Blood pressure response in 24 hours in patients with high blood pressure treated with two nifedipine formulations once a day

Article metrics

Abstract

A double-blind, comparative and prospective study with nifedipine once a day was undertaken, in patients with mild and moderate high blood pressure. Blood pressure was measured by mercury sphygmomanometer in two positions: resting and sitting at 3, 6 and 12 weeks of treatment and by ambulatory blood pressure monitoring (ABPM) over 24 h; both were carried out before and after the treatment and the uniformity in the pressure levels were obtained by means of the Smoothness Index. Fifty-four patients were included in the trial, 28 in the microgranules group and 26 in the osmotic pump group. These groups were similar at the baseline in age, gender, weight, height, diastolic and systolic blood pressure. The nifedipine microgranules group had a heart rate higher than the nifedipine osmotic pump group at baseline (XM = 75.58 vs XB = 70.75). Blood pressure decreased significantly during the first 3 weeks; 85% in the microgranules group and 75% in the osmotic pump group reached a blood pressure 140/90 mm Hg at the end of the study. Three patients in the microgranules group and two in the osmotic pump group required an additional antihypertensive drug. In both groups, the average blood pressure over 24 h was lowered without differences between groups. A decrease was induced in the heart rate in both groups which reached a marginal statistical significance in the microgranules nifedipine group. No changes were induced in the laboratory tests; two patients in the microgranules (8%) nifedipine group and five in the nifedipine osmotic pump group, adverse effects were observed, of which only one in each group required stopping the treatment.

Introduction

Calcium antagonists represent an alternative in the blood pressure (BP) treatment recommended as first-line drugs.1 Among this type of drug, the dihydropyridine derivatives have been the most widely used.2 Within this class, nifedipine has shown to be effective in controlling high blood pressure3,4 however its side effects due to its potency and short biological half-life have led to the introduction of a sustained release formulation, the nifedipine GITS (gastrointestinal therapeutic system) with a controlled and continuous release over 16–18 h, with plasmatic levels maintained for 24 h with a single daily dosage5 in order to reduce BP equally and maintaining their therapeutic efficacy.6 In Venezuela, another nifedipine formulation is available in the form of microgranules7,8 with a programmed release and maintenance of constant plasmatic levels over 24 h with the administration of a single daily dosage, with a galenic different from that of the osmotic pump.

Calcium antagonists cause their antihypertensive action by blocking the dependent voltage calcium L channels; they also have an antiatherogenic property, because the vascular smooth muscle has this type of calcium channel, they restore the endothelial function expressed as the endothelial response to the acetilcholine in patients with high BP treated with nifedipine, suggesting a reduction in the oxidative stress in the endothelium with an increase in the bioavailability of nitric oxide,9 also in the INTAC study a decrease was reported in the number of new lesions and a lower progression of coronary artery injuries.10

The GITS nifedipine or osmotic pump (NOP) and in nifedipine microgranules (NMG) have been shown to have a good sustained antihypertensive effect and good tolerance6,11,12 in clinical studies. This study has been executed to assess the impact of both nifedipine formulations on BP measured with the sphygmomanometer and ambulatory blood pressure monitoring (ABPM) in outpatients with mild and moderate high BP.

Methods

Patients with essential moderate hypertension were selected, with a diastolic BP (DBP) between 90–115 mm Hg and systolic BP (SBP) <200 mm Hg, aged between 18 and 65 years of either sex, for a comparative study between NOP and NMG in a double-blind randomised and prospective design. During the initial selection, patients with the following diagnoses are excluded: serious concomitant diseases, pregnancy or lactation and known intolerance to nifedipine, subsequent to a routine clinical history, laboratory and medical examination.

Basal measurements were made after 2 weeks of placebo. At the end of that phase, patients with a DBP between 90 and 115 mm Hg (average of three measurements taken at 2-min intervals after an initial rest period of 5 min using a mercury sphygmomanometer, in a sitting position and with trained staff) were assigned at random to receive 30 mg of nifedipine supplied once a day in the form of NOP or NMG. A written consent has been obtained from patients after explaining the protocol which has been previously accepted by the ethics committee. BP measurements, heart rate (HR) and adverse effects reports were made after 3, 6, and 12 weeks of treatment. If by the third week a DBP <90 mm Hg and SBP <140 mm Hg had not been reached, the dose was increased to 60 mg per day; if by the sixth week, BP was not controlled, enalapril is added and these patients were withdrawn.

Before and after the treatment period, laboratory examinations and ABPM were measured using an Auto Cuff recorder, model 1001 (Biotrac) by oscillometric method. The patients were instructed to perform their usual activities and stop when BP was measured. The monitor was programmed to obtain measurements every 15 min between 07.00 and 23.00 h, and every 30 min during night time (23.00 to 07.00 h). MABP (outpatient non-invasive monitoring) reports SBP, DBP, HR and mean arterial pressure (MAP) over 24 h, day and night.

Statistical analysis

The Student's t-test is used for dependent samples and Wilcoxon range analyses to evaluate changes that occur between treatment phases for HR, SBP, DBP, both recorded by mercury sphygmomanometry or by ABPM. In both cases, 5% is determined for the significance level. To compare the two treatments, the t-test is used for independent samples and the non-parametric Mann-Whitney test.

Results

A total of 54 patients, 44 of the female gender and 10 of the male gender, participated and completed the study with an average age of 54 years. Four patients were excluded for having more than 10% of all readings lost or incorrect. They were allocated at random as follows:

  • NMG group: 28 participants, received microgranules nifedipine, 12 weeks

  • NOP group: 26 participants, received osmotic pump nifedipine, 12 weeks

The demographic data

In the NMG group there were 22 of the female gender and six of the male gender, with an average age of 54.8 ± 8.9 years, weight of 53.8 ± 10.8 kg and height of 1.59 ± 0.07 cm. In the NOP group there were 22 of the female gender and four of the male gender, an average age of 53.8 years, weight of 69.3 ± 12 kg and a height of 1.56 ± 0.07. No significant differences were found between ages (P = 0.69887), weight (P = 0.94797), height (P = 0.18390) between study groups.

Changes in BP and HR by mercury sphygmomanometer (Table 1, Figures 1, 2 and 3)

Figure 3
figure3

Heart rate.

Figure 2
figure2

Systolic blood pressure.

Figure 1
figure1

Diastolic blood pressure.

Table 1 shows the changes in SBP, DBP and HR in supine position, which were also performed in a sitting position in a similar way and with statistical significance.

Table 1 Evolution of pressures using a sphygmomanometer

SBP

NOP group: baseline value was 162.2 ± 16 mm Hg with a decrease of BP upon 12 weeks of −16 ± 10.4 mm Hg −10% P < 0.0001. NMG group: baseline value of 163.17 ± 14.2 with decrease of BP upon 12 weeks of 22 ± 11.78 mm Hg, −14% P = 0.0001. There were no significant differences of basal value between NOP and NMG groups, (P = 0.777), and after 12 weeks of treatment (P = 0.96). The decrease response in BP was observed after 3 weeks of treatment in both groups (P = 0.000).

DBP

NOP group: baseline value was of 97 ± 7.3 mm Hg after 12 weeks was reduced in −17 ± 5.95 mm Hg%, −18% P < 0.001. NMG group: baseline value 95.6 ± 5.7 mm Hg, with a decrease after 12 weeks of 15 ± 7.9 mm Hg, 16% P < 0.0001. There were no significant differences of the baseline value between groups (P = 0.585) and after 12 weeks (P = 0.26) between NOP and NMG. A significant decrease was observed in both groups after 3 weeks of treatment P < 0.0001. Eighty-five percent of the NMG group and 75% of the NOP group showed a BP below 140/90 mm Hg after 12 weeks of treatment.

HR

NOP group: baseline value was 70.6 ± 6.5 with significant increase after 12 weeks of +3 ppm P = 0.008, +5%. NMG group: basal value was 75.5 ± 7.5 with decrease after 12 weeks −3 ppm (P = 0.003), −5%. Comparison of values between NOP and NMG groups in the baseline P = 0.005 was significant and final P = 0.2186 was not significant.

Changes in median BP by ABPM (Figures 4 and 5, Table 2)

Figure 5
figure5

ABPM 24-h osmotic pump.

Figure 4
figure4

ABPM microgranules.

ABPM over 24 h, at the beginning both groups showed similar hour pressures. At the end of the treatment period, a significant decrease was observed from the placebo value in MAP of 24 h with both treatments, as well as MAP during day and night without differences between the two drugs (Table 2).

Table 2 Ambulatory blood pressure monitoring

Side effects and tolerance

Both formulations were well tolerated; two patients in the NMG group presented ankle oedema and five patients of the NOP group showed side effects (two with oedema, one with headache and tachycardia, two with facial flushing). The drug was not stopped in any of the cases during the treatment period.

Discussion

Our results suggest that nifedipine in microgranules and the osmotic pump type, used as monotherapy once a day for 12 weeks in the treatment of patients with high blood pressure from mild to moderate, induce a prompt and similar decrease in BP, 75% under treatment with NOP, and 85% with NMG, reached at the end of the study a BP of <140/90 mm Hg.

The outpatient control of BP with the use of a mercury sphygmomanometer shows a significant decrease after 3 weeks of treatment, maintaining its stability after 12 weeks, without differences in the response between study groups. Reduction in BP reduces the cardiovascular morbimortality. The INSIGHT13 study was designed for this purpose and revealed a reduction of events of 50% under treatment with osmotic pump nifedipine, when compared with the treatment of diuretics (hydro- chlorothiazide and amiloride). On the other hand, a meta-analysis with randomised studies, double-blind with antihypertensive agents and its action in the regression of the ventricular hypertrophy, the calcium antagonists are in second place with 9%, after the IECA, with 13% before diuretics 7% and beta-blockers 6%.14 Ventricular hypertrophy is an independent risk factor for coronary heart disease, cardiac insufficiency and fatal arrhythmias.15 The HOT study cleared doubts about the intensity of the decrease in BP using felodipine, another calcium antagonist; decrease of BP below 80 mm Hg was associated with lower number of events and deaths of cardiovascular origin.16

Heart rate in this study shows a slight increase under treatment with NOP and a slight decrease with NMG. This fact is due to the changes of nifedipine with controlled release formulations and the development of agents with long biological half lives.17 These results with NOP were similar in other studies in which there was an increase of the HR and of the double product in the morning hours.18

The therapeutic efficacy of the osmotic pump nifedipine has been fully established.5,6 In this study, it is compared with nifedipine with another form of release by microgranules which enables a slow release, used as monotherapy for high blood pressure and stable effect for 24 h, with the same dose once a day, for which ABPM is used with the calculation and measurement of MAP in 24 h, minimising the variability of BP when comparing both formulations.19

By fulfilling the primary object of this design and leaving for subsequent assessments other considerations such as circadian behaviour, trough–peak ratio, ‘uniformity index’ and double product, we can confirm as a main result equal considerations of therapeutic effect as that achieved with the taking of BP with a sphygmomanometer, also a similar and significant decrease in BP from the third week. Beginning with a similar basal level of BP, both formulations reduce BP without significant differences after the third week within a context of good tolerance and few side effects.

Figure 5
figure6

ABPM 24-h microgranules vs osmotic pump.

References

  1. 1

    Guidelines Subcommittee 1999 World Health Organization-International Society of Hypertension. Guidelines for the Management of Hypertension J Hypertens 1999 17: 151–183

  2. 2

    Brawnwald E . Mechanism of action of calcium-channel blocking agents N Engl J Med 1983 307: 1618–1627

  3. 3

    Kaplan NM . Calcium entry blockers in the treatment of hypertension JAMA 1989 262: 817–823

  4. 4

    Frishman WH, Charlap S, Michelson EL . Calcium-channel blockers in systemic hypertension Am JCardiol 1986 58: 157–160

  5. 5

    Chung M, Reitberg DP, Gaffney M . Clinical pharmacokinetics of nifedipine gastrointestinal system: a controlled-release formulation of nifedipine Am J Med 1987 83 (Suppl 3): 10–14

  6. 6

    Salazar A, Arocha I . Antihypertensive efficacy and tolerance of the osmotic formulation of nifedipine: Venezuelan Multicenter Study Acta Clinica (Bayer) 1993 4: 11–15

  7. 7

    Scientific Technical Report of a new nifedipine to be administered every 24 hours Laboratorios Leti, Venezuela 1997

  8. 8

    Coll Y, Rizzo A . Pharmacokinetics assessment of repeated doses of microgranules nifedipine 30 mg Tensomax ® Scientific Higher Board, Barcelona, Spain 1993

  9. 9

    Waiters D et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis Circulation 1990 821: 940–953

  10. 10

    Lichtlen PR et al on behalf of the INTAC GroupInvestigator. Retardation of angiographic progression of coronary artery disease by nifedipine. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTAC) Lancet 1990 335: 1109–1103

  11. 11

    Collet H, Uzcategui I, Freites M, Gonzalez M . Efficacy and tolerance of a new nifedipine formulation to be administered once a day in the form of micro particles Arch Ven Farm Therap 1997 16: 78–81

  12. 12

    Roa E et al. Blood pressure profiles in 24 hours inpatients with high blood pressure treated with two nifedipine formulations. Preliminary report TEMATICA 2000 1: 16–19

  13. 13

    Ruilope L . New prospects in the treatment of artery hypertension (Results of the INSIGHT). Conference within the framework of the XIX South American Congress of Cardiology. Caracas, 9 June 2000

  14. 14

    Schmieder R, Martus P, Klingbeil A . Reversal of left ventricular hypertrophy in essential hypertension JAMA 1996 275: 1507–1513

  15. 15

    Yurenev AP, Dyakonova HG, Novkov ID . Management of essential hypertension inpatients with different degrees of left ventricular hypertrophy Am J Hypertens 1992 5: 5182–5189

  16. 16

    Hansson L, Zanchetti A, Carruthers G, Dablof B . Effects of intensive blood pressure lowering and low dose aspirin inpatients with hypertension: principal result of the Hypertension Optimal Treatment (HOT) randomized trial Lancet 1998 351: 1755–1762

  17. 17

    Frishman WH, Katz B . Controlled-release drugs delivery systems in cardiovascular disease treatment. In: Frishman WH, Sonmenblick ED (eds) Cardiovascular Pharmacotherapeutics McGraw Hill: New York 1997 1363–1374

  18. 18

    White WB et al. Comparison of effects of controlled onset extended release verapamil at bedtime and nifidepine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate and the heart rate-blood pressure product Am J Cardiol 1998 81: 424–431

  19. 19

    White WB . Analysis of ambulatory blood pressure data in antihypertensive drug trials J Hypertens 1991 21 (Suppl 1): S27–S32

Download references

Acknowledgements

The authors are grateful to Mrs Carmen Zulay Ibarra for her collaboration in performing the statistical analysis.

Author information

Correspondence to M González.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rodríguez-Roa, E., Octavio, A., Mayorca, E. et al. Blood pressure response in 24 hours in patients with high blood pressure treated with two nifedipine formulations once a day. J Hum Hypertens 16, S151–S155 (2002) doi:10.1038/sj.jhh.1001363

Download citation

Keywords

  • nifedipine
  • blood pressure
  • microgranules
  • osmotic pump

Further reading