Introduction

Calcium channel blockers (CCBs) are antihypertensive agents widely prescribed for decades [1], [2]. CCBs are heterogeneous, not only in ingredient and formulation, but also in indication [3]. Short-acting nifedipine used to be a common treatment option for severe hypertension [4]. However, several studies have reported the serious outcome from rapid fluctuation of blood pressure after sublingual use of nifedipine [5], [6]. Although the Food and Drug Administration (FDA) in the USA has announced the warning about the use of short-acting nifedipine in the management of hypertension crisis in 1996 [7], such a medical practice is still observed worldwide [8], [9]. A long-term observational study of short-acting nifedipine use has been seldom reported.

The aim of the current study was to investigate the trend of ambulatory nifedipine utilization in Taiwan according to the nationwide insurance claims from 1997 to 2011. Special attention would be paid to the extent and situations of prescribing short-acting nifedipine on a PRN (pro re nata) order.

Materials and Methods

Results

In the visit-based sampling datasets of our current study, the number of records increased from 489,636 in 1997 to 614,719 in 2011 (Table 1). The annual visits with prescriptions of antihypertensive agents also increased from 6.7% (32,629/489,636) in 1997 to 10.6% (65,134/614,719) in 2011 (p<0.001 in linear-by-linear association). The CCBs had remained as the popular antihypertensive agents. Not only increased the share of CCBs in prescriptions with antihypertensive agents annually from 42.2% (13,767/32,629) in 1997 to 48.1% (31,349/65,134) in 2011 (p<0.001), but also their share in all visits had a continuous growth from 2.8% (13,767/489,636) in 1997 to 5.1% (31,349/614,719) in 2011 (p<0.001).

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Table 1. Characteristics of ambulatory visits in Taiwan, 1997–2011 (0.2% sampling).

https://doi.org/10.1371/journal.pone.0091858.t001

Despite the growth of CCBs, there was a decreasing trend of nifedipine utilization in prescriptions with antihypertensive agents from 18.9% (6,154/32,629) in 1997 to 6.4% (4,142/65,134) in 2011 (p<0.001 in linear-by-linear association). During the study period, 1.3% (10,254/761,898) of prescriptions with antihypertensive agents and 2.9% (10,254/353,224) of prescriptions with CCBs contained a PRN order of short-acting capsule-form nifedipines. While the use of short-acting capsule-form nifedipines significantly decreased, the number of PRN orders did not decrease accordingly among visits with short-acting capsule-form nifedipines (447 in 1997 and 784 in 2011).

A total of 10,232 patients have ever received short-acting capsule-form nifedipines on a PRN order during 1997–2011 (445 in 1997 and 783 in 2011). More than one half of these nifedipines on a PRN order were prescribed by the internists and to the elderly patients; almost four-fifths of these nifedipines on a PRN order were prescribed during non-emergent consultations (Table 2).

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Table 2. Ambulatory prescriptions with short-acting nifedipine as a PRN (pro re nata) order in Taiwan, 1997–2011 (0.2% sampling).

https://doi.org/10.1371/journal.pone.0091858.t002

Discussion

In this current study, we used a nationwide sampling database with a sampling ratio of 0.2%, so one beneficiary was rarely sampled more than twice. Based on the nationally sampled datasets, our study revealed that the CCBs continued to be the popular antihypertensive agents in Taiwan from 1997 to 2011. Besides, the short-acting nifedipines were still in use on the market. Although the share of short-acting nifedipines in all prescriptions with antihypertensive agents decreased with time, short-acting nifedipines on a PRN order did not vanish in clinical practice.

The continuous popularity of CCBs in Taiwan was due to increasing use of newer-generations CCBs instead of medication persistency. The CCB utilization in Taiwan did not seem to be influenced by the worldwide CCB controversy starting in 1995 [14]. Unlike some utilization studies of CCBs in other countries [1], [15], [16], the lack of prescription data prior to 1997 in Taiwan precluded us from conducting a before-and-after analysis to understand the impact of the CCB controversy. On the other side, although we could not truly identify the sublingual nifedipine for treating acute hypertension in our study, the PRN use of short-acting nifedipine in Taiwan was not influenced by the disapproval of the Food and Drug Administration in the USA in 1995 as to the sublingual use of nifedipine either [17].

Patients of different ages might respond to the sublingual nifedipine differently. While even a low dose of sublingual nifedipine could induce risk of myocardial or cerebral ischemia in elderly patients [8], [18], the short-acting nifedipine for treating acute hypertension in children was still recommended by some authors [19]–[22]. Because the prevalence of hypertension and hypertensive emergencies was highly related to age, we could hardly observe the PRN use of short-acting nifedipine in children in our study. Instead, the predominant use by the elderly in Taiwan deserved concern. Another concern was about the setting in which short-acting nifedipine on a PRN order was prescribed. While the adverse reaction could be more easily monitored and managed at the hospitals, the take-home medication would let the patients get into danger unsupervised.

Hypertension is a chronic disease and the current guidelines recommend a long-term maintenance of normal blood pressure (BP) level. For severe BP elevation, the treatment goal is to reduce 20–25% of mean BP within the first hour and below 160/100–110 mmHg within the next 2–6 hours. The rapid and excessive reduction of BP from effect of short-acting nifedipine should be avoided to prevent organ ischemia [23], [24]. In Beers Criteria, the use of immediately-released nifedipine is also strongly considered as the potentially inappropriate medication and should be avoided for the elderly [25]. Despite these recommendations, Grise et al. reported that the rate of change in BP was greater at real-world emergency department setting than the guideline recommended [26]. In our study, physicians remained accustomed to the habit of prescribing short-acting nifedipine as a PRN order both in emergency and outpatient department, and the predominant users were the elderly. The reason that physicians still prescribe inappropriate drugs for patients is unclear. McGlynn et al. have reported the gap between physicians' knowledge and their clinical practice [27]. Prescriptions of short-acting nifedipine for hypertensive patients might successfully vanish from intervention with educational efforts [9].

Our descriptive study has some limitations. We had not yet studied the risks from inadequate dosing [28], interacting drugs [29], and co-morbidity. Further stratification of the results by patients' or physicians' characteristics was not performed because of the relatively small number of short-acting nifedipine PRN use in our sampling datasets. The outcome of the PRN use of short-acting nifedipine was also beyond the scope of our study of visit-based sampling datasets. Besides, the relative factors or prescribing habits of individual physicians could not be studied from the visit-based sampling datasets [30]. Furthermore, the actual use of a PRN medication at ambulatory setting could hardly be confirmed in the prescription database. Neither could the PRN use of accumulated drugs at home be known.

Conclusions

In conclusion, the physicians in Taiwan still had the inadequate habit of prescribing short-acting nifedipines both on regular use and on PRN use. The reason for such practices and the impact on patients' health deserve attention.

Acknowledgments

This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes in Taiwan. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health or National Health Research Institutes.