3-1 METHODS
Study Population
This study uses a 200,000-person representative random sample from the computerized reimbursement database of the NHI, between January 1997 and December 2004. Details on the gender and date of birth of the patients, the date of prescription, commercial names of drugs, drug dosages/duration and costs for each prescription are recorded in the reimbursement files.
Patients initially identified were newly-diagnosed with essential hypertension on at least three occasions, were being treated for this condition, and had received their first antihypertensive medication between 1 January 1998 and 31 December 2004. In order to verify that a case was a new one, a period of at least one year was required (January to December of 1997) without any treatment and/or diagnosis relating to hypertension.
To prevent potential confounding by comorbidities in the prescription patterns of antihypertensive agents at different clinical facilities, patients diagnosed with suspected diabetes mellitus, ischemic heart disease, diseases of pulmonary circulation, other forms of heart diseases (including dysrhythmia and heart failure), stroke or renal diseases were
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excluded from the sample. In order to ensure adherence to these criteria, any of the above diagnoses may not have appeared in any hospitalization file prior to the patient having been diagnosed as hypertensive, and the diagnoses may not have appeared more than three times in ambulatory outpatient files. We discarded those diagnoses appeared only once or twice in ambulatory outpatient files to exclude suspected or uncertain cases where claims were filed to allow for further diagnostic examination.
Prescription Patterns of New Cases of Hypertension
All antihypertensive drug prescription records from ambulatory care claims and prescriptions dispensed at contracted pharmacies were retrieved and analyzed for our sample of newly-diagnosed patients aged ≥30 years. Patients were stratified by gender
and age, with age being split into two sub-groups: the younger group (30-54 years of age) and the older group (≥55 years). The clinical facilities were classified into four types,
medical centers, regional hospitals, local hospitals and primary care clinics, based upon the level of medical care provided and the size of the institution as recognized by the NHI.
Antihypertensive drugs were categorized according to the 1999 World Health Organization–International Society Hypertension Guidelines for the Management of Hypertension (WHO/ISH, 1999) and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)
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[12,13]. Six major categories of antihypertensive drugs generally are available, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs), diuretics, and others (all other antihypertensive classes including alpha-blockers).
Prescriptions for a chronic disease in Taiwan, such as hypertension, most frequently involved the prescribing of drugs for 28- to 90-day periods, which would allow the patient visit a doctor every one to three months. Since each prescription may have contained different combinations of drugs and durations of medication, analysis of the data was undertaken using the prescription rate as calculated as the number of prescriptions containing a specific antihypertensive agent divided by the total number of prescriptions.
A comparison of the prescription time trend was undertaken for each year, beginning with the first antihypertensive prescription. Daily drug costs, excluding all pharmacy service fees or other peripheral costs, were also calculated for each prescription. The drug costs are set by the Bureau of National Health Insurance and universally applied to clinical facilities regardless of their sizes.
Statistical Analysis
After being weighted by duration of medication, daily drug costs are expressed as time-weighted means, while other results are expressed as means ± standard deviation
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(SD). The Chi-square test was carried out to determine the statistical significance of the differences between the prescription rates, with the Cochran-Armitage test also performed to assess the linear time trends over the sample period from the time of the initial treatment. Means of daily drug costs were compared using the Student t-test. Finally, multiple logistic regression analysis was performed to identify possible influential factors as a result of the prescribing of a single class of antihypertensive medication as a mono-therapy. SAS version 9.1 for Windows was used for the analysis of all of the data in this study. All tests were two-sided, and a P value of <0.05 was considered statistically significant. Whenever multiple comparisons were performed, Bonferroni adjustments were made accordingly.
3-2 RESULTS
The dataset contained a total of 15,835 patients over the age of 30 years who had received their initial dose of antihypertensive drugs for essential hypertension between 1 January 1998 and 31 December 2004. Of this total, 9,299 were excluded on the basis that one or more earlier comorbidities had been recorded. We were therefore left with a total of 6,536 patients and 178,754 prescriptions for antihypertensive agents for subsequent analysis.
Of the total sample of 6,536 patients, 3,268 (50.0%) were women and 49.3% was
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≥55 years old, with a mean of 55.9 and SD of 12.3 years. The mean follow-up duration
after the first prescription of antihypertensive medication was 42.8 ± 27.2 months, while the average number of overall prescriptions was 27.3 ± 26.0. Each prescription included 1.64 ± 0.84 antihypertensive drugs prescribed for an average period of 22.3 ± 10.5 days.
The mean number of actual medical visits over the entire period of study was 25.1 ± 24.5.
Antihypertensive Prescriptions among Newly-Diagnosed Patients
Over half of the prescriptions for newly-diagnosed cases of uncomplicated hypertension involved single antihypertensive drug therapy (n = 94,797; 53.0%), with women and older patients receiving more mono-therapies. Medical centers and regional hospitals prescribed more combination therapies, as compared with primary care clinics (Table 3.1). The percentage of mono-therapy treatments declined over time from the initial diagnosis, whereas there was a gradual increase in the percentage of combination therapies (Figure 3.1). The 10 most frequently prescribed antihypertensive regimens, ranked in order of prescribing frequency, were as follows: CCBs (17.7%), beta-blockers (14.5%), ACEIs (8.2%), CCBs + beta-blockers (7.7%), others (5.3%), diuretics (4.4%), CCBs + ACEIs (4.0%), ARBs (3.0%), CCBs + ARBs (2.6%), beta-blockers + diuretics (2.4%).
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A summary of the total number of prescriptions for the different categories of antihypertensive drugs is provided in Table 3.2, where it is shown that the most frequently prescribed antihypertensive agents were CCBs (n = 92,574; 51.8%), with beta-blockers as the second most frequently prescribed, followed by ACE inhibitors, diuretics, others and ARBs.
The prescription rate for ARBs, which was the highest in medical centers (22.6%), was almost five times the rate for primary care clinics, and was also higher than the prescription rate for ACE inhibitors and diuretics. There was an increase with time in the number of prescriptions for ARBs, CCBs and diuretics, whereas the number of prescriptions for ACE inhibitors remained stable (Figure 3.2).
Mono-Therapies for New Cases of Uncomplicated Hypertension
Among all of the mono-therapy prescriptions, the most frequently prescribed antihypertensive agents were CCBs (n = 31,711; 33.5%) and beta-blockers (n = 25,835;
27.3%). Older patients (aged over 55 years) were treated with CCBs more often than younger patients, with beta-blockers being more frequently prescribed among the latter group.
The prescription rates for beta-blockers were higher among women and younger patients (P<0.0001), while the prescription rates for diuretics were higher among
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women and older patients (P<0.0001). In contrast, ACE inhibitors and ARBs were more frequently prescribed for younger patients. Medical centers and regional hospitals were found to have prescribed ARBs much more often than primary care clinics (P<0.0001), where the prescribing of ACE inhibitors was found to be much more common (P<0.0001) (Table 3.3).
With the passage of time from the date of the initial therapy, there was a significant increase in the prescription rate for ARBs, from 3.8% in the first year to 10.3% in the seventh year (P<0.0001). There was also an increase over time in mono-therapies comprising diuretics; however, there was a reduction over time in the trends for mono-therapies involving beta-blockers or ACE inhibitors (P<0.0001). The time trends for mono-therapies are summarized in Figure 3.3.
Daily Drug Costs for Different Antihypertensive Mono-Therapies
The daily costs for mono-therapy medication, in order from low to high, are as follows.
Diuretics were the cheapest with a mean of US$0.17, followed by beta-blockers (US$0.27) and others (US$0.28). The costs for CCBs and ACE inhibitors were almost the same (US$0.56), while the costs for ARBs, at a daily average of US$0.85, were about five times those of diuretics. With the exception of the class of ‘other’ drugs, the means of the daily drug costs did not vary significantly by gender, age or clinical
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Factors Associated with Initial ARB Mono-Therapy Prescriptions
As Table 3.4 shows, following adjustment by multiple logistic regression analysis, those prescriptions involving ARBs as an antihypertensive mono-therapy were found to be associated with subsequent diagnoses of diabetes mellitus (odds ratio (OR) = 1.5; 95%
confidence interval (CI) 1.4-1.7), regional hospitals (OR = 3.6, 95% CI 3.3-3.9), medical centers (OR = 5.8, 95% CI 5.3-6.2), and the period after the year 2001 (OR = 2.4 for 2001-2, and 4.5 for 2003-2004).
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