the antihypertensive efficacy of nifedipine alone and in combination in general practice

Current Medical Research and Opinion Vol. 10, No. 8 , 1987

The antihypertensive efficacy of nifedipine alone and in combination in general practice

J. Duffy, M.Sc., and G. Macdonald, M.B., Ch.B., M.R.C.G.P.

Medical Department. Baver UK Ltd.. Newbuty, England

Curr. Med. Res. Opin., (1987). 10,566. Received: 22nd August 1957

Summary A multi-centre study in general practice involving 3242 hypertensive patients, aged up to 70 years, was carried out to evaluate the efficacy and tolerability of nifedipine used alone or in combination with other antihypertensive agents in step- care treatment. Patients were treated for up to 8 weeks with one of four regimens: nifedipine monotherapy; diuretic and nifedipine; beta-blocker plus nifedipine; and nifedipine added to a combination of diuretic and beta-blocker. All patients received 20 mg nifedipine, in slow-release tablet form, twice daily: at Week 4, dosage was increased to 40 mg twice daily in 8.5% patients because their supine diastolic blood pressure stilt exceeded 9.5 mmHg. Changes in mean bloodpressure of the total studv group for systolic and diastolic, supine and standing, were highly significant both from baseline (Week 0) to Week 4 (p<0.0001) and from baseline to Week 8 (p<0.0001). Mean blood pressure reduction was 29/18 mmHg supine and 27/18 mmHg standing. Statistical differences in blood pressure response between age, sex and treatment groups were not of clinical significance. Statistic- allv significant reductions in heart rate (mean 1.9 beats/min, p<0.001) and body weight (mean 0.48 kg, p<0.001) were noted, but were not of clinical relevance. Nifedipine produced a net increase of 12% in side-effects at Week 4 compared to the profile at entty.

Key words: Nifedipine - antihypertensive agents - hypertension - family practice

Introduction Nifedipinet is a calcium antagonist which produces a variety of haemodynamic and metabolic effectse In hypertension, its main action is to cause peripheral vasodilatation, thus reducing peripheral resistance, and the decrease in blood pressure is such that the percentage reduction is directly related to its initial height.4 Used alone or in combination with other antihypertensive agents in step-care treatment, nifedipine has proved to be an effective and well-tolerated form of therapy, and the introduction onto the market in 1982 of a slow-release tablet formulation ('Adalat' Retard 20 mg) allowed smooth 24-hour control of raised blood pressure with twice daily dosage.'

t'Adalat', trade mark Bayer

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J. Duffy and G . Macdonald

The object of the present study was to evaluate in general practice the efficacy and tolerability of this formulation of nifedipine when used alone or in combination with other widely used antihypertensive drugs in the treatment of patients with essential hypertension.

Patients and methods Patients eligible for inclusion in the study were those with a supine systolic blood pressure exceeding 165 mmHg and a diastolic blood pressure (Korotkoff V ) exceeding 95 mmHg on two separate occasions during the 4 weeks prior to entry. Newly diagnosed as well as patients already being treated with a diuretic, a beta- blocker or both were considered. Patients excluded from the study were those aged over 70 years, women capable of child bearing, those with arrhythmias or within 4 weeks of a myocardial infarction, and those in cardiac failure or with significant hepatic or renal disease.

The protocol for this study was approved by the Ethical Committee of the Mid- Downs Health Authority (East Unit). After attending the surgery on two recent occasions for the purpose of blood pressure monitoring, patients satisfying all the entry criteria and giving their informed consent to participate were accepted for the %week study.

All patients were to receive nifedipine, used alone or in combination with other existing antihypertensive therapy, according to one of the following drug regimens: Group 1 - newly diagnosed patients or those changing from previous therapy because of lack of response or side-effects received nifedipine monotherapy; Group I1 - nifedipine was added to a diuretic for those patients whose blood pressure was inadequately controlled; Group I11 - nifedipine was used in combination with a beta-blocker in patients responding insufficiently to a beta- blocker alone; and Group IV - nifedipine was used as third-line therapy in combination with a beta-blocker and a diuretic. N o other vasodilator or alternative combinations of first-line and second-line therapy could be used, and clinicians were asked not to alter drugs or doses of concomitant antihypertensive medication once patients had been entered into the study. Any such changes or other protocol violations necessitated rejection of the data by the statisticians from the analysis of the results and only those patients attending on at least two occasions, i.e. at entry and Week 4, are included. details of any concurrent iilness and treatment. Patients were then instructed to take 1 tablet of 20 mg nifedipine twice daily (at 08.00 and 20.00 hours) and asked to return 4 weeks later for review. If the diastolic blood pressure exceeded 95 mmHg at Week 4, the dosage of nifedipine was increased to 40 mg twice daily. If the diastolic blood pressure was 95 mmHg or less at Week 4, patients continued on 20 mg nifedipine twice daily until the next review at Week 8.

Blood pressure (after 5 minutes supine and 2 minutes standing), heart rate and body weight were measured on entry and at each review visit. Blood pressure was measured during surgery hours after the 08.00 hours dose so that measurements were obtained 1 to 10 hours after the intake of nifedipine. Standard mercury sphygmomanometers were used by most physicians.

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At each review any new physical findings were evaluated, doses of all concomitant therapy were checked, and the patients were asked to volunteer the nature of any side-effects in response to a standard question: "Did your treatment upset you?". The severity of any such effects was rated on a scoring system from O=nil to 4= intolerable. Throughout the treatment period, the physician was encouraged to record any symptoms or signs relating to therapy, and at the end of the study to indicate whether the patient would continue on nifedipine or not.

Statistical analysis included analysis of variance, paired t-tests and assessment of the data within 95% confidence intervals. If the confidence intervals do not include zero, then the mean change is significantly different from zero, and this can be interpreted as a statistically significant difference.

Due to the large number of patients included in the analysis, most variables showing a degree of change will do so to a statistically significant level. However, it must be borne in mind that the change(s) seen in all variables must be assessed in terms of clinical significance as well as of statistical significance.

Results A total of 1052 general practitioners recruited patients to the study, and assessment cards from 3242 patients fulfilling all protocol criteria were included in the analysis, of whom 2993 completed 8 weeks of treatment. There were 1490 (46%) males and 1752 (54%) females. The age distribution of the patients reflected that Figure 1. Supine systolic and diastolic blood pressure measurements before and during the - study period in each treatment group: mean values

Group I Group II (n= 1877) (n=602)

2001

0 T 8 O T 8

Group III (n = 330)

Group IV (n=433)

0 7 Time (weeks)

Note: standard errors of mean all < 1, except Group I1 systolic blood pressure at Weeks 4 and 8 where S.E.M.= 1.1

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J. Duffy and G. Macdonald

of the anticipated study population: 222 (8%) were aged 44 years or less, 751 (26%) were aged 45 to 54 years, 1488 (46%) 55 to 64 years, and 781 (20%) were between 65 and 70 years. Hypertension was newly diagnosed in 1176 (36%) patients. The most commonly specified ‘other relevant conditions’ were angina pectoris (25%), obstructive airways disease and peripheral vascular disease (each 7%), myocardial infarction (5%) , diabetes mellitus (3%) and gout (2%). Some patients had one or more pathological conditions.

The majority of patients, 1877 (58%), were treated with nifedipine monotherapy (Group I). The second largest treatment group, 602 (19%), received diuretic plus nifedipine (Group 11), whilst 330 (10%) received beta-blocker and nifedipine (Group 111). Finally, 433 (13%) patients received triple-therapy (Group IV).

Response Mean supine blood pressure measurements were used when examining the data for differences (baseline to Week 8) in response to treatment with age, sex or treatment group. Small differences were found in blood pressure response between the various groups but these differences were not of clinical significance (Figure 1).

In this study, there was a tendency for a greater blood pressure response with increasing age in each treatment group, which correlates with the higher initial systolic blood pressure of the older age groups. The response of different age groups on nifedipine monotherapy is shown in Figure 2.

Figure 2. nifedipine monotherapy in each age group: mean values

Supine systolic and diastolic blood pressure measurements before and during

<44 years 45 to 54 years 5.5 to 64 years 6.5 to 70 years 2o01 (n=156) (n=461) (n=8?3) (n=437)

: t I 0 i 8 0 7 8 0?8 0 4 8

Time (weeks) Note: all standard errors of mean < 1 .O, except <44 years group diastolic blood pressure where S.E.M.< 1.5

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For the purposes of this study, ‘blood pressure control’ in all treatment groups was deemed to have been achieved when the supine diastolic blood pressure was reduced to 90 mmHg or less. Using this criterion, control of blood pressure was achieved in 1481 (46%) patients by Week 4, and in 1979 (61%) by Week 8. As might be expected from the large size of the study population, changes in mean systolic or diastolic blood pressure, supine and standing, were highly significant both from baseline (Week 0) to Week 4, and from baseline to Week 8 for the total study population (p<O.OoOl), and for each treatment group (95% confidence intervals for the changes do not include zero).

In all treatment groups, mean heart rate was reduced by 1.9 beats/min and body weight by 0.48 kg. Both were statistically (p<O.OOl) but not clinically significant reductions.

Dosage At Week 4, the dosage of nifedipine was doubled to 40 mg twice daily in 274 (8.5%) patients because their diastolic blood pressure still exceeded 95 mmHg.

Patient withdrawals A total of 249 (8%) patients discontinued nifedipine between entry and Week 8, mainly due to adverse reactions.

Of the 3242 patients included in the analysis there were 8 deaths; 5 were due to myocardial infarction, 1 to cerebrovascular accident and 2 were described as sudden death, but autopsies were not performed on these to clarify the precise cause.

Side-effec t s At the entry visit (Week O ) , 330 (10%) patients reported side-effects presumably associated with their concomitant therapy. By Week 4,723 (22%) of the patients reported side-effects, the level decreasing to 371 (12%) patients at Week 8. The majority of side-effects reported were graded as of ‘mild’ or ‘moderate’ severity (Table I). At Week 4, a larger number of side-effects was reported as ‘severe’ or ‘intolerable’, accounting for most of those patients who withdrew due to adverse reactions.

Table 1. treatment

Number of patients snd severity grading of side-effects reported on entry and during

Side-effects Week 0 Week 4 Week 8

Total no. patients analyzed ~~

3242 3242 2993

Patients not reporting 2912 2519 2622 any side-effects No. patients with side-effects 330 723 37 1

Severifv grading Slight Moderate Severe Intolerable

1 67 340 210 115 152 95 31 117 39 17 114 27

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A wide variety of side-effects was reported. Table I1 lists those most frequently reported and those most commonly cited as"typica1' side-effects associated with nifedipine. Interestingly, and not previously reported, those side-effects marked with an asterisk were reported more frequently by females in a fema1e:male ratio of approximately 2: 1. The incidence of side-effects was similar across all treatment groups.

Table 11. Incidence of the most frequently reported side-effects: number of patients

Side-effect Week 0 Week 4 Week 8

Vascular headache* Vasodilation :flushing Anginal pain Palpitations/tachycardia Arrhythmia Dizziness Nausea* Somnolence* Tremor Impotence Oedema* Cold extremities* Rash

66 20 10 5 3

37 16 6 3 8 7

22 2

217 156

7 35

5 93 65 31 7 3

38 5 7

84 71 3

18 4

43 25 14 1 2

24 4 2

*More commonly reported by females than by males

When side-effects were studied in conjunction with concomitant disease states, 43% occurred in patients with co-existing cardiovascular disease. Side-effects were not related to the magnitude of the reduction in supine diastolic blood pressure. Patients with the lowest blood pressure response reported fewest side- effects, and those with intermediate responses reported more side-effects than those with the greatest blood pressure reduction.

Continuation of treatment At the end of the 8-week treatment period, physicians indicated that 86% of the 2993 patients remaining in the study would continue with nifedipine therapy.

Discussion The results of this study in a large population of hypertensive patients treated in general practice support the findings of other investigators such as Hornung et a/.,' Landmark? and Lund-Johansen and O m ~ i k . ~ These data provide further evidence of the antihypertensive efficacy of nifedipine tablets, with an overall mean supine blood pressure reduction of 29/18 mmHg. The results compare favour- ably with those of other antihypertensive therapies assessed in similar studies: for example, atenolol/chlorthalidone produced a mean blood pressure reduction of 15/10 mmHg in 6510 patients? although the time of measurement is not recorded relative to the last dose of drug.

In this study, nifedipine was effective in both sexes, all treatment groups and all ages. Higher entry blood pressure, particularly systolic, was associated with the

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older patients and the greater reduction was evident in those patients with the higher entry blood pressure. This is consistent with the findings of MacGregor et aL5 in normotensive and hypertensive subjects, of Mimran and Ribsteins in patients already treated with a diuretic and converting enzyme inhibitor, and of Murphy et aL7 when nifedipine was added to combined beta-blocker/diuretic therapy.

In conclusion, nifedipine when given in a dosage of 20 mg (‘Adalat’ Retard 20 mg) twice daily (or 40 mg twice daily as required by less than 9% of the patient population studied) appears to be an effective and well-tolerated antihypertensive, whether used alone or in combination with other agents, for the treatment of hypertensive patients seen in general practice.

Acknowledgements We appreciate the co-operation of the 1052 general practitioners who participated in this study, and express grateful thanks to Mr. L. Dinneen and Miss J. Smart for the data compilation and statistical analysis, and to Miss C. Foster for typing the manuscript.

References 1. Hornung, R. S., Gould, B. A., Jones, R. I., Sonecha, T. N., and Raftery, E. B., (1983). Nifedipine tablets for systemic hypertension: a study using continuous ambulatory intraarterial recording. Am. J. Cardiol., 51, 1323-1327. 2. Landmark, K., (1985). Anti-hypertensive and metabolic effects of long-term therapy with nifedipine slow-release tablets. J. Cardiovasc. PharrnacoL, 7,12-17. 3. Lund-Johansen, P., and Omvik, P., (1983). Haemodynamic effects of nifedipine in essential hypertension at rest and during exercise. J. Hypertension, 1,159-163. 4. MacGregor, G. A., Markandu, N. D., Rotellar, C., Smith S. J., and Sagnella, G. A., (1983). Acute response of nifedipine is related to pre-treatment blood pressure. Postgrad. Med. J., 59,

5. MacGregor. G. A., Rotellar, C., Markandu, N. D., Smith S. J., and Sagnella, G. A., (1982). Contrasting effects of nifedipine, captopril and propranolol in normotensive and hypertensive subjects. J. Cardiovasc. Pharmacol., 4, S358-362. 6. Mimran, A., and Ribstein, J., (1986). Effect of nifedipine in hypertension not controlled by converting enzyme inhibitor and diuretic. Postgrad. Med. J., 62, Suppl. 1, 135-138. 7. Murphy, M. B., Scriven, A. J. L., and Dollery, C. T., (1983). Role of nifedipine in treatment of hypertension. Br. Med. J., 287,257-259. 8. Sorkin, E. M., Clissold, S. P., and Brogden, R. N., (1985). Nifedipine. A review of its pharmacodynamic properties and therapeutic efficacy in ischaemic heart disease, hypertension and related cardiac disorders. Drugs, 30, 182-274. 9. Tweed, J. A., and Edwards, K. G., (1984). Atenolol/chlorthalidone tablets in the manage- ment of hypertension in general practice. A multi-centre study. Acta Ther., 10,lS-22.

SUPPI. 2,91-94.

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the antihypertensive efficacy of nifedipine alone and in combination in general practice

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