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Chapter 2 Methodological aspects Chapter 2.1 Indications for antihypertensive drug use in a prescription database BLG van Wijk, OH Klungel, ER Heerdink, A de Boer Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University Submitted CHAPTER 2.1 Summary Background: Drugs termed antihypertensives are prescribed and registered for other indications than hypertension alone. In pharmacoepidemiological studies, this could introduce several forms of bias. The objective of this study was to determine the extent to which drugs classified as antihypertensive drugs are prescribed for other diseases than hypertension. Methods: The NIVEL database was used, containing prescriptions from a sample of general practitioners in The Netherlands. Classes of antihypertensive drugs were analyzed separately, based on ATC-codes: miscellaneous antihypertensives, diuretics, beta-blockers, calcium channel blockers and agents acting on the renin angiotensin system. In addition, these classes were further subdivided based on their specific mechanism of action. All first prescriptions of a patient in the database for an antihypertensive drug were selected. ICPC diagnoses studied were: increased blood pressure, hypertension without organ damage, hypertension with organ damage and hypertension with diabetes mellitus for which the above- defined antihypertensive drugs were prescribed. Results: Of 24,812 patients who received a first prescription for an antihypertensive drug, 63.0% received a first prescription for hypertension related diagnoses (diuretics: 54.1%, beta-blockers: 59.1%, calcium channel blockers: 60.3%, agents acting on the renin angiotensin system: 82.8% and miscellaneous antihypertensives: 64.6%). Subdividing and restricting these subgroups based on their mechanism of action yields a higher percentage of first prescriptions with hypertension related diagnoses (low-ceiling diuretics: 78.8%, selective beta- blockers: 69.9% and dihydropyridine calcium channel blockers: 76.8%). Conclusion: If a prescription database lacking diagnoses is used to study antihypertensive drugs in relation to hypertension treatment, the results have to be interpreted with caution because of the potential misclassification that may occur. Subdividing the antihypertensive drug classes and restricting to subgroups decreases this misclassification. 22 Indications for antihypertensive drugs Background Prescription databases offer a relatively easy and inexpensive way to obtain information on drug utilization, e.g. side-effects, adherence to treatment, persistence and prevalence, in daily practice. A number of databases are available and have been used for a large number of pharmacoepidemiological studies, e.g. MediPlus (German, UK, France), GPRD (UK), Saskatchewan Health (Canada), Medicaid (US), Local health Unit of Ravenna (Italy) Uniformed Services Prescription Database Project (USPDP) and PHARMO (The Netherlands)1-8. A limitation of some of these databases is that they lack the indication for which a drug is prescribed1,3. In some cases, one drug can be assigned to a single indication with a large degree of certainty e.g. in case of insulin and diabetes mellitus. With antihypertensive drugs, there is more uncertainty because antihypertensive drugs can also be prescribed for e.g. angina pectoris, heart failure, cardiac arrhythmias, but also for other than cardiovascular diseases e.g. migraine prophylaxis or anxiety (beta blockers). This could introduce several forms of bias. In this study we aimed to assess for which diagnoses antihypertensive drugs are prescribed in The Netherlands and whether this differed between the different types of antihypertensive drugs. Methods We used a sample from the Second Dutch National Survey of General Practice which was carried out in 2001 by the Netherlands Institute for Health Services Research (NIVEL). This database has been described elsewhere9. In short, 195 general practitioners in 104 practices registered all physician-patient contacts during 2001. All prescription drugs were coded according to the Anatomical Therapeutic Chemical (ATC) classification system10. We studied the following classes of antihypertensive drugs: miscellaneous antihypertensives (ATC-code C02), diuretics (ATC-code C03), beta-blockers (ATC-code C02), calcium channel blockers (ATC-code C08) and agents acting on the renin angiotensin system (ATC-code C09). Furthermore, we subdivided these classes into subgroups based on their mechanism of action. Miscellaneous antihypertensives were subdivided in alpha-blockers and centrally acting antihypertensives. Diuretics were subdivided into low-ceiling diuretics, high ceiling diuretics and potassium sparing agents. Beta-blockers were subdivided into selective beta-blockers, non-selective beta- blockers, alphabeta-blockers and sotalol (which is not registered for hypertension). Calcium channel blockers were subdivided into dihydropyridine calcium channel 23 CHAPTER 2.1 blockers, verapamil and diltiazem. Agents acting on the renin angiotensin system were subdivided into ACE-inhibitors and angiotensin II receptor blockers. All first prescriptions of a patient in the database for a defined class were selected. Diagnoses were coded according tot the International Classification of Primary Care11. Hypertension related diagnoses studied were: increased blood pressure (K85), hypertension without organ damage (K86), hypertension with organ damage (K87) and diabetes mellitus for which the above-defined antihypertensive drugs were prescribed (T90). Other diagnoses studied were angina pectoris (K74), congestive heart failure (K77) and cardiac arrhythmias (K78). Differences in percentages of prescriptions for hypertension related diagnoses between diuretics and the other four classes, as well as for the low-ceiling diuretics and the other thirteen subgroups based on their mechanism of action, were tested, using the chi- square test. Results The results are shown in table 1. A total of 24,812 first prescriptions from an equal number of patients were evaluated. Of these prescriptions, 63% were for hypertension related diagnoses. The fraction of prescription for other cardiovascular and non-cardiovascular diagnoses was generally different among the antihypertensive drug classes, the lowest for diuretics and the highest for agents acting on the renin angiotensin system. 24 Indications for antihypertensive drugs Table 1: Different diagnoses for which antihypertensive drugs are prescribed from 24,812 first prescriptions of 24,812 patients Miscellaneous Diuretics Beta-blockers CCBs AARAS Number 212 7,360 9,468 2,307 5,465 Hypertension 137 (64.6%) 3,980 (54.1%) 5,592 (59.1%) 1,391 (60.3%) 4,526 (82.8%) related CHF 0 (0%) 988 (13.4%) 44 (0.5%) 18 (0.8%) 176 (3.2%) Angina pectoris 2 (0.90%) 75 (1.0%) 556 (5.9%) 223 (9.7%) 72 (1.3%) Cardiac 0 (0%) 56 (0.8%) 219 (2.3%) 91 (3.9%) 24 (0.4%) arrhythmias Other 4 (1.90%) 1,351 (18.4%) 1,200 (12.7%) 292 (12.7%) 220 (4.0%) cardiovascular Other non- 69 (32.6%) 910 (12.4%) 1,857 (19.6%) 292 (12.7%) 447 (8.2%) cardiovascular CCBs=calcium channel blockers; AARAS=agents acting on the renin angiotensin system; CHF=congestive heart failure If the five major classes of antihypertensive drugs are divided into subgroups based on their mechanism of action, the percentage of patients with a prescription for a hypertension related diagnosis is generally higher for low-ceiling diuretics, selective beta-blockers, alpha-beta-blockers and dihydropyridine calcium channel blockers (table 2). Of all patients receiving a first prescription for alpha-blockers, 17.3% had a diagnosis of benign prostate hypertrophy. Of all patients receiving a first prescription for a non-selective beta-blocker, 38.1% had an anxiety or tension related diagnosis. In addition, patients receiving a first prescription for diltiazem, 37.8% had a diagnosis of angina pectoris and 23.8% of the patients receiving verapamil had a diagnosis of cardiac arrhythmias. All four classes differed significantly from diuretics with regard to the percentage of hypertension related diagnosis (all four p-values<0.001). All subgroups differed significantly from low- ceiling diuretics (p<0.001) except dihydropyridine calcium channel blockers (p=0.117). 25 CHAPTER 2.1 Table 2: different diagnoses for which antihypertensive drugs are prescribed from 24,812 first prescriptions of 24,812 patients; classes are subdivided into subgroups based on their mechanism of action Hypertension Other Other non- related cardiovascular cardiovascular Miscellaneous antihypertensives (N=212) 137 (64.6%) 6 (2.8%) 69 (32.6%) • Alpha-blockers (N=110) 73 (66.4%) 2 (1.8%) 35 (31.8%) • Central acting (N=102) 64 (62.7%) 4 (3.9%) 34 (33.3%) Diuretics (N=7,360) 3,980 (54.1%) 2,470 (33.6%) 910 (12.4%) • Low ceiling (N=3,456) 2,722 (78.8%) 484 (14.0%) 250 (7.2%) • High ceiling (N=2,264) 328 (14.5%) 1,492 (65.9%) 444 (19.6%) • Potassium sparing (N=1,640) 930 (56.7%) 494 (30.1%) 216 (13.2%) Beta-blockers (N=9,494) 5,513 (58.1%) 2,196 (23.1%) 1,785 (18.8%) • Selective (N=7,494) 5,237 (69.9%) 1,442 (19.2%) 815 (10.9%) • Non-selective (N=1,366) 208 (15.2%) 200 (14.6%) 958 (70.1%) • Alpha-beta (N=98) 68 (69.4%) 18 (18.4%) 12 (12.2%) • Sotalol (N=536) 0 (0%) 536 (100%) 0 (0%) Calcium channel blockers (N=2,307) 1,391 (60.3%) 624 (27.0%) 292 (12.7%) • Dihydropyridine (N=1,615) 1240 (76.8%) 209 (12.9%) 166 (10.3%) • Verapamil (N=345) 88 (25.5%) 192 (55.6%) 65 (18.8%) • Diltiazem (N=347) 63 (18.2%) 223 (64.3%) 61 (17.6%) AARAS (N=5,465) 4,526 (82.8%)
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