Safety profile of lacidipine: update from a clinical trials database.
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Aged↗
Biomedical subjects
P Tcherdakoff
Publications and source records attributed to P Tcherdakoff.
[Right adrenal recurrence of pheochromocytoma discovered 24 years after ablation of two ectopic pheochromocytomas].
The classical localisation of chromaffin cell tumours is intra-adrenal. Ectopic or multiple tumours are not rare and are commonly observed in children. The authors report a case of ectopic pheochromocytoma with a double localisation in a 14 year old child (renal pedicle and right retropleural space), in which surgical ablation resulted in an immediate and sustained correction of the hypertension. Hypertension recurred 24 years later and a classical right adrenal pheochromocytoma was demonstrated by methyl-iodo-benzylguanidine (M.I.B.G.) scintigraphy and abdominal CT scan. Right adrenalectomy resulted in normalisation of the hypertension once again without antihypertensive therapy with a follow-up of three years. Regular follow-up is necessary after ablation of a pheochromocytoma, especially in children, even in the absence of a phacomatosis or multiple endocrine neoplastic syndromes.
Adolescent↗
Safety of the calcium antagonist lacidipine evaluated from a phase III-IV trial database.
OBJECTIVE: We reviewed the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer. Although a number of prospective, randomly allocated trials under way at present are investigating the effects of treatment with calcium antagonists on cardiovascular morbidity and mortality, these results are not yet available. Therefore, the present approach may be useful. A fuller account of this work has been published in Blood Pressure. DESIGN: Since 1985,50 phase III-IV trials have been performed to investigate antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment. Only data from trials completed before 1 January 1995 are presented here. SUBJECTS: In all, 16590 patients were treated with lacidipine; 13419 in open studies and 3171 in double-blind comparative trials. A total of 1810 patients were given active comparative treatment and 451 were given placebo. Altogether, 5124 person-years of data were obtained. MAIN OUTCOME MEASURES: Numbers of both fatal and non-fatal cardiovascular events were estimated. Efficacy (change in blood pressure and heart rate), adverse event rates and drop-out rates were compared for the different treatment regimens. RESULTS: In all trials, 2-6 mg lacidipine was effective in lowering blood pressure. In the controlled trials, systolic/diastolic blood pressure fell from 166/102 to 144/85 mmHg and the heart rate fell from 75.6 to 74.1 beats/min. The estimated event rate for a possible myocardial infarction in all studies was 5.46/1000 person-years; the fatal (all-cause) event rate was 5.27/1000 person-years and the estimated fatal cardiovascular event rate was 2.93/1000 person-years. There were 21 malignant events during treatment with lacidipine, for all studies yielding a crude incidence of 4.10/1000 person-years. In patients treated with lacidipine, the age-standardized (according to the world population) incidences were 1.49 (men) and 0.79/1000 person-years (women) compared with 2.74 (men) and 2.09/1000 person-years (women) in the European Community in 1990. The overall incidence in the comparative studies of one or more adverse events included 30.3% for lacidipine, 43.8% for other calcium antagonists, 18.7% for diuretics, 48.7% for beta-receptor blockers, 10.4% for angiotensin converting enzyme inhibitors and 15.7% for placebo. The adverse effects of lacidipine were, as expected, headaches, flushing, pedal oedema and palpitations. CONCLUSIONS: Lacidipine proved to be an effective and well tolerated drug in almost 19000 hypertensive patients. It displayed a reasonable adverse profile that was typical of a calcium antagonist of the dihydropyridine group. This analysis has two obvious limitations: (1) it is a retrospective analysis; and (2) the data were obtained from a large cohort of patients, but most were treated with lacidipine for a relatively short period of time. Although we found a lower fatal event rate than that reported by Collins et al., their meta-analysis included 10 times more person-years than our analysis, and therefore our event rate may be less accurate. Further prospective studies are under way at present to determine whether these drugs can produce reductions in atherosclerosis or in the incidence of cardiovascular disease.
Adolescent↗
Safety aspects of treatment with lacidipine--a slow-onset, long-acting calcium antagonist.
OBJECTIVE: The aim was to review the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer- a novel approach which may be of some value while awaiting the outcome of calcium antagonist treatment in prospective, randomised trials of cardiovascular morbidity and mortality. DESIGN: This paper includes data from clinical trials finished before 1 January 1995. Since 1985, 50 phase III-IV trials have been performed investigating antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment. SUBJECTS: In all, 16,590 patients received lacidipine; 13,419 in open studies and 3171 in double blind, comparative trials. Altogether, these patients contributed 5 124 person-years (p.y.). Furthermore, active comparative treatment was given to 1810 patients and placebo to 451. MAIN OUTCOME MEASURES: Both fatal and non-fatal cardiovascular events have been estimated. Efficacy (change in blood pressure and heart rate), adverse event rates, and drop-out rates have been compared for the different treatment regimes. Also the reasons for dropping out of studies have been compared. Adverse effects were also analysed as to their time of occurrence and duration. RESULTS: Blood pressure was lowered by 2-6 mg lacidipine; in the controlled trials from 166/102 to 144/85 mmHg. Heart rate dropped from 75.6 to 74.1 beats per minute. The estimated event rate for a possible myocardial infarction in all studies was 5.46 per 1000 p.y. The fatal (all causes) event rate was 5.27 per 1000 p.y., and the estimated fatal cardiovascular event rate 2.93 per 1 000 p.y. In one long-term study (48 weeks) comprising 2282 patients (1658 p.y.), the observed fatal (all causes) event rate was 4.2 per 1 000 p.y. The overall incidence in the comparative studies of (one or more) adverse events was: for lacidipine 30.3%, other calcium antagonists 43.8%, diuretics 18.7%, beta-receptor blockers 48.7%, ACE inhibitors 10.4%, and placebo 15.7%. The adverse effects of lacidipine were the expected ones, e.g. headache, flushing, pedal oedema, and palpitations. CONCLUSION: When analysing the data on file for lacidipine and some comparatory drugs in almost 19000 hypertensive patients we have found lacidipine to be an effective and well tolerated drug with a reasonable adverse profile typical for a calcium antagonist of the dihydropyridine group. Our study has the obvious limitations of a retrospective analysis of data obtained from a large cohort of patients, most of whom received lacidipine for a relatively short period of time. The present results indicate a lower fatal event rate than previously reported in the actively treated hypertensives in Collins' meta-analyses, comprising ten times more person-years than our analysis. Prospective studies with lacidipine focusing on possible reductions of atherosclerosis as well as incidence of cardiovascular disease are required and are well under way.
Adult↗
French large-scale study evaluating the tolerability and efficacy of lacidipine.
In a large, open, multicenter study, 2,206 outpatients with mild-to-moderate essential hypertension were recruited by 755 cardiologists throughout France. Patients received treatment with lacidipine for 12 weeks at a dose of 2-6 mg once daily. In 1,637 evaluable patients, lacidipine was shown to reduce blood pressure from a mean of 173/101 mm Hg at baseline to 147/85 mm Hg after 12 weeks, with negligible effects on heart rate. Adverse events were experienced by 29% of patients, of which only 20% were definitely or probably related to lacidipine; these adverse events were generally mild and led to premature discontinuation of treatment in only 8.7% of cases. Overall assessment of efficacy and tolerability by practitioners was very satisfactory. Acceptability and ease of use were assessed highly by the large majority of patients. Subgroup analysis of patients > or = 65 years showed no significant difference when compared to younger patients in terms of efficacy and tolerability. The current study therefore confirms, in a large study population and in general practice, that lacidipine, in a once-daily dose of 2-6 mg, has a significant antihypertensive effect and is well tolerated.
Aged↗
[Non-invasive ambulatory measurement of arterial pressure. Recommendations of the measurement group of the French Society of Arterial Hypertension].
Ambulatory blood pressure monitoring is being widely used now that relatively simple, reliable and well-tolerated, non-invasive blood pressure measuring devices have become available. The following recommendations are only to help physicians to use this technique in their daily practice: only use homologated devices; ambulatory monitoring should be performed during normal, everyday activities; at least one measurement of blood pressure should be taken every 1/4 hour during the day time (7 h-22 h) and every 1/2 hour during the night (22 h-7 h); the arm must be absolutely still and relaxed during the measurement; the function of the measuring device should be checked when the patient is fitted up and when the device is removed; data processing should provide at least: all values of blood pressure and heart rate, and their times of measurement, the mean values of systolic end diastolic blood pressure and heart rate during the day and during the night, the maximal and minimal systolic and diastolic blood pressure values, a chronogramme of the values. Reasonable indications of ambulatory blood pressure monitoring include: elimination of the "white coat" effect: to confirm the diagnosis of borderline hypertension; to demonstrate inversion of diurnal rhythm in severe hypertension; to demonstrate episodic hyper or hypotension; to confirm certain cases of toxaemia of pregnancy. It is also justified in the evaluation of antihypertension therapy, especially in cases of suspected drug resistance.
Ambulatory Care↗
Percutaneous recanalization of a renal artery in aortic dissection.
Chronic renal failure acutely worsened in a patient with a type B aortic dissection. Aortography revealed an occlusion of the left renal artery without renal intimal tear. Percutaneous recanalization, performed with a self-expandable stent, resulted in improvement in the renal function. This technique offers a new therapeutic choice in patients with visceral complications of aortic dissection.
Aortic Dissection↗
Comparative study on monotherapy with sustained-release diltiazem 300 mg and enalapril 20 mg in mild to moderate arterial hypertension.
The antihypertensive efficacy of sustained-release diltiazem 300 mg at a single daily dose was evaluated and compared to that of enalapril 20 mg at a single daily dose, and to a combination therapy of enalapril 20 mg with sustained-release diltiazem 300 mg in patients with mild to moderate arterial hypertension (supine diastolic blood pressure between 95 and 115 mm Hg). After a washout period and a placebo period, each lasting 2 weeks, 96 patients were randomized in this double-blind study to three parallel groups that were treated for 28 days. In the groups treated with diltiazem, enalapril, or the combination of both, the drop in arterial blood pressure was 20, 11, and 19 mm Hg for supine diastolic blood pressure (supine DBP): 18, 12, and 19 mm Hg for standing diastolic blood pressure (standing DBP); 22, 20, and 23 mm Hg for supine systolic blood pressure (supine SBP); and 21, 19, and 24 mm Hg for standing systolic blood pressure (standing SBP), respectively. The reduction in DBP was significantly more pronounced in the group treated with sustained-release diltiazem 300 mg than in the group treated with enalapril 20 mg. Cardiac tolerance was good for patients treated with sustained-release diltiazem 300 mg alone or the combination therapy: no orthostatic hypotension or lengthening of the PR interval in the electrocardiogram was observed. Although side effects of sustained-release diltiazem 300 mg occurred more frequently, they were not severe and disappeared immediately when treatment was suspended.
Blood Pressure↗
[Treatment of pregnancy hypertension with betablockaders. Follow-up of 31 pregnancies].
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Adrenergic beta-Antagonists↗
[Hypertension in pregnant women and beta-blockers. Follow-up of 31 pregnancies].
The authors have conducted a study of 24 women (mean age: 28 years) whose 31 pregnancies were treated with a beta-blocker (propranolol, in most cases). The overall results were compared with data from the literature. The return to normal of the blood pressure (BP) was excellent (23 cases or 74.2%). The BP was poorly controlled in 8 out of 31 cases among which were found the 4 fetal deaths of the study. There was no toxemia, no maternal complications, no theoretical neonatal effect of the beta-blockers (nor bradycardia nor hypoglycaemia). As for fetal hypotrophy, it was more frequent when the ABP did not return to normal (57% hypotrophy vs 39%) and the beta-blocker, by causing a return to normal of the BP, decreases its incidence. In addition, the mean length of treatment exceeded 2.35 weeks in normotrophic newborns in comparison with the hypotrophic newborns. Concomitantly, the return to normal of the blood pressure is improved in normotrophic newborns. The risk of fetal hypotrophy attributed to the beta-blockers is therefore confirmed and these drugs even have a favorable effect on the birth weight.
Adult↗
[Role of scintigraphy in the localization of pheochromocytomas].
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3-Iodobenzylguanidine↗
[Malignant pheochromocytoma. A case].
A case of malignant phaeochromocytoma is reported. The primary tumour was removed in 1970. Metastases were diagnosed in 1979 and management of the condition included antihypertensive treatment with alphamethylparatyrosine, antitumoral chemotherapy and surgical reduction of secreting tissue. In these rare tumours malignancy can only be confirmed by metastases, i.e. presence of chromaffin cells in loci where they are not usually found. Histology is of little value. High levels of catecholamine precursors or their metabolites in the urine may be a sign of malignancy, but some asymptomatic tumours are only revealed by metastases. Computerized tomography and radioisotope scanning with I131 metaiodobenzylguanidine are the best available methods to locate the lesions. In view of the small number of cases and of the unpredictable course (sometimes spread over many years) of malignant phaeochromocytomas, the effectiveness of treatments with alphamethylparatyrosine, chemotherapy and radiotherapy is difficult to evaluate.
Adrenal Gland Neoplasms↗
[Ectopic pheochromocytoma. Diagnosis by digital intravenous angiography].
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Angiography↗
[The causes of arterial hypertension. Importance, research, mechanisms and significance].
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Adrenal Gland Diseases↗
[Coarctation of the abdominal aorta: diagnosis, pathogenesis, medical or surgical treatment. 7 cases].
Seven cases of coarctation of the abdominal aorta are reported. The diagnosis, suggested by the presence of arterial hypertension associated with nonperception of the arterial pulse in the lower limbs and/or systolic murmur in the abdomen, is supported by non-invasive investigations, such as Döppler flowmetry of lower limb arteries and ultrasonography of the abdominal aorta. Arteriography, however, is mandatory because of frequently associated lesions of other arteries, notably renal and/or intestinal arteries. The type and location of these lesions are of prime importance to therapeutic decision. According to the results of the present study, surgery may not be required in all cases and may be replaced, in some very specific circumstances, by medical treatment. There is still disagreement concerning the congenital or acquired origin of this type of aortic coarctation and the mechanism of hypertension. The various theories put forward are discussed.
Adolescent↗
[Are the theoretical drawbacks of beta-blocker treatment in pregnancy being confirmed? A review of the literature].
The use of beta-blocking drugs in the treatment of hypertension during pregnancy has been the subject of controversies on the basis of theoretical hazards due to the pharmacology and pharmacokinetic characteristics of these drugs. A review of the literature on the subject shows that: The danger of premature contractions, abortion or premature delivery does not seem to increase with the use of beta-blockers. The blood supply is not more impaired with beta-blockers than with other antihypertensive drugs according to fetal growth, birth-weight, frequency of perinatal deaths or APGAR score. Although beta-blocking drugs pass into fetal circulation, neonatal bradycardia, respiratory distress or hypoglycemia do not seem more frequent with beta-blockers. Beta-blockers pass from maternal plasma into milk but the 24 hour dose brought to the newborn by maternal feeding is so slight as to be negligible. Thus, the cumulative data and the favorable opinions of many authors, the greater efficiency of beta-blockers authorizes the use of these drugs in the treatment of hypertension in pregnancy, where it seems to improve the outcome of the pregnancy and the state of the fetus at birth.
Adrenergic beta-Antagonists↗
[Current clinical problems of pheochromocytoma].
The diagnostic problem of pheochromocytomas raises two questions: should all hypertensives be routinely investigated for this condition, and what is the best diagnostic method? As this is a rare condition, systematic screening gives a low return; considering the large number of hypertensive patients, it is also costly. On the other hand, as systematic autopsy studies have shown, the missed diagnosis can be serious (especially during pregnancy or surgery). Screening for this condition is proposed when the clinical features are suggestive, in pregnancy, when surgery is undertaken in a hypertensive patient and in all cases of method is still a matter of controversy: urinary hormonal levels (especially metanephrine levels) are supported by some workers, whilst serum catecholamine levels are supported by others. In any case, pharmacodynamic tests should only be used when these two methods are inconclusive. The long term prognosis of operated pheochromocytoma is less favourable then used to be thought: a certain number have persistent benign hypertension which may require treatment and which may become malignant at a later date. Adrenal medullary hyperplasia is a clinical entity which should be recognised.
Adrenal Gland Neoplasms↗
[Treatment of pheochromocytoma].
Apart from the problems of preparation for surgery, the difficulties lie mainly in general anaesthesia. Blood pressure variations and cardiac arrhythmias must be prevented. Anaesthesia must be given with a lot of care and must be deep, and some stages are particularly dangerous: induction, intubation (it is best to give a local anaesthetic with lignocaine), manipulation during dissection which should be very gentle, ablation of the tumour or clamping the draining veins. Treatment of the arrhythmias detected on ECG monitoring is based mainly on the use of lignocaine. Continuous monitoring of intra-arterial pressure is used to detect any variation. Only the severe bouts of hypertension need correction with phentolamine or nitroprussiate. In cases of shock, the essential point of management is to reestablish an adequate circulating volume: intravenous fluids are best given with control of pulmonary pressures which allows dangerous overload to be avoided. The specific problem of malignant pheochromocytoma is two-fold: treatment of the hypertension, at best with alpha-methyl-tyrosine or otherwise, with labetolol or prazosine, and treatment of the tumour, which has still not been resolved, and for which trials of chemotherapy are in progress.
Adrenal Gland Neoplasms↗