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Abstract and Introduction
Abstract
Background: This study set out to assess the safety and efficacy
of amlodipine in two cohorts of patients who were attended in primary- and
specialised-care centres, respectively.
Methods: Prospective,
observational, multicentre pharmacovigilance study including patients aged
>18 years who presented with a diagnosis of hypertension (systolic
blood pressure [SBP] ≥140mm Hg and diastolic blood pressure [DBP] ≥90mm
Hg) of >6 months' duration, which was either untreated or uncontrolled,
and who were followed up by general practitioners and specialists over a
period of 4?6 months.
Results: Of the total of 4277 patients
included in the study, 2520 (58.9%) were attended in primary care and 1757
(41.1%) in specialised care. 2982 patients (69.7%) were receiving
monotherapy, the rest were receiving combined therapy. Over the course of
the study, 308 patients (7.2%) experienced adverse events related to the
study drug, mostly mild to moderate in nature. There were 20 serious
events, although none was related to the study drug. By the end of the
study, 1617 patients (37.8%) had achieved the therapeutic goal (SBP
<140mm Hg and DBP <90mm Hg), with the greatest degree of control
being registered among patients receiving combined therapy compared with
monotherapy (38.7% vs 35.7%), and in those treated in a specialised-care
setting versus a primary-care setting (43.5% vs 33.8%; p <
0.005).
Conclusions: Amlodipine was shown to be a well tolerated
and effective drug in one in three patients, and achieved the therapeutic
goal in a higher proportion of patients at specialised-care centres
compared with those in primary care, and in those receiving combined
therapy compared with monotherapy.
Introduction
Cardiovascular diseases are currently the leading cause of death in developed countries, annually accounting for close to 40% of deaths in Spain[1] and almost one million deaths in the US.[2] Their greatest relevance lies not only in their high morbidity and mortality, but also in the ensuing degree of disability to which they give rise and the socioeconomic repercussions resulting from this.[3,4]
While all factors must be borne in mind when it comes to assessing an individual's total risk, one of the most important of these is arterial hypertension because its prevalence in the Spanish adult population is at least 20?25%.[5]
Of the two million potential years of life lost each year in Spain, 230 000 are estimated to be attributable to hypertension.[6] Furthermore, in Spain, hypertension accounts for 6% of all medical visits and 18% of consultations for chronic disorders, constituting the most frequent reason for consultation in primary care.[7]
In terms of the therapeutic goal to be achieved, the leading international guidelines, such as those of the Seventh Report of the Joint National Committee (JNC VII),[8] the 1999 World Health Organization/International Society of Hypertension (WHO/ISH) report,[9] the British,[10] Canadian[11] and domestic guidelines[12] issued by the 2000 Spanish Cardiology Society (Sociedad Española de Cardiología) and Spanish Hypertension Society (Sociedad Española de Hypertension),[13] all agree that this should entail a decline in sustained stable blood pressure (BP) to figures below a systolic blood pressure (SBP) of 140mm Hg and a diastolic blood pressure (DBP) of 90mm Hg.
Although the real effect of antihypertensive treatment on the Spanish population of hypertensive patients is not known with total accuracy, taken as a whole the data available in this country point to BP control rates of 13% to 36%.[5,14-17]
Long-acting calcium antagonists such as amlodipine have been shown to be effective among and well tolerated by both young and elderly persons, without any need for adjusting the dosage,[18-21] whether as monotherapy or in combined therapy with other antihypertensive drugs,[19,20] and are recommended as one of the main treatments for arterial hypertension by the leading international guidelines.[2,10,11,22] Likewise, in the recently published ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial),[23] amlodipine has shown itself to be effective not only in decreasing cardiovascular morbidity and mortality, but also in bringing about a significant reduction in SBP and DBP.
The principal aim of this study was to evaluate the safety and efficacy of amlodipine in two cohorts of patients, one of which was attended at primary-care and the other at specialised-care centres. The assessment criterion used was the therapeutic goal attained by the patients as per JNC VII[8] and 1999 WHO/ISH Guidelines,[22] as well as the reduction in BP achieved during follow-up. In addition, we assessed the degree of patient satisfaction with drug tolerability.
Materials and Methods
Patients
The study population comprised male and female outpatients aged 18?80 years, with arterial hypertension of >6 months' duration (according to 1999 WHO/ISH[22] and JNC VII[8] guidelines) who were eligible for treatment with amlodipine. Patients were either newly diagnosed or, alternatively, previously diagnosed but not pharmacologically controlled to an accepted target level as per the 1999 WHO/ISH criteria (SBP ≥140mm Hg and/or DBP ≥90mm Hg).[22]
The study exclusion criteria were: known or suspected pregnancy; known hypersensitivity to dihydropyridine-type calcium antagonists; cerebrovascular accident or infarction in the preceding 3 months; congestive heart failure, unstable angina or severe arrhythmia; severe hepatic, renal, endocrine, gastrointestinal or haematological disease; alcohol abuse; and any psychological or psychiatric impairment that might hinder or prevent compliance with the protocol.
Prior to enrolment, informed oral consent was obtained from all patients in accordance with the Declaration of Helsinki guidelines.
Study Design
Both arms were open-label, prospective, observational, multicentre studies, with ambulatory patients randomly selected by general practitioners (NORCON [estudio sobre seguridad y efectividad de amlodipino en pacientes no controlados farmacológicamente en el ámbito de la atención primaria] study[24]) and by medical specialists engaged in hypertension diagnosis and management (physicians attached to hospital hypertension units, nephrologists, internists, etc.) [NOTA (estudio de farmaco- vigilancia para evaluar la seguridad y la efectividad de amlodipino en pacientes hipertensos tratados en atención especializada) study], nationwide.
Based on the researchers' judgement, patients were divided into two groups, namely, those who could be treated with amlodipine monotherapy, and those who needed to take amlodipine in combined therapy with other drugs.
Patients were followed up for 4?6 months, during which a total of two follow-up visits were made. This follow-up time was considered sufficient for the purpose of assessing the efficacy of the drug, plus monitoring any possible adverse effects resulting from the treatment.
Adverse events that occurred during the study period were classified as mild or serious depending on the investigator's criteria. A serious adverse event was defined as any untoward occurrence during drug administration that resulted in death, was life-threatening, necessitated hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or incapacity, or consisted of a congenital anomaly or birth defect.
Treatment was started with amlodipine 5mg once daily at the first visit. It was left to the researchers' discretion to increase the dosage to 10mg once daily if the WHO-recommended BP levels[22] had not been reached after 2 months of therapy.
The principal variables covered by this study were: demographic factors; physical examination; concomitant treatment; adverse drug events; withdrawal from the study and causes; efficacy of amlodipine, measured as the percentage of patients who achieved SBP values of <140mm Hg and DBP values of <90mm Hg by the end of treatment; and concomitant medication.
These studies were formally reported to the Spanish Drug Agency (Agencia Española del Medicamento [AEM]) and conducted in accordance with prevailing Spanish and European Union recommendations for post-authorisation, observational pharmaco-epidemiological studies. In accordance with statutory requirements, the study protocol was submitted to and approved by the Alcorcón Hospital Ethics Committee.
Statistical Analysis
A descriptive analysis was made, with calculation of means and standard deviations for the quantitative variables, and proportions for the qualitative variables. The chi-squared (χ2) test was used for comparison of proportions. An ANOVA repeated-measures test was used for analysis of assessment of SBP and DBP, and for comparison of these variables against other qualitative-type variables (factors). In the case of a posteriori comparisons, the Bonferroni method was used to correct for violations of the sphericity assumption. Logistic regression was performed to analyse the factors associated with BP control. The model was constructed by choosing the variables in accordance with their clinical importance and/or the results of the crude analyses. For analysis of the time needed to achieve control of BP, we used a Cox multivariate regression model, adjusting for previously selected variables, with days taken as the unit of time.
The confidence level used for all comparisons was 95%. All statistical calculations were performed using the SPSS computer software program, version 12.0 (SPSS, Chicago, IL, USA).
Results
Patients
A total of 4277 patients were included. 2520 patients (58.9%) of a total of 2628 treated in primary care (from the NORCON study) were chosen for study evaluation, while the rest could not be included because of a lack of some of the variables needed for the study. 1757 patients (41.1%) were attended at specialised-care centres. At 2 months' follow-up, 4185 patients were located, so that the percentage lost to follow-up was 2%. A total of 4083 patients completed the study, amounting to a loss of 4.5%, and indicating, in turn, that the participation rate was 95.5% on termination of treatment.
Of the study population, 46.9% were men and 53.1% were women. The mean age of the total group was 61.30 (SD 10.48) years, and was 61.66 (SD 10.24) years in the primary-care group and 60.78 (SD 10.79) years in the specialised-care group (p < 0.0001 between groups). With regard to the presence of other concomitants diseases, 23.8% (418) of the patients who received specialised care had dyslipidaemia, whereas only 7.7% (193) of the patients who received primary care did, and 23.3% (409) of the patients receiving specialised care had diabetes mellitus versus 8.3% (208) of the primary-care patients. The principal demographic and clinical characteristics are shown in table I .
The percentage of patients receiving monotherapy was 69.7%, while the remaining 30.3% were treated with combined therapy. In terms of the origin of patients, 86.3% of those attended in primary care versus only 46.0% attended in specialised care were given monotherapy (p < 0.001).
The concomitant treatment received was classified into five groups, with the most consumed group of drugs being ACE inhibitors (34.7% of patients), followed by diuretics (24.4%), β-adrenoceptor ant- agonists (β-blockers; 10.5%) and α-adrenoceptor antagonists (2.7%). This drug consumption pattern remained in evidence when we stratified according to the setting in which the patient was treated (primary or specialised care) [ table I ].
Efficacy of Treatment
The mean reduction in SBP across the study period (4?6 months) was from 166.52 (SD 14.81)mm Hg at visit 1 to 145.48 (SD 21.62)mm Hg at visit 2, and finally to 134.46 (SD 30.66)mm Hg at visit 3, which represented an overall decrease of 19.3%. DBP declined from 97.44 (SD 8.09)mm Hg at visit 1 to 85.65 (SD 12.91)mm Hg at visit 2, and finally to 79.09 (SD 18.28)mm Hg at visit 3, an overall decrease of 18.8%. For both SBP and DBP the reductions were statistically significant (p < 0.0001) at each visit, denoting a clear decrease in these values over time of patient follow-up.
Although a comparison of mean between-group SBP and DBP values yielded reductions in all categories compared ( table II ), these only behaved differently according to age and patient setting (primary or specialised care), with the greatest reductions being obtained in older patients and in those treated in primary care.
With respect to the daily dose of amlodipine administered, most patients (62.9% [2690/4227]) concluded the study on 5mg, whereas in 31.9% (1366/4227) of patients the dose had to be increased to 10mg; this information was not documented in the remaining patients. The percentage of patients that terminated treatment at the end of the study on 5mg was statistically higher in primary care (p < 0.0001) than it was in specialised care: 67.2% (1690/2516) versus 60.6% (1000/1648).
At the conclusion of the study, 1617 patients (37.8%) had achieved the therapeutic goal (SBP <140mm Hg and DBP <90mm Hg). As can be seen in table III , the proportion of patients who achieved control of their hypertension declined with age, and the proportion of male patients achieving the therapeutic goal was greater than that of female patients.
The percentage of patients who achieved control of their hypertension proved significantly higher among those placed on a 5 mg/day dosage of amlodipine compared with those receiving a 10 mg/day dosage, and in those treated in a specialised-care setting compared with those in primary care. Following multivariate adjustment using logistic regression, monotherapy with amlodipine and specialised-care status were seen to have an influence on enhanced control of BP ( table IV ).
Using a Cox proportional hazards multiple regression model, BP control was observed to be achieved 34% more swiftly in patients who were attended in a specialised- versus a primary-care setting (OR = 1.34; CI 1.217, 1.465).
Tolerability
Over the course of the study, 308 patients (7.2%) experienced adverse events related to the drug under study, with 196 (63.6%) of these appearing in the first 2 months of treatment (visit 2) and the remaining 112 (36.4%) at the final visit. Of the 308 patients, 191 (62.0%) reported oedema, 43 (13.9%) reported headache, whether isolated or associated with dizziness and/or difficulty in breathing, and 74 (24.0%) reported diverse effects.
There were only 20 serious adverse events (pneumococcal pneumonia, meningitis, hyponatraemia, hyperkalaemia, resting dyspnoea, acute renal failure, iliac adenopathy, stroke [5], tuberculosis, bilaterial ischaemia [2], leukaemia, lymphoma, infarction [2], intestinal neuropathy), none of which was related to the drug under review: 13 occurred in primary care and seven in specialised care.
Drug tolerability was judged as 'excellent' by 46.3% (1980/4277) and as 'good' by 41.1% (1756/4277) of patients.
Discussion
Amlodipine is a calcium antagonist that has been shown to be effective and well tolerated[18,19,21,23] both as monotherapy and as combined therapy with other antihypertensive drugs.[19,20]
In the current study, the participation rate across follow-up was 95.5%, a figure higher than those recorded in similar pharmacovigilance studies.[24-26]
A total of 7.2% of patients experienced some adverse event, mostly of a mild to moderate nature. Furthermore, the adverse events observed were in accordance with the pharmacodynamic characteristics of the drug under study, with the most frequent being oedema, followed by headache, irrespective of patient setting (primary or specialised care). Different studies report oedema as being the most prevalent adverse effect produced by amlodipine.[27,28] The percentage of appearance of adverse effects proved to be lower than that reported in the literature by others, for example Ram et al.,[29] Kubota et al.,[30] and Julius.[31] Drug tolerability was judged to be 'excellent' or 'good' by 87.4% of patients, figures similar to those obtained by Cross et al.[32]
Most patients who maintained drug therapy did so by combining amlodipine with an ACE inhibitor, followed by a diuretic, in line with what is currently the most generally accepted trend, as may be seen from a number of recently published studies.[33-35] Although this trend remains in evidence, the recently published Controlpres 2001[36] nonetheless shows a clear decline in the use of ACE inhibitors, diuretics and calcium antagonists, in favour of a slight rise in the use of β-blockers, particularly angiotensin II receptor antagonists, in primary care.
The reductions in BP registered over the course of the current study were slightly greater than those reported in other studies conducted outside standard drug-use conditions.[28,32,37] In the ALLHAT study, amlodipine significantly reduced SBP after 5 years of treatment in patients with high cardiovascular risk, and DBP was significantly lower among patients treated with amlodipine versus those treated with chlorthalidone or lisinopril.[23]
In line with other studies,[38-41] we observed that the percentage of patients who achieved control of their hypertension (SBP <140mm Hg and DBP <90mm Hg) in specialised-care units was significantly higher than that obtained in primary-care centres and higher than that obtained in studies targeting the general population.[42-46] The degree of control achieved is particularly noteworthy in view of the following: firstly, the type of patient referred to specialised units generally has hypertension that is difficult to control, and overall patient care is thus required because other cardiovascular risk factors are also present; and secondly, observational studies undertaken in Spain in primary-care and cardiology outpatient settings indicate BP control figures of 16.8%[33] and 28.8%.[14]
This high percentage of patients achieveing BP control in the specialised-care group might be attributable to the choice of researchers (specialists in management of hypertension in specialised units), to a longer follow-up of treatment compliance by the researchers, and, possibly, to a keener awareness on the part of patients as regards management of their hypertension.
The recently published QUALIHTA (estudio de evaluación de la calidad de la asistencia actual del paciente hipertenso atendido en Unidades Especializadas en España) study[47] indicates that existing specialised-care units in Spain make for improved overall care of the hypertensive patient, and that control of hypertension in such units can be achieved in up to 51.7% of patients, a substantial percentage.
Limitations
A limitation to this study was the fact that it was an open-label pharmacovigilance study, which did not have a control group receiving another anti- hypertensive drug, and in which the efficacy of the target drug was assessed by comparing BP values registered by patients at the initial and final visits.
Conclusions
Amlodipine has been shown to be a well tolerated and effective drug under conditions of standard clinical practice, serving to achieve the therapeutic goal more rapidly and to a greater degree in patients treated at specialised- versus primary-care centres.
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Table I. Patient Characteristics at the Commencement of the Study. Data are Given as Number (Percent) Unless Otherwise Specified
Variables Total Primary care Specialised care Age (y) [mean ? SD] 61.30 ? 10.48 61.66 ? 10.24* 60.78 ? 10.79 Sex (n = 4277 ) men 2006 (46.9) 1141 (45.3) 864 (49.2) women 2271 (53.1) 1379 (54.7) 893 (50.8) BMI (kg/m2) [n = 4001] normal (19?24) 799 (20) 487 (20.7) 312 (18.9) overweight (25?29) 2173 (54.3) 1298 (55.2) 875 (53.1) obese (30-39) 963 (24.1) 532 (22.6) 431 (26.2) morbidly obese (≥40) 66 (1.6) 36 (1.5) 30 (1.8) Concomitant antihypertensive medication (n = 4277) no 2982 (69.7) 2174 (86.3)* 808 (46.0) yes 1295 (30.3) 346 (13.7) 949 (54.0) Group of concomitant antihypertensive drugsa diuretics 1045 (24.4) 897 (35.6)* 148 (8.4) β-blockers 447 (10.5) 326 (12.9) 121 (6.9) ACE inhibitors 1483 (34.7) 1052 (41.7) 431 (24.5) α-blockers 116 (2.7) 66 (2.6) 50 (2.8) others 408 (9.5) 184 (7.3) 225 (12.8) BP classification (JNC VII) [n = 4277] stage 1 (SBP 140?159mm Hg or DBP 90?99mm Hg) 1546 (36.1) 952 (37.8)* 594 (33.8) stage 2 (SBP >160mm Hg or DBP >100mm Hg) 2731 (63.8) 1568 (62.2)* 1163 (66.2) aThis variable had the possibility of multiple responses.
BMI = body mass index; BP = blood pressure; DBP = diastolic BP; JNC VII = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure;[8] SBP = systolic BP. * p < 0.05, statistically significant differences between the two groups.
Table II. Reductions in Blood Pressure Across the Study Period. Data are Given as Mean ? SD
Variables Visit 1 (n = 4277) Visit 2 (n = 4185) Visit 3 (n = 4083) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) Age (y) <35 156.90 ? 13.82 99.11 ? 8.73 146.50 ? 14.27 89.27 ? 9.21 135.64 ? 23.73 81.75 ? 14.67 35?44 160.81 ? 15.13 99.67 ? 7.88 139.87 ? 23.71 85.35 ? 14.63 132.31 ? 25.33 80.95 ? 16.23 45?54 163.49 ? 14.39 98.80 ? 7.91 143.21 ? 23.57 86.43 ? 14.24 132.28 ? 31.33 79.08 ? 18.96 55?64 166.05 ? 14.26 98.14 ? 7.23 145.81 ? 19.60 86.44 ? 11.71 134.32 ? 29.84 79.50 ? 17.87 >65 169.16 ? 14.66 96.14 ? 8.35 146.89 ? 22.27 84.64 ? 13.16 135.42 ? 32.58 78.27 ? 19.09 Sex Men 166.02 ? 3.84 97.52 ? 7.93 144.98 ? 22.02 85.42 ? 13.36 134.42 ? 29.72 79.19 ? 17.82 Women 167.06 ? 15.56 97.48 ? 8.13 145.95 ? 21.30 85.87 ? 12.53 134.48 ? 31.65 78.98 ? 18.77 BMI (kg/m2) Normal (19?24) 165.90 ? 14.29 96.52 ? 8.21 144.46 ? 23.28 84.37 ? 13.82 133.43 ? 31.98 78.02 ? 18.99 Overweight (25?29) 166.03 ? 14.32 97.61 ? 7.65 145.52 ? 20.20 85.98 ? 12.17 134.66 ? 29.26 79.43 ? 17.52 Obese (30-39) 167.89 ? 15.54 97.95 ? 8.64 146.34 ? 22.53 86.16 ? 13.35 135.11 ? 32.06 79.03 ? 18.98 Morbidly obese (≥40) 170.88 ? 19.66 100.46 ? 7.95 154.49 ? 20.40 90.37 ? 9.61 138.36 ? 30.22 81.28 ? 17.33 Concomitant treatment No 166.34 ? 14.59 97.32 ? 7.92 145.76 ? 22.57 85.78 ? 13.50 134.23 ? 32.11 78.86 ? 19.13 Yes 166.91 ? 15.03 97.74 ? 8.20 145.06 ? 20.12 85.45 ? 11.90 134.78 ? 28.48 79.38 ? 16.99 Patient treatment setting Primary care 165.94 ? 14.77 97.76 ? 8.11 145.35 ? 25.16 85.70 ? 15.00 131.81 ? 37.76 77.6 ? 22.43 Specialised care 167.59 ? 14.73 97.05 ? 7.89 145.70 ? 14.10 85.56 ? 8.48 138.76 ? 11.33 81.46 ? 18.30 BMI = body mass index; DBP = diastolic blood pressure; SBP = systolic blood pressure.
Table III. Relationship Between Blood Pressure Control and the Variables Sex, Age, Body Mass Index (BMI), Concomitant Treatment, Final Dose, Adverse Events and Patient Treatment Setting
Variable Achieved
therapeutic goal (%)Sex men 39.9 women 35.9 Age (y)* <35 40.8 35-44 46.0 45-54 43.7 55-64 38.1 >65 33.8 BMI (kg/m2) normal (19?24) 40.6 overweight (25?29) 38.2 obese (30-39) 35.3 morbidly obese (≥40) 28.8 Concomitant treatment no 38.7 yes 35.7 Final dose (mg/day)* 5 41.4 10 22.3 Adverse events no 38.9 yes 27.9 Patient treatment setting* primary care 33.8 specialised care 43.5
Table IV. Factors Related to Blood Pressure Control
Variable Crude OR (95% CI) Adjusted OR (95% CI) Sex men 1 1 women 0.845 (0.747, 0.957) 0.889 (0.777, 1.017) Age (y) <35 1 1 35?44 1.232 (0.657, 2.318) 1.174 (0.607, 2.272) 45?54 1.125 (0.626, 2.022) 1.156 (0.624, 2.140) 55?64 0.892 (0.499, 1.594) 0.917 (0.498, 1.690) >65 0.739 (0.415, 1.317) 0.782 (0.426, 1.430) BMI (kg/m2) normal (19?24) 1 1 overweight (25?29) 0.908 (0.769, 1.071) 0.911 (0.767, 1.082) obese (30-39) 0.800 (0.659, 0.971) 0.853 (0.697, 1.043) morbidly obese (≥40) 0.593 (0.342, 1.028) 0.618 (0.352, 1.083) Concomitant treatment no 1 1 yes 0.877 (0.766, 1.005) 0.730 (0.619, 0.819) Patient treatment setting primary care 1 1 specialised care 1.510 (1.332, 1.711) 1.675 (1.441, 1.946) BMI = body mass index; OR = odds ratio.
References
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The authors would like to thank all the physicians who participated in this study for the effort made in the follow-up and data collection, without whose help and dedication this research project would not have been possible.
This study was supported by a grant from Pfizer, SA, Madrid, Spain.
Correspondence and offprints: Dr Y. Valcárcel, Facultad de Ciencias de la Salud, Departamento de Medicina Preventiva y Salud Pública, Universidad Rey Juan Carlos, Avda. de Atenas s/n, 28922-Alcorcón, Madrid, Spain. E-mail: yolanda.valcarcel@urjc.es
1Faculty of Health Sciences, Rey Juan Carlos University, Madrid, Spain
2Medical Division and Health Outcomes Research, Medical Division, Pfizer, Madrid, Spain