

Spannbrucker et al. (1988)

Reyes et al. (1990a)

Porceliati et al. (1990)

Achhammer &

Eberhard (1990)

Boelke et al.

(1990a)

Boelke et al.

(1990b)

Data show a decrease in mean sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP), except in Reyes et al. (1990) where supine blood pressure was reported, and in Boelke et al. (1990a) where median values were reported. * = p < 0.05 group

comparison.

Torasemide in Essential Hypertension

~ 4.8

(5 4.6 E 4.4 g } ----- -------------+ 4.2 :.::

4.0 § Cii 3.8 en 3.6

, a ~ 1.00 (5 E g 0.95

E :::J

.~ 0.90 c g> E 0.85 E :::J Q;

----- =-

en 0.80 -'-.,----,-----r-------,

b o 4 12

Weeks

24

Fig. 2. Influence of once-daily application of torasemide 2.S or Smg (-) and the fixed combination of hydrochlorothi­azide/triamterene 2S/S0 to SO/IOOmg (- - -) on serum potas­sium (a) and magnesium (b) during 24 weeks (adapted from Achhammer & Eberhard \990). Data were measured at the time points shown on the x axis.

was similar with thiazides: most often dizziness, followed by muscle cramps, asthenia, headache and nausea.

The low incidence of adverse events with to­rasemide, especially hypokalaemia, can be re­garded as a consequence of the low dose used in these studies. Hypokalaemia and increased blood glucose occur with indapamide, hydrochlorothi­azide and chlorthalidone as monotherapy, and with the fixed combination of hydrochlorothiazide and amiloride.

6. Long term Efficacy and Safety

In addition to the comparative studies de­scribed above which lasted up to 24 weeks, a dose­controlled double-blind study was carried out in newly diagnosed patients with hypertension (DBP between 100 and 115mm Hg) comparing torasem-

87

ide 2.5 and 5mg once daily over 48 weeks (Baum­gart et al. 1990). 98 patients qualified for statistical evaluation after 48 weeks according to a protocol which allowed only 1 dose doubling after 4 weeks in case of insufficient response, too early for the full antihypertensive effect of 2.5 or 5mg according to the available results of other studies cited. How­ever, torasemide 2.5 to 5mg administered once daily exerted an antihypertensive effect similar to 5 to 10mg over time; the steady-state effect was reached after 12 weeks.

Before dose doubling at week 4, the effect of 5mg was somewhat more pronounced than that of 2.5mg, which is also reflected in the percentage of patients in which the dose was doubled (38% in the 2.5mg group and 19% in the 5mg group). However, in patients continuing on the initial doses the blood pressure reduction was similar for both doses (fig. 3).

Torasemide was well tolerated. One patient withdrew with allergic exanthema, and transient adverse events were reported in 10% of the patients (hypokalaemia and gastrointestinal complaints each 2%; exanthema, headache and dizziness each 1.4%; pruritus, paraesthesia and chest pain each in 1 patient). The trend in laboratory values of serum concentrations of potassium, magnesium and uric acid, and blood glucose is given in figure 4a, and that of triglycerides, cholesterol, low density lipo­protein (LDL)-cholesterol and high density lipo­protein (HDL)-cholesterol in figure 4b for torasem­ide 2.5 and 5mg given over 48 weeks. The initial small change in potassium in the range of -0.15 mmol/L was only seen within the first 4 weeks of application. No significant changes were seen in magnesium, glucose, triglycerides, and total as well as HDL- and LDL-cholesterol. Uric acid increased slightly but significantly during the first 6 months and tended to decrease to normal values thereafter.

7. Conclusion

Diuretics have been a cornerstone of modern antihypertensive treatment over the past 3 dec­ades. Their use has been challenged because they may produce metabolic disturbances such as glu-

88

cose intolerance, increases in serum cholesterol and triglycerides as well as decreases in serum potas­sium and magnesium. Large intervention trials with diuretics or iJ-blockers have generally demon­strated a significant reduction in stroke, but failed to provide a significant reduction in myocardial in­farction. There has been speculation that the meta­bolic sequelae as well as arrhythmias caused by po­tassium depletion associated with diuretic use partly offset the cardiovascular benefit of this class of drugs. In a recent meta-analysis of 14 randomised trials with predominantly diuretic-based therapy involving 37 000 patients and a mean duration of treatment of 5 years, the incidence of myocardial infarction was reduced by 14%, less than that ex­pected from epidemiological data (Collins et al. 1990). In contrast, there is no evidence of an effect of newer agents such as ACE inhibitors and cal­cium channel blockers on stroke or heart attacks. This may change in the future as the US Trial on Diet and Drug Treatment of Mild Hypertension (TOMHS) study and the Captopril Prevention

Oi J:

110·

100

E .s 90

Drugs 41 (Suppl. 3) 1991

Project address this question (Captopril Preven­tion Project 1990; Stamler 1987). Recent studies have shown that using the lowest effective dose of a diuretic avoids significant changes in metabolic parameters, which usually occur only at the high doses often used in the large scale intervention studies (Carlson et al. 1990; McVeigh et al. 1988) or recommended and used as standard dosage reg­imens today. Traditionally, furosemide used in the available standard diuretic dose of 40mg has not been widely accepted as an effective antihyperten­sive treatment. Based on an overview of published comparative trials, McMahon (1990) concluded that thiazides are more effective than furosemide in reducing blood pressure in the treatment of hypertension. Furosemide has been advocated as an addition to other standard antihypertensives in hypertensive crisis or in hypertensive patients with renal impairment. However, when assessing the metabolic effects of furosemide in hypertensive patients, a trend for less potassium loss and influ­ence on glucose metabolism compared with thia-

~'r- '" ~ ------ --------- - --------- - - - --------------0-m a

80

70~rT,__rr_~_r--~------------_,--------------~------------~

01 2 45 7 9 12 24

Weeks

36 48

Fig. 3. Decrease in diastolic blood pressure (DBP) in patients with essential hypertension responding to the initially applied dose of either torasemide 2.5 (-) or Smg (- - -) [Baumgart et at. 1990). Data were measured at the time points shown on the x axis.

Torasemide in Essential Hypertension

a

4.60 ~ Potassium (mmoI/L) 4.55 4.50 4.45

4.40 ~::-::fp-=:;';.,.,J,..t-_~L-:;::' 4.35 'L 4.30 4.25

1.05~ Magnesium (mmol/L)

1.00 0.95 k_ 0.90 J:.';;;.-~~F-=.t:-!1;t--'~_~ __ "'"i1T 0.85 ¥ l.

0.80

6.4J Uric aCid (mg/dl)

6.2 6.0 5.8 5.6 5.4 5.2

95.0j 92.5 90.0 87.5 85.0 82.5 80.0

Blood glucose (mg/dl)

b

Triglycerides (mg/dl)

~~~~ I 170 ..,.~ .......... ...--

160

~:~~ Total cholesterol (m_g-/d-I)-t---i-__ -:r

240

230

170 160

~~~I LDL-cholesterol (mg/dl)

~~~ f--f--f--------f--------f-------{

Weeks

ii I HDL-cholesterol (mg/d .... l) -.I..._--t--_-1

54 52 50 iii i o 4 12 24

I 36

i 48

89

Fig. 4. Influence oftorasemide 2.Smg (-) or Smg (- - -) once daily on serum parameters and blood glucose during 48 weeks' treatment in patients with essential hypertension (adapted from Baumgart et al. 1990). LDL = low density lipoprotein; HDL = high density lipoprotein. Data were measured as the time points shown on the x axis.

zides has been described (Bloomgarden et al. 1984; McMahon 1990; Mroczek et al. 1978).

Recently published data show that newly de­veloped loop diuretics, used in lower than regular doses in patients with oedema (e.g. muzolimine 15 to 20mg or torasemide 2.5 to 5mg), lower blood pressure to a similar extent compared with thia­zides and other drug classes used in hypertension (Cocchieri et al. 1985; Kirsten et al. 1985; Lucsko et al. 1985; Pirelli & Stella 1983). As shown for low doses of torasemide, the influence on metabolic and electrolyte parameters is minimal or absent. Low doses of those loop diuretics are generally well tol­erated without causing polyuria or the striking and intensive fluid excretion over the first hours after application. A low dose of torasemide 2.5 to 5mg

does not increase potassium or magnesium excre­tion in the first hours after application compared with placebo, even if natriuresis is slightly and sig­nificantly increased, which may serve as an ex­

planation for the noneffect of this dose on electro­lyte parameters in long term treatment. Further studies are needed to elucidate the mechanism of action whereby low doses of either loop or thiazide diuretics reduce blood pressure, because the initial volume contraction reported for usual doses of thiazides is not to be expected with these smaller doses. Vasodilatation mediated by small shifts in intracellular electrolytes and no counter-regulation via increases in the renin-angiotensin system in­duced by diuretics may partly explain the anti­hypertensive effect of low doses of diuretics.

90

References

Achhammer I, Eberhard R. Comparison of serum potassium lev­els during long-term treatment of hypertensive patients with 2.5mg torasemide/day or 50mg triamterene/25mg hydro­chlorothiazide/day. In Kruck et a!. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology, Vo!. 8/1, pp. 211-220, Gustav Fischer Verlag, Stuttgart, 1990

Amery A, Fagard R, Lijnen P, Staessen J, Van HoofR. Treatment of the elderly hypertensive patient. Journal of Hypertension 8 (Supp!. 2): 39-47, 1990

Bakris E, Frohlich ED. Evolution of antihypertensive therapy. Journal of the American College of Cardiology 14: 1595-1688, 1989

Baumgan P, Walger P, van Eiff M, Achhammer I. Long-term efficacy and tolerance of torasemide in essential hypert.ension. In Kruck et a!. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology, Vo!. 8/1, pp. 169-182, Gustav Fischer Verlag, Stuttgart, 1990

Beermann B, Groschinski-Grind M. Pharmacokinetics of hydro­chlorothiazide in man. European Journal of Clinical Pharma­cology 12: 297-303, 1977

Beermann B, Groschinsky-Grind M. Antihypertensive effect of various doses of hydrochlorothiazide and its relation to the plasma level of the drug. European Journal of Clinical Pharmacology 13: 195-201, 1978

Bloomgarden ZT, Ginsberg-Fellner F, Rayfield EJ, Bookman J, Brown WV. Elevated hemoglobin Ale and low-density lipo­protein cholesterol levels in thiazide-treated diabetic patients. American Journal of Medicine 77: 823-827, 1984

Boelke T, Achhammer I, Meyer-Sabellek W A, Streitberg P, Tages­llnd Nachtrhythmik ambulanter 24 - h Blutdruckwerte von iil­teren essentiellen Hypertonikern bei Therapie mit verschie­denen Antihypertonika. Hochdruck 10: 40, 1990a

Boelke T, Achhammer I, Meyer-Sabellek WA. Blutdrucksenkung und metabolische Veranderungen bei essentiellen Hypertoni­kern nach Lanzeitgabe unterschiedlicher Diuretika. Hoch­druck 9: 40-41, 1990b

Brunner HR, Menard J, Waeber B, et a!. Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations. Journal of Hypertension 8: 3-11,1990

Captopril Prevention Project. A prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension. Journal of Hypertension 8: 985-990, 1990

Carlson JE, Kober L, Torp-Peterson C, Johansen P. Relation be­tween dose of bendrofluazide, antihypertensive effect and ad­verse biochemical effects. British Medical Journal 300: 975-978, 1990

Cocchieri M, Chiuini E, Fortunati F, Fedeli L, Solinas P. Efficacy of two different doses of muzolimine in the treatment of mild hypertension. Zeitschrift fur Kardiologie 74 (Supp!. 2): 56-59, 1985

Collins R, Peto R, McMahon S, et a!. Blood pressure, stroke and coronary heart disease. Part 2. Short-term reductions in blood pressure: overview of randomised drug trials in their epi­demiological context. Lancet 335: 827-838, 1990

Dupont AG, Schoors D, Six RO, Vanhaelst L. Antihypertensive efficacy of low dose torasemide in essential hypertension: a placebo-controlled study. Journal of Human Hypertension 2: 265-268, 1988

Freis ED. Critique of the clinical importance of diuretic induced hypokalemia and elevated cholesterolleve!. Archives of Inter­nal Medicine 149: 2640-2648, 1989

Joint National Committee, The 1988 report of the Joint National

Drugs 41 (Suppl. 3) 1991

Committee on detection, evaluation and treatment of high blood pressure. Archives ofinternal Medicine 148: 1023-1038, 1988

Kau ST. Diuretics: what we have and what we need. In Reyes A.1. and Leary W.P (Eds) Clinical Pharmacology and Thera­peutic Uses of Diuretics. Progress in Pharmacology and Clinical Pharmacology 6/3, pp. 1-63, Gustav Fischer Verlag, Stuttgart, 1988

Kirsten R, Molz KH, Tzonev I, Nelson K. Clinical evaluation of muzolimine and indapamide during treatment for essential hypertension. Zeitschrift fUr Kardiologie (Supp!. 2): 66-72, 1985

Komajda M, Klimczak K, Boutin B, et a!. Effects of indapamide on left ventricular mass and function in systemic hypertension with left ventricular hypertrophy. American Journal of Car­diology 65: 37H-42H, 1990

Lambe R, Kennedy 0, Kenny M, Darragh A. Study of the tol­erance and diuretic properties of torasemide following oral or intravenous administration to healthy volunteers. European Journal of Clinical Pharmacology 31 (Supp!. 1): 9-14, 1986

Leary WP, Reyes AJ. Renal excretory actions of diuretics in man: corrections of various current errors and redefinition of basic concepts. In Reyes AJ, Leary WB. (Eds) Clinical Pharmacology and Therapeutic Uses of Diuretics. Progress in Pharmacology and Clinical Pharmacology 6/3, pp. 153-166, Gustav Fischer Verlag, Stuttgart, 1988

Lucsko M, Kerihuel JC, Chaignon M, Aubert PH, Guedon J. Comparative study of muzo limine and acebutolol in the treat­ment of moderate hypertension. Zeitschrift fUr Kardiologie (Supp!. 2): 73-76, 1985

Mace PJE, Littler W A, Glover DR, et a!. Regression of left ven­tricular hypertrophy in hypertension: comparative effects of three different drugs. Journal of Cardiovascular Pharmacology 7 (Supp!. 2): 52-55, 1985

Matcrson B, Oster J, Michael UF, Bolton SM, Burton ZC, et a!. Dose response to chlorthalidone in patients with mild hyper­tension: efficacy of a lower dose. Clinical Pharmacology and Therapeutics 24: 192-198, 1978

McMahon FG. Management of essential hypertension. The once­a-day era. pp. 297-378. Futura Publishing Company Inc., Mount Kisco, New York, 1990.

McMahon S, Petro R, Cutler J, et a!. Blood pressure, stroke and coronary heart disease. Pan I. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335: 765-774, 1990

McVeigh G, Galloway D, Johnston D. The case for low dose diuretics in hypertension: comparison oflow and conventional doses of cyc1openthiazide. British Medical Journal 297: 95-98, 1988

Medical Research Council Working Party. MRC trial of treat­ment of mild hypertension: principal results. British Medical Journal 291: 97-104, 1985

Morgan TO. Metabolic effects of various antihypertensive agents. Journal of Cardiovascular Pharmacology 15 (Supp!. 5): 39-45, 1990

Mroczek WJ, Martin CH, Hattwick MAW, KennedyM. Once daily furosemide therapy in diuretic-treated hypertensive patients. Current Therapeutic Research 24: 824-830, 1978

Mueller G, Haecker W. Torasemide a new loop diuretic in the treatment of essential hypertension without renal impairment. Abstract no. 13. Cardiovascular Pharmacotherapy Interna­tional Symposium, Geneva, 1985

Pagano G, Dal Molin V, Bozzo C, Carta Q. Interference on me­tabolism induced by muzolimine and chlorthalidone in type II hypertensive diabetics. Zeitschrift fUr Kardiologie 74 (Supp!. 2): 80-83, 1985

Pirelli A, Stella M. Comparison of the antihypertensive effects of methyldopa and muzolimine in arterial hypertension. In An­dreucci VE (Ed.) Recent advances in diuretic therapy, pp. 127-135, Exerpta Medica, Amsterdam, 1983

Porcellati C, Verdecctria P, Schillaci G, et a!. La torasemide, nuovo diuretico dell'ansa, nel trattamento dell'ipertensione arteriosa.

Torasemide in Essential Hypertension

Studio controllata in doppia cecita. Basi-Razion Terapia 20: 407-410, 1990

Reyes AJ, Leary WP, van der Byl K, Manaraj B. Renal excretory pharmacodynamics of diuretics in man: companson between furosemide, hydrochlorothiazide and torasemide. In Re.yes AJ & Leary WP (Eds) Clinical Pharmacology and Therapeutic Uses of Diuretics. Progress in Pharmacology and Chmcal Pharma­cology 6/3, pp. 83-151, Gustav Fischer Verlag, Stuttgart, 1988

Reyes AJ, Chiesa PD, Santucci MR, Batista LB, Olhaberry JV, et al. Hydrochlorothiazide versus a non-diuretic dose of to­rasemide as once-daily antihypertensive monopharmacother­apy in elderly patients. A randomized and double-blind study. In Kriick et al. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology, Vol. 8/1, pp. 183-210, Gustav Fischer Verlag, Stuttgart, 1990a

Reyes AJ, Leary WP, van der Byl K. Excretions of urinary fluid and solutes after single doses of furosemide and hydrochloro­thiazide and of four different single doses of the diuretic to­rasemide in healthy subjects. In Kriick et al. (Eds) Torasemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology,Vol. 8/1, pp. 47-72, Gustav Fischer Verlag, Stuttgart, 1990b

Romano C, Copercini B, Ghiringhelli P, Gnocchi E, Pecchini E. Etozoline induced urine excretion of water and solutes 10

patients with hypertension. In Andreucci VE & Dal Canton A (Eds) Diuretics: basic, pharmacological and clinical aspects, pp. 289-291, Martinus Nijhoff Publishing, Boston, 1987

Russo D, Cofelice G, Conte G, Giunta A, Maione S, et al. Anti­hypertensive mechanisms of muzolimine. In Andreucci VE & Dal Canton A (Eds) Diuretics: basic, pharmacological and clinical aspects, pp. 268-270, Martinus Nijhoff Publishing, Boston, 1987

Shigmatsu S, Hiramatsu K, Aizawa T, et al. Regression of left ventricular hypertrophy in patients with essential hyperten­sion: outcome of 12 years antihypertensive treatment. Cardi­ology 77: 280-286, 1990

Skarfors ET Lithell HO, Selernius I, Aberg H. Do antihyperten­sive drugs precipitate diabetes in predisposed man? British Medical Journal 298: 1147-1152, 1989

91

Spannbrucker N, Achhammer I, Metz P, Glocke M. Comparative study on the antihypertensive efficacy of torasemide and in­dapamide in patients with essential hypertension. Arzneimit­tel-Forschung 38: 190-193, 1988

Spieker C, Zidek W, Hacker W, Schmidt W, Vetter H. Assess­ment of intracellular sodium and calcium in essential hyper­tension during diuretic treatment. Arzneimittel-Forschung 38: 188-190, 1988

Spieker C, Zidek W, Vetter H. Acute effect oftorasemide on the renin activity and on intracellular electrolytes in hypertensive patients. In Kriick eeal. (Eds) Torasemide: Clinical Pharlna­cology and Therapeutic Applications. Progress in Pharmacol­ogy and Clinical Pharmacology, Vol. 8/1 , pp. 221-226, Gustav Fischer Verlag, Stuttgart, 1990

Stamler J, Prineas RJ, Neaton JD, Gnmm RH, McDonald RH, et al. Background and design of the new US trial on diet and drug treatment of "mild" hypertension (TOMHS). American Journal of Cardiology 59: 5 IG-60G, 1987

Swales JD, Ramsay LE, Coope JR, Pocock SJ, Robertson JIS, et al. Treating mild hypertension. Agreement from the large trials. Report of the British Hypertension Society working party. British Medical Journal 298: 694-698, 1989

Swales JD. First line treatment in hypertension. Still /'l-blockers and diuretics. British Medical Journal 301 : 1172-1173, 1990

Thompson WG. Review. An assault on old friends: Thiazide di­uretics under siege. American Journal of Medical Sciences 300: 152-158, 1990

Zidek W, Losse H, Dorst KG, Zumkley H, Vetter H. Intracellular sodium and calcium in essential hypertension. Klinische Wochenschrift 60: 859-862, 1982

Zidek W, Losse H, Schmidt W, Fehske KJ, Vetter H. Intracellular electrolytes during antihypertensive treatment with a loop di­uretic. Journal of Hypertension 2: 393-395, 1984

Correspondence and reprints: Dr P. Metz, Project Development, Boehringer Mannheim GmbH, Sandhoferstrasse 116, D-6800 Mannheim 31 , Federal Republic of Germany.