Heart and Metabolism

New therapeutic approaches: safe prescribing in the elderly

Nicolas Wisniacki, Michael Lye
Department of Geriatric Medicine, University of Liverpool, Liverpool, UK
Correspondence: Dr Nicolas Wisniacki, Department of Geriatric Medicine, University Clinical Departments, The Duncan Building, Daulby Street, Liverpool L69 3GA, UK.
Tel: +44 151 706 4062, fax: +44 151 706 4064, e-mail: n.wisniacki@liv.ac.uk

Introduction
Elderly patients comprise 18% of the population but receive almost 25% of all prescribed medications.[1] However, the bases for some of these prescriptions are not well established and many may be unnecessary.[2,3] The prevalence of inappropriate drug prescription in older patients may be as high as 14% to 24% in community-dwelling older people[4,5] and 12% to 40% in nursing home residents.[5,6] It has been suggested that improving prescribing practices for elderly patients may substantially reduce morbidity and health care expenses.[6]
Our aim in this review is to discuss some important features and difficulties found in the process of prescription for elderly patients. We will include aspects of pharmacological and nonpharmacological treatment, and, as an example, will focus on congestive heart failure due to its high incidence and prevalence among the elderly.

Drugs and aging
It is difficult to generalize the pharmacokinetic and pharmacological characteristics of drugs taken by elderly patients. Several factors, such as multiple diseases, environmental influences, genetic variation, and the physiological changes of aging, may influence drug effect and metabolism in this group of patients.[7]

Pharmacokinetics
The pharmacokinetic characteristics of drugs are associated with age-related changes in the elderly. Drug absorption appears to be unchanged with increasing age.[7] The volume of distribution of water-soluble drugs (eg, digoxin) is smaller in the elderly, with a consequent higher plasma concentration than in the younger patient given the same dose.[8] Conversely, an age-related increase in body fat at the expense of muscle, leads to a greater volume of distribution of lipid-soluble drugs (eg, amiodarone).[9] Both pathways of drug excretion, liver metabolism and renal excretion, may be changed in elderly patients. Hepatic mass decreases with age and the clearance of drugs with low intrinsic clearance would therefore be expected to be reduced. Increasing age is associated with a reduction in presystemic metabolism (first pass) of drugs with a high rate of hepatic extraction (eg, propranolol, tricyclic antidepressants, and antiarrhythmic agents).[7] Age-related decline in glomerular filtration rate and tubular excretion modifies the half-life and plasma concentration of drugs with predominantly renal excretion.[10] Simple prerenal impairment associated with dehydration secondary to influenza or a chest infection may lead to life-threatening intoxication by an otherwise safely administered drug.[11]

Pharmacodynamics
Drug effects on the body also show modifications by the aging process. b-Adrenergic agonists and antagonists have been shown to be less effective in this population due to receptor downregulation.[12,13] The clinical relevance of this requires further investigation.
Adverse drug reactions in elderly patients have been extensively studied. However, the available information is incomplete because older people have been systematically excluded from the clinical trials that have given us the most reliable information.[14] The frequency of adverse drug reactions is higher in older patients because of the increased number of prescribed medications and the higher incidence of comorbidity. After controlling for the number of medications prescribed, the effect of age disappears, as shown in some studies.[15] Adverse drug reactions have been recognized as an important reason for hospital admission of elderly patients, contributing to between 3% and 12% of all geriatric admissions.[3,16,17]

Evidence-based prescribing
Randomized, placebo-controlled trials provide the strongest evidence available to take into account before selecting treatment. Several powerful randomized clinical trials have established the role of pharmacological treatments for patients with congestive heart failure. These include the use of ACE inhibitors,[18,19] b-blockade,[10,20,21] and spironolactone,[22] which impact positively on mortality and morbidity, and digoxin,[23] which reduces hospitalization and improves symptoms in chronic heart failure.
Although there is important evidence to support the use of these drugs, the majority of the trials have excluded patients older than 70 years, and the number of very old patients (over the age of 85 years) is practically minimal (Table I).[14]

Table I. Participation by age and gender in randomized clinical trials (adapted from reference 24).

Only the ELITE trials (Evaluation of Losartan in the Elderly), originally designed to demonstrate equivalence between drugs, were focused on a population of elderly heart failure patients. Surprisingly, only some of the landmark clinical trials actually had an upper age limit for inclusion: VHeFT-II[27] (Vasodilator Therapy with Hydralazine Isosorbide Dinitrate Trial II), 75 years; CIBIS-I28 (Cardiac Insufficiency Bisoprolol Study I), 75 years; US Carvedilol Heart Failure Study,[10] 85 years. The number of females recruited in some trials was as low as 20% (Table I), and the exclusion of women at least in part reflects the exclusion of older patients, as older females with heart failure are more prevalent.[24] Ongoing trials such as PEP-CHF[29] or PREAMI[30], specifically designed to include elderly patients over 70 years with heart failure or over 65 with post myocardial infarction will help to identify the role of ACE inhibitors in those patients.
Can we extrapolate the results from the randomized clinical trials in relatively young individuals to the treatment of older people? Clinical guidelines suggest that the therapeutic approach in elderly patients with systolic dysfunction should be similar to that in younger patients.[31] As discussed previously, precautions need to be taken and doses adapted due to altered pharmacokinetic and pharmacodynamic properties in the light of older age and comorbidities. The prescription of short-acting, powerful loop diuretics to elderly patients with relative immobility due to Parkinson’s disease should be circumspect at the very least. Older patients with congestive heart failure are more likely to have preserved systolic function. Such patients have not been included in the major treatment trials.[32] Patients with comorbidities are usually excluded from clinical trials and there is a lack of information about potential drug and disease interactions. In clinical trials, patients receive special care, including better monitoring for adverse reactions, plasma biochemistry, and, in some cases, a careful monitoring of plasma drug levels, whereas in clinical practice this is impossible.
We know that the evidence available fails to cover a large majority of patients with heart failure who are older than those in the trials, and we therefore have to rely on clinical acumen and general principles when treating these older patients.

Concordance with treatment
Nonconcordance with treatment may be one of the most important problems in the management of elderly patients.[33] In clinical practice, almost half of the patients for whom appropriate therapy has been prescribed fail to receive full benefit through inadequate concordance with treatment.[33,34] Concordance is reduced when the regimen is complex, of long duration, dependent on an alteration to the patient’s lifestyle, inconvenient, or expensive.
For example, treatment for chronic congestive heart failure is complex, includes a minimum of two different medications (in most cases four or five), requires following multiple dosing schedules, and is for life. Nonconcordance with drug treatment and diet has been reported to be the leading cause of decompensation in chronic heart failure, accounting for almost 50% of hospital readmissions.[35]
The limitations of the different methods available to monitor drug concordance and the restricted information from randomized clinical trials do not reflect the real magnitude of the problem. In the DIG (Digitalis Investigators’ Group) trial,[23] 70% of patients in the digoxin arm were still taking digoxin at the end of the follow-up period, demonstrating the high adherence to treatment in the clinical trial situation. An epidemiological study evaluated the compliance of digoxin in elderly patients in clinical practice and showed that only 10% of the patients filled enough prescriptions to acquire the amount of drug prescribed.[36] Clinical trials reflect idealized circumstances, whereas most patients are treated in the real world of poor concordance and limited monitoring.
Changes could be introduced to the treatment strategy to improve all patients’ drug concordance. These include a less complex regimen by reducing the number of different medications required, avoiding nonessential medicine and unnecessary doses; and breaking the treatment regimen into less complex stages that can be implemented sequentially, minimizing both inconvenience and forgetfulness by matching the regimen schedule to the patient’s regular daily activities.[33] Other helpful approaches are the use of tablets with drug combinations, longer acting drugs, and regimens that require less frequent doses. Relatives and carers can be recruited to aid concordance and are especially beneficial for a cognitively impaired patient.

Nonpharmacological interventions
Nonpharmacological management, including diet and lifestyle modification, are therapeutic strategies that have shown benefit in several conditions such as hypertension,[37] coronary heart disease, and congestive heart failure.[31] To improve the therapeutic effect of the pharmacological and nonpharmacological treatments in elderly patients, multidisciplinary interventions have been established to augment patients’ information and improve concordance.[38,39] Support programs that may well include teaching sessions or pharmacists’ home visits to reinforce the information on pharmacological treatment, have increased medication compliance by up to 85% and reduced the hospital readmission rate in approximately 50%.[40,41]
The overall effect of the multidisciplinary approach in elderly patients with congestive heart failure includes a decrease in readmissions, improvement of quality of life, and, most importantly, reduction of cost of care.38 The effect of the relatively inexpensive interventions seems to continue for a long period, and not only immediately after the moment of the intervention.[41]

Conclusions
Drug therapy should be adjusted according to individual age effects on pharmacokinetics and pharmacodynamics in older people. Unnecessary medications should be avoided to reduce adverse reactions and nonconcordance associated with multiple drug therapies. Simplicity should be the watchword. Nonpharmacological management including lifestyle and diet modifications, and multidisciplinary support programs should be more widely used. Further studies that include more elderly patients are urgently needed to establish the best management protocols based on cost-benefit results.

Future perspective
Our ability to prolong life with pharmacological interventions is an obvious benefit of research. However, years gained must not be at the expense of quality of life (Figure 1).

Figure 1. Life-prolonging intervention and effect on handicap. Without intervention (solid line) time spent handicapped (a) is short. Intervention (broken line) prolongs life (c + b) but if period of handicap is much longer than the non-handicapped gain (c) the value of the intervention must be questioned.

If the years gained are to be characterized by increasing disability and handicap, are they really worthwhile? Our objective, especially in older patients, must be to “compress morbidity,” thus relieving disability rather than simply adding worthless years to life.

REFERENCES

1: JAMA 1998 Oct 14;280(14):1249-52