Chn Drug Invest 1997, 13 Supp l 1 163-168 1173-2563/97/CXXJ1-Ol63/S03 00/0

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Tolerability of Amlodipine A Meta-Analysis

Gian Piero Perna, Mario Stanislao and Giovanni De Luca

Department of Cardiology, 'Casa Sollievo della Sofferenza' Hospital, IRCCS San Giovanni Rotondo (FG), Italy

Summary We examined the tolerability and safety of amlodipine in a large population of patients (n = 12831) by performing a meta-analysis of 16 consecutive studies in which this drug was used for treatment of hypertension (n = 9638; 75%) or ischaemic heart disease (n = 3193; 25%) and data were standardised and referred to a central core laboratory. Adverse events were reported by patients in response to an open questionnaire and completed at standardised times after starting amlodipine.

Overall, the percentage of patients who experienced amlodipine-related adverse effects was about 15%, and only 3% of patients were withdrawn from amlodipine therapy because of drug intolerance.

Four adverse events (peripheral oedema, headache, flushing and altered heart rate) occurred in I % or more of amlodipine recipients; these are typical of dihydropyridines and are predominantly related to arteriolar vasodilation.

Rare adverse events attributable to idiosyncratic or allergic response (skin rash) were reported.

Other adverse events (gastrointestinal disorders, tremor, polyuria, cough, etc.) were ill defined, and their nature was unclear.

Finally, the percentage of patients with amlodipine-related adverse effects was not influenced by drug dosage or disease status, and a comparison of amlodipine's tolerability with that of alternative calcium antagonists, P-blockers or ACE inhibitors showed a significantly lower occurrence (17 .3 vs 39.7% of patients, p < 0.00 I).

Amlodipine is a second generation calcium

antagonist of the dihydropyridine class[l] that is ef­

fective when used alone or in combination with

other drugs in the treatment ofhypertension[I-3] and

coronary artery disease.! 1,4) Several studies have

demonstrated that amlodipine is a well tolerated

drug, associated with only mild and infrequent

adverse events. [1,4-6) However, it is only by pooling

adverse event data from a substantial number of

small scale studies that we can reach firm conclu-

sions regarding the tolerability of investigational

or newly launched drugs. Findings obtained in this

manner are more likely to be representative of a

drug's true tolerability than those derived from a

single clinical trial of the same drug. Pooling of

adverse event data is, however, a meaningful tech­

nique only if subsequent data management is ap­

propriately standardised and centralised.

We have examined the tolerability of amlo­

dipine in a large population of patients with hyper-

164

tension or ischaemic heart disease by performing a meta-analysis of 16 different studies in which the drug was used and data were standardised and re­ferred to a central core laboratory.

1. Methods

1.1 Patients

We examined tolerability data from 16 clinical studies performed consecutively between January 1991 and June 1993 at several participating cen­tres. Of a total of 12 831 patients included in the analysis, 9638 (75%) were recruited for treatment of hypertension and 3193 (25%) for treatment of ischaemic heart disease.

In all studies, existing antihypertensive or anti­anginal medication was discontinued at least 2 weeks before entering the study. In most studies, amlodipine was administered at an initial dose of 5mg for 2 weeks, and this dose could be doubled to 10mg; in 5 studies (n = 85), patients only re­ceived amlodipine 10mg.

Patient exclusion criteria included the presence of significant renal, hepatic, endocrine or haematological disease, migraine, pregnancy, hy­persensitivity to dihydropyridines and concurrent therapy with cimetidine or quinidine. All patients gave their informed consent. The duration of the treatment period with amlodipine ranged from 4 to 24 weeks.

1.2 Data Collection

Adverse events were voluntarily reported by pa­tients at each visit in response to an open question­naire (International Adverse Experience Report), the same for all participating centres, which was completed at standardised times at the end of the study period and/or when a serious adverse event was reported during treatment. A record was made of the severity and the relationship to treatment of each adverse event and, if it was considered to be treatment related, patients were questioned about the level of disruption to their daily activities. Adverse events of uncertain attribution were con­sidered not drug related. Treatment was discon-

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Perna et al.

tinued for serious or persistent adverse events re­lated to the drug, or when requested by the physi­cian or patient. Data collection and management were referred to a central core laboratory.

1,3 Data Analysis

To perform the meta-analysis, we subdivided the 16 studies into 3 clusters. These were (A) non­comparative studies of drug efficacy: 12584 patients; (B) comparative parallel group studies (vs other calcium antagonists, ACE inhibitors or ~-blockers) : 127 patients treated with amlodipine (15 received combination therapy with ~-blockers) and 126 patients treated with other drugs; and (C) crossover studies vs placebo or other drugs (other calcium antagonists or ACE inhibitors): 120 pa­tients, For cluster A, we estimated the percentage of patients with adverse events, the percentage of patients with drug-related adverse effects and the percentage of patients withdrawn because of ad­verse events. For clusters Band C, we evaluated the same percentages by treatment groups, and compared the percentage of patients with adverse events (both drug related and not drug related),

Furthermore, for all patients treated with amlodipine (clusters A + B + C), we estimated the percentage of patients with adverse events in rela­tion to amlodipine dose (5 or IOmg), Finally, we showed the most frequently reported adverse events by daily dose and and disease status (hyper­tension or ischaemic heart disease).

For estimated percentages of patients with ad­verse events, a 95% confidence interval was calcu­lated using the approximation of binomial to nor­mal distribution,

Intergroup differences were assessed as follows by use of previously described statistical methods:[7J

Considering the j-th study, let Tj be the differ­ence in the proportions of patients with adverse events between the two treatment groups,

Tj = aj/Mlj - bj/M2j

where aj = the number of patients experiencing ad­verse events with amlodipine, bj = the number of patients experiencing adverse events with other

Clin. Drug Invest. 1997; 13 Suppl. 1

Tolerability of Amlodipine: A Meta-Analysis

Table I. Number of patients with adverse events in noncomparative studies of amlodipine (cluster A patients)

Patients evaluated

Patients with adverse events

Patients with drug-related adverse effects

Patients withdrawn because of adverse events

No. of patients (%) [95% GI)

12584

2691 (21.4) [20.7-22.1)

1925 (15.3) [14.7-15.9)

407 (3.2) [2.9-3.5)

Abbreviation: GI = confidence interval.

drugs, M Ij = the total number of patients treated with amlodipine, and M2j = the total number of patients treated with other drugs.

This statistic is the estimate (resulting from the j-th study) of the absolute difference between the probabilities of onset of adverse events in the groups. Its variance is defined as follows:

Vj = aj cj/(M )j)3 + bj dj/(M2j)3

where cj = the number of patients experiencing no adverse events with amlodipine, and dj = the num­ber of patients experiencing no adverse events with other drugs .

The differential effect of the two treatments (amlodipine and other drugs), evaluated over all studies, was calculated considering the internal precision of each single estimate by use of the cal­culation T = 0: TjlVj) • (L IlVj)- 1 (summation extended to the number of studies analysed) with a variance VeT) = (L IlVjt l .

Under the null hypothesis Ho that the percent­age of patients with adverse events is the same in the two treatment groups, the variable Z = T /."jy (T)

is the standardised normal. The underlying model is a fixed effects model that implies: Tj = e + £j where £j is a random variable with mean equal zero and variance ~j estimated by Vj.

A probability level of p < 0.05 was considered to be statistically significant.

2. Results

Of the 12 584 patients treated with amlodipine in noncomparative studies (cluster A), 2691 pa­tients (21.4%) mentioned one or more adverse

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165

events, and these were related to the drug in 1925 patients (15.3%). A total of 407 patients (3.2%) required discontinuation of amlodipine because of poor tolerability. The percentage of patients with adverse events in cluster A are presented in table I.

Among the 127 patients treated with amlodipine in cluster B (15 patients received combination ther­apy with ~-blockers), 29 patients (22.8%) experi­enced adverse events, and these were considered to be drug related in 22 patients (17 .3%). Four pa­tients (3.1 %) required discontinuation of amlodip­ine therapy. In the parallel treatment groups, a total of 53 of 126 patients (42%) experienced adverse events while receiving drugs other than amlodipine (calcium antagonists, ACE inhibitors or ~­

blockers), an incidence significantly higher (Z = -2.73895; p < 0.01) than that seen with amlodipine. 50 patients (39.7 %) experienced drug-related adverse events, an incidence also sig­nificantly greater than that seen with amlodipine

Table II. Number of patients with adverse events in comparative parallel group studies (cluster B patients)

Amlodipine Other drugs

No. of patients 127 126

No. of patients (%) with 29 (22.8) 53 (42)" adverse events [95% GI) [15.5-30.1) [33.4-50.7)

No. of patients (%) with 22 (17.3) 50 (39.7)" drug-related adverse effects [10.7-23.9) [31.1-48.2) [95%CI]

No. of patients (%) withdrawn 4 (3.1) 10(7.9) because of adverse events [0.1-6.2] [3.2-12.7] [95%GI]

Abbreviation: GI = confidence interval. • p < 0.01 versus amlodipine; •• p < 0.001 versus amlodipine.

Table III. Number of patients with adverse events in crossover studies of amlodipine (cluster G patients)

No. of patients

No. of patients (%) with adverse events [95%GI)

No. of patients (%) with drug-related adverse effects [95% GI)

No. of patients (%) withdrawn because of adverse events [95% GI]

Amlodipine

120

23 (19.2) [12.1-26.2]

19(15.8) [9.3-22.4]

1 (0.8) [0.0-2.5]

Abbreviation: GI = confidence interval.

Other drugs

120

27 (22.5) [15.0-30.0]

25 (20.8) [13.6-28.1]

1 (0.8) [0.0-2.5]

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166

Table IV. Number of patients with adverse events (AE) after treatment with amlodipine 5 or 10mg

Dosage/day No. patients treated

Amlodipine 5mga 12746

Amlodipine 10mg 8184

No. patients with AE (%) [95% CI]

1755 (13.8) [13.2-14.4]

1184 (14.5) [13.7-15.2]

a Patients received amlodipine 5 mg/day for at least 2 weeks and up to 24 weeks.

Abbreviation: CI = confidence interval.

Table V. Nature of all adverse events (related and nonrelated to drug therapy) reported in all study patients receiving amlodipine (clusters A+ B + C) [n = 12 831]

Adverse event No. of events

Adverse events (total) 3357

Peripheral oedema 1464

Headache 689

Flushing 245

Changes in heart rate 167

Dizziness 96

Nausea 67

Weakness 124

Diminished libido 16

Skin rash 61

(Z = -3.62518; p < 0.001). Ten patients (7.9%) in the non-amlodipine treatment group were with­drawn from treatment because of poor toler­ability. Patients with adverse events in cluster B are presented in table II.

Of the 120 patients who participated in cross­over studies (cluster C), 23 (19.2%) experienced adverse events during amlodipine therapy; 19 of these patients (15.8%) had adverse effects that were considered to be drug related. On crossing over to the comparator agent (placebo or active drug), 27 patients (22.5%) experienced adverse

Perna et al.

events, and these were assumed to be drug related in 25 patients (20.8%). One patient (0.8%) was with­drawn from treatment while receiving amlodipine and one while receiving another drug. No signifi­cant difference was apparent between patients who received amlodipine and those treated with other drugs with respect to the percentages of patients with adverse events (Z = 0.44352; p > 0.1) or drug-related adverse effects (Z = 0.472129; p > 0.1). Data from the patients in cluster C are pre­sented in table III.

The percentage of patients with adverse events did not appear to be significantly related to amlodipine dose (Z = 1.2972; P > 0.05) [table IV]. Different types of adverse events experienced by patients receiving amlodipine are listed in table V, while figures I and 2 show the percentages of most frequent adverse events by amlodipine dose and disease status, respectively. Tolerability data in re­lation to disease status (hypertension or ischaemic heart disease) are presented in table VI.

3. Discussion

Our results confirm previous reports that amlodipine is a well tolerated drug with mild and infrequent adverse effects.!4-61 In fact, in a large population of patients with hypertension or isch­aemic heart disease, we found the frequency of drug-related adverse effects to be approximately 15%, and only 3% of patients were withdrawn from amlodipine therapy because of severe or persistent drug intolerance. However, this finding is more likely to be representative of amlodipine tolerabil­ity than those derived from single clinical trials. Furthermore, the low incidence of adverse events in amlodipine study patients does not appear to be

Table VI. Patients with adverse events analysed in relation to disease status

No. of patients

No. of patients (%) with adverse events [95% CI]

No. of patients (%) with amlodipine-related adverse effects [95% CI]

No. of patients (%) withdrawn because of adverse events [95% CI]

Hypertension

9638

2108 (21.9) [21.0-22.7]

1508 (15.6) [14.9-16.4]

336 (3.4) [3.1-3.9]

Abbreviations: CI = confidence interval; IHD = ischaemic heart disease.

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IHD Total

3193 12831

635 (19.9) [18.5-21.3] 2743

458 (14.3) [13.1-15.6] 1966

76 (2.4) [1.9-2.9] 412

Clin. Drug Invest. 1997; 13 Suppl. 1

Tolerability of Amlodipine: A Meta-Analysis

10

8

~ 6

'" C .!!! iii a. 4

2

o Oedema Flushing Headache Changes in

heart rate

.5mg o 10mg

Others

167

Fig. 1. The most frequently reported adverse events associated with amlodipine, assessed in relation to daily dose [5mg (n = 12746) or 10mg (n = 8184)]. In 12 of the 16 studies, patients started amlodipine treatment at a daily dose of 5mg; this dose could be doubled to 10mg after 2 weeks of treatment.

12

10

8

4

2

o Oedema Flushing Headache

• Hypertension o Ischaemic heart disease

Changes in heart rate

Others

Fig. 2. The most frequently reported adverse events associated with amlodipine, assessed in relation to disease status [hypertension (n = 9638) or ischaemic heart disease (n = 3193)].

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168

the result of biased selection, as all studies per­formed consecutively in Italy for amlodipine effi­cacy assessment have been considered.

As frequently occurs when tolerability data are elicited by open questioning in diverse patient pop­ulations, a variety of adverse events were listed by amlodipine-treated patients. These can be divided into 3 classes: (i) those consistent with the drug's known pharmacological properties and ensuing from its desired therapeutic effect; (ii) those attrib­utable to idiosyncratic or allergic-type responses and related to the chemical structure of the drug rather than its desired pharmacological effect; and (iii) nondescript, ill defined effects whose nature remains unclear.

Only 4 adverse events, namely peripheral oedema, headache, flushing, and changes in heart rate, occurred in 1 % or more of amlodipine recip­ients. These, the most frequently reported adverse events associated with amlodipine, are typical of dihydropyridines as a class and are predominantly related to arteriolar vasodilation. lSI These adverse events, in particular peripheral oedema, are re­ported to be dose related. 11,5,6] In our study, no sub­stantial difference was found in the incidence of adverse events, including peripheral oedema, at the 2 different dose levels of amlodipine (5 or IOmg). It should be borne in mind, however, that 12 of the 16 studies included in this meta-analysis initiated amlodipine treatment with a daily dose of 5mg; if the drug was poorly tolerated at this dose it is unlikely that the physician would have increased the dose. Those patients who received the higher dose of IOmg may therefore be regarded as a selected subgroup. Disease status (hypertension or ischaemic heart disease) also did not seem to influence the incidence of adverse events seen with amlodipine.

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Perna et al.

Idiosyncratic reactions such as skin rash were rarely reported with amlodipine. Some other ad­verse events were ill defined and their nature was unclear; they included gastrointestinal disorders, tremor, polyuria and cough. Comparison of the tol­erability of amlodipine with that of the other drugs (cluster B, comparative studies) indicated a signif­icantly lower incidence of adverse events in pa­tients treated with amlodipine, a finding reported previously.fs,6] This was not confirmed in cluster C (crossover studies), in which amlodipine has a similar pattern of adverse events compared with that of other drugs.

References I. Murdoch D, Heel RC. Amlodipine: a review of its pharmaco­

dynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1991; 41: 478-505

2. Heber ME, Bridgen G, AI-Khawaja I, et al. 24-hour blood pres­sure control with the once-daily calcium antagonist, amlodip­ine. Br J Clin Pharmacol 1989; 27: 59-65

3. Mrozek WJ, Burris JF, Allenby KS. A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1988; 12 Suppl. 7: 579-84

4. Chaine RA, Feldman RL, Giles TD, et al. Randomized placebo­controlled trial of amlodipine in vasospastic angina. J Am Coli Cardiol 1993; 21: 1365-70

5. Hosie J. Bremner AD, Fell PJ, et al. Comparison of early side effects with amlodipine and nifedipine retard in hypertension. Cardiology 1992; 80 Suppl. I: 54-9

6. Waeber B, Borges ET, Christeler P, et al. Amlodipine compared to nitrendipine in hypertensive patients: the effects on tolera­tion in relationship to the onset of action. Cardiology 1992; 80 Suppl. I: 46-53

7. Berlin JA, Laird NM, Sacks HS, et al. A comparison of statisti­cal methods for combining event rates from clinical trials. Stat Med 1989; 8: 141-51

8. Struyker-Boudier HA, Smits JFM, De Mey GR. The pharma­cology of calcium antagonists: a review. J Cardiovasc Phar­macol 1990: 15 Suppl. 4: 1-10

Correspondence and reprints: Dr Gian Piero Perna, Depart­ment of Cardiology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, 71013 San Giovanni Rotondo (FG), Italy.

Clin. Drug Invest. 1997: 13 Suppl. 1