Extent of use of immediate-release formulations of calcium channel blockers as antihypertensive monotherapy by primary care physicians: multicentric study from Bahrain.

RP Sequeira, KA Jassim Al Khaja, VS Mathur 
 Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain. , Bahrain

Correspondence Address:
R P Sequeira
Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain.
Bahrain

Full Text

The calcium channel blockers are an important class of antihypertensive drugs in the management of hypertension.[1] An increase in the number of available calcium channel blockers (CCBs), either as new formulations of existing drugs or as new chemical entities over recent years has contributed to an ever-changing scenario regarding their appropriate use compared with other antihypertensive drugs. Among the dihy-dropyridine and non-dihydropyridine CCBs, the first-generation drugs have been clearly superseded and are not recomm-ended for use in hypertension. While the second-generation drugs represent an adequate therapeutic approach, the third-generation CCBs offer distinct advantages.[2]

The first-generation of CCBs, exemplified by the earlier drugs such as nifedipine, diltiazem and verapamil are characterised by a rapid onset of action, a tendency to produce reflex sympathetic activation and short duration of action-necessitating multiple daily administrations. Concern has been expressed that these characteristics of short-acting nifedipine may be dangerous for patients recovering from an acute myocardial infarction, especially for those on monotherapy.[3]

The present study examines the pattern of CCBs as monotherapy in the management of uncomplicated hyper-tension, diabetic hypertension and in elderly hypertensive patients. In addition, an analysis of the pattern of utilisation of short-acting versus long-acting CCBs, especially of nifedipine has been attempted.

::   Patients and methods

Data regarding antihypertensive drug utilization among uncomplicated hypertensive, and diabetic-hypertensive patients were collected from seven out of 18 health centers located in Bahrain. Each health centre with up to 11 primary care physicians provides free medical services to all citizens and residents registered at each centre. These health centers were selected randomly to provide a fair geographical distribution and to allow for population density sampling. The seven health centers represented a patient population (i.e. patients registered in the individual health centers) of approximately 229,300 (46%) out of 498,120 officially registered individuals, and were collectively assured to reflect the prescribing behaviour of primary care physicians among all the centers.

All patients with hypertension who received antihypertensive drugs, and patients with diabetic hypertension who received antidiabetic (oral antidiabetics and insulin) and antihypertensive drugs concomitantly were included in the study. The relevant data was collected using chronic dispensing cards specially designed for chronically ill patients. These cards are kept in the pharmacy in order to facilitate monitoring of the drug refilling process and provide a dispensing record for each health center’s pharmacy. Each card included information such as the name of the patient, address, file number, the patient’s personal number and a list of all prescribed drugs. In addition, records of drugs dispensed such as date of dispensing, number of items and amount dispensed per refill (or physician visit) were available. For refilling process, the patients had to present their population registration card (PRC) and accordingly the chronic disease dispensing card could be easily retrieved for use in subsequent dispensing.

Those cards which included data on cardiovascular drugs such as antihypertensives, antidysrhythmics, antianginals, cardiac glycosides, antithrombotic drugs and lipid lowering drugs prescribed together with or without antidiabetics were collected as part of an ongoing comprehensive study. Data collection was carried out between November1998 and January1999. Patients with uncomplicated hypertension, and diabetic hypertension were included in the present study. A patient was identified as hypertensive if he or she received one or more antihypertensives, and was identified as diabetic with hypertension, if he or she received one or more antihypertensives together with one or more antidiabetic drugs. However, hypertensive patients with or without diabetes mellitus were excluded from the study if they also had: ischaemic heart disease as suggested by a prescription of antianginal drugs with antihypertensives and antiplatelet / antithrombotic drugs; cardiac glycosides in combination with other cardiovascular drugs, possibly for congestive heart failure and / or dysrhythmias.

All sampled chronic dispensing cards were audited and those which fulfilled the above criteria were analyzed using the Statistical Package for the Social Sciences (SPSS/PC+, version 9.0). The detailed methodology including the organization of health care system in Bahrain has been described earlier.4

::   Results

In 3838 patients with uncomplicated hypertension, 2414 were treated with monotherapy; the rank orders of most frequently prescribed drugs were: ?-blockers, ACE-inhibitors, CCBs, diuretics, methyldopa and other drugs. Calcium channel blockers were prescribed for 11.1% of all patients treated with monotherapy regimen. [Table:1] shows the proportion of various CCBs used as monotherapy: IR-nifedipine (5.4%), sustained release (SR)-nifedipine (5.5%) together comprised the most commonly prescribed drugs; CCBs such as IR-verapamil and amlodipine were rarely prescribed.

Amongst 1463 diabetic hypertensive patients, 943 were treated with monotherapy. The general pattern of preference for various classes of antihypertensives was similar to uncomplicated hypertension. Again, CCBs were the third most commonly prescribed drugs in 18% of patients on monotherapy [Table:1]. Moreover, nifedipine was prescribed in majority of these patients either as IR-formulation (8.2%) or as SR-formulation (8.6%). In contrast to uncomplicated hyperten-sion cohort, IR-diltiazem was used in 1% of diabetic hypertensive patients on monotherapy. IR-verapamil and amlodipine prescribed in 0.1% of patients each [Table:1].

In 764 elderly hypertensives (> 65 years), 432 were on monotherapy; of these 20.2% were on CCBs and nifedipine was prescribed most frequently, either as IR-formulation (9.8%) or as SR-formulation (10%). Immediate-release verapamil and amlodipine each was used in 0.2% of patients on CCBs based monotherapy [Table:1].

::   Discussion

Calcium channel blockers have emerged as alternatives to the conventional antihypertensives, such as the ?-blockers and diuretics. They are especially valuable for patients with ischaemic heart disease, and are devoid of the several metabolic adverse effects associated with ?-blockers and diuretics[1],[5]such as impaired glucose homeostasis and dyslipidemia which are of concern in diabetic hypertension. ACE-inhibitors have emerged as alternative drugs for these patients due to their lack of adverse effects on glucose homeostasis and dyslipidemia, and are effective in minimizing the progression of proteinuria due to diabetic nephropathy.[6] Several diabetic hypertensive patients, particularly those with a dry cough resulting from ACE-inhibitor may require an alternative, such as a calcium channel blocker. Although CCBs as a class of drugs, and nifedipine formulations used extensively in our study in particular, have a neutral effect on blood glucose and lipid levels, their effect on diabetic nephropathy is uncertain.[1],[6]

Literature survey strongly suggests that the problem of increased cardiovascular events may go beyond short-acting nifedipine. Other short-acting dihydropyridines that also induce intermittent increases in sympathetic activity are likely to be similar to nifedipine in their effects.[7] It has been suggested that a reflex increase in sympathetic activity resulting from short-acting CCBs to be the underlying mechanism for pro-ischaemic and dysrrhy-thmogenic effects of these drugs.[7],[8] In the presence of subclinical atherosclerosis, especially in diabetic hypertension, short-acting dihydropyridines may exert pro-ischaemic effects. It has been clearly demonstrated that short-acting dihydropyridines are not the drug of choice for regression of left ventricular hypertrophy and as monotherapy are likely to lead to a detrimental outcome in patients with subclinical forms of coronary artery disease.[8]

The issue of the cardiovascular safety of CCBs has been widely debated following the publication of three major articles: (1) a case-control study on the occurrence of myocardial infarction in hypertensive patients treated with a short-acting CCB,[9] (2) a meta-analysis of 16 randomised secondary prevention trials on nifedipine in patients with coronary heart disease,[7] and (3) a prospective control study in hypertensive elderly patients of the comparative risk of mortality with CCBs, ACE-inhibitors, or ?-blockers.[10]

The prospective cohort study[9] showed that with respect to ?-blockers, the relative risk for mortality (95% CI) were short acting nifedipine 1.7 (1.1-2.7), diltiazem 1.3 (0.8-2.1), verapamil 0.8 (0.4-1.4), and ACE-inhibitors 0.9 (0.6-1.4). Even if selective factors influencing the use of specific drugs in high-risk patients could not be discounted, the results showed a significantly reduced survival of elderly hyper-tensives treated with nifedipine compared with ?-blockers. Several investigators have challenged these conclusions, arguing that bias in patient-selection, and data-selection in meta-analysis would have distorted the findings.[10],[11]

More recently, a meta-analysis of 60 published randomised clinical trials that enrolled at least 10 patients with stable angina, and compared any nifedipine formulation, either as monotherapy or combination therapy, with a non-dihydro-pyridine drug or placebo control for at least one week,[12] there was an increased risk of cardiovascular events in patients on nifedipine. Episodes of increased angina were more frequent with IR- nifedipine (OR=4.19; CI: 1.41-12.49) and with nifedipine monotherapy (OR = 2.61; CI: 1.30-5.26). This meta-analysis has further supported the adverse effects of nifedipine on cardiovascular events in patients with stable angina are primarily due to more frequent episodes of angina when monotherapy with IR-formulation is used. Modified - release formulation and concurrent use of ?-blockers do not appear to be associated with increased risk. However, effects of nifedipine on morbidity and mortality remain untested in the setting of hypertension.

It has to be emphasized that only long-acting formulations of nifedipine and diltiazem have been approved by the US Food and Drug Administration (FDA) for antihypertensive therapy.[13] A warning has been issued by the FDA, National Heart, Lung and Blood Institute (NHLBI),[14] and WHO/ISH Guidelines Subcommittee[1] concerning the poor safety of short-acting formulations of nifedipine.

In all the categories of hypertensives studied, out of approximately 10-20% of patients treated with CCBs as monotherapy, almost half were treated with short-acting nifedipine; a large proportion (75%) of them were above 50 years of age. In view of the concerns about the dubious safety of CCBs, we feel that the observed trend in prescribing short-acting CCB is clearly undesirable. It can potentially lead to an increased risk of myocardial infarction especially in patients with subclinical forms of coronary artery diseases. A policy decision by regulatory agency is required in Bahrain to discourage the use of such short-acting formulations of nifedipine, particularly as monotherapy. In addition, it is important to include a long-acting CCB in the essential drugs list for primary care, perhaps amlodipine, which should dissuade primary care physicians from using short-acting nifedipine formulations. Also, the importance of educational interventions aimed at enhancing physicians’ awareness and prescribing skills, should be addressed.

::   Acknowledgment

We acknowledge the help and assistance given by the Bahrain Ministry of Health and to Mrs. Radha Raghavan who has been of immense help in preparing and typing of the manuscript.