Long-term persistence with antihypertensive drugs in new ... - Nature

Journal of Human Hypertension (2002) 16, 439–444  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh

ORIGINAL ARTICLE

Long-term persistence with antihypertensive drugs in new patients E Degli Esposti1, A Sturani2, M Di Martino3, P Falasca1, MV Novi1, G Baio4, S Buda3 and M Volpe5 1

Health Directorate, Ravenna Local Health Unit, Ravenna, Italy; 2Hypertension Unit, Department of Nephrology, S.M. delle Croci Hospital, Ravenna, Italy; 3CliCon S.r.l., Health, Economics and Outcomes Research, Ravenna, Italy; 4University of Siena, R.M. Goodwin Faculty of Economics, EPRIS Research Group, Siena, Italy; 5Chair of Cardiology, Department of Experimental Medicine and Pathology, University ‘La Sapienza’, Rome, Italy

The objective of this study was to investigate stay-ontherapy patterns over 3 years among patients prescribed different classes of antihypertensive drugs for the first time. A retrospective analysis of information recorded in the drugs database of the Local Health Unit of Ravenna (Italy) was carried out on 7312 subjects receiving a first prescription for diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists between 1 January and 31 December 1997. Patients were followed up for 3 years. All prescriptions of antihypertensive drugs filled during the follow-up periods were considered. The patients continuing or discontinuing the initial treatment, the duration of treatment, and the doses taken were all calculated, as well as main factors influencing the persistence rate. The drugs prescribed were predominantly ACE-inhibitors, followed by calcium channel blockers, diuretics, beta-blockers and angiotensin II antagonists. A total of 57.9% of patients continued their initial treatment during the 3-year followup period, 34.5% discontinued the treatment, whilst

7.6% were restarted on a treatment in the third year. Persistence with treatment was influenced by: age of patient (persistence rate increasing proportionately with advancing years), type of drug first prescribed (persistence rate higher with angiotensin II antagonists, progressively lower with ACE-inhibitors, beta-blockers, calcium channel blockers and diuretics), gender of patient (persistence was better in males), age of general practitioner (GP) (the younger the GP, the better the persistence rate) and gender of GP (better stay-on-therapy rate with male GP prescribing). In the case of patients treated continuously, mean daily dose increased progressively over the 3 years. With adequate markers, helpful data can be collected from prescription claims databases for the purpose of monitoring the persistence of patients in continuing their medication, and the quality of antihypertensive treatment in a general practice setting. Journal of Human Hypertension (2002) 16, 439–444. DOI: 10.1038/sj/jhh/1001418

Keywords: hypertension; antihypertensive drugs; administrative databases

Introduction Persistence with treatment is a crucial element in determining the success of any long-term therapy. The full benefit of antihypertensive treatment observed in randomised clinical trials1–3 can be obtained only when hypertensive patients keep taking their medication as a matter of regular habit. Frustratingly, low compliance remains a major therapeutic problem in subjects treated for the first time with antihypertensive drugs.4 Many patients with hypertension drop out of care inside the first Correspondence: E Degli Esposti, MD, c/o CliCon S.r.l., Via San Vitale, 5, 48100 Ravenna, Italy. E-mail: edegliesposti얀iol.it Received 15 November 2001; revised and accepted 27 February 2002

year and only two-thirds of those who remain under care take enough medication to control their blood pressure.5,6 Many factors can influence the extent of adherence to antihypertensive therapy. Persistence rates are inversely correlated with the number of drugs prescribed, complexity of dosage regimen, and with the cost of drug; whilst are directly correlated with the tolerability of the treatment, and with a strong and trusting physician–patient relationship.7 The aim of the present study was to investigate stay-on-therapy patterns over 3 years, among patients who were receiving different classes of antihypertensive drugs for the first time.

Materials and methods This is a record linkage study, in which a retrospective analysis was conducted using the database of

Utilisation of antihypertensive drugs E Degli Esposti et al

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dispensed drugs held by an Italian Local Health Unit (LHU of Ravenna, Italy). LHUs are government organisations which provide healthcare services to the entire population living in a given area and work toward the achievement of public health objectives pursued by the National Health Service (NHS). All drug prescriptions written for the residents of Ravenna (approximately 350 000 inhabitants), totally or partially reimbursed by the NHS, are documented in the database. An automatically assigned national health number identifies each subject. Since 1 January 1996, the data file has been gathering all prescriptions dispensed, each bearing the NHS number, birth date and gender of the single patient. Also recorded, moreover, are the date of prescription, the general practitioners (GPs) identification code, the Anatomical-Therapeutic-Chemical (ATC) code of the drug/s, number of packs dispensed, number of tablets in each pack, milligrams of active principle in each tablet, and cost per pack. The result is a database providing a long-term record of all drugs prescribed for each patient. All information on antihypertensive drugs dispensed is collected on a routine basis to enable computation of the reimbursement payable to the pharmacists, who supply the drugs to patients. All patients enrolled in the present study were at least 20 years of age, and had been prescribed antihypertensives for the first time in the period between 1 January 1997 and 31 December 1997, namely diuretics (ATC code C03), beta-blockers (ATC code C07), calcium channel blockers (ATC code C08), angiotensin-converting enzyme (ACE)inhibitors (ATC code C09A), or angiotensin II antagonist, ie losartan (ATC code C09C), which was the only angiotensin II antagonist available in Italy during that period. Patients were excluded if they had received a prescription for any antihypertensive drug during the previous 12 months. Subjects were excluded if on the date of their first prescription they had been dispensed two or more classes of antihypertensive agents, or a combination product including two different classes of antihypertensive drugs. Also excluded were those who had received a single prescription or only two prescriptions for the antihypertensive drugs considered in the present study, indicating a course of treatment lasting less than 7 days. The observation period for each patient was 3 years starting from the date of the first prescription. Patients who died or moved away during the followup period were excluded. Prescriptions for other antihypertensive drugs filled during the follow-up period, used in combination with or as substitutes for the active principles studied in this paper, were also taken into account. On the basis of prescriptions received in the year preceding the period of inclusion in the study, patients were defined as diabetic if they had received at least three prescriptions for antidiabetic drugs (ATC code: A10), as cardiopathic if they had

Journal of Human Hypertension

received at least three prescriptions for drugs acting on the cardiovascular system (ATC code: C01), and as asthmatic or having chronic obstructive pulmonary disease (COPD) if they had received at least three prescriptions for respiratory drugs (ATC code: R03). The presence of cardiovascular diseases (acute myocardial infarction, which is ICD 9 code 410, coronary heart disease, ICD 9 code 411– 414, heart failure, ICD 9 code 428– 429) was determined by analysing hospital admissions in the 5 years preceding inclusion in the study. Analysis of persistence We identified three patterns of persistence attributable to patients: (1) continuers—those who received at least two prescriptions for antihypertensive drugs during each year of the 3-year follow-up period; (2) discontinuers—those who received at least two prescriptions for antihypertensive drugs during the first year (lost in second year) or during the first and the second year (lost in third year) of the follow-up period; (3) retreaters—those who received at least two prescriptions for antihypertensive drugs during the first and the third year of the follow-up period, having suspended their therapy during the second year. For continuers, we also calculated the mean daily dose (MDD) (tablets/day) taken by each patient as the number of tablets of antihypertensive drugs purchased each year, divided by 365. Statistics Results are expressed as mean values (± standard deviation). We performed all statistical analyses using SPSS-Windows version 10.0 (SPSS Inc, Chicago, USA), considering P values less than 0.05 as significant. In the case of continuers, the hypothesis that mean daily dose is unaffected by 1 year’s stay-ontherapy was verified, in the case of continuers, using a nonparametric Friedman test for dependent samples.8 Persistence was assessed using survival analysis methods.9 Having tested the proportional hazards assumption, a Cox regression model was used: the number of days elapsing from the first to the last prescription was taken as an estimate of the duration of treatment, and the follow-up period was limited to 1005 days. The following independent variables were considered: age of patient, gender of patient, comorbidity if any, previous hospitalisations if any, class of drug prescribed at enrolment, administrative district, age and gender of GP, number of patients on the GPs list. The variables to be included in the model were selected thereafter adopting a stepwise method,10 which in the pro-


cesses of removal uses the Wald statistic (Pvalue(in) = 0.05, P-value(out) = 0.10).

Results Applying the inclusion and exclusion criteria noted above (Figure 1), 7312 patients were identified, numbering 3154 males (equivalent to 43.1%) and 4158 females (equivalent to 56.9%), aged between 20 and 100 years. The class of antihypertensive drug most frequently selected as first choice was that of ACE-inhibitors (prescribed for 2418 patients, equivalent to 33.1% of the population considered in the study), followed by calcium channel blockers (prescribed for 1882 patients, equivalent to 25.7% of the population), diuretics (prescribed for 1648 patients, equivalent to 22.6% of the population), beta-blockers (prescribed for 1166 patients, equivalent to 15.9% of the population) and angiotensin II antagonists (prescribed for 198 patients, equivalent to 2.7% of the population). The characteristics of the five cohorts of patients, identified according to the drug on which they were started, are indicated in Table 1. As regards the extent to which individuals persisted with their treatment, 4231 patients (equivalent to 57.9%) continued, 2525 patients (equivalent to 34.5%) discontinued (1999 after the first year and 526 after the second), and 556 patients (equivalent to 7.6%) were restarted on a therapy during the third year of the follow-up period, having suspended treatment during the second year. The stepwise process (Table 2) showed that persistence

441

Table 1 Characteristics of the patients Mean age (years) Diuretics 65.4 ± 16.8 Beta-blockers 54.4 ± 13.9 Calcium 62.3 ± 15.2 channel blocker ACE-inhibitors 61.1 ± 14.8 Angiotensin II 60.5 ± 13.9 antagonist

Male (%)

CoPrevious Mean age morbidity events of GP (%) (%) (years)

32.5 38.5 50.1

15.0 4.2 8.6

13.6 9.9 17.2

46.5 ± 7.4 47.1 ± 7.8 46.6 ± 7.6

47.3 42.4

7.8 7.1

12.8 13.6

46.4 ± 7.4 47.2 ± 7.4

in staying on therapy was influenced significantly by five variables: the age of the patient, with older patients tending to continue longer with treatment than younger patients; the drug on which the patient was started, with those who were prescribed an angiotensin II antagonist tending more to persist with antihypertensive therapy than those taking an ACE-inhibitor, a beta-blocker, a calcium channel blocker or a diuretic; the gender of the patient, with male patients tending to show more persistence than female patients; the age of the GP, inasmuch as patients registered with a young GP appear to stay on therapy longer than patients registered with an older GP; and the gender of the GP, inasmuch as patients registered with a male GP appear to stay on therapy longer than patients registered with a female GP. The first of these two variables (age of patient and class of drug initially prescribed) are those hav-

Figure 1 Flow chart of excluded patients. Journal of Human Hypertension


442

Table 2 Cox regression model: predictors of persistence

␤a

Patient age**

s.e.

Table 3 Mean daily dose (MDD) purchased per year in continuers and number of antihypertensive classes

Wald statistic

Hazard ratio (CI 95%)b

−0.024 0.001

408.4

–

138.9

0.976 (0.974 to 0.978) –

Class of drug (angiotensin II antagonist)** ACE inhibitors*

0.456

Beta-blockers**

0.626 0.143

19.2

Calcium channel blockers** Diuretics**

0.729 0.141

26.9

0.965 0.141

47.1

Patient gender (female)* GP age*

−0.112 0.037

9.4

0.006 0.002

9.9

GP gender (female)*

−0.093 0.043

4.6

0.14

10.6

1.577 (1.198 2.076) 1.869 (1.414 2.472) 2.073 (1.574 2.731) 2.624 (1.992 3.457) 0.894 (0.832 0.961) 1.006 (1.002 1.011) 0.911 (0.836 0.992)

MDD (tablets/day) Mean no. of classes prescribed

Year 1

Year 2

0.8 ± 0.56 1.68

0.95 ± 0.67 1.52

Year 3 1 ± 0.68 1.54

to

to

Table 4 Mean daily dose (MDD) and number of antihypertensive classes purchased per year according to the starting drug in continuers

to

Year 1

Year 2

Year 3

1.75

1.52

1.55

0.69 ± 0.5

0.9 ± 0.6

1.02 ± 0.69

1.6

1.46

1.5

0.73 ± 0.47

0.92 ± 0.91

0.98 ± 0.76

1.68

1.54

1.57

0.97 ± 0.73

1.06 ± 0.75

1.12 ± 0.74

1.64

1.52

1.54

0.76 ± 0.47

0.92 ± 0.54

to

to to to

Variables are listed by order of entry in the model; in brackets is indicated the reference category of categorical variables (hazard ratio = 1). a Related to 1 year age increment. bAdjusted for other variable in table. *P ⬍ 0.05, **P ⬍ 0.001. Global ␹2 = 550.55, P ⬍ 0.001.

ing the greatest influence on persistence. When persistence is analysed on the basis of the drug prescribed, remaining constant on the effect of other covariates (Figure 2), it is shown that patients who were started on angiotensin II antagonists display a significantly greater persistence with antihypertensive therapy than those who were started on the other four classes of drug. Among the 4231 patients classified as continuers, mean daily dose increased significantly over the 3 years of treatment (Friedman statistic = 625.867, P ⬍ 0.001), whereas the number of classes of drug

Diuretics Average no. of classes prescribed Mean MDD (tabs/day) Beta blockers Average no. of classes prescribed Mean MDD (tabs/day) Calcium channel blockers Average no. of classes prescribed Mean MDD (tabs/day) ACE-inhibitors Average no. of classes prescribed Mean MDD (tabs/day) Angiotensin II antagonists Average no. of classes prescribed Mean MDD (tabs/day)

2

1.74

0.8 ± 0.39

1 ± 0.61

1 ± 0.58

1.58 1.12 ± 0.74

prescribed fell significantly from the first to the second year, remaining steady thereafter from the second to the third year (Table 3). This pattern was similar across the five groups of patients identified on the basis of the drug prescribed at enrolment (Table 4). The analysis conducted on the basis of MDD (Table 5) showed that the cumulative percentage of patients taking a MDD ⭐1 tablet per day dropped substantially from 75.5% to 60.2% during 3 years of follow-up; correspondingly the cumulative percentage of patients taking a MDD ⬎1 tablet per day increased from 24.5% to 39.8%. Table 5 Mean daily dose (MDD) distribution (percentage values) Tables per day

Figure 2 Cox regression model, persistence with treatment by class of drug (adjusted for age and gender of patient, and age and gender of GP). Journal of Human Hypertension

⬍0.5 0.5 ⭐ tab ⬍ 1 1 ⭐ tab ⬍ 2 ⭓2

Year 1

Year 2

Year 3

31.9 43.6 20.5 4.0

21.9 44.4 27.1 6.6

18.1 42.1 31.4 8.4


Discussion The clinical, social, and economic importance of treating hypertension requires the implementation of tools for monitoring the use of antihypertensive drugs so that they will give an understanding as to what extent data from randomised and controlled trials are applicable in real clinical practice. It is a basic factor of clinical trials that, to be effective in achieving blood pressure control, antihypertensive therapy is given in adequate doses, in a continuous manner, and for a long period of time. With antihypertensive drugs, accordingly, patient stay-on-therapy plays a crucial role in obtaining normotension and consequently lowering cardiovascular morbidity and mortality. In clinical practice, it is difficult to have a large amount of information on blood pressure control rate unless the cohort of subjects considered is small, whereas utilising claims databases, it becomes possible to gather data on persistence with antihypertensive therapy prescribed in a whole population, as already shown.11,12 The issue of stay-on-therapy can be seen as having at least two dimensions. The first dimension is related to the proportion of patients persisting with their prescribed antihypertensive drugs, and the second dimension is given by factors influencing its rate. Our study showed that some 60% of patients who were prescribed antihypertensives for the first time had stayed on therapy for the duration of the followup. Moreover, the protracted follow-up period enabled us to observe that around 8% of patients in the study restarted on antihypertensives after a lengthy break. Other studies conducted on the basis of prescription databases assess patients persisting with treatment at percentages ranging between 41 and 86%.11,13–17 These results however are not effectively comparable since some of the studies included new and established patients together, followed up for periods of less than 12 months,11,13,16 whereas others related only to new patients, followed up for a period of 12 months,14,15 or 54 months.17 The gradual increase in the average number of tablets taken over 3 years by continuers (from 0.8 to 1 tablet/day), and the reduction in number of individuals who took less than half a tablet per day (from 31.9% to 18.1% of patients treated), reflects in clinical practice that which in randomised controlled trials (RCTs) is the titration procedure, pursued in an attempt to achieve the target of normotension. The clear difference is in the time over which this process takes place: generally a few weeks in the case of RCTs and many months (if not years) in clinical practice. Consequently, the presence of an appreciable percentage of patients who suspend treatment or are undertreated, as a result of continuing to take antihypertensives in doses significantly lower than those usually adopted in RCTs, in some cases for extended periods, could help to explain the low percentage of normotensive patients docu-

mented in various real-world clinical practice situations.18–21 It is difficult to sustain the hypothesis that drugs can be really effective in controlling blood pressure when used in a range of doses lower than those recommended. Although there is no positive evidence, we suppose that patients who repeat prescriptions on a regular basis will be taking their medication, and this is a reasonable assumption in the case of treatment for a chronic condition such as hypertension. The easiest alternative to a true evaluation is to investigate directly by asking whether or not patients are actually taking the prescribed drugs. The findings may be encouraging, but not so conclusive as might be expected.22,23 In our opinion, the analysis of drug databases according to the procedures described above could provide an effective tool in evaluating patient stay-on-therapy and the probable efficacy of antihypertensive treatment. The second dimension characterising the question of compliance includes factors that influence persistence with treatment. Perseverance in matters of therapy depends on the complex relationship that exists between doctor and patient, and accordingly, account was taken of the information held in our database, which, albeit not exhaustive in respect of all the potential compliance-determining factors in play, nonetheless allows an evaluation of the specific elements characterising two aspects of the relationship. Firstly, one of the factors having greatest influence is the age of the patient: younger patients display a generally poorer rate of persistence where antihypertensive treatment is concerned, as previously reported,24 and this is more evident in females than in males. Secondly, but no less importantly, persistence is influenced by the class of drug on which the patient is started. The long-term persistence rate of patients who started antihypertensive treatment on losartan, the only angiotensin II antagonist available in Italy at that time, was significantly higher when compared with those who started on ACE-inhibitors, beta-blockers, calcium channel blockers, and diuretics respectively. Although this result could have been influenced by the relative small sample size of patients treated with angiotensin II antagonists, differences displayed are highly significant even after a 3-year follow-up, suggesting that the choice of initial drug has a significant bearing on persistence. A similar result has been reported previously in a 12 months follow-up study.12 The database we used in this study does not take into account baseline and subsequent blood pressure levels, any appearance of side effects, or clinical outcomes. Therefore, the reasons that are able to explain the relationship between the persistence with antihypertensive treatment, and the conditions of the patient, or the therapeutic decision made by GP, are not yet clear. This represents the major limitation of our analysis. However, it can be assumed that drug efficacy and tolerability play a critical role

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in the persistence with antihypertensive treatment, especially when considering that physicians would not prolong a therapy without evidence of tolerability or efficacy. In randomised and controlled clinical trials, the angiotensin II antagonist losartan showed a higher tolerability compared with that observed with other antihypertensive classes.25 The tolerability profile of a drug might therefore be one of the reasons to clarify the results of this study, but this remains an interesting hypothesis that requires to be confirmed. In conclusion, we believe that a chronological reading of prescriptions for antihypertensive drugs represents a useful tool in assessing drug utilisation from an epidemiological point of view and for the detection of key factors influencing persistence with treatment.

Acknowledgements Funding: Ravenna Local Health Unit and Merck Sharp & Dohme Italia S.p.A. The co-operation in this study of Dr Alessandro Capone is gratefully acknowledged.

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