Cardiovascular Drugs and Therapy 4: 941-946, 1990 ,c; Kluwer Academic Publishers, Boston. Printed in U.S.A.

Long-Term Therapy with Slow-Release Nifedipine in Essential Hypertension Francesco A rrigo, Fausto Consolo lstituto Pluridisciplinare di Clinica Medica e Terapia Medica Generale e Speciale, Cattedra di Cardiologia, Policlinico Universitario G. Marrino, UniverMty of Messina, Messina. Italy

Summary. The purpose of this study, designed as an open multicenter trial, was to test the antihypertensive efficacy, patient acceptability, and side effects of long-term treatment with slow-release nifedipine in a large population. The drug

was studied in 330 outpatients with essential hypertension, WHO stage 1-2, recruited in 20 hospital centers. After washout period was completed, nifedipine (20 mg bid) was given for 1 month (phase 1). Then, the treatment was extended for 4

months (phase 2) with variable doses (range 20-80 mg daily). No other antihypertensive drugs were administered during phase 1. However diuretics, beta blockers, or captopril were added to nifedipine during phase 2 in 11 patients. Seventy patients did not meet criteria for inclusion at washout. During phase 1 and 2, 66 additional patients were excluded due to side effects, the need of other antihypertensive drugs, or noncompliance. Systolic blood pressure significantly lowered (10% or more) in 84% patients in phase 1 and in 76% in phase 2. No responders were 6.1% and 3.6~, respectively. Diastolic blood pressure was normalized in 60% of patients after 5 months of therapy. Effects on blood pressue were equal in young patients and in the .elderly, but a minimal rise in heart rate was recorded in younger patients. At least one side effect occurred in 46.6c~ patients, mainly headache (15.4%), hot flashes (13.3%), ankle edema (12.8G), or palpitation (6.6%). Sixteen patients (8.2~) were obliged to stop nifedipine treatment due to the severity of the side effects. This trial confirms the efficacy of nifedipine in hypertension, both in young and in aged patients. The adherence of patients to the twice-daily regimen was very good, without the development of tolerance in long-term treatment. The drug does not affect the physiologic cardiovascular response to standing, but induces several relatively common, very seldom severe, adverse reactions.

Key Words. nifedipine, hypertension, elderly hypertensives

Calcium-channel blockers have a n t i h y p e r t e n s i v e efficacy due to t h e i r v a s o d i l a t o r effect, and their use in the t r e a t m e n t of h y p e r t e n s i v e p a t i e n t s is increasing [1-3]. Nifedipine differs from o t h e r nondihydropyridine calcium-channel blockers because of its more p o t e n t v a s o d i l a t i n g effect [4,5] and the absence of a clinically e v i d e n t n e g a t i v e inotropic action. Although the antih y p e r t e n s i v e action of nifedipine was first proved in

1972 [6,7], its use in l o n g - t e r m t h e r a p y was not wides p r e a d due to its s h o r t half-life and b r i e f d u r a t i o n of action. More recently, slow-release nifedipine, a c r y s t a l line p r e p a r a t i o n with d e l a y e d e n t e r a l absorption, has been available for clinical use and this form o v e r c o m e s some of the previous limitations. One s l o w - r e l e a s e nifedipine t a b l e t produces constant p l a s m a concentrations and reduces blood p r e s s u r e over 9-10 hours [8]. These p r o p e r t i e s s u g g e s t t h e d r u g could be admini s t e r e d only twice daily, thus reducing a d v e r s e reactions and i m p r o v i n g p a t i e n t acceptance. N e v e r theless, few clinical studies on slow-release nifedipine have been completed. The purpose of this study, designed as an open mult i e e n t e r trial, was to e v a l u a t e the a n t i h y p e r t e n s i v e efficacy, side effects, and p a t i e n t acceptance of longt e r m t h e r a p y with slow-release nifedipine in a l a r g e population.

Me~o~ Slow-release nifedipine was studied in o u t p a t i e n t s with p r i m a r y , u n t r e a t e d h y p e r t e n s i o n or who had not taken d r u g s for at least 2 weeks. The s t u d y was carried out in 20 hospital centers, and each c e n t e r recruited 20 h y p e r t e n s i v e patients. The following criteria were used for inclusion in the study: a) age range, 30-75 years; b) blood p r e s s u r e above 165/95 m m H g in t h r e e r e p e a t e d m e a s u r e m e n t s in supine position; c) no s e c o n d a r y h y p e r t e n s i o n revealed by routine procedures; d) no clinical evidence of h e a r t failure, A-V block, s e v e r e o b s t r u c t i v e a r t e r i a l disease, pregnancy, or malignancy; and e) W H O s t a g e 1 (uncomplicated hypertension) or 2 (at least one t a r g e t organ damaged). The p u r p o s e and design of the investigation were explained to p a t i e n t s , and informed consent was obtained.

Address for correspondence and reprint requests: Prof. Francesco Arrigo, via P Longo 3/a, 98100, Messina, Italy. 941

942

Arrigo and Consolo

The study design included three phases: 2 weeks with no antihypertensive drugs (washout); 1-month treatment with constant slow-release nifedipine at a dose of 20 mg bid (phase 1); and a 4-month treatment with variable slow-release nifedipine doses (phase 2). Only patients fitting established criteria at the end of the washout period were admitted to the treatment. Some few patients with unsatisfactory effect during phase i were treated with increased doses of the drug, while patients needing other antihypertensive drugs were excluded from the study. During phase 2, the drug dosage was individually adjusted (20-80 rag/day) to achieve a better effect and other drugs (diuretics, beta blockers, or captopril) were added in some patients. All patients were evaluated at the end of washout, at the end of phase 1, and after 2 and 4 months during phase 2. Each clinical evaluation included an interview and measurements of body weight, heart rate, and aterial blood pressure. Blood pressure (cuffstethoscope method) and heart rate were measured after 5 minutes of rest in the supine position and after 2 minutes standing. Care was taken to record any pharmacologic therapy performed and any patient's complaint that might be due to the drug. The laboratory examination--performed after washout and at the end of phase 2-comprised urinalysis, blood cell counts, hemoglobin, plasma electrolytes, serum glucose, creatinine, uric acid, cholesterol, triglycerides, gamma-glutamyl-transpeptidase, blood urea, creatinine clearance, standard 12-lead electrocardiogram, fundus oculi, and chest roentgenogram. The efficacy of the treatment was rated by at least a 10% reduction in systolic blood pressure and by a reduction in diastolic blood pressure to < 90 mmHg. The percentage of responders and the changes in blood pressure and heart rate were analyzed in the overall population and in two age subgn'oups. Analysis of variance in randomized block experiments was used to assess the statistical significance of difference observed in blood pressure, heart rate, and body weight. Dunnet's and Tukey's tests for multiple comparison were performed. The significance of variations of laboratory findings was assessed using the paired Student's t test. Data from ECG, ocular fundus, and chest x-ray were statistically analyzed using the Chi-square test.

Results After the washout period, 70 patients did not meet the criteria for admission, while 330 patients started nifedipine treatment (20 mg bid). During phase 1, 32

cases were excluded due to side effects or the addition of other drugs and 16 patients did not undergo control visits; therefore, 282 cases entered phase 2 treatment. During phase 2, four patients withdrew because of side effects, while two cases needed drugs other than diuretics, captopril, or beta blockers, and 12 others missed follow-up appointments. The remaining 264 patients were included in the final evaluation. In 189 cases (71.6%) the nifedipine dose of 40 mg/ day was kept constant. Out of the remaining patients, 17.4% were treated with variable doses (20-80 mg/ day) and 11% received 60 mg/day of nifedipine plus other drugs. These three gxoups did not differ in age or sex; the hypertension duration was longer, and the WHO stage was higher in patients needing other drugs. The values of body weight, supine and standing heart rate, and blood pressure are reported in Table 1. Both systolic and diastolic blood pressure reduced significantly (p > 0.001) after 1 month and fell further after 5 months. Normalization of diastolic blood pressure was achieved in 32.7% of patients after 1 month and in 60% after 5 months, while the number of no responders was 6.1c~ and 3.6%, respectively. Responders with a 10% reduction of systolic blood pressure were 84% in phase 1 and 76% in phase 2. In the age subgn'oups, no differences were found between patients over and under 60 years (Table 2). However, younger patients manifested little but significant elevation in heart rate. ECG, ocular fundus, chest x-ray, and laboratory values were all unchanged, except for uric acid, serum cholesterol, and triglycerides (Table 3). Adverse reactions were evaluated in patients not taking drugs other than nifedipine (Table 4). Ninetyone patients (46.6%) had at least one side effect, but only a few had more than one. Sixteen patients (8.2%) stopped treatment because of severe side effects. Headache, mild in 26 and strong in four cases, was the most frequent complaint, often associated with hot flashes and flushing of the face. The most common unwanted effect was ankle edema, observed in 25 patients. In these eases body weight was unchanged and administration of diuretics relieved the disturbance in four patients. Patients suffering fl'om palpitations manifested slightly increased (nine cases) or normal (two cases) heart rate, while two patients showed an obvious sinus tachyeardia. Cutaneous rash (three cases) led to treatment interruption that resulted in complete recovery in a few days. Rare side effects included salivation, and leg pain at rest in one ease with obstructive arterial disease, hiccuping, tremor, tinnitus, and weakness. The drop-out rate was 20% in the total group of

Slow-Release Nifedil~i*w it~ Essetdial Hypertettsio~

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Table I. Heart rate, blood pressure, ,rot hod!l weight in 264 h!lperte~lsi~,es d ~ "it g Ioug-term therap?l witll slow-release ttifedit)itle (20-,k'O mgldct!l) Control

Phase 1

Phase 2

HR Rate Supine Standh~g

76.4 + 10.6 80.4 +_ 11.0

78.3 _+ 8.3 82.1 ~ 8.7"

77.4 -+ 6.6 8 0 . 8 • 7.0

Systolic blood pressure ( r a m H g ) Supine Standing Diastolic b l o o d p r e s s u r e ( m m H g )

183.4 • 181.1 •

16.5 15.8

156. I - 17.6 153.7 _+ 17.1

145.9 -+ 13.5 ~' 143.9 • 12.5 ~'

Supine Standing Body weight, kg

103.8 _+ 7.5 104.0 + 8.6 71.4 _+ 11.2

89.6 _+ 8.8 89.0 m 8.8 71.1 +- 11.1

8 3 . 0 • 7.2 b 83.1 ~ 7.3 ~' 70.4 • 10.5:'

" p > 0.05 vs. control. p > 0.001 vs. control. bp > 0.001 vs. p h a s e 1. Means _* SD.

Table 2. Respot~se to sh)w-rcle.,se ni/'cdlpit~e aceordb~g to t)atietll .ge. OM!t c.ses Ire,ted with tlifedipiue who completed the stud!/ were bwluded. H e a r t rate

Systolic BP

Diastolic B P

c~ resp.

Group

Meal] age

C

P2

C

P2

C

P2

Yes

No

1

49.4

76.3

77.8"

180.9

142.6 t'

103.3

3.4

_+ 7.0 64.9 + 3.9

_+ 9.8 76.7 + 12.2

_+ 6.7 76.9 + 6.4

z 5.8 187.7 + 13.9

+_ 11.2 149.0 t' _+ 13.5

• 7.8 103.2 _+ 6.8

82.6 b _+ 6.4 82.8 ~' • 6.5

96.5

(146) 2 (90)

95.5

4.4

" = p < tl.025; b = p < 0.001 vs. control. M e a n s = SD. G r o u p 1: < 60 yrs; gq'oup '2: > 60 y r s .

Table 3. Laboralorg fitMit~gs b(;/?,'e lherapg (conttvl) attd at the eud of phase 2 h'eatmetlt with shin'-release t~(/edipbm. Laboratory

Units

Pts

Control

Phase 2

P value

U r i c acid

mg~ mgC/c mg~

221 206 204

5.19 • 1.36 216.0 • 50.30 148.0 _+ 64.6

5.06 _+ 0.95 2 0 4 . 0 • 37.9 135.3 • 4 4 . 6

< 0.01 < 0.01 < 0.01

Cholesterol Triglycerides

Mean wflues z SD. All o t h e r values (see text) w e r e u n c h a n g e d .

patients entering the study. The causes of withdrawal were side effects (6.6%), need of other drugs (4.2%), inefficacy of nifedipine (0.6%), or unknown (8.48%).

Discussion The antihypertensive activity of nifedipine has been recognized since 1972 [61 and was further demonstrated both after single administration and on longterm therapy [9,10]. Our results confirm that the drug reduces blood pressure in patients with mild to moderate arterial hypertension. The primary goal of any antihypertensive therapy

should be the reduction of blood pressure to normal values [11]. If this restrictive criterion is applied, many large studies fail to prove the efficacy of various drugs and 10-70% of treated hypertensive patients are currently not controlled. In the present study, a reduction < 90 mmHg of diastolic blood pressure was achieved in 60% of enrolled patients. If cases of dropout--mainly due to side effects or nonadherence to the protocol, and in only a few instances to inefficacy of the therapy-- are excluded from the referring population, the percentage of normalization is 75%. Nonresponders (12 cases, mean age 61.2 _+ 7.4 years) had mostly complicated (stage 2) and long-lasting (45.2 +_

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Arrigo and Consolo

Table 4. Adverse reactions d~r

prolonged slow-release nifedipbw therapy in patients m~l laking an!! other dr~g. Patient

Effect

No.

Headache Hot flashes Ankle edema Flushing Palpitations Heartburn Dizziness Nausea Rash Sexual dysfunction Confusion Tinnitus Hiccup Tremor Weakness Leg pain

30 26 25 20 13 8 4 3 3 2 2 1 1 1 1 1

37 months) hy-pertension. However, as this study was designed as an open trial with no placebo group, the very high efficacy rate could have been enhanced by the placebo effect, which may account for the hypotensire action in a significant proportion of cases (11% in the Australian trial) [12]. It has been suggested [13] that calcium antagonists are more active with increasing patient age due to the protective effect on calcium overload in vascular smooth cells [14,15] and to a reduced occurrence of side effects [16]. We did not find any relationship between age and the efficacy of nifedipine, in agreement with other studies showing that this drug is active both in elderly and in young hypertensives [17,18]. Development of tolerance, reported for some vasodilating agents during long-term therapy, is a critical concern in hypertensive patients, being one of the main reasons for failure of therapy. No tolerance was seen in our study: Once the hypotensive effect was reached, there was no return to hypertensive values. Pharmacokinetic properties of nifedipine tablets result in prolonged and constant serum concentrations, paralleled by a fairly constant reduction in blood pressure over a 24-hour period [19]. This fact will improve patient compliance to taking the drug and lessen the occurrence of side effects. In hypertensive patients, the compliance is reflected by the regularity of blood pressure control and tablet assumption, and by the drop-out rate [20]. In our study, 80% of enrolled patients regularly underwent controls over 5 months and monthly returned to the referring center for tablet study. Further, it is likely that only the patients who withdrew from the drug regimen for unknown reasons

Discontinued study 15.38 13.33 12.82 10.25 6.66 3.38 2.05 1.54 1.54 1.02 1.02 0.51 0.51 0.51 0.51 0.51

(8.8%) were not compliant. Thus, our results show good compliance for monotherapy with nifedipine tablets in most patients. Side effects were frequent but had, in general, little clinical significance. Only a few patients had to stop the drug because of skin rash, ankle edema, or headache. The most relevant symptom was ankle edema, not associated with overt heart failure or with an increase in serum sodium or body weight. There is general agreement that nifedipine induces interstitial fluid accumulation as a result of arteriolar dilatation without venodilation [21]. Nevertheless, diuretics or withdrawal of nifedipine may relieve edema in a few days. In conclusion, the trial confirms the effectiveness of slow-release nifedipine in lowering blood pressure. The drug displays its antihypertensive efficacy both in young patients and in the elderly without affecting the physiologic responses to standing or the sodium balance. Minor unwanted effects are quite common, but their severity seldom requires the interruption of treatment. In a twice-daily dose, adequate control of blood pressure can be achieved over 24 hours, as shown by ambulatory intraarterial recordings [22]. References 1. Hagino K. Application ofipoveratril in thepharmacotherapy of hypertension. Jpn J Clin E,rp Med 1968;45:208-213. 2. Zanchetti A. Perspectives in antihypertensive treatment. In: Zanchetti A, Krikler D' eds. Calcium antagonists in cardiovascular therapy. Amsterdam: Excerpta Medica, 1981: 292. 3. Muiesan G, Agabiti Rosei E, et al. Antihypertensive and

Slow-Release N~fedipbw in Essential Hypertension

4.

5.

6.

7.

8.

9. 10.

11.

12. 13.

humoral effects of verapamil and nifedipine in essential hypertension. J Cardiov(~sc Pharm(wol 1982;4:$325. Grun G, Fleckenstein A. Die elektromechanische entkopplung der glatten gefassmuskulatur als gn'undprinzip (letcoronardilatationdurch 4-(2-nitrophenyl)-2, 6-dimethyl-l,4dihydrol)iridin-e arbosam'e-dimethylester (Bay 1040, nifbdipine). Arz~leim-Forscil (Drlqi Research) 1972;22:334-343. Robinson BF, Dobbs R J, Kelsey CR. Effects of nifedipine on resistance vessels, arteries and veins in man. Br J ('lb~ Pharmacol 1980;10:433-439. Murakami M, Murakami E, Takekoshi N, et al. Antihypertensive effect of nifedipine, a new coronary dilator. ,]p~ Heart J 1972;13:128-135. Olivari MT, Bartorelli C, Polese A, et al. Treatment of hyt)ertension with nifedipine, a calcium antagonist agent. Circ~dation 1979;59:1056-1060. Taburet AM, Singlas E, Colin JN, et al. Pharmacokinetic studies on nifedipine tablet: Correlation with antihypertensive effects. H!lperle~sio~t 1983;5(Suppl II):29. Murphy MB, Striven AJI, Dollery CT. Role of nifedipine in the treatment of hypertension. Br Med J 1983;287:257-262. Bonaduce D, Canonico V, Mazza F, et al. Evaluation of the efficacy of slow release nifedipine in systemic hypertension by ambulatory intraarterM blood pressure monitoring. J Cardiovasc I']larmacol 1985;7:145-151. Menard J, Chatellier G, Degoulet P, et al. How much can blood pressure be lowered? H!lperte~sio~ 1983;5(Suppl III):21. Management Committee: The Australian Therapeutic trial in mild hypertension. Latwet 1980;1:1261-1267. Leonetti G, Sala C, Bianchini C, et ah Antihypertensive and

14.

15. 16.

17.

18.

19.

20.

21.

22.

945

renal effects of orally administered verapamil. E u r J Pharnlacol 1980;18:375-382. Henry PD. Calcium antagonist as cell protectant. In: Terroux P, Waters DD, eds. Proc 1st lnt Can N(fedipine Syrup. Amsterdam: Excerpta Medica, 1983:196. Nayler WG. Calcium antagonists. E~o" Heart J 1980;1:225238. Schnai) p P, Hernamm H, Cernak P, Kalay J. Nifedipine monotherat)y in the hypertensive elderly: A placebocontrolled clinical trial. Cto'r Med Res Opbl I986;10:407413. Erne P, Bolci P, Bertel O, et ah Factors influencing the h~q)otensive effect of calcium antagonists. Hgperte~sio~z 1983;5(Suppl II):97-102. Midtbo K. Efficacious and safe. In: Calcium antagonists-New perspectives. Oxford Medical Education Service, 1985:6. Thibonnier M, Sassano P, Corvol P. Evaluation de l'effect antihypertenseur des formes capsule et comprime de nifedipine dans l'hypertension. Arch Mal Coeto" 1985;78:25-31. Haynes RB, Sackett DL, Gibson ES, et al. Improvement of medication compliance in uncontrolled h~)ertension. Lancet 1976;1:1265. Opie LH, Jee LD. Nifedipine: Exanding indications in hyl)ertension. In: Opie LH, ed. Calci~on a~da.qo~lisls a~d cardio~,ascMar disease. New York: Raven Press. 1984:333342. Hornung RS, Gould BA, Jones RI, et ah Nifedipine tablets for h,,q)ertension: A study using continuous ambulatory intra-arterial recording. A m J Cardiol 1983;51:17,23-1327.