DOUBLE-BLIND RANDOMISED CROSSOVER TRIAL OF MODERATE SODIUM RESTRICTION IN ESSENTIAL HYPERTENSION

Saturday 13 February 1982 DOUBLE-BLIND RANDOMISED CROSSOVER TRIAL OF MODERATE SODIUM RESTRICTION IN ESSENTIAL HYPERTENSION

GRAHAM A. MACGREGOR NIRMALA D. MARKANDU FIONA E. BEST DIANA M. ELDER GIUSEPPE A. SAGNELLA JANICE M. CAM MARILYN SQUIRES Blood Pressure Unit, Department of Medicine, Charing Cross Hospital Medical School, London W6 8RF

Nineteen unselected patients with mild to moderate essential hypertension, whose blood pressure after two months’ observation average supine on no treatment was 156/98 mm Hg, were advised not to add salt to food and to avoid sodium-laden foods. After 2 weeks of sodium restriction patients were entered into an 8-week double-blind randomised crossover study of ’Slow Sodium’ (Ciba) versus slow sodium placebo. The mean supine blood pressure was 7&mid ot; 1 mm Hg (6º·1%) lower in the fourth week of placebo than that in the fourth week of slow sodium (p<0·001). Urinary sodium excretion in the fourth week of slow sodium was 162±9 mmol/24 h and that in the fourth week of placebo was 86 mmol±9 mmol/24 h (p<0·001). There was no difference in potassium excretion. These results suggest that moderate sodium restriction achieved by not adding salt and avoiding sodium-laden foods should, if not already, become part of the management of essential

with sodium, has been claimed to lower blood pressure in patients with mild to moderate essential hypertension,"- 10 but the studies that yielded this finding have been criticised for their lack of adequate controls, their open nature, and the methodology of blood pressure measurement.ll-13 Indeed, these studies have been dismissed by some authorities. 12,13 We therefore conducted a double-blind randomised crossover study of the effect of a modest restriction of dietary sodium intake on unselected patients with mild to moderate essential hypertension. Patients and Methods

Summary

hypertension. Introduction NEARLY 80 years ago, Ambard and Beaujard1 showed that salt restriction lowered blood pressure. The fall in blood pressure was attributed to a reduction in chloride intake. Subsequent observations confirmed this finding.2,3 Most of these patients also had renal disease. Other workers4-7 have shown that very low levels of sodium intake, around 10 mmol/day, greatly reduce blood pressure; most of their patients had malignant hypertension. Watkins et al. showed clearly that in patients with severe hypertension an increase in sodium intake from 10 mmol to about 25-35 mmol/day would raise the blood pressure towards pre-treatment levels. A 10 mmol/day sodium diet in the western world requires special foods and is extremely difficult even for the most compliant patient. A more modest reduction of sodium intake, achieved by not adding salt and avoiding foods loaded

Patients referred by local general practitioners to the blood pressure unit were included in the study if, after 2 months of observation on no treatment, their supine diastolic pressure was between 90 and 110 mm Hg and no underlying cause for their high blood pressure had been found. Patients either had not previously received blood pressure lowering treatment or if they had, it was stopped at least 2 months before the start of this study. Patients with renal failure, ischaemic heart disease, or cerebrovascular disease, or who were taking the oral contraceptive pill or any other drug, were excluded from the study. Informed consent was obtained from each

patient.

Twenty-five patients were considered for the study. Six were excluded because they could not restrict their intake of sodium-four of the six ate out a lot and did not find it practical to change their sodium intake; the other two refused to alter their diet. All the nineteen who entered the study completed it. Fourteen were male and five female; twelve were White and seven Black. Their mean age was 49 years (range 30-66). Blood pressure on entry to the trial varied from 135 to 185 mm Hg systolic and 90 to 110 mm Hg diastolic; their average pressure was 156/98 mm Hg. During the two-month run-in observation period patients were seen in the blood pressure unit every fortnight for blood pressure measurements. At the end of this observation period blood pressure, pulse rate, 24 h urinary (x 2) sodium, potassium, and creatinine, and weight were measured. Blood was taken for measurement of urea, creatinine, electrolytes, plasma renin activity, and aldosterone. Patients were then instructed by the metabolic ward dietician on how to reduce sodium intake to about 60-80 mmol/day. No attempt was made to alter their potassium intake. The reduction in sodium intake was to be made by not adding salt either at table or during cooking and by avoiding foods known to be loaded with sodium. Where appropriate, whoever did the cooking in the subject’s household was also seen by the dietician and by a doctor. Brief, clear instruction sheets about the diet were also given to the patients. At each visit, the nurses in the blood pressure unit reinforced the dietician’s instructions. All measurements were repeated after 2 weeks of this moderate sodium restriction. The nineteen patients were then entered into a randomised double-blind 8268 ©

352

study of one month with ’Slow Sodium’ tablets (Ciba, 10 mmol of sodium per tablet) versus one month with an equivalent number of slow sodium placebos (Ciba). The number of tablets that each patient was to take was that estimated to restore the sodium intake to the subject’s usual intake; the estimate was based on the difference between the means of the two 24 h urinary sodium before and the means of those during the restricted sodium intake. Any one individual took the same number of tablets each day, but between individuals the .number varied from seven to twelve per day. Subjects continued to restrict sodium intake throughout the time

crossover

they were taking tablets. During the trial patients were seen every fortnight, when all measurements were repeated. Each patient was seen on the same day of the week, at the same time of day, by the same nurse, in the same room. Blood pressure was measured in the same arm by nurses using semi-automatic ultrasound sphygmomanometers

(’Arteriosonde’)14 with attached recorders. The measurements were therefore free from any observer bias. Supine and standing blood pressures were the means of five readings taken at 1-2 min intervals with the patients in the corresponding positions; supine pressures were measured before standing pressures. Pulse rate was measured on a Cambridge 3048 pulse monitor. Patients were carefully instructed verbally and by printed instructions on how to collect 24 h specimens of urine. The mean of two 24-hour urinary estimations was taken as the urinary sodium excretion at that time. Blood samples were taken without stasis after the patient had been sitting upright for 10 min some time between 10 A.M. and 12 noon. Plasma renin activity15 and aldosterone 16 were measured by radioimmunoassay. Mean arterial pressure was calculated by adding one-third of the pulse pressure to the diastolic pressure. All results are. reported as means±SEM. Statistical analysis was performed by paired Student’s t tests. and diastolic blood pressure and urinary sodium excretion on normal diet, two weeks after dietary sodium restriction, and at two-weekly intervals during the randomised crossover trial of slow sodium v. placebo.

Fig. 1-Average systolic

Results Blood Pressure

After 2 weeks of moderate sodium restriction there

was a

highly significant fall in both systolic and diastolic pressures (fig. 1). Mean supine blood pressure in the second week of sodium restriction was 7’ 6 mm Hg or 6’ 5% (p<0’ 001) lower than that when a normal diet was being eaten. Mean supine blood pressure remained low

at 2 and at 4 weeks of the was it not placebo period; significantly different from the blood pressure in the second week of sodium restriction before entry into the trial (fig. 1). However, after 2 weeks of slow sodium, both systolic and diastolic pressures were significantly higher than those in the second week of placebo period (fig. 1). Mean supine blood pressure 2 weeks after slow sodium was 5’ 6 mm Hg greater than 2 weeks after placebo (p<0’ 025). The difference in systolic and diastolic pressures between slow sodium and placebo periods was more significant in the fourth week (fig. 1), when the difference in supine blood pressure was 7’ 1 mm Hg (p<0 001); the mean supine blood pressure in the fourth week of placebo was 61% lower than that in the fourth week of slow sodium. Changes in standing blood pressure were similar to those in supine blood pressure (table). The difference in the blood pressure between the slow sodium and placebo periods was not affected by the order in which the tablets were given.

Urinary Sodium, Potassium,

and Creatinine

The means of the two 24 h urinary sodium estimations measured during each stage of the trial are shown in fig. 1. Mean urinary sodium excretion fell from 191±19 mmol/24 h while subjects were on a normal diet to 83±11 mmol/24 h when they restricted sodium intake. Mean 24 h sodium excretion during both the second and the fourth week of the placebo period resembled that during sodium restriction

***p<0’001;

**p<0-01;

*p<0-05

Slow sodium to placebo. :FP
comparing equivalent measurement on on

normal diet

to two

weeks of dietary

alone. 24 h urinary sodium excretion in the second and fourth weeks of slow sodium was significantly higher than that in the sodium restriction only period; sodium excretion in the fourth week of slow sodium was 76 mmol more than that in 24 h urinary the corresponding placebo period (p<0’001). sodium excretion in the second and fourth weeks of slow sodium was not significantly different from that during the normal diet. All patients had lower urinary sodium excretion in the fourth week of placebo than they did in the fourth week of slow sodium (fig. 2). 24 h urinary potassium and creatinine excretion (mean of two) did not change significantly throughout the study (table).

Plasma Renin Activity and Aldosterone Six of the nineteen patients had plasma renin activity below the normal range for their sodium excretion on their normal diet; the other thirteen had normal activity. Changes in plasma renin activity during the trial are shown in the table. During sodium restriction alone, plasma renin activity rose; it was also high during the placebo period, but low during the slow sodium period. Changes in plasma aldosterone followed a similar pattern (table). Other Variables

Changes in plasma sodium and potassium are shown in tbe table. When on their normal diet the nineteen patients had,

353 EFFECTS OF SODIUM RESTRICTION WITH OR WITHOUT SLOW SODIUM OR PLACEBO

Results are given as mean±SEM.

,

differences between effects of slow sodium and placebo. §p<0’001 for differences between effects of normal diet and sodium restriction alone.

*p<0’05,p<0-01,:p<0’001 for

plasma creatinine of 89±33 6 jamolll and mean blood 3 mmol/l; these two variables showed no urea of5’0±0’3 significant change during the trial. Average supine pulse rate on their normal diet was 79±2 3 beats/min. Mean standing pulse rate on their normal diet was 90-+-22 beats/min. There was no significant change in either supine or standing pulse rate during the trial. By the second week of sodium restriction alone there was a significant fall in weight (table). Mean weight in the fourth week of placebo was significantly lower (0’ 5 kg, p<0’ 05) than that in the fourth week of slow sodium (table). When levels in the fourth week of the placebo period were compared with those in the fourth week of the slow sodium period the fall in blood pressure was greater in some patients than in others (fig. 3). This fall in blood pressure did not correlate significantly with the plasma renin activity or aldosterone during the slow sodium period or the change in

mean

Fig. 2-Changes in 24 h urinary sodium estimations between fourth week of placebo and fourth week of slow sodium.

renin activity or aldosterone level that occurred between the slow sodium and placebo periods; nor did it correlate with the change in urinary sodium excretion or with age. However, the difference in blood pressure between the fourth week of the placebo and the fourth week of slow sodium correlated with the blood pressure levels in the fourth week of slow sodium (for absolute fall in blood pressure, for percentage fall in blood pressure, r=0’60, p<0’005, r=0-53 p<0’02). There was no significant difference in blood pressure changes between Black and White patients. The fall in mean blood pressure between that in the fourth week of slow sodium and that in the fourth week of placebo was 7 -8 mm Hg (p<0 005) in Black patients and 5 -5mm Hg (p<0 01) in White patients. All patients completed the trial without having adverse effects. Although it was not the object of the trial to look at the long-term effect of moderate sodium

plasma

Fig. 3-Changes

in

mean

blood pressure between fourth week of

placebo and fourth week of slow sodium.

354

restriction, nine of the nineteen patients have continued for 6-9 months so far on this moderately-restricted sodium diet with good control of their blood pressure without the need for

drug therapy. Discussion This double-blind randomised crossover study clearly shows that, in these unselected patients with mild to moderate essential hypertension, sodium restriction, achieved by not adding salt to the food and avoiding foods with large amounts of added sodium, does lower blood pressure. The 6’ 1 % fall in mean blood pressure is in the same range as that produced by a diuretic alone or a beta-blocker alone. Our study was only a short-term one, but a longer-term study of moderate sodium restriction has suggested that the effect on blood pressure increases with time.9 The mechanism by which sodium restriction reduces blood pressure is not clear. Alteration in sodium intake causes little change in blood pressure in normotensive subjects.17,18 In a more acute study in which both normotensive and hypertensive subjects restricted sodium intake to 10 mmol/day for 5 days, the hypertensives but not the normotensive subjects had a fall in blood pressure. The fall in blood pressure that occurred was directly related to the severity of blood pressure and inversely related to the activity of the renin-angiotensin system.19 This inverse relation might suggest that in essential hypertension a blunting of the response of the renin-angiotensin system to sodium restriction (so that the rise in angiotensin II for a given loss of extracellular volume is depressed) increases the fall in blood pressure that occurs with sodium restriction. This phenomenon seems to be similar to that described for diuretics20 in which the hypotensive effect is least in those who respond to sodium depletion with the largest rise in

angiotensin II.21 Previous open studies$-1° have also shown that moderate sodium restriction reduces blood pressure in those with mild to moderate essential hypertension. However, Parijs et al. found that, although moderate sodium restriction reduced 24 h urinary sodium excretion from 200 to 93 mmol/day, significant falls in blood pressure could only be detected by blood pressure measured at home. In contrast, Morgan et al. found in their controlled trial that although salt restriction reduced urinary sodium excretion only from 191 mmol to 159 mmol/24 h, it reduced blood pressure significantly.9 Hunt’s nutritional therapy of essential hypertension includes calorie reduction as well as sodium restriction to about 60 mmol/day; he claimed that many patients become normotensive on his regimen. 10 These previous trials have been carefully analysed by both Swalesll and Simpson,12 who remain sceptical of the value of moderate sodium restriction. Our results clearly support these open studies and would suggest that for most patients with mild to moderate essential hypertension the first line of treatment should be sodium restriction. Diuretics, which are as effective as sodium restriction in lowering blood pressure, can cause adverse metabolic effects. Patients with severe more hypertension are often treated with a combination of drugs, particularly a combination of betablocker and diuretic. Sodium restriction plus a beta-blocker might be equally effective. There is already evidence that a high sodium intake reduces the effect of a diuretic on blood pressure,8 and a restricted sodium intake has been advocated.22 A reduction in sodium intake would also enhance the effect of angiotensin converting-enzyme

blood pressure. Patients with essential are being considered for treatment should who hypertension at least have their sodium intake assessed before the start of treatment and should be advised not to add salt to their food. The major problem with sodium restriction is whether the patient will adhere to the diet. In the western world processed food almost invariably contains added sodium as chloride, glutamate, or nitrite. Under the careful conditions of our study, most patients were able to restrict sodium intake without great inconvenience and were able to comply with this diet for 10 weeks. Nevertheless, sodium restriction had to be carefully reinforced and encouraged and was only possible if the person who cooked the food for a subject’s household was cooperative. For those people who eat away from home most of the time, sodium intake is very difficult to control. The growth of the "junk food" industry causes further problems because such food is heavily loaded with sodium. A well-known brand of hamburger and chips without customeradded salt contained 95 mmol of sodium, and a well-known brand of fried chicken contained 75 mmol of sodium per portion. Even more extreme was a small Chinese take-away meal which contained 225 mmol of sodium. One individual comfortably ate two of these within 45 min (G. A. MacGregor et al. unpublished). One way of helping to reduce sodium intake would be for processed food to be clearly labelled with its approximate sodium content; where practical, restaurants and take-away food shops could also display the approximate sodium content of their food. We deliberately did not alter potassium intake. In rats an increase in potassium intake lessens the blood pressure rise caused by increasing sodium intake. 23 Substitution of potassium salts for sodium may also improve patient compliance with a restricted sodium diet. However, further studies need to be done on the effect of an increase in potassium intake on blood pressure in essential hypertension before this substitution is advocated.

inhibitors

on

This work was supported by the Wellcome Trust. We thank Dr Robm Elsdon-Dew (Ciba, Horsham) for supplies of ’Slow Sodium’ and placebo.

Correspondence should be addressed to G. A. MacG. REFERENCES 1. Ambard

L, Beaujard

E. Causes de

l’hypertension

arterielle. Arch Gen Med 1904, i:

520-33. 2. Allen

FM, Sherrill JW. The treatment of arterial hypertension. J Metab Res 1922; 2: 429-545. 3. Volhard F. Nieren und ableitende harnwege. In: von Bergmann G, St. Staehelin R, eds Hanbuch der inneren Medizin. Berlin: Springer, 1931; 6: 1. 4. Kempner, W. Treatment of hypertensive vascular disease with rice diet Am J Med 1948; 4: 545-77. 5. Murphy RJF. The effect of "rice diet" on plasma volume and extracellular fluid space in hypertensive subjects. J Clin Invest 1950; 29: 912-17. 6. Watkin DM, Froeb HF, Hatch FT, Gutman AB. Effects of diet in essential hypertension: II. Results with unmodified Kempner rice diet in fifty hospitalized patients. Am J Med 1950; 9: 441-93. 7. Medical Research Council. The rice diet in the treatment of hypertension. Lancet 1950; ii: 509-13. 8. Parijs J, Joossens JV, Van der Linden L, Verstreken G, Amery AKPC. Moderate sodium restriction and diuretics in the treatment of hypertension. Am Heart 1973; J 85: 22-34. 9. Morgan T, Gillies A, Morgan G, Adam W, Wilson M, Carney S. Hypertension treated by salt restriction. Lancet 1978; i: 227-30. 10. Hunt JC. Management and treatment of essential hypertension. In: Genest J, Koiw E Kuchel O, eds. Hypertension. New York: McGraw-Hill, 1977: 1068-85 11. Swales JD. Dietary salt and hypertension. Lancet 1980; i: 1177-79. 12. Simpson FO. Salt and hypertension: a sceptical review of the evidence. Clin Sci 1979 57: 463s-80s. 13. Pickering G. Position paper: dietary sodium and human hypertension. In. Laragh JH Buhler FR, Seldin DW, eds. Frontiers in hypertension research. New York Springer Verlag, 1981: 37-42. 14. George CF, Lewis PJ, Petrie A. Clinical experience with use of ultrasound sphygmomanometer. Br Heart J 1975; 37: 804-07.

355

NEW DESIGN FOR CLINICAL TRIAL OF ANTIHYPERTENSIVE DRUGS APPLIED TO

of average blood pressure drop, incidence of side-effects, and so on. The purpose of this paper is to describe a design that

PINDOLOL, CLOPAMIDE, AND COMBINATIONS

mimics the physician’s approach to the problem each patient presents. The model was applied to test different dosages of the diuretic, clopamide, the (3-blocker, pindolol, and some combinations thereof. The hypothesis was that a combination of the two drugs would be the optimum treatment in most patients with mild and moderate

THEREOF

J. ASPLUND

G. NYBERG N. ANAGREUS J. LEPPERT

B. ÅSTRÖM R. BERGSTRÖM S. KULLMAN

J. ÖVERMO

J. LESSEM Sahlgrenska Hospital, Göteborg; Falu Hospital, Falun; Västerås Hospital, Västerås; Härnösand Hospital, Härnösand; Härnösand, Torshälla Group Practice Centre, Torshälla; and Malmö Allmänna Hospital, Malmö, Sweden A

&bgr;-blocker (pindolol) and a diuretic (clopamide) were given in different dosages, and in different combinations, to 71 patients with two singly to moderate essential hypertension. The trial design mild was such that patients took both drugs singly and in combination, and in different doses, according to a set plan. The best regimen for each patient was determined by taking into account not only blood pressure but also resting heartrate, body-weight, serum potassium, and serum urate. For 19 patients (27%) monotherapy was best—pindolol for 16 and clopamide for 3. For the remaining patients, a combination of pindolol 10 mg and clopamide 5 mg was best for 39, and in 35 of these one tablet daily was sufficient. All patients reached the preset target blood-pressure. The differences in proportions responding best to the following pairs of regimens compared—monotherapy vs combination, and combination of clopamide 5 mg and pindolol 5 mg vs combination of clopamide 5 mg and pindolol 10 mg-were significant (2p <0·01). The process by which the best treatment is chosen according to this study design resembles much more closely that followed in general medical practice, than does the process in the conventional hypertension trial, in which only average effects are reported and compared. Summary

Introduction

design of the conventional controlled trial of an antihypertensive agent does not usually give information on how each individual fares; instead it produces results in terms THE

MacGregor GA. Measurement of plasma renin activity by radioimmunoassay after prolonged cold storage. Clin Chim Acta 1978; 88: 45-48. James VHT, Wilson GA. Determination of aldosterone in biological fluids. In: Reid E, ed. Assay of drugs and other trace compounds in biological fluids. Methodological developments in biochemistry Vol. 5. Amsterdam: Elsevier/North Holland, 1976:

15 Roulston JE, 16

149-58 17. Luft FC, Rankin LI, Bloch R. et al. Cardiovascular and humoral responses to extremes

of sodium intake in normal black and white 18

men.

Circulation 1979; 60: 697-706. blood pressure.

Burstyn P, Hornall D, Watchorn, C. Sodium and potassium intake and Br Med J1980; 281:

537-39. Markandu ND, Roulston JE, Jones BE, Jones JC, MacGregor GA. Relation between arterial pressure, dietary sodium intake and renin system in essential hypertension. Br Med J 1981; 283: 94-97. 20. Vaughan ED, Carey RM, Peach MJ, Ackerly JA, Ayers CR. The renin response to diuretic therapy: a limitation of anti-hypertensive potential. Circ Res 1978; 42: 376-81 21 MacGregor GA, Markandu ND, Roulston JE, Jones BE. The antihypertensive action of spironolactone: The importance of the response of the renin-angiotensin system to the loss of sodium and water. In: Addison GM, Wirenfeldt N, Corvol P, et al. (eds). Aldosterone antagonists in clinical medicine. Amsterdam: Excerpta Medica, 1978, 466-74 22 Winer BM. The anti-hypertensive actions of benzothiadiazines. Circulation 1961; 23: 211-18 23 Meneely GR, Ball COT. Experimental epidemiology of chronic sodium chloride toxicity and the protective effect of potassium chloride. Am J Med 1958; 25: 713-25.

19. Parfrey PS,

hypertension. There was uncertainty as to which combination wouldbe best. Despite quite extensive clinical evidence that 5 mg clopamide + 10 mg pindolol was very effective,1-3 previous experiences with clopamideand pindolol5 indicated that 5 +5 mg combination might be as good, but this combination has not been properly investigated. There was also some evidence against a real benefit of more extreme dose ratios, such as 5 + 15 or 15 +5 mg. Therefore, clopamide 5 mg daily, in combination with pindolol 5 and 10 mg daily were the two combinations (5 +5 and 5 + 10, respectively) chosen. The study was conducted in five centres. Patients and Methods Men and women aged 25 to 65 years with essential hypertension W.H.O. grades I and II were eligible if the diastolic pressure was not more than 125 mm Hg and if the supine mean arterial pressure (MAP = diastolic pressure + one third of the pulse pressure) was at least 117 mm Hg for the young group (ages 25-39), or 127 mm Hg for the middle-aged group (ages 40-59), or 133 mm Hg for the old group (ages 60-65). Any previous treatment was withdrawn for 4 weeks. The baseline pressure was the last of at least three measurements made 1-2 weeks before treatment was started. The baseline pressure was entered at the top ofa"path-plan" (fig. 1), and the patients started either with clopamide 5 mg once daily or pindolol 5 mg once daily. If at the following visit the target pressure was attained, it was entered in the triangle; if not, it was entered in the square. Subsequent treatments followed the arrowed paths. When the hexagons were reached, treatment took a single path, whatever the pressure. At each visit (every 2 weeks) blood pressure was taken with a Hawksley random zero manometer after a rest of 10 min supine and 2 min standing. Heart rate was measured immediately after the pressure readings. Side-effects mentioned spontaneously were noted and graded on a 3-point scale (1=mild, "nuisance value"; 2="moderate"; 3="severe", justifying discontinuation of the study). Blood samples for plasma determinations of potassium and urate were drawn. Body-weight was measured. The "best treatment" was determined in the following way. A target pressure was defined: supine MAP of < 110 mm Hg for the young group, of< 117 mm Hg for the middle-aged, and of< 127 mm Hg for the old. That treatment which produced the lowest pressure (provided target had been reached) was taken as best treatment if the pressure achieved was at least 5 mm Hg lower than the next lowest pressure. If no best treatment could be determined in this way, the regimen which produced the lowest mean pressure, plus all those that produced pressures <5 mm Hg different from the lowest pressure, became candidates for best treatment. The best treatment was arrived at by eliminating, in the following order, treatments associated with:

(1) Supine heart rate of>80/min; (2) Body-weight >0’ 5 kg greater than the lowest recorded with other eligible treatments; (3) Plasma potassium >0 - 2mmol/1 lower than the highest value obtained with eligible treatments; (4) Plasma urate >50 mol/1 higher than the lowest value obtained with eligible treatments. Finally, if more than one treatment remained, the best treatment was that which produced the lowest standing mean arterial pressure. The following patients were excluded from the study-patients with pronounced obstructive pulmonary disease, atrioventricular