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European Journal of Heart Failure 2004 6(2):235-243; doi:10.1016/j.ejheart.2003.08.003
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© 2003 European Society of Cardiology

Specialist care of heart failure improves appropriate pharmacotherapy at the expense of greater polypharmacy and drug-interactions

Mark Ledwidge, Bronagh Travers, Mary Ryder, Enda Ryan and Kenneth McDonald*

Heart Failure Unit St Vincent's University Hospital, Elm Park, Dublin 4, Ireland

* Corresponding author. Tel.: +353-1-2094147; fax: +353-1-2094149. E-mail address: kenneth.mcdonald{at}ucd.ie


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Background: There is growing concern at the nature and extent of polypharmacy in heart failure (HF), which may be associated with increased drug interactions, adverse drug effects and a poor understanding of and compliance with therapy.

Aims: This study evaluates polypharmacy in a relatively unselected community heart failure population following emergency admission and determines the impact of an in-hospital, specialist heart failure care programme on appropriate pharmacotherapy, polypharmacy and drug interactions.

Methods: We analysed the medication profiles of 91 consecutive patients with an emergency admission for HF to our institution on admission and discharge. The numbers of inappropriate medicines, inappropriate dosages and omitted medicines according to guidelines were recorded. Medication profiles were analysed for potential drug–drug, drug–liver and drug–kidney interactions using standard criteria.

Results: In the study population, average age 71.1±10.4 years, 65.9% were male, 68.1% had left ventricular systolic dysfunction and the average ejection fraction on transfer to the specialist HF service was 38±13%. A total of 66 inappropriate medicines, 107 omitted medicines and 37 inappropriate dosage regimens were identified in the cohort on admission. These figures had dropped to 31, 33 and 19, respectively, on discharge, with per patient averages decreasing significantly (all P<0.0001). However, polypharmacy and potential drug interactions increased by 33% and 62%, respectively, from admission to discharge (P<0.0001) as did drug–kidney interactions and drug–liver interactions. Only ischemic aetiology and hypercholesterolaemia predicted polypharmacy in this cohort on discharge, whereas age, sex, renal function and heart failure type did not.

Conclusions: Specialist care of heart failure following emergency admission results in more appropriate pharmacotherapy of heart failure. However, increased polypharmacy and drug–interactions are an inevitable consequence independent of age, sex and renal function. We advocate a practice of systematic evaluation of polypharmacy in all heart failure patients to identify potential problems and modify therapy where appropriate.

Key Words: Pharmacotherapy • Polypharmacy • Heart failure (HF)

Received October 23, 2002; Revised June 12, 2003; Accepted August 28, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Medical therapy for heart failure (HF) has become complex with proven benefit from multiple therapies, including ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blockers and spironolactone [1–5]. While HF populations have been frequently characterised by under-use and under-dosing of evidence-based therapies in the past [6,7], there is now growing concern at the nature and extent of polypharmacy in this condition.

Polypharmacy may be associated with increased drug interactions and poor understanding of and compliance with therapy, both of which have been linked to poorer outcome [8,9]. Recent research has shown that, alongside chronic obstructive pulmonary disease (COPD), asthma and diabetes, heart failure is most responsible for extensive polypharmacy in a community based population [9,10]. Furthermore, these conditions frequently co-exist, meaning that drug therapy in HF has become multiple, confusing and is complicated by pharmacological therapy for concomitant conditions [11].

Moreover, with the progressive changes in pharmacokinetic characteristics of drugs due to age-related physiological changes in heart failure, the more successful we become at reducing mortality in heart failure, the more difficult it will be to avoid clinically significant drug–drug and drug–disease interactions [12,13]. With the evidence-based drive to ‘add-in’ newer therapies on top of the existing armamentarium, polypharmacy may be more prevalent and more challenging to those involved in HF care in the future [8].

Despite a growing body of data on the challenges of polypharmacy there are few published data detailing the nature, extent and potential impact of polypharmacy in a community heart failure population. Several authors have expressed concern about drug–drug and drug–disease interactions, which may limit the effectiveness of therapies in heart failure [8,9,13–15]. Recently, drug-related causes were a major component of heart failure readmissions in the setting of a controlled, multicentre study [16]. However, while specialist care and disease management programmes are known to improve heart failure pharmacotherapy [17,18], no report of specialist heart failure programmes to date has detailed the full extent and independent predictors of associated polypharmacy and drug–interactions.

This study aims to evaluate the detailed nature and extent of polypharmacy in a relatively unselected community heart failure population following emergency admission for heart failure. Furthermore, it determines the impact of an in-hospital, specialist heart failure care programme on appropriate pharmacotherapy, polypharmacy and drug interactions. Finally, it attempts to determine the factors, which influence polypharmacy and to make recommendations about future approaches to the challenge of polypharmacy in the context of specialist care programmes for heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by the St. Vincent's University Hospital Ethics Committee. Patients were selected from those with an emergency admission and a primary diagnosis of heart failure who were transferred to the heart failure service, All patients underwent investigations for HF including echocardiography and right and left heart catheterisation, where indicated, to determine left ventricular (LV) systolic function (LVSD, defined as an ejection fraction <45%).

Specialist heart failure nurses recorded all medications, doses and dose frequencies from admission charts, which in turn were obtained by patient/carer interview or from the last prescription written by the Family Doctor. Information on discharge was taken from hospital discharge prescriptions.

Full medication profiles were obtained for 91 patients and evaluated with particular reference to evidence based guidelines for heart failure therapy [19]. While ACE inhibitor/angiotensin receptor blocker therapy is prescribed at maximally tolerated doses in all indicated patients, beta blockade was not routinely initiated as an in-patient at the time of this study in view of the unproven benefit in NYHA Class IV HF. As there is no defined approach to the management of HF and normal systolic function, patients with this type of heart failure were managed as deemed appropriate by the attending cardiologist.

The numbers of inappropriate medicines (i.e. that are contra-indicated in heart failure or should be avoided where possible [19]), inappropriate dosages (according to the guidelines [19] or drug license) and omitted medicines (i.e. medicines that should be prescribed where possible in heart failure [19]) on admission and discharge were recorded. Inappropriate medicines, outlined in the ESC Guidelines [19], include non-steroidal anti-inflammatory agents, calcium antagonists, corticosteroids, class 1 anti-arrhythmic agents, tricyclic antidepressants and lithium. In addition, we counted high sodium containing antacids and effervescent formulations as inappropriate for a severe heart failure population. The omission of ACE inhibitors on admission was only deemed inappropriate in patients with known heart failure due to left ventricular systolic dysfunction.

The medication profiles were also analysed by computer programme for potential drug–drug interactions (PDIs) using PharmAssist® software Vs. 11.41 (Copyright Professor Peter Weedle, Infomed Ltd.) and standard reference texts (BNF 43, Pharmaceutical Press and British Medical Association, March 2002, Appendix 1; Stockley, IH, Drug Interactions 5th Edition, Pharmaceutical Press, London). PDIs were categorised using the software as low-risk (unlikely to be clinically significant), moderate-risk (clinically significant, but unlikely to be life threatening) and high risk (clinically significant and potentially life-threatening).

Because of the importance of liver and renal function in determining the pharmacokinetic characteristics of medicines (especially distribution, metabolism and elimination), all admission and discharge medications were individually categorised using standard criteria (BNF 43, Pharmaceutical Press and British Medical Association, March 2002, Appendices 2 and 3) for drug–liver interactions (DLIs) and drug–kidney interactions (DKIs). These interactions were further categorised as low-risk (sub-clinical unless severe disease and/or potentially requiring dose adjustment) or high risk (high risk of toxicity and/or requiring removal of medicine). A sample evaluation of a patient on admission and discharge is provided in Panel 1.Scheme 1


Figure 1
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  		Scheme 1
 
The primary endpoints in this study are the following on admission and discharge: the average number of drugs and doses per patient: the average number of inappropriate, omitted and incorrectly dosed medicines. Secondary endpoints were: potential drug–drug interactions, drug–liver interactions and drug–kidney interactions per patient on admission and discharge. In addition, we analysed data on admission and discharge for independent predictors of polypharmacy.

Statistical models employed include t-tests for continuous variables and Chi-squared analysis for discrete variables. Data are presented as the mean value±the standard deviation (S.D.) for continuous variables and absolute or relative frequencies for discrete variables. Univariate and multivariate analyses were carried out to determine the independent predictors of polypharmacy. The multivariate model included variables with univariate p-values of ≤0.25 and the likelihood ratio test was conducted to identify independent variables with low explanatory power.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
In the study population of 91, 65.9% were male, 68.1% had left ventricular systolic dysfunction, 89% had an available carer and the average age was 71.1±10.4 years. Blood pressure and heart rate on admission was 137/78±27/16 mmHg and 87.8±19.4 BPM, respectively. The average ejection fraction on transfer to the specialist HF service was 38±13%. Fifty-six percent were in sinus rhythm and the aetiological cause of heart failure was judged to be as follows: ischaemic 50.5%; valvular 19.8%; hypertensive 9.9%; idiopathic 8.8%; diabetic 5.5%; other 11.1%. Just under half the population (45.0%) had previously diagnosed heart failure and the average length of in-hospital stay for the cohort was 14.2±8.0 d. The following co-morbidities/risk factors for heart failure were noted: raised blood pressure (41.8%), smoking (37.4%), raised cholesterol (27.5%), and diabetes (20.9%). The average reported weekly intake of alcohol in the cohort was 8.9±14.4 units with 13% of patients having a reported weekly intake of 16 units or greater.

Discharge medication for heart failure revealed that of the 62 patients with an ejection fraction <45%, 59 (95.1%) received an ACEI and 1 (1.6%) received an ARB. Of the 59 patients on ACEi, 28 (47%) were on high dose, 24 (26%) were on target dose and 7 (12%) were on low dose therapy (average dose, enalapril equivalents 26.9±11.1 mg). Digoxin was prescribed in 46 patients (74%, average dose 0.164±0.075 mg) and loop diuretics in all 62 patients (100%, average dose, frusemide equivalents in 60.3±30.3 mg).

A total of 66 inappropriate medicines, 107 omitted medicines and 37 inappropriate dosages were identified in the cohort on admission. These figures had dropped to 31, 33 and 19, respectively, on discharge. The average numbers of inappropriate drugs, omitted drugs and dosage errors per patient significantly decreased from admission to discharge (all P<0.01, Figs. 1–3). The majority of inappropriate medicines were non-steroidal anti-inflammatory agents, calcium antagonists (including amlodipine in patients with ischemic cardiomyopathy), corticosteroids and class 1 anti-arrhythmic agents. Other inappropriate medicines were high sodium containing antacids, tricyclic antidepressants and incidences of therapeutic duplication. Omitted medicines were ACE inhibitors in previously diagnosed systolic HF, heart-rate controlling medication and/or Warfarin in patients with atrial fibrillation, lipid lowering therapy with hypercholesterolaemia, antihypertensive medication in patients with known and uncontrolled hypertension and anti-diabetic medication in indicated patients. The majority of inappropriate dosages related to guideline doses and dose frequencies of ACE inhibitors [19].


Figure 2
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  		Fig. 1 Average number of inappropriate drugs per patient on admission and discharge (n=91).

 


Figure 3
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  		Fig. 2 Average number of omitted drugs per patient on admission and discharge (n=91).

 


Figure 4
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  		Fig. 3 Average number of dosage errors per patient on admission and discharge (n=91).

 
However, the total number of drugs, the average number of drugs and the number of doses per patient showed significant increases from admission to discharge (OR: 1.33 and 1.23, respectively, P<0.0001, Table 1). The polypharmacy increased from just under five medications per patient on admission to an average of 6.6 per patient on discharge with median values for each of 5 (Fig. 4). The average number of doses per drug showed a trend towards decline from admission to discharge from 1.26±0.33 to 1.18±0.26 (P=0.066).


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  		Table 1 Total and average drugs prescribed on admission and discharge (n=91)

 


Figure 5
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  		Fig. 4 Numbers and frequency of drugs prescribed on admission and discharge (n=91).

 
Similarly, the average numbers of potential drug–drug interactions (PDIs) increased significantly in all categories (see Table 2). There were a total of 457 separate PDIs identified in the study cohort on admission and this rose to 740 PDIs on discharge (an increase of 162%). The majority of PDIs were minor and moderate (50.8% and 46.9%, respectively, on discharge).


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  		Table 2 Total and average potential drug interactions (PDIs) on admission and discharge

 
Finally, the average numbers of drug–liver (Table 3) and drug–kidney (Table 4) interactions increased significantly from admission to discharge.


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  		Table 3 Total and average drug–liver interactions (DLIs) on admission and discharge

 


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  		Table 4 Total and average drug–kidney interactions (DKIs) on admission and discharge

 
Significant correlations were observed between numbers of drugs prescribed and drug–drug, drug–kidney and drug–liver interactions (all P<0.001). Furthermore, there was a significant correlation between polypharmacy and medication errors (P<0.001). Whereas age, gender, renal function and heart failure type did not influence polypharmacy in this cohort (univariate analysis on admission, Table 5), both univariate and multivariate analysis of polypharmacy on discharge showed a strong predictive role for hypercholesterolaemia (OR: 1.25, P=0.003) and ischemic aetiology (OR: 1.27, P=0.001) only.


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  		Table 5 Univariate predictor model with polypharmacy on admission as outcome measure

 
There were more inappropriate dosage regimes in the systolic group at baseline, (0.04±0.21 per patient vs. 0.55±0.75 per patient, respectively, P=0.0021) reflecting ACE inhibitor dosing and dose frequency in the group with systolic dysfunction. As expected, newly diagnosed patients (n=45), had significantly lower polypharmacy (4.93±3.06 vs. 6.35±2.75, P=0.0082) and lower rates of drug–drug interaction on admission (4.91±4.90 vs. 6.79±4.97, P<0.0001). However, these patients also showed a trend to lower rates of polypharmacy on discharge (6.51±2.46 vs. 7.38±2.65, P=0.0589) despite having similar age profiles, gender profiles, ejection fractions and NYHA classifications.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Acknowledgments
 References
 
These data demonstrate the nature and extent of polypharmacy in an unselected community heart failure population admitted for acute decompensation. They suggest a positive impact of a hospital based specialist heart failure service on the quality of prescribing for patients admitted with heart failure, in terms of inappropriate, omitted and incorrectly dosed medications. However, they also demonstrate that the average number of medications and doses significantly increase as a result of the in-hospital stay. Furthermore, because the numbers of potential drug–drug, drug–liver and drug–kidney interactions significantly increase, and may be an inevitable consequence of good in-hospital care of heart failure, significant medication related challenges remain in the specialist management of this condition.

More than a decade of large, randomised-controlled trials in left ventricular systolic dysfunction has advanced our ability to medically improve the morbidity and mortality of the disease. However, the accumulation of evidence by ‘adding-on’ pharmacological agents has created a problem with co-prescription of multiple, interacting medications in heart failure. The average number of medications in the present study had increased by 33% from admission to discharge and, at 6.6 per patient, is higher than that reported in previous hospital and community based studies [10,25,26]. This may be explained by the fact that the patients in our study were selected following emergency admission, implying disease progression and greater polypharmacy compared to more stable heart failure populations. Significant correlations were observed between polypharmacy and drug interactions and, accordingly, the average number of drug–drug interactions using objective criteria also increased by 62% to an average of 8.0 per patient.

Only hypercholesterolaemia and ischemic aetiology predicted higher polypharmacy in this cohort on discharge primarily because of the use of antiplatelet, anti-ischaemic (beta blockers and ACE inhibitors) and lipid lowering therapy where appropriate. While other authors have identified factors such as age, sex and renal function as significantly increasing polypharmacy in general populations [10,20], the present study suggests that polypharmacy and drug interactions of community heart failure populations may not be significantly affected by these variables.

Therefore, the rising polypharmacy in the present study may be ascribed to disease progression and the consequent systematic application of the multi-component pharmacological evidence base by a specialist heart failure service. Other authors have suggested that rising polypharmacy in heart failure is related to the accumulating evidence base in this condition [8,16,21]. However, it is interesting to note that there were no significant differences in polypharmacy between those with systolic and diastolic dysfunction, for which the evidence bases are, respectively, developed and poor. Polypharmacy similarities at baseline between these patients may reflect the difficulty in distinguishing systolic and diastolic dysfunction in the community on the basis of clinical assessment alone. Moreover, sustained increases in polypharmacy in the group with diastolic dysfunction at discharge may reflect the attempts of the heart failure service to effectively manage the co-morbidities frequently associated with this condition such as hypertension and dyslipidaemia.

Whatever the causes of polypharmacy in heart failure, it is likely that it will increase in the future, not least because multiple mechanisms underlie the disease which are all the subject of medical research. A time dependent increase in polypharmacy in an elderly community population has already been observed [10].

The adverse consequences of rising polypharmacy may eventually limit the benefit of the pharmacological intervention [16]. It is interesting to note, in this context, that a number of recent studies looking at newer ‘add-on’ therapies in heart failure have failed to demonstrate the anticipated benefit [22,23].

Moreover, the adverse consequences of polypharmacy are and will continue to be complicated by the nature of heart failure itself. Firstly, this is a disease of the elderly and is associated with significant co-morbidity, each with its own evolving evidence base [11]. Secondly, the pharmacokinetics of medications in heart failure will inevitably and progressively change [24] since the majority of drugs are metabolised and/or eliminated by the liver and kidneys which are subject to progressive functional decline. Thirdly, as a chronic disease, outcome in heart failure is strongly influenced by patient self-care and compliance with prescribed therapy which is limited by more complex drug regimes [25]. In the setting of the rising polypharmacy observed here, the use of agents with simplified dosage regimens is preferred.

The data show no difference in the level of drug–kidney interactions in patients with poor renal function. This may point to a lack of focus on drug pharmacokinetics. Dedicated clinical pharmacy resources applied to the polypharmacy of heart failure patients are required to provide detailed analysis of potential drug interactions and their implications, as in the example given in Panel 1. Recommendations arising from such analyses may help reduce the large proportion of hospital admissions in the elderly and in those with heart failure which are medication-related [16,27]. In heart failure, drugs taken in the previous 48 h are a major cause of hospital admission and many of these incidents may be preventable [16]. More worryingly, a recent hospital-based study showed that 18% of in-hospital deaths were fatal adverse drug reactions and that medications for heart failure, coronary artery disease and COPD were most frequently implicated [9].

It is noteworthy that even in a population treated in a specialist heart failure unit, there remains inappropriate pharmacotherapy on discharge, which may reflect a number of issues. Firstly, the indications and contra-indications for therapy are relative, not absolute and clinicians should use clinical judgement as to appropriate pharmacotherapy on a case-by-case basis. Furthermore, there may be irrational prescribing in practice even in specialist units and an ongoing process of self-audit is required to minimise errors. Finally, specialist units may have a narrow focus of expertise and may have a tendency to neglect the management of concomitant diseases. This may point to the need for more interdisciplinary collaboration in the management of heart failure patients and the important role of the general practitioner. Notwithstanding the above, the data show that a specialist heart failure unit significantly improves the quality of pharmacotherapeutic prescribing.

There are a number of limitations to this study. Firstly, as a specialist heart failure service, this study focuses on the quality of prescribing in relation to heart failure care only. Consequently, these data do not evaluate the quality of prescribing related to concomitant diseases managed by other speciality services. There are relatively small numbers of patients involved in the study. However, the large number of observations per patient has allowed meaningful statistical analysis of the polypharmacy and drug–interactions of the population. The criteria for drug interactions contained in the BNF are not exhaustive. However, as a standard reference applied equitably to the patients on admission and discharge, it provides a means of assessing the impact of the specialist heart failure service on medications in the context of an emergency admission for heart failure. Finally, this study is limited to prescribed medications and does not attempt to evaluate over-the-counter medicines and associated polypharmacy, which may contribute significantly to morbidity in this patient population [16].

More data is needed which could offer clinicians options to individualise therapy in heart failure rather than simply adding-in medication according to evidence base accumulated in highly selected patient populations [8]. While there is currently insufficient information on the exact nature of altered pharmacokinetics of many drugs prescribed in people with heart failure, the focus of guidelines may shift even more towards the practical approach of tailoring drug therapy according to clinical markers of efficacy, such as blood pressure and heart rate, or biomarkers such as BNP [28].


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Acknowledgments
 References
 
Specialist care of heart failure results in more appropriate pharmacotherapy of heart failure. However, increased polypharmacy and drug–interactions are an inevitable consequence and are independent of age, gender, renal function and heart failure type. We advocate a practice of systematic evaluation of polypharmacy in each patient, perhaps by a clinical pharmacist, to identify potential problems and modify therapy where appropriate.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
References
 
The authors wish to acknowledge Professor Peter Weedle, School of Pharmacy, University College Cork for his input on drug interactions.


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

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Current guidelines in the management of chronic heart failure: Practical issues in their application to the community population
Eur J Heart Fail, March 16, 2005; 7(3): 317 - 321.
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