Original Article
Factors involved in the discontinuation of antihypertensive drug therapy: an analysis from real life data Giuseppe Mancia a,b,c, Antonella Zambon d, Davide Soranna d, Luca Merlino e, and Giovanni Corrao d
Objectives: We have previously shown that in Italian region of Lombardy (about 10 million citizens), adherence to antihypertensive treatment is low, and that this is associated with a greater risk of hospitalization for cardiovascular events. In this study, we used a healthcare database to study the factors involved in discontinuation of antihypertensive drug prescriptions in real life. Methods and results: The analysis was restricted to 493 623 new users of antihypertensive drugs (no prescriptions in the previous 3 years) recruited in 2003, 2006 and 2009. Discontinuation was defined as lack of prescription renewal for at least 3 months. Each patient was followed at most for 1 year. The adjusted risk of treatment discontinuation depended on the type of initial antihypertensive treatment (diuretic monotherapy associated with higher risk) and it was lower in men (17%) and older (21 to 29%) patients, in patients with co-treatment with antidiabetic drugs, or hospitalization for cardiovascular or renal disease (12 to 27%), but greater in patients under co-treatment with antidepressant drugs or hospitalization for concomitant pulmonary, rheumatic, neoplastic or neurological diseases (R9 to R32%). An unexpected relationship between discontinuation of treatment and density of the population of patient’s residence, with a much greater discontinuation in metropolitan areas, was observed. Conclusions: In a real life setting, discontinuation of antihypertensive treatment is affected in an opposite direction by a large number of factors: type of antihypertensive treatment, co-treatments, clinical conditions and even demographic characteristics of the geographical area where the patient lives. Knowledge of these factors may help the effort to reduce this phenomenon. Keywords: antihypertensive drugs, databases, discontinuation, persistence Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; ICD9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification
INTRODUCTION
W
e have previously shown that in the population of Lombardy, a region with more than 10 million residents located in Northern Italy, adherence to antihypertensive drug treatment is extremely low [1–3]. The data were derived from the regional healthcare utilization database, which provides pharmacy-dispensing information. This includes the dates and types (drugs, dosages and number of pills) of outpatient medical prescriptions, which allows to calculate drug coverage from treatment initiation throughout the follow-up, and thus to detect prescription discontinuation. We were also able to link these data with the first ever admission to the regional public and private hospitals, which showed that treatment discontinuation and low prescription coverage over time were closely associated with the incidence of coronary and cerebrovascular events [4,5]. The Regional Health Utilization databases of the Lombardy region [6] provide data that are relevant to another important question, that is the relationship between discontinuation of antihypertensive treatment of any type and patients’ demographic, environmental, clinical and therapeutic characteristics, thereby allowing to investigate the role played by a variety of factors in favouring or opposing persistence to treatment in a real life setting and with the whole citizenship as the target population.
METHODS Setting and study cohort In Italy, healthcare is provided by the National Health Service. As reported in detail previously [1,2,6], an Journal of Hypertension 2014, 32:1708–1716 a IRCCS Istituto Auxologico Italiano, Milan, bCentro Interuniversitario di Fisiologia Clinica e Ipertensione, cUniversity of Milano-Bicocca, dDepartment of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca and eOperative Unit of Territorial Health Services, Region Lombardia, Milan, Italy
Correspondence to Professor Antonella Zambon, Dipartimento di Statistica e Metodi Quantitativi, Sezione di Biostatistica, Epidemiologia e Sanita` Pubblica, Universita` degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi, 8, Edificio U7, 20126 Milan, Italy. Tel: +39 02 64485814; fax: +39 02 64485899; e-mail: antonella.zambon@ unimib.it Received 10 January 2014 Revised 26 March 2014 Accepted 26 March 2014 J Hypertens 32:1708–1716 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000222
1708
www.jhypertension.com
Volume 32 Number 8 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antihypertensive drug discontinuation determinants
automated system of databases was established in the Lombardy region since 1997, aimed at collecting information on the use of health services by the population. The available information includes demographic and administrative data, and outpatient prescriptions of drugs for which pharmacists are refunded by the National Health Service (and therefore free of charge to patients) such as antihypertensive, antidiabetic and lipid-lowering drugs. They also include diagnostic data (main and secondary diagnoses) at the time of discharge from public or private hospitals classified according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) For each patient, the different sets of data can be linked together by a single identification code. To preserve privacy, each identification code is automatically converted into an anonymous code, the inverse process being prevented by deletion of the conversion table. In the present study, the target population was represented by all National Health Service beneficiaries who were aged between 40 and 80 years and had their residence in Lombardy. From these, patients who received one or more antihypertensive drug prescriptions in 2003 were identified and the date of first prescription (index prescription) was considered as the index date. A similar approach was used to recruit patients who received at least one or more antihypertensive drug prescriptions in 2006 and in 2009. In each cohort, we included only patients who had not received antihypertensive drug prescriptions in the 3 years preceding the index date to limit the analysis to newly treated hypertensive individuals [7]. Long-term drug users were excluded because variations of risk discontinuation over time make confounders different from those of new users and results are difficult to be interpreted [7,8]. Patients older than 80 and with less than 40 years were excluded because in the years from 2003 to 2009, the hypertension guidelines did not recommend drug treatment in very elderly hypertensive individuals [9]; and hypertension is much rarer at a young age with a more common involvement of secondary causes as well [10]. Patients accepted as the final cohorts accumulated person-years of follow-up from the index date until the earliest among the dates of discontinuation of antihypertensive drug treatment or censoring, that is death, emigration, or 1 year after the index prescription because most discontinuations of antihypertensive drugs occur within 1 year after initiation of drug treatment [1,2,5].
Assessing treatment discontinuation We identified prescriptions of antihypertensive drugs dispensed to the cohort members at treatment start and during follow-up. The duration of each prescription was calculated by dividing the total amount of the drug prescribed by the defined daily dose. Starting from the index date, treatment was considered uninterrupted or persistent if, regardless of the drug prescribed, the time span between the end of one prescription and the beginning of the following one was 90 days or shorter. If the between-prescription time span was longer than 90 days, treatment discontinuation was assumed, discontinuation thus being the absence of any prescription of antihypertensive drugs over the selected time. The date at which the last coverage of prescription Journal of Hypertension
expired was considered as the date of treatment discontinuation.
Covariates At the index date, the following data were collected: sex; age; the initially prescribed antihypertensive drug category [diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, calcium antagonists, beta-blockers or alpha-blockers] in monotherapy; the diuretic category included thiazides, chlorthalidone and indapamide, but also loop diuretics and mineralocorticoid antagonists, because the preferential use of these two agents in a condition in which hypertension is a common precursor such as heart failure [11] often serves also the purpose of achieving a blood pressure (BP)-lowering effect; the initially prescribed combinations (extemporaneous or fixed dose)of two or more antihypertensive drugs; pharmacy-dispensing prescriptions free of charge of lowering, antidiabetic and antidepressant drugs in the 3-year interval prior to the index date; hospital admission with a main or secondary diagnosis of cardiovascular (coronary, cerebrovascular and heart failure), renal, pulmonary, rheumatic, neoplastic diseases and dementia in the 3-year interval prior the index date; density of the population in the municipality of each cohorts member (National Institute of Statistics: http://www.istat.it/it/popolazione); and calendar year of cohort recruitment.
Data analysis Except when addressing trends of discontinuation over time and space (see below), data from the three cohorts (2003, 2006 and 2009 years) were pooled. The chi-square or t-test was used, when appropriate, to assess differences in demographic, clinical and therapeutic characteristics between patients discontinuing or not discontinuing treatment. Multivariate Cox proportional-hazard regression model was used to estimate the hazard ratios [and their 95% confidence interval (CI)] adjusted for all other covariates. Two regressions based on different classification of the type of initial antihypertensive drug treatment were fitted. Model 1 considered the effect of each starting monotherapy with respect to diuretic monotherapy, whereas model 2 considered the effect of combination treatment with a diuretic (extemporaneous or fixed dose) or without a diuretic, respectively, taking diuretic and non-diuretic (all drugs other than a diuretic together) as reference. Combinations without a diuretic could not be included because at the time of the study this condition was not refunded by the National Health Service. The Wald test was applied in the second model to evaluate the equality of hazard ratios. Because blockers of the rennin–angiotensin system are frequently given to patients with renal disease, cardiovascular disease or diabetes, models 1 and 2 were used also to analyse patients without these comorbidities at baseline. For the patients included in the 2009 cohort, we estimated the proportion of discontinuers in each of the 1544 regional municipalities. These proportions were standardized for sex and 10-year intervals of age. The standardized proportions of treatment discontinuers were smoothed for the values of the eight nearest municipalities by the Kernel approach [12]. The Kernel estimates were visualized on a www.jhypertension.com
1709
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mancia et al.
regional map as quintile categories of discontinuation proportions. The SAS statistical package was used for the analyses (SAS, Version 9.3; SAS Institute, Cary, North Carolina, USA). The map was built by Arcmap (version 9.3). For all hypotheses, tested two-tailed P-values less than 0.05 were considered to be significant.
RESULTS
Patients receiving an antihypertensive drug prescription in 2003, 2006 or 2009 n = 4 840 057
Incident users n = 493 623
Exclusion
As shown in Fig. 1, data were initially obtained from the 48 40 057 patients who in 2003, 2006 or 2009 received at least one antihypertensive drug prescription. Of these, 43 46 434 individuals were excluded because they had already received an antihypertensive drug prescription within the 3-year period before the index date. Thus, 493 623 patients represented the study cohort. Table 1 shows the number of patients with different initial drug treatments, the co-treatment rates and the percentage of previous hospitalizations in the entire study population as well as in treatment continuers and discontinuers. At the index date, mean age of the cohort was 59 years, with a male prevalence of 48%. In the population as a whole, treatment started with monotherapy in 69% of the patients and with combination therapy with two or more drugs in the remaining 31% (22% on fixed-dose and 9% on extemporaneous drug combinations). The most common initial monotherapy was that with an ACE inhibitor (26%), followed by beta-blockers (14%), angiotensin receptor antagonists (11%), calcium antagonists (11%), diuretics (5%) and alpha blockers (2%): Co-treatment with antidiabetic, lipid-lowering and antidepressant drugs involved 7, 12 and 11% of the patients, respectively. On the basis of hospitalizations over the previous 3 years, cardiovascular disease was the most common concomitant disease (14%), whereas neoplastic, pulmonary, renal and other diseases involved much smaller fractions of the population. Among the 493 623 cohort members, 282 117 (57%) showed at least one episode of discontinuation within the year after starting drug therapy. As shown in Fig. 2, taking diuretic monotherapy as comparison, the adjusted hazard ratio of discontinuation showed a minimal value in patients starting treatment with angiotensin receptor antagonist monotherapy (hazard ratio 0.30), followed by ACE inhibitor (0.35), and, at a considerable distance, calcium antagonist (0.52), beta-blocker (0.54) and alpha-blocker (0.69) monotherapies. For calcium antagonists, the risk of discontinuation was less for the dihydropiridine than for the non-dihydropiridine class (0.47 and 0.85, respectively). As shown in Fig. 3, compared with diuretic monotherapy, the risk of discontinuation was less for extemporaneous (0.29), and fixed-dose
Patients with an antihypertensive drug prescription in the previous three years n = 4 346 434
FIGURE 1 Flow chart showing the initial target population, the number of patients removed because of the exclusion criteria and the final number on which analysis of the data was performed.
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(0.61) combinations with a diuretic. The risk was also less for extemporaneous combinations without a diuretic vs. non-diuretic monotherapy (0.69). Similar results were obtained when the analyses were performed in patients without renal disease, cardiovascular disease or diabetes at baseline (Supplemental Figure S1, http://links.lww.com/ HJH/A358). The effects of demographic factors, co-treatments and concomitant diseases on treatment discontinuation (model 1 analysis, see Methods section) are shown in Fig. 4. The risk of treatment discontinuation was less in men than in women (17%), in patients in whom antihypertensive drugs were prescribed with antidiabetic agents (–12%) and in patients with cardiovascular (–27%) or renal (– 22%) disease at baseline. Moreover, the risk decreased progressively with the increasing age of the patients, being 21–29% less in older age categories than in the 40–49-yearold one. In contrast, the risk was greater when co-treatment consisted of antidepressant agents (þ19%) as well as when there were concomitant non-cardiovascular or renal diseases, with a maximum increase in the case of dementia (þ32%). Figures 5 and 6 show the risk of treatment discontinuation according to the density of the population within the Lombardy region. The smoothed standardized proportions of patients discontinuing treatment were markedly heterogeneous across the regional municipalities, the highest values usually coinciding with the metropolitan areas (i.e. the capitals of the different provinces in which the region is divided) (Fig. 5). In line with the above observation, the risk of treatment discontinuation adjusted for all the considered covariates, increased progressively as the population density increased (Fig. 6). Among treatment discontinuers, 45% started the antihypertensive treatment in 2003, 28% in 2006 and the remaining patients in 2009. With respect to the 2003 cohort, the adjusted risk of treatment discontinuation was about 30% less in the 2006 cohort and showed a further small reduction in the 2009 cohort (Fig. 7).
DISCUSSION Our study confirms that in a real life setting, discontinuation of antihypertensive drug treatment is related to the drug class [1,13–20] that is prescribed, namely that discontinuation is maximal for diuretics, less for calcium antagonists, beta-blockers and alpha-blockers, and minimal for ACE inhibitors and even more for angiotensin receptor antagonists, for which the risk of discontinuing treatment is about three times less than for diuretics. It further confirms that discontinuation is lower in patients starting treatment with a combination of drugs, rather than with monotherapy, this being the case both when the combination includes a diuretic, the comparison being with diuretic monotherapy and does not include a diuretic, the comparison being monotherapy without a diuretic [2]. Thus, physicians have a large number of options from which to select a treatment strategy that is less likely to be later abandoned. This has important clinical implications because adherence to a treatment regimen with documented protective effects markedly affects clinical Volume 32 Number 8 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antihypertensive drug discontinuation determinants TABLE 1. Demographic, clinical and therapeutic characteristics of the entire cohort and according to patients’ persistence with antihypertensive drug therapy during the one-year follow-up at the date of index prescription
No. of patients Age (years) [mean (SD)] Male prevalence (%) Starting antihypertensive drug therapy (%) Monotherapy on diuretics ACEIs ARBs CAs b-blockers a-blockers Combination therapy (fixed-dose with D) Combination therapy (extemporaneous with diuretics) Combination therapy (extemporaneous no diuretics) Co-treatments (%) Antidiabetic drugs Lipid lowering agents Antidepressants Concomitant diseases (%) Cardiovascular Renal Pulmonary Rheumatic Neoplastic Dementia
Entire cohort
Continuers
Discontinuers
P-value
493 623 59 (11) 48
211 506 60 (10) 54
282 117 58 (11) 45
Factors involved in the discontinuation of antihypertensive drug therapy: an analysis from real life data Giuseppe Mancia a,b,c, Antonella Zambon d, Davide Soranna d, Luca Merlino e, and Giovanni Corrao d
Objectives: We have previously shown that in Italian region of Lombardy (about 10 million citizens), adherence to antihypertensive treatment is low, and that this is associated with a greater risk of hospitalization for cardiovascular events. In this study, we used a healthcare database to study the factors involved in discontinuation of antihypertensive drug prescriptions in real life. Methods and results: The analysis was restricted to 493 623 new users of antihypertensive drugs (no prescriptions in the previous 3 years) recruited in 2003, 2006 and 2009. Discontinuation was defined as lack of prescription renewal for at least 3 months. Each patient was followed at most for 1 year. The adjusted risk of treatment discontinuation depended on the type of initial antihypertensive treatment (diuretic monotherapy associated with higher risk) and it was lower in men (17%) and older (21 to 29%) patients, in patients with co-treatment with antidiabetic drugs, or hospitalization for cardiovascular or renal disease (12 to 27%), but greater in patients under co-treatment with antidepressant drugs or hospitalization for concomitant pulmonary, rheumatic, neoplastic or neurological diseases (R9 to R32%). An unexpected relationship between discontinuation of treatment and density of the population of patient’s residence, with a much greater discontinuation in metropolitan areas, was observed. Conclusions: In a real life setting, discontinuation of antihypertensive treatment is affected in an opposite direction by a large number of factors: type of antihypertensive treatment, co-treatments, clinical conditions and even demographic characteristics of the geographical area where the patient lives. Knowledge of these factors may help the effort to reduce this phenomenon. Keywords: antihypertensive drugs, databases, discontinuation, persistence Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CI, confidence interval; ICD9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification
INTRODUCTION
W
e have previously shown that in the population of Lombardy, a region with more than 10 million residents located in Northern Italy, adherence to antihypertensive drug treatment is extremely low [1–3]. The data were derived from the regional healthcare utilization database, which provides pharmacy-dispensing information. This includes the dates and types (drugs, dosages and number of pills) of outpatient medical prescriptions, which allows to calculate drug coverage from treatment initiation throughout the follow-up, and thus to detect prescription discontinuation. We were also able to link these data with the first ever admission to the regional public and private hospitals, which showed that treatment discontinuation and low prescription coverage over time were closely associated with the incidence of coronary and cerebrovascular events [4,5]. The Regional Health Utilization databases of the Lombardy region [6] provide data that are relevant to another important question, that is the relationship between discontinuation of antihypertensive treatment of any type and patients’ demographic, environmental, clinical and therapeutic characteristics, thereby allowing to investigate the role played by a variety of factors in favouring or opposing persistence to treatment in a real life setting and with the whole citizenship as the target population.
METHODS Setting and study cohort In Italy, healthcare is provided by the National Health Service. As reported in detail previously [1,2,6], an Journal of Hypertension 2014, 32:1708–1716 a IRCCS Istituto Auxologico Italiano, Milan, bCentro Interuniversitario di Fisiologia Clinica e Ipertensione, cUniversity of Milano-Bicocca, dDepartment of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca and eOperative Unit of Territorial Health Services, Region Lombardia, Milan, Italy
Correspondence to Professor Antonella Zambon, Dipartimento di Statistica e Metodi Quantitativi, Sezione di Biostatistica, Epidemiologia e Sanita` Pubblica, Universita` degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi, 8, Edificio U7, 20126 Milan, Italy. Tel: +39 02 64485814; fax: +39 02 64485899; e-mail: antonella.zambon@ unimib.it Received 10 January 2014 Revised 26 March 2014 Accepted 26 March 2014 J Hypertens 32:1708–1716 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000222
1708
www.jhypertension.com
Volume 32 Number 8 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antihypertensive drug discontinuation determinants
automated system of databases was established in the Lombardy region since 1997, aimed at collecting information on the use of health services by the population. The available information includes demographic and administrative data, and outpatient prescriptions of drugs for which pharmacists are refunded by the National Health Service (and therefore free of charge to patients) such as antihypertensive, antidiabetic and lipid-lowering drugs. They also include diagnostic data (main and secondary diagnoses) at the time of discharge from public or private hospitals classified according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) For each patient, the different sets of data can be linked together by a single identification code. To preserve privacy, each identification code is automatically converted into an anonymous code, the inverse process being prevented by deletion of the conversion table. In the present study, the target population was represented by all National Health Service beneficiaries who were aged between 40 and 80 years and had their residence in Lombardy. From these, patients who received one or more antihypertensive drug prescriptions in 2003 were identified and the date of first prescription (index prescription) was considered as the index date. A similar approach was used to recruit patients who received at least one or more antihypertensive drug prescriptions in 2006 and in 2009. In each cohort, we included only patients who had not received antihypertensive drug prescriptions in the 3 years preceding the index date to limit the analysis to newly treated hypertensive individuals [7]. Long-term drug users were excluded because variations of risk discontinuation over time make confounders different from those of new users and results are difficult to be interpreted [7,8]. Patients older than 80 and with less than 40 years were excluded because in the years from 2003 to 2009, the hypertension guidelines did not recommend drug treatment in very elderly hypertensive individuals [9]; and hypertension is much rarer at a young age with a more common involvement of secondary causes as well [10]. Patients accepted as the final cohorts accumulated person-years of follow-up from the index date until the earliest among the dates of discontinuation of antihypertensive drug treatment or censoring, that is death, emigration, or 1 year after the index prescription because most discontinuations of antihypertensive drugs occur within 1 year after initiation of drug treatment [1,2,5].
Assessing treatment discontinuation We identified prescriptions of antihypertensive drugs dispensed to the cohort members at treatment start and during follow-up. The duration of each prescription was calculated by dividing the total amount of the drug prescribed by the defined daily dose. Starting from the index date, treatment was considered uninterrupted or persistent if, regardless of the drug prescribed, the time span between the end of one prescription and the beginning of the following one was 90 days or shorter. If the between-prescription time span was longer than 90 days, treatment discontinuation was assumed, discontinuation thus being the absence of any prescription of antihypertensive drugs over the selected time. The date at which the last coverage of prescription Journal of Hypertension
expired was considered as the date of treatment discontinuation.
Covariates At the index date, the following data were collected: sex; age; the initially prescribed antihypertensive drug category [diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, calcium antagonists, beta-blockers or alpha-blockers] in monotherapy; the diuretic category included thiazides, chlorthalidone and indapamide, but also loop diuretics and mineralocorticoid antagonists, because the preferential use of these two agents in a condition in which hypertension is a common precursor such as heart failure [11] often serves also the purpose of achieving a blood pressure (BP)-lowering effect; the initially prescribed combinations (extemporaneous or fixed dose)of two or more antihypertensive drugs; pharmacy-dispensing prescriptions free of charge of lowering, antidiabetic and antidepressant drugs in the 3-year interval prior to the index date; hospital admission with a main or secondary diagnosis of cardiovascular (coronary, cerebrovascular and heart failure), renal, pulmonary, rheumatic, neoplastic diseases and dementia in the 3-year interval prior the index date; density of the population in the municipality of each cohorts member (National Institute of Statistics: http://www.istat.it/it/popolazione); and calendar year of cohort recruitment.
Data analysis Except when addressing trends of discontinuation over time and space (see below), data from the three cohorts (2003, 2006 and 2009 years) were pooled. The chi-square or t-test was used, when appropriate, to assess differences in demographic, clinical and therapeutic characteristics between patients discontinuing or not discontinuing treatment. Multivariate Cox proportional-hazard regression model was used to estimate the hazard ratios [and their 95% confidence interval (CI)] adjusted for all other covariates. Two regressions based on different classification of the type of initial antihypertensive drug treatment were fitted. Model 1 considered the effect of each starting monotherapy with respect to diuretic monotherapy, whereas model 2 considered the effect of combination treatment with a diuretic (extemporaneous or fixed dose) or without a diuretic, respectively, taking diuretic and non-diuretic (all drugs other than a diuretic together) as reference. Combinations without a diuretic could not be included because at the time of the study this condition was not refunded by the National Health Service. The Wald test was applied in the second model to evaluate the equality of hazard ratios. Because blockers of the rennin–angiotensin system are frequently given to patients with renal disease, cardiovascular disease or diabetes, models 1 and 2 were used also to analyse patients without these comorbidities at baseline. For the patients included in the 2009 cohort, we estimated the proportion of discontinuers in each of the 1544 regional municipalities. These proportions were standardized for sex and 10-year intervals of age. The standardized proportions of treatment discontinuers were smoothed for the values of the eight nearest municipalities by the Kernel approach [12]. The Kernel estimates were visualized on a www.jhypertension.com
1709
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mancia et al.
regional map as quintile categories of discontinuation proportions. The SAS statistical package was used for the analyses (SAS, Version 9.3; SAS Institute, Cary, North Carolina, USA). The map was built by Arcmap (version 9.3). For all hypotheses, tested two-tailed P-values less than 0.05 were considered to be significant.
RESULTS
Patients receiving an antihypertensive drug prescription in 2003, 2006 or 2009 n = 4 840 057
Incident users n = 493 623
Exclusion
As shown in Fig. 1, data were initially obtained from the 48 40 057 patients who in 2003, 2006 or 2009 received at least one antihypertensive drug prescription. Of these, 43 46 434 individuals were excluded because they had already received an antihypertensive drug prescription within the 3-year period before the index date. Thus, 493 623 patients represented the study cohort. Table 1 shows the number of patients with different initial drug treatments, the co-treatment rates and the percentage of previous hospitalizations in the entire study population as well as in treatment continuers and discontinuers. At the index date, mean age of the cohort was 59 years, with a male prevalence of 48%. In the population as a whole, treatment started with monotherapy in 69% of the patients and with combination therapy with two or more drugs in the remaining 31% (22% on fixed-dose and 9% on extemporaneous drug combinations). The most common initial monotherapy was that with an ACE inhibitor (26%), followed by beta-blockers (14%), angiotensin receptor antagonists (11%), calcium antagonists (11%), diuretics (5%) and alpha blockers (2%): Co-treatment with antidiabetic, lipid-lowering and antidepressant drugs involved 7, 12 and 11% of the patients, respectively. On the basis of hospitalizations over the previous 3 years, cardiovascular disease was the most common concomitant disease (14%), whereas neoplastic, pulmonary, renal and other diseases involved much smaller fractions of the population. Among the 493 623 cohort members, 282 117 (57%) showed at least one episode of discontinuation within the year after starting drug therapy. As shown in Fig. 2, taking diuretic monotherapy as comparison, the adjusted hazard ratio of discontinuation showed a minimal value in patients starting treatment with angiotensin receptor antagonist monotherapy (hazard ratio 0.30), followed by ACE inhibitor (0.35), and, at a considerable distance, calcium antagonist (0.52), beta-blocker (0.54) and alpha-blocker (0.69) monotherapies. For calcium antagonists, the risk of discontinuation was less for the dihydropiridine than for the non-dihydropiridine class (0.47 and 0.85, respectively). As shown in Fig. 3, compared with diuretic monotherapy, the risk of discontinuation was less for extemporaneous (0.29), and fixed-dose
Patients with an antihypertensive drug prescription in the previous three years n = 4 346 434
FIGURE 1 Flow chart showing the initial target population, the number of patients removed because of the exclusion criteria and the final number on which analysis of the data was performed.
1710
www.jhypertension.com
(0.61) combinations with a diuretic. The risk was also less for extemporaneous combinations without a diuretic vs. non-diuretic monotherapy (0.69). Similar results were obtained when the analyses were performed in patients without renal disease, cardiovascular disease or diabetes at baseline (Supplemental Figure S1, http://links.lww.com/ HJH/A358). The effects of demographic factors, co-treatments and concomitant diseases on treatment discontinuation (model 1 analysis, see Methods section) are shown in Fig. 4. The risk of treatment discontinuation was less in men than in women (17%), in patients in whom antihypertensive drugs were prescribed with antidiabetic agents (–12%) and in patients with cardiovascular (–27%) or renal (– 22%) disease at baseline. Moreover, the risk decreased progressively with the increasing age of the patients, being 21–29% less in older age categories than in the 40–49-yearold one. In contrast, the risk was greater when co-treatment consisted of antidepressant agents (þ19%) as well as when there were concomitant non-cardiovascular or renal diseases, with a maximum increase in the case of dementia (þ32%). Figures 5 and 6 show the risk of treatment discontinuation according to the density of the population within the Lombardy region. The smoothed standardized proportions of patients discontinuing treatment were markedly heterogeneous across the regional municipalities, the highest values usually coinciding with the metropolitan areas (i.e. the capitals of the different provinces in which the region is divided) (Fig. 5). In line with the above observation, the risk of treatment discontinuation adjusted for all the considered covariates, increased progressively as the population density increased (Fig. 6). Among treatment discontinuers, 45% started the antihypertensive treatment in 2003, 28% in 2006 and the remaining patients in 2009. With respect to the 2003 cohort, the adjusted risk of treatment discontinuation was about 30% less in the 2006 cohort and showed a further small reduction in the 2009 cohort (Fig. 7).
DISCUSSION Our study confirms that in a real life setting, discontinuation of antihypertensive drug treatment is related to the drug class [1,13–20] that is prescribed, namely that discontinuation is maximal for diuretics, less for calcium antagonists, beta-blockers and alpha-blockers, and minimal for ACE inhibitors and even more for angiotensin receptor antagonists, for which the risk of discontinuing treatment is about three times less than for diuretics. It further confirms that discontinuation is lower in patients starting treatment with a combination of drugs, rather than with monotherapy, this being the case both when the combination includes a diuretic, the comparison being with diuretic monotherapy and does not include a diuretic, the comparison being monotherapy without a diuretic [2]. Thus, physicians have a large number of options from which to select a treatment strategy that is less likely to be later abandoned. This has important clinical implications because adherence to a treatment regimen with documented protective effects markedly affects clinical Volume 32 Number 8 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Antihypertensive drug discontinuation determinants TABLE 1. Demographic, clinical and therapeutic characteristics of the entire cohort and according to patients’ persistence with antihypertensive drug therapy during the one-year follow-up at the date of index prescription
No. of patients Age (years) [mean (SD)] Male prevalence (%) Starting antihypertensive drug therapy (%) Monotherapy on diuretics ACEIs ARBs CAs b-blockers a-blockers Combination therapy (fixed-dose with D) Combination therapy (extemporaneous with diuretics) Combination therapy (extemporaneous no diuretics) Co-treatments (%) Antidiabetic drugs Lipid lowering agents Antidepressants Concomitant diseases (%) Cardiovascular Renal Pulmonary Rheumatic Neoplastic Dementia
Entire cohort
Continuers
Discontinuers
P-value
493 623 59 (11) 48
211 506 60 (10) 54
282 117 58 (11) 45
