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European Journal of Heart Failure 2003 5(2):195-200; doi:10.1016/S1388-9842(02)00256-8
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© 2002 European Society of Cardiology

Patterns of pharmacotherapy in patients hospitalised for congestive heart failure

Marcel L. Bouvya,b,*, Eibert R. Heerdinka, Hubert G.M. Leufkensa and Arno W. Hoesc

a Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS) P.O. Box 80082, 3508 TB Utrecht, The Netherlands
b SIR Institute for Pharmacy Practice Research Leiden, The Netherlands
c Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, The Netherlands

* Corresponding author. Tel.: +31-30-2537324; fax: +31-30-2539166 E-mail address: m.bouvy{at}pharm.uu.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: In the 1990s, a number of cardiovascular drugs were evaluated in randomised clinical trials. Treatment guidelines for heart failure were modified to include these evidence-based treatments.

Aim: To evaluate the impact of new medical treatments for heart failure between 1990 and 1998.

Methods and results: A retrospective cohort study of 2764 patients with a first hospital admission for heart failure between 1990 and 1998. The percentage of patients treated with different cardiovascular drugs after hospitalisation was calculated and compared over time. Use of loop diuretics remained steady approximately 80%, digoxin decreased from 57.6 to 42.7%, angiotensin converting enzyme (ACE) inhibitors showed a slight increase from 49.8 to 54.8%, beta-blockers almost tripled from 11.3 to 28.7%, low dose prophylactic acetylsalicylic acid quadrupled from 9.9 to 39.9%. Kaplan–Meier survival estimates showed highest continuation rates of drug treatment for antithrombotics and diuretics, intermediate for digoxin and ACE inhibitors and low for beta-blockers. More than a quarter of the users discontinued beta-blockers in the first year after hospitalisation.

Conclusions: We observed an increase in the prescribing of several important drug classes, reflecting changes in treatment guidelines during the study period. However, our findings show that not all patients were receiving optimal treatment. More research into the reasons for this is warranted.

Key Words: ACE-inhibitors • Beta-blockers • Diuretics • Digoxin • Antithrombotics • Heart failure • Medication patterns • Persistence of therapy

Received April 15, 2002; Revised July 16, 2002; Accepted September 17, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The ‘epidemic’ of increasing rates of heart failure, thought to have peaked in the mid-1990s, still remains an important cause of morbidity and mortality in the elderly today [1–3]. In the 1990s, a number of cardiovascular drugs, such as digoxin, angiotensin converting enzyme (ACE) inhibitors and beta-blockers, were evaluated in randomised clinical trials. The DIG trial showed that digoxin reduced the rate of hospitalisation both overall and for worsening heart failure [4]. ACE inhibitors were shown to reduce mortality in heart failure patients [5–8]. Beta-blockers were shown to provide similar benefits [9–12]. Treatment guidelines for heart failure were modified to include these evidence-based treatments. Attempts should be made to initiate ACE inhibitors or beta-blockers in all patients with heart failure [13]. Despite an initial increase in the numbers of patients treated using these drugs, the dissemination of the evidence-based treatments to routine clinical practice has been repeatedly reported to be low [14–17]. Discontinuation rates among patients have been reported to be high when ACE inhibitors and beta-blockers are started, further reducing the percentage of patients receiving optimal therapy during a recommended time period [18,19]. As an example, one third of hospitalised patients stopped taking their ACE inhibitor within 6 months of hospital discharge [18].

There are large differences between studies examining prescriptions of drug therapy for patients with heart failure. Population-based studies have reported high rates for under-utilisation of evidence-based therapy for patients with heart failure [14,19–21]. Hospital-based studies, especially in specialised heart centres, show higher uptake of use of ACE inhibitors and beta-blockers [21–25]. However, as most studies of prescribing and drug utilisation in patients with heart failure are cross-sectional, they do not always present data on continuation of therapy after hospital discharge.

This study aimed to evaluate the impact of new medical treatments for heart failure on the actual pharmacotherapy patients received after a first hospital admission for heart failure between 1990 and 1998. We also described the changes in cardiovascular drug treatment before and after hospitalisation for heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients and data
Data were retrieved from the pharmo record linkage system—a database containing drug-dispensing records from community pharmacies and linked hospital discharge records of a defined population of 300 000 residents of six medium-sized cities in the Netherlands. In the PHARMO system, data from all community pharmacies in a number of medium-sized cities in the Netherlands are collected. These data are virtually complete (99%). Pharmacy data and hospital discharge data are anonymously linked using gender, date of birth and general practitioner code. This linking has been shown to be very accurate [26]. We selected a cohort of 3822 patients with at first hospitalisation for heart failure according to discharge diagnosis between 1990 and 1998 (icd 428). The heart failure discharge diagnoses were validated in a separate study and were shown to be accurate [27]. Patients were excluded because of death during the hospitalisation (n=456) or because it was not possible to link hospital and pharmacy data (n=602; e.g. patients who did not collect their medication in the community pharmacy such as nursing home residents). Medication histories were collected from 1989 to 1999. Drugs were coded according to the Anatomical Therapeutic Chemical classification.

2.2. Exposure definition
A patient was defined as a user when there was at least one prescription for any drug dispensed in the 6 months after hospitalisation for heart failure. Continuous use was defined as the presence of at least one prescription for any drug in every year after the first hospitalisation. Patients who disappeared from the cohort either because they died, moved outside the scope of PHARMO or for other reasons were censored.

2.3. Analysis
We calculated the percentage of patients using several cardiovascular drugs in the 6 months after the first hospitalisation for heart failure between 1990 and 1998. Then, 3 cohorts of patients admitted between 1990–1992, 1993–1995, and 1996–1998 were formed. The percentages of patients using cardiovascular drugs in the 6 months before and after the first hospitalisation for heart failure and also in the years before and after the hospitalisation in the different cohorts were determined. The percentages calculated for these three cohorts are an aggregate of patients starting, continuing, discontinuing and restarting (sometimes after hospital readmission) the drugs. We used Kaplan–Meier survival estimation to evaluate continuation of drug therapy for individual patients who started drugs after hospitalisation for heart failure. All analyses were performed with Microsoft Excel 97, Microsoft Visual FoxPro 6.0 and SPSS (SPSS for Windows 10.0) software.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Study population
The study cohort comprised 2764 patients with a first hospitalisation for heart failure, with 6805 person-years of follow-up after hospitalisation (mean follow-up period 2.5 years per patient). The age and gender distribution among patients admitted to the hospital remained constant during the study period (Table 1).


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  		Table 1 Drug treatment of patients in 6 months after hospital admission for heart failure

 
3.2. Changes in drug treatment after hospitalisation for heart failure
Table 1 shows the changing patterns of cardiovascular drug use after hospital discharge for heart failure during the years 1990–1998. During this time, loop diuretics remained the most frequently used drugs for heart failure (80% of patients). The use of ACE inhibitors increased from 49.8% in patients in 1990 to 54.8% in 1998. Angiotensin II (AII) antagonists were first prescribed in 1995 and were used by 6.5% of patients in 1998. The use of digoxin decreased from 51.9 to 37.6% during the study period. Over this time, use of beta-blockers almost tripled from 11.3 to 28.7%. The use of oral anticoagulants increased slightly from 34.3 to 39.6% while the use of low dose prophylactic acetylsalicylic acid (ASA) nearly quadrupled from 9.9 to 39.9%. The use of calcium channel blockers remained constant at approximately 25%. The use of ibopamin, the only available inotropic agent for chronic use in the Netherlands, increased from 1.1 to 13.5% between 1990 and 1994 and subsequently decreased to 0.6% in 1998. The use of prophylactic nitrates (mostly isosorbidedinitrate) increased from 27.9% in 1990 to 38.5% in 1998. There was also a clear increase in the use of antilipaemics from 2.1% in 1990 to 14.9% in 1998.

3.3. Drug treatment before and after hospitalisation for heart failure
There was an increase in the use of ACE inhibitors, diuretics, digoxin, antithrombotics and nitrates after hospitalisation in all three cohorts between 1990 and 1998 (Fig. 1–10). Use of beta-blockers decreased between 1990 and 1992, with a slight increase thereafter. The use of antilipaemics increased over time, but was not related to the year of the hospital admission.


Figure 1
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  		Fig. 1–10 Use of medication in the years before (–2, –1, –0.5) and after (0.5–8) first hospitalisation for heart failure.

 
3.4. Continuation of drug treatment started after hospitalisation for heart failure
Highest continuation rates were observed for antithrombotics and diuretics, intermediate continuation for digoxin and ACE inhibitors and low continuation patterns for beta-blockers ({approx}28% discontinued beta-blockers in the first year after hospitalisation) (Fig. 11).


Figure 2
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  		Fig. 11 Long term continuation of therapy.

 
The definition of patients as (continuous) users when there was at least one prescription for a drug in a year may have led to some overestimation of (continuous) use since some patients did not collect enough prescriptions to cover the whole year. When we applied more strict definitions for continued use, i.e. at least 2 and 3 prescriptions per year, this led to slightly lower percentages. Patterns, however, remained the same (data not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
There have been considerable changes in the treatment of heart failure patients between 1990 and 1998; changes which are reflected in an increased number of drugs available and evidence-based guidelines to support physicians in the use of these drugs in practice. This study of the patterns of pharmacotherapy reveals that there is under-use of drugs and premature discontinuation of prescribing.

Although our results showed a slight increase in the number of heart failure patients receiving ACE inhibitors after discharge form hospital, there appeared to be a large proportion who did not receive them. This would suggest that ACE inhibitors were still not initiated in many subjects who might benefit. Strikingly, the use of ACE inhibitors even showed a small decrease at the end of the 1990s when the use of AII antagonists showed a rise. This could indicate a tendency to switch patients with troublesome side effects from ACE inhibitors to AII antagonists, despite the fact that the treatment of heart failure patients with AII antagonist monotherapy is not evidence-based. Our figures showed a slightly lower uptake of ACE inhibitors than other hospital-based studies [22–25]. Unlike our study, these previous studies were performed in hospitals with special interest in heart failure treatment. An alternative explanation may be that a small proportion of patients who were prescribed ACE inhibitors in our study did not fill the prescriptions they received in the hospital.

We found that the number of patients that received beta-blockers after hospital admission almost tripled, but was still low. This finding is in accordance with other studies and may be related to the fact that many elderly patients with heart failure do not tolerate beta-blockers or that physicians are reluctant to initiate beta-blockers because of the potential of initial worsening of heart failure symptoms [28].

Digoxin has been used as a drug for more than 200 years and still remains an important drug in heart failure treatment, its use decreased only slightly over our study period.

The increase and decrease in use of ibopamin shown in our study reflects the quick uptake and fall of this inotropic agent after the findings of observational studies and the early termination of the PRIME II-trial [29,30].

The use of oral anticoagulants has always been relatively high in The Netherlands where there is a sophisticated system for monitoring international normalised ratio. The increase in the use of ASA is striking, since there are no recent trials proving a mortality benefit for the use of ASA in heart failure. Observational studies, however, do support the use of ASA in heart failure [31]. Moreover it is plausible that the majority of patients with heart failure have coronary artery disease and therefore another indication for treatment with ASA.

There are no studies that have proven a mortality benefit of calcium channel blockers in heart failure. Although long-acting dihydropyridines can probably be given safely to patients with heart failure who need additional treatment for angina pectoris or hypertension [32,33], it seems unlikely that 25% of patients need calcium channel blockers. Calcium channel blockers are prescribed most often for indications other than heart failure, in particular ischaemic heart disease, hypertension and atrial fibrillation. The use of calcium channel blockers in patients with heart failure should always be reconsidered.

Our study showed that hospitalisation for heart failure has a major impact on patients’ medication. When we compared the use of cardiovascular drugs before and after a patient's first hospitalisation for heart failure, a steep increase in the use of several drugs was noted (Fig. 1–10). The increase in drug use after hospitalisation shows the major influence of cardiologists on drug treatment in patients with heart failure.

Loop diuretics were continued in most patients. This is probably related to the severity of heart failure; patients often need diuretics to diminish symptoms related to fluid retention.

Continuation of treatment with ACE inhibitors was higher than reported in Ref. [18], but we observed high discontinuation rates for beta-blockers especially in the first year of use. The reason for this may be the beta-blocker related initial worsening of heart failure symptoms [28]. Alternatively, some patients may have stopped using beta-blockers because of adverse drug reactions. As a consequence, many patients might be denied maximum morbidity and mortality reducing therapy.

Our study was performed in patients with at least one hospitalisation for heart failure and, consequently, will have led to a selection of patients with relatively severe heart failure. This study is therefore not fully applicable to patients with less severe heart failure in the community.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Cardiovascular pharmacotherapy in the 1990s has been strongly influenced by hospitalisation for heart failure. Treatments using drugs with proven effect on morbidity and mortality have increased, but some drugs such as ACE inhibitors and beta-blockers, in particular, may still be under-used. More research into the reasons why patients are not prescribed these drugs or discontinue using them is warranted.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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