Abstract
BACKGROUND
Several antihypertensive drugs are available for the primary prevention of cardiovascular disease (CVD). However, existing evidence on prescription patterns was primarily generated among patients at high CVD risk with short-term follow-up, and failed to capture impacts of time and patient characteristics. Our objective was therefore to describe longitudinal prescription patterns for antihypertensive drugs for the primary prevention of CVD among patients with arterial hypertension in the United Kingdom.
METHODS
This population-based cohort study used data from the Clinical Practice Research Datalink, included 660,545 patients with hypertension who initiated an antihypertensive drug between 1998 and 2018. Antihypertensive treatments were measured by drug class and described overall and in subgroups, focusing on first-line therapy (first antihypertensive drug(s) recorded after a diagnosis of hypertension) and second-line therapy (antihypertensive drug(s) prescribed as part of a treatment change following first-line therapy).
RESULTS
Angiotensin-converting enzyme (ACE) inhibitors (29.0%), thiazide diuretics (22.1%), and calcium-channel blockers (CCBs) (21.0%) were the most prescribed first-line therapies. ACE inhibitors have been increasingly prescribed as first-line therapy since 2001. Men were more likely to be prescribed ACE inhibitors than women (43.5% vs. 32.1%; difference: 11.4%; 95% confidence interval [CI], 11.0%–11.8%), and Black patients were more likely to be prescribed CCBs than White patients (63.6% vs. 37.0%; difference: 26.6%; 95% CI, 24.8%–28.4%).
CONCLUSIONS
Antihypertensive prescription patterns for the primary prevention of CVD among patients with hypertension are consistent with treatment guidelines that were in place during the study period, providing reassurance regarding the use of evidence-based prescribing.
Keywords: antihypertensive drugs, blood pressure, cardiovascular disease prevention, hypertension, prescription patterns
Graphical Abstract
Graphical Abstract.
Arterial hypertension is well established as a leading risk factor for cardiovascular disease (CVD).1 Consequently, the management of hypertension is a key component of the primary prevention of CVD. Hypertension guidelines recommend initial management through lifestyle modification,2 followed by the use of antihypertensive medications among patients whose blood pressure (BP) remains poorly controlled.
Several drugs have been approved for the treatment of hypertension. Yet, previous studies investigated the utilization in specific groups of patients with hypertension, usually those at relatively higher estimated CVD risk,3,4 and followed them for a relatively short period of time.3–5 Furthermore, most previous studies reported overall use of antihypertensive drugs and did not consider the impact of calendar time and changes in treatment guidelines on treatment patterns, including the order and duration of using antihypertensive drugs.6–9 Given the high prevalence of hypertension and the importance of BP control for CVD prevention, there remains a need to better understand how antihypertensive drugs are used in real-world settings. This information would allow for the identification of inconsistencies between everyday clinical practice and recommendations in guidelines. If important inconsistencies are identified, this information could inform continuing medical education programs, drug list for reimbursement, and other policies. The objectives of this study were therefore to describe prescription patterns of antihypertensive drugs overall, by time, and by clinically important subgroups for the primary prevention of CVD among patients with hypertension and to examine the relationship between changes in guidelines and antihypertensive prescription patterns in the United Kingdom.
METHODS
Data source
This study was conducted using data extracted from the Clinical Practice Research Datalink (CPRD), a clinical database which contains anonymized electronic medical records for a representative population-based sample of ~16 million individuals seen at >700 general practitioner practices in the United Kingdom.10 It contains information regarding patients’ demographic characteristics, lifestyle information (e.g., smoking), medical diagnoses, laboratory test results, and clinical measures (e.g., BP). In addition, prescriptions written by the general practitioner are recorded in the CPRD, including the product prescribed, dosage, and quantity. Repeat prescriptions, which are available to patients who take a medication on a regular basis but do not need to see their physician between prescriptions, are also recorded. CPRD data have been previously validated and are of high quality.11,12 Importantly, hypertension is primarily managed in a primary care setting in the United Kingdom,13 making the CPRD well suited for this study.
Study population
The cohort included patients who initiated an antihypertensive drug between 1 January 1998 and 30 June 2018. Given multiple indications for some antihypertensive drugs, we required patients have either a recorded diagnosis of hypertension or an elevated BP reading (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) on or before cohort entry. Cohort entry was defined by the date of the first antihypertensive prescription in a treatment-naive patient. Antihypertensive medications included thiazide and thiazide-like diuretics (thiazide diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCBs), beta-blockers, alpha-blockers, loop diuretics, potassium-sparing diuretics, central-acting agents, direct vasodilators, and renin inhibitors.
We excluded patients aged <18 years at cohort entry, those with a previous antihypertensive prescription in the year before cohort entry, and patients with <1 year of history in the CPRD before cohort entry. To focus on primary prevention, we excluded patients with a history of myocardial infarction, stroke, hospitalized angina, revascularization, or heart failure at any time before cohort entry. Due to different recommendations on prescribing antihypertensive drugs, we excluded patients with a history of any of following comorbidities at any time before cohort entry: severe proteinuria, end-stage renal disease, polycystic kidney disease, cancer, dementia, organ transplantation, or pregnancy. Patients were followed until death, end of registration in the CPRD, or end of study (28 February 2019), whichever occurred first. Patients were not censored upon diagnosis of CVD or any comorbidities during follow-up.
Prescription patterns
We assessed prescriptions written by the general practitioner for the antihypertensive drug classes described above. Prescriptions for fixed-dose combination pills contributed to each of component drug classes. Since treatment guidelines2,6,9 provide recommendations for up to 4 lines of therapy, we focused on the first 3 treatment changes that were prescribed to each patient since initiation. Whenever a treatment change occurred, all prescriptions the patient was still receiving were assumed to contribute to the next line therapy, which started on that date. Treatment changes were defined by a prescription from a new antihypertensive drug class not previously prescribed (add-on or switch), or not receiving prescription(s) for a previously prescribed drug class for >6 months (discontinuation). For each antihypertensive drug class prescribed, we assumed that the duration of time started at the date of the prescription for that class, continued for the duration of the prescription, and ended at the occurrence of a treatment change or the end of prescription of that class, whichever occurred first. For example, if a patient has been prescribed ACE inhibitors at the cohort entry and was prescribed an ACE inhibitor and a CCB at a subsequent visit, the first-line and second-line therapy would be “ACE inhibitor,” and “combination of ACE inhibitor and CCB,” respectively (see Supplementary Figure S1 online for more detail).
Baseline characteristics
We assessed patient demographic and clinical characteristics at cohort entry (Supplementary Figure S1 online). Demographic characteristics were age, sex, and race/ethnicity. Clinical characteristics included smoking status, body mass index, SBP, DBP, comorbidities (such as atrial fibrillation, type 2 diabetes mellitus), and family history of CVD. We estimated patients’ QRISK3,14 a 10-year CVD risk score previously developed using general practitioner data in the United Kingdom and recommended for risk stratification by the UK’s National Institute for Health and Care Excellence (NICE).9 Low, intermediate, and high CVD risk were defined using the QRISK3 score (<10%, 10%–19.9%, and ≥20%, respectively). In addition, we assessed prescription of statins, other antihyperlipidemic agents, acetylsalicylic acid, oral anticoagulants, and antipsychotics. Smoking, body mass index, and BP were measured in the 5 years, 1 year, and 6 months before cohort entry, respectively. Comorbidities and family history of CVD were measured any time before cohort entry, and medication prescribed was measured in the year before cohort entry. Patients with missing race/ethnicity data were assumed to be White. To calculate QRISK3 score, missing data for smoking status, height, weight, SBP, and DBP were imputed via multiple imputation with fully conditional specification.15,16
Statistical analysis
Baseline demographic and clinical characteristics were described overall, by sex, by calendar year of initiation, and by CVD risk. Prescription patterns included: (i) proportion of patients who were prescribed each treatment combination; and (ii) duration of time for which patients were prescribed it. We constructed histogram and sunburst figures to describe prescription patterns of a specific line of therapy and each line of therapy separately. Histograms were created overall and by calendar year of initiation for first-line therapy, where we created 3 cut-points to correspond with the publication of NICE and British Hypertension Society (BHS) treatment guidelines.8,17,18 Considering the short amount of time in our study cohort prior to 2001 and the lack of guidelines prior to 1999, we focused our assessment of prescription patterns in the calendar years 2001–2005, 2006–2011, and 2011 onward. We visualized patterns that represent ≥1% of the population in the histograms (see Supplementary Tables online for full prescription patterns). Given the impact of calendar time and to focus on prescription patterns under the more contemporary guidelines, we restricted subsequent analyses to patients who initiated antihypertensive medication in 2011 or later and created histograms by sex, and by age at initiation for first-line therapy and overall for second-line therapy. Sunburst figures were created overall, by sex, by calendar year, by age, by race, and by CVD risk level of initiation (see Supplementary Figures online for more detail). Data management and descriptive analyses were performed using SAS 9.4 (SAS Institute) and R 3.6.1 (https://cran.r-project.org).
RESULTS
The cohort included 660,545 patients who initiated antihypertensive drugs (Supplementary Figure S2 online). The mean age was 59.7 (SD: 13.5) years, and 51.1% were women (Table 1). Among 28.4% of patients whose race data were available, the majority (92.3%) were White. A total of 39.6%, 30.6%, and 29.8% of patients were at high, intermediate, and low CVD risk, respectively. The mean SBP and DBP at cohort entry were 162.5 (SD: 20.9) and 93.9 (SD: 12.3) mm Hg, respectively. The mean follow-up duration was 6.4 years (minimum: 6 days; maximum: 21.1 years). Compared with men, women were older, and less likely to be at high CVD risk (33.5% vs. 46.0%). Accordingly, they were less likely to be prescribed statins, antihyperlipidemic, and antidiabetic drugs. Compared with patients who initiated antihypertensive drugs in 2001–2005, or 2006–2010, those who initiated in 2011 or later were younger, less likely to be female, and had lower SBP and DBP at cohort entry (Table 2). Moreover, they were more likely to have a history of atrial fibrillation, type 2 diabetes mellitus, and to be prescribed antihyperlipidemic drugs and statins.
Table 1.
Baseline characteristics of patient with hypertension at the time of their first prescription for an antihypertensive drug, overall, and by sex
| Characteristic | Overalla | Malea | Femalea |
|---|---|---|---|
| (n = 660,545) | (n = 322,865) | (n = 337,680) | |
| Female | 337,680 (51.1) | 0 (0.0) | 337,680 (100.0) |
| Age (years) | 59.7 ± 13.5 | 58.3 ± 12.6 | 61.0 ± 14.2 |
| ≤50 | 170,789 (25.9) | 88,579 (27.4) | 82,210 (24.3) |
| 51–60 | 178,988 (27.1) | 95,912 (29.7) | 83,076 (24.6) |
| 61–70 | 162,773 (24.6) | 82,829 (25.7) | 79,944 (23.7) |
| >70 | 147,995 (22.4) | 55,545 (17.2) | 92,450 (27.4) |
| Year of initiation | |||
| Prior to 2001 | 58,531 (8.9) | 24,282 (7.5) | 34,249 (10.1) |
| 2001–2005 | 215,030 (32.6) | 100,372 (31.1) | 114,658 (34.0) |
| 2006–2010 | 204,369 (30.9) | 103,864 (32.2) | 100,505 (29.8) |
| 2011–2018 | 182,615 (27.6) | 94,347 (29.2) | 88,268 (26.1) |
| Race or ethnic group | |||
| White | 173,250 (26.2) | 84,363 (26.1) | 88,887 (26.3) |
| Black | 5,050 (0.8) | 2,317 (0.7) | 2,733 (0.8) |
| Hispanic | 119 (0.0) | 47 (0.0) | 72 (0.0) |
| Asian | 9,081 (1.4) | 4,635 (1.4) | 4,446 (1.3) |
| Unknown/missing | 473,045 (71.6) | 231,503 (71.7) | 241,542 (71.5) |
| Smoking status | |||
| Nonsmoker | 260,408 (39.4) | 113,774 (35.2) | 146,634 (43.4) |
| Former smoker | 141,018 (21.3) | 83,316 (25.8) | 57,702 (17.1) |
| Light smoker (<10 cigarettes/day) | 14,772 (2.2) | 6,903 (2.1) | 7,869 (2.3) |
| Moderate smoker (10–19 cigarettes/day) | 22,988 (3.5) | 10,683 (3.3) | 12,305 (3.6) |
| Heavy smoker (≥20 cigarettes/day) | 20,190 (3.1) | 11,842 (3.7) | 8,348 (2.5) |
| Unknown/missing | 201,169 (30.5) | 96,347 (29.8) | 104,822 (31.0) |
| Systolic blood pressure (mm Hg) | |||
| Mean ± SD | 162.5 ± 20.9 | 162.4 ± 20.0 | 162.6 ± 21.7 |
| Missing | 86,130 (13.0) | 39,797 (12.3) | 46,333 (13.7) |
| Diastolic blood pressure (mm Hg) | |||
| Mean ± SD | 93.9 ± 12.3 | 95.3 ± 12.3 | 92.7 ± 12.1 |
| Missing | 86,130 (13.0) | 39,797 (12.3) | 46,333 (13.7) |
| QRISK3 10-year CVD score | |||
| Mean ± SD | 19.5 ± 13.9 | 21.5 ± 13.2 | 17.6 ± 14.3 |
| Low risk (<10%) | 196,755 (29.8) | 64,189 (19.9) | 132,566 (39.3) |
| Intermediate risk (10%–19.9%) | 201,968 (30.6) | 110,042 (34.1) | 91,926 (27.2) |
| High risk (≥20%) | 261,822 (39.6) | 148,634 (46.0) | 113,188 (33.5) |
| BMI (kg/m2) | |||
| Mean ± SD | 30.0 ± 6.4 | 29.9 ± 5.6 | 30.2 ± 7.1 |
| <18.5 kg/m2 | 2,791 (0.4) | 700 (0.2) | 2,091 (0.6) |
| 18.5–24.9 kg/m2 | 58,229 (8.8) | 24,383 (7.6) | 33,846 (10.0) |
| 25.0–29.9 kg/m2 | 108,650 (16.4) | 61,862 (19.2) | 46,788 (13.9) |
| 30.0–39.9 kg/m2 | 111,585 (16.9) | 58,723 (18.2) | 52,862 (15.7) |
| ≥40 kg/m2 | 21,284 (3.2) | 7,554 (2.3) | 13,730 (4.1) |
| Missing | 358,006 (54.2) | 169,643 (52.5) | 188,363 (55.8) |
| Family history of CVD | 1,685 (0.3) | 834 (0.3) | 851 (0.3) |
| Comorbidities | |||
| Atrial fibrillation | 17,480 (2.6) | 10,173 (3.2) | 7,307 (2.2) |
| Chronic kidney disease | 17,938 (2.7) | 7,251 (2.2) | 10,687 (3.2) |
| Type 2 diabetes mellitus | 107,650 (16.3) | 60,210 (18.6) | 47,440 (14.0) |
| Drug use | |||
| Number of antihypertensive agents | 1.0 ± 0.2 | 1.1 ± 0.3 | 1.0 ± 0.2 |
| Acetylsalicylic acid | 48,994 (7.4) | 24,144 (7.5) | 24,850 (7.4) |
| Anticoagulants (oral) | 12,325 (1.9) | 6,498 (2.0) | 5,827 (1.7) |
| Antidiabetic drugs | 38,442 (5.8) | 22,548 (7.0) | 15,894 (4.7) |
| Antihyperlipidemic drugs | 79,311 (12.0) | 43,724 (13.5) | 35,587 (10.5) |
| Statin | 77,222 (11.7) | 42,749 (13.2) | 34,473 (10.2) |
Abbreviations: BMI, body mass index; CVD, cardiovascular disease.
aData are presented as n (%) or mean ± SD.
Table 2.
Baseline characteristics of patient with hypertension at the time of their first prescription for an antihypertensive drug by the year of initiation
| Characteristic | 2001–2005a | 2006–2010a | Since 2011a |
|---|---|---|---|
| (n = 215,030) | (n = 204,369) | (n = 182,615) | |
| Female | 114,658 (53.3) | 100,505 (49.2) | 88,268 (48.3) |
| Age (years) | 60.6 ± 13.6 | 59.4 ± 13.5 | 58.4 ± 13.2 |
| ≤50 | 50,283 (23.4) | 54,923 (26.9) | 52,900 (29.0) |
| 51–60 | 58,145 (27.0) | 54,407 (26.6) | 51,232 (28.1) |
| 61–70 | 52,328 (24.3) | 51,295 (25.1) | 44,818 (24.5) |
| >70 | 54,274 (25.2) | 43,744 (21.4) | 33,665 (18.4) |
| Race or ethnic group | |||
| Caucasian | 46,978 (21.8) | 56,811 (27.8) | 59,738 (32.7) |
| Black | 729 (0.3) | 1,449 (0.7) | 2,747 (1.5) |
| Hispanic | 22 (0.0) | 40 (0.0) | 51 (0.0) |
| Asian | 1,649 (0.8) | 2,777 (1.4) | 4,333 (2.4) |
| Unknown/missing | 165,652 (77.0) | 143,292 (70.1) | 115,746 (63.4) |
| Smoking status | |||
| Nonsmoker | 67,070 (31.2) | 95,447 (46.7) | 82,725 (45.3) |
| Former smoker | 33,974 (15.8) | 53,781 (26.3) | 48,984 (26.8) |
| Light smoker (<10 cigarettes/day) | 3,941 (1.8) | 5,384 (2.6) | 4,847 (2.7) |
| Moderate smoker (10–19 cigarettes/day) | 6,057 (2.8) | 8,297 (4.1) | 7,770 (4.3) |
| Heavy smoker (≥20 cigarettes/day) | 6,111 (2.8) | 7,691 (3.8) | 5,634 (3.1) |
| Unknown/missing | 97,877 (45.5) | 33,769 (16.5) | 32,655 (17.9) |
| Systolic blood pressure (mm Hg) | |||
| Mean ± SD | 165.2 ± 21.5 | 161.2 ± 20.2 | 159.2 ± 19.8 |
| Missing | 30,722 (14.3) | 20,623 (10.1) | 21,338 (11.7) |
| Diastolic blood pressure (mm Hg) | |||
| Mean ± SD | 94.5 ± 12.2 | 93.5 ± 12.2 | 93.1 ± 12.3 |
| Missing | 30,722 (14.3) | 20,623 (10.1) | 21,338 (11.7) |
| QRISK3 10-year CVD score | |||
| Mean ± SD | 19.5 ± 14.1 | 19.0 ± 13.7 | 20.0 ± 14.0 |
| Low risk (<10%) | 65,344 (30.4) | 62,600 (30.6) | 50,308 (27.5) |
| Intermediate risk (10%–19.9%) | 64,230 (29.9) | 63,974 (31.3) | 56,728 (31.1) |
| High risk (≥20%) | 85,456 (39.7) | 77,795 (38.1) | 75,579 (41.4) |
| BMI (kg/m2) | |||
| Mean ± SD | 29.5 ± 6.0 | 30.1 ± 6.4 | 30.7 ± 6.6 |
| <18.5 kg/m2 | 807 (0.4) | 951 (0.5) | 843 (0.5) |
| 18.5–24.9 kg/m2 | 18,437 (8.6) | 20,044 (9.8) | 15,446 (8.5) |
| 25.0–29.9 kg/m2 | 32,986 (15.3) | 37,637 (18.4) | 31,066 (17.0) |
| 30.0–39.9 kg/m2 | 29,911 (13.9) | 39,032 (19.1) | 37,001 (20.3) |
| ≥40 kg/m2 | 5,008 (2.3) | 7,413 (3.6) | 8,106 (4.4) |
| Missing | 127,881 (59.5) | 99,292 (48.6) | 90,153 (49.4) |
| Family history of CVD | 28 (0.0) | 323 (0.2) | 1,334 (0.7) |
| Comorbidities | |||
| Atrial fibrillation | 5,125 (2.4) | 5,595 (2.7) | 5,453 (3.0) |
| Chronic kidney disease | 498 (0.2) | 9,171 (4.5) | 8,185 (4.5) |
| Type 2 diabetes mellitus | 23,208 (10.8) | 25,287 (12.4) | 54,745 (30.0) |
| Drug use | |||
| Number of antihypertensive agents | 1.1 ± 0.3 | 1.0 ± 0.2 | 1.0 ± 0.2 |
| Acetylsalicylic acid | 15,048 (7.0) | 17,501 (8.6) | 13,159 (7.2) |
| Anticoagulants (oral) | 3,418 (1.6) | 3,950 (1.9) | 4,184 (2.3) |
| Antidiabetic drugs | 11,879 (5.5) | 11,595 (5.7) | 12,562 (6.9) |
| Antihyperlipidemic drugs | 14,920 (6.9) | 29,580 (14.5) | 33,183 (18.2) |
| Statin | 14,211 (6.6) | 28,981 (14.2) | 32,700 (17.9) |
Abbreviations: BMI, body mass index; CVD, cardiovascular disease.
aData are presented as n (%) or mean ± SD.
Figure 1 describes overall prescription patterns for antihypertensive drugs. ACE inhibitors (29.0%) were the most frequently prescribed first-line therapy, followed by thiazide diuretics (22.1%), and CCBs (21.0%). The mean duration of prescriptions written to patients who initiated central-acting agents (193 days) or loop diuretics (222 days) was shorter than those initiated ACE inhibitors (800 days) or thiazide diuretics (540 days) (Table 3).
Figure 1.
Distribution of first-line therapy prescribed in a population-based cohort of patients with hypertension. Only treatments that were prescribed to >1% of population are included. Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
Table 3.
Distribution of first-line therapy prescribed in a population-based cohort of patients with hypertension
| Treatment | Patients | Duration of prescription |
|---|---|---|
| (N = 660,545) (%) | (Mean ± SD) [days] | |
| ACE inhibitors | 191,816 (29.0%) | 800.3 ± 1,082.2 |
| Thiazide diuretics | 145,968 (22.1%) | 540.0 ± 928.0 |
| CCBs | 138,703 (21.0%) | 616.6 ± 924.0 |
| Beta-blockers | 87,211 (13.2%) | 581.4 ± 966.9 |
| Loop diuretics | 36,579 (5.5%) | 222.2 ± 510.8 |
| ARBs | 16,779 (2.5%) | 920.5 ± 1,216.3 |
| Central-acting agents | 12,054 (1.8%) | 192.8 ± 453.3 |
| Beta-blockers + thiazide diuretics | 3,976 (0.6%) | 829.4 ± 1,140.2 |
| Alpha-blockers | 3,673 (0.6%) | 458.7 ± 766.2 |
| Loop diuretics + potassium diuretics | 2,681 (0.4%) | 523.4 ± 779.0 |
| ACE inhibitors + thiazide diuretics | 2,671 (0.4%) | 863.1 ± 1,192.8 |
| ACE inhibitors + beta-blockers | 2,556 (0.4%) | 853.4 ± 1,124.0 |
| ACE inhibitors + CCBs | 2,306 (0.3%) | 768.5 ± 1,025.3 |
| Potassium diuretics | 1,951 (0.3%) | 325.1 ± 601.5 |
| CCBs + thiazide diuretics | 1,739 (0.3%) | 777.8 ± 1,150.1 |
| ACE inhibitors + loop diuretics | 1,302 (0.2%) | 574.2 ± 841.7 |
| ARBs + thiazide diuretics | 1,135 (0.2%) | 961.1 ± 1,238.0 |
| Beta-blockers + CCBs | 1,122 (0.2%) | 736.3 ± 1,112.9 |
| Potassium diuretics + thiazide diuretics | 1,093 (0.2%) | 694.7 ± 1,044.2 |
| Others | 5,230 (0.8%) | 695.0 ± 966.5 |
Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
Prescription patterns varied by calendar year of initiation (Figure 2). The prescription of ACE inhibitors and CCBs as first-line therapies has increased since 2001–2005, whereas the prescription of thiazide diuretics and beta-blockers decreased. Thiazide diuretics (37.7%) and beta-blockers (20.0%) were the 2 most frequently prescribed first-line therapies from 2001 to 2005, which have been ACE inhibitors (39.6%) and CCBs (22.9%) since 2006 (Table 4). As second-line therapies, the use of combination therapy changed with calendar year of initiation (Supplementary Figure S5 online): 10.3% of patients received a combination of a beta-blocker and a thiazide diuretic in 2001–2005, a combination that was rarely prescribed thereafter (<1%).
Figure 2.
Distribution of first-line therapy prescribed in a population-based cohort of patients with hypertension by the year of initiation (2001–2005, 2006–2010, 2011+). Only treatments that were prescribed to >1% of population are included. Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
Table 4.
Distribution of first-line therapy prescribed in a population-based cohort of patients with hypertension by calendar year of initiation
| Treatment | 2001–2005 | 2006–2010 | 2011+ |
|---|---|---|---|
| (N = 215,030) | (N = 204,369) | (N = 182,615) | |
| ACE inhibitors | 35,478 (16.5%) | 80,855 (39.6%) | 69,395 (38.0%) |
| Thiazide diuretics | 80,983 (37.7%) | 32,049 (15.7%) | 9,488 (5.2%) |
| CCBs | 20,285 (9.4%) | 46,856 (22.9%) | 66,086 (36.2%) |
| Beta-blockers | 42,943 (20.0%) | 16,371 (8.0%) | 14,395 (7.9%) |
| Loop diuretics | 11,331 (5.3%) | 11,151 (5.5%) | 10,164 (5.6%) |
| ARBs | 6,612 (3.1%) | 5,568 (2.7%) | 3,797 (2.1%) |
| Central-acting agents | 3,908 (1.8%) | 3,998 (2.0%) | 3,335 (1.8%) |
| Beta-blockers + thiazide diuretics | 2,730 (1.3%) | 279 (0.1%) | 77 (0.0%) |
| Alpha-blockers | 1,738 (0.8%) | 725 (0.4%) | 409 (0.2%) |
| Loop diuretics + potassium diuretics | 1,222 (0.6%) | 564 (0.3%) | 213 (0.1%) |
| ACE inhibitors + thiazide diuretics | 1,298 (0.6%) | 752 (0.4%) | 366 (0.2%) |
| ACE inhibitors + beta-blockers | 667 (0.3%) | 912 (0.4%) | 887 (0.5%) |
| ACE inhibitors + CCBs | 449 (0.2%) | 793 (0.4%) | 985 (0.5%) |
| Potassium diuretics | 593 (0.3%) | 594 (0.3%) | 599 (0.3%) |
| CCBs + thiazide diuretics | 764 (0.4%) | 492 (0.2%) | 269 (0.1%) |
| ACE inhibitors + loop diuretics | 566 (0.3%) | 354 (0.2%) | 191 (0.1%) |
| ARBs + thiazide diuretics | 579 (0.3%) | 351 (0.2%) | 165 (0.1%) |
| Beta-blockers + CCBs | 430 (0.2%) | 245 (0.1%) | 293 (0.2%) |
| Potassium diuretics + thiazide diuretics | 501 (0.2%) | 112 (0.1%) | 33 (0.0%) |
| Others | 1,953 (0.9%) | 1,348 (0.7%) | 1,468 (0.8%) |
Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
Data are presented as number of patients (%).
Among patients who initiated treatments since 2011, prescription patterns varied with sex, and age at initiation (Figure 3a,b). Men were less likely to be prescribed loop (3.6% vs. 7.7%; difference: 4.1%; 95% confidence interval [CI]: 3.9%–4.4%) or thiazide diuretics (3.5% vs. 7.0%; difference: 3.5%; 95% CI: 3.3%–3.7%) as first-line therapy than women but were more likely to be prescribed ACE inhibitors (43.5% vs. 32.1%; difference: 11.4%; 95% CI: 11.0%–11.8%). The prescription of ACE inhibitors decreased, while the prescription of thiazide diuretics and CCBs increased across increasing age categories. The prescription of loop diuretics was higher among patients aged 70+ years than among younger patients. Race (Supplementary Figure S7 online) and estimated CVD risk level (Supplementary Figure S8 online) also impacted patterns. Compared with White patients, Black patients were more likely to be prescribed CCBs (63.6% vs. 37.0%; difference: 26.6%; 95% CI, 24.8%–28.4%). More diverse prescription patterns were observed among Black than among White patients. Compared with patients at low CVD risk, high-risk patients were less likely to receive prescriptions of ACE inhibitors but more likely to receive prescriptions of CCBs or loop diuretics as first-line therapy.
Figure 3.
Distribution of first-line therapy prescribed in a population-based cohort of patients with hypertension since 2011: (a) by sex and (b) by age at initiation. Only treatments that were prescribed to >1% of population are included. Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
The top 3 second-line therapies among patients who initiated treatments since 2011 (Figure 4) were ACE inhibitor and CCB (12.1%), ACE inhibitors (4.5%), ARBs (4.4%), other than patients who did not receive second-line therapy (49.0%), and those who had a gap of >6 months after the first-line therapy (10.0%).
Figure 4.
Distribution of second-line therapy prescribed in a population-based cohort of patients with hypertension since 2011. Only treatments that were prescribed to >1% of population are included. Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; CCBs, calcium-channel blockers; Thiazide diuretics, thiazide and thiazide-like diuretics.
DISCUSSION
In the United Kingdom, over the past 20 years, ACE inhibitors were the most commonly prescribed first-line therapy. Over time, there was an increase on the prescription of ACE inhibitors and CCBs and a decrease in the prescription of thiazide diuretics and beta-blockers, as well as fewer prescriptions for combination therapies. Among patients who initiated treatment in 2011 onward, observed prescription patterns varied with patient characteristics: decreased prescription of ACE inhibitors and increased prescription of CCBs as first-line therapy with increasing age; less frequent prescription of ACE inhibitors among women than men; and greater prescription of CCBs among Black patients than other race/ethnicities. These patterns are consistent with UK treatment guidelines that were in place during the study period.
Treatment patterns of antihypertensive drugs are well investigated in specific subgroups, such as elderly Medicare beneficiaries3,4 and patients who were treated in a healthcare delivery system.5 However, most studies did not follow patients at low CVD risk longitudinally or consider the impact of time. Nonetheless, we compared the prescription patterns observed in the subgroup of patients to previous studies: high-risk patients in the United States were more frequently prescribed ACE inhibitors and combination therapy and less frequently prescribed CCBs as first-line therapy than high-risk patients in the United Kingdom. One study19 investigated longitudinal treatment patterns including patients at low CVD risk from 4 countries. While this study had several strengths, it had important limitations: baseline characteristics were not described, preventing the assessment of clinically important subgroups, and given the differences across jurisdictions in drug availability, formulary restrictions, and treatment guidelines, an overall pooled treatment pattern may be difficult to interpret.
Treatment patterns reflect recommendations made in the 1999,17 2006,8 201118 UK treatment guidelines. In 1999, the BHS guidelines17 recommended low-dose thiazide diuretics as first-line therapy for patients with hypertension. Given the strong treatment effects of ACE inhibitors20 and the protective effects of CCBs on myocardial infarction,21 heart failure,22 and renal function,23 these 2 classes were added to the recommended first-line therapies in 2006.8 As expected, these treatment classes had similar prevalences of use during the study period. Regarding second-line therapy, these commonly observed therapies were combinations; all of which were recommended by UK guidelines at 1 point during the study period. More patients were prescribed ACE inhibitors than ARBs, which may be related to a UK policy24 that favors the use of ACE inhibitors over ARBs because of their lower costs.25
The variations in patterns by calendar year of initiation are consistent with the evidence from randomized controlled trials26–29 and related treatment guidelines8,17,30 during this period. First, the aforementioned changes of first-line therapy recommendations in guidelines led to the increase of the prescription of ACE inhibitors and CCBs since 2006. Furthermore, the reduction in the number of frequently prescribed second-line therapies mirrored changes in guidelines: between the 1999 and 2006 guidelines,8,17 the number of recommended second-line therapies decreased. The combination of thiazide diuretic and beta-blocker was rarely prescribed after 2006, when the guidelines8 stopped recommending it given concerns regarding an increased risk of type 2 diabetes mellitus.30,31
Prescription patterns varied with other patient characteristics. These observed differences are aligned with evidence in randomized controlled trials and recommendations in guidelines: (i) Black patients were more likely to receive prescriptions of CCBs, since they respond to them better than to other antihypertensive drugs32,33; (ii) women were less likely to receive prescription of ACE inhibitors, possibly due to safety concerns, including urinary tract infections34 and dry, persistent coughs,35 side effects that are more commonly reported among women; (iii) the prescription of ACE inhibitors as first-line therapy decreased with increasing age at the expense of prescription of CCBs, reflecting recommendations for ACE inhibitors and CCBs in patients aged ≤55 and >55 years, respectively.
Further research is needed to describe treatment patterns in more diverse populations. While the present study examined use in the United Kingdom, the generalizability of our results to other jurisdictions is unclear. Future studies should describe treatment patterns in other jurisdictions that affected by different treatment guidelines and other local conditions. There remains a need to examine patterns in more diverse populations that include a greater proportion of Black and Hispanic individuals as the use and effectiveness of some antihypertensive drugs appear to differ by race/ethnicity due to variations in genetics and lifestyle. Furthermore, the impact of specific policies on these population should be further investigated: surprisingly, a real-world study indicated changes in treatment guidelines did not affect the use of antihypertensive drugs among Black patients.36
Our study has several strengths. It used a well-validated, population-based data to describe prescription patterns for hypertension in a real-world setting. With its large sample size and the representative nature, the results are highly generalizable to everyday clinical practice in the United Kingdom. We were able to examine clinically relevant subgroups and 11 classes of antihypertensive drugs. Finally, given the longitudinal nature of the data recorded in the CPRD (including prescriptions written by general practitioners), the use of this data source allowed us to describe prescribing across different lines of therapy, representing a key addition to the literature.
It has some limitations. First, to estimate CVD risk, we assumed that patients with missing race/ethnicity were White. According to the 2011 UK Census,37 >80% of the population was White. Moreover, a study38 that linked CPRD to another database with comprehensive information on ethnicity showed that missing ethnicity is more likely to be White. Therefore, we believe our assumption is reasonable. Second, sample size was large overall, the size of some subgroups was modest, and some prescription patterns were estimated on a relatively small number of patients. Third, we measured baseline comorbidities that occurred before the cohort entry date. With patients having different durations of observation in the CPRD prior to cohort entry, information bias is possible. We used this approach because, unlike administrative claims databases from North America, chronic conditions tend to only be recorded in the CPRD at initial diagnosis and at visits specific to that condition (as opposed to all visits). Consequently, the use of a shorter, fixed look-back could result in an important underestimation of the prevalence of comorbidities. Last, this study is observational, comparisons across subgroups may be affected by confounding and should not be interpreted as causal effects. For example, the observed difference in prescription patterns by CVD risk level maybe explained in part due to differences in age across groups.
In summary, this study described longitudinal antihypertensive prescription patterns for the primary prevention of CVD among patients with hypertension in the United Kingdom. These prescription patterns are consistent with treatment guidelines that were in place during the study period. These findings provide important reassurance that physicians were following available hypertension treatment guidelines and suggest that they adapted their prescribing practices as guidelines were updated.
FUNDING
This project is funded by Canadian Institutes of Health Research (CIHR; grant number CIHR-425772).
DISCLOSURE
Drs Douros, Platt, and Filion report grants from the CIHR, outside of the submitted work. Dr Douros is supported by a salary support award from the Fonds de recherche du Québec—santé (FRQS; Quebec Foundation for Research—Health). Dr Platt holds the Albert Boehringer I Chair in Pharmacoepidemiology and has received personal fees from Amgen, Analysis Group, Merck, and Pfizer, all outside of the submitted work. Dr Filion is supported by a salary support award from the FRQS and holds a William Dawson Scholar award from McGill University. Dr Jiao is an employee of CHEORS; this work was completed during his postdoctoral training at McGill University.
Supplementary Material
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