Inappropriate prescribing in the elderly

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1 Journal of Clinical Pharmacy and Therapeutics (2007) 32, REVIEW ARTICLE Inappropriate prescribing in the elderly P. Gallagher MB MRCPI, P.Barry MB MRCPI and D. O Mahony MD FRCPI FRCP Department of Geriatric Medicine, Cork University Hospital, Wilton, Cork, Ireland SUMMARY Background and objective: Drug therapy is necessary to treat acute illness, maintain current health and prevent further decline. However, optimizing drug therapy for older patients is challenging and sometimes, drug therapy can do more harm than good. Drug utilization review tools can highlight instances of potentially inappropriate prescribing to those involved in elderly pharmacotherapy, i.e. doctors, nurses and pharmacists. We aim to provide a review of the literature on potentially inappropriate prescribing in the elderly and also to review the explicit criteria that have been designed to detect potentially inappropriate prescribing in the elderly. Methods: We performed an electronic search of the PUBMED database for articles published between 1991 and 2006 and a manual search through major journals for articles referenced in those located through PUBMED. Search terms were elderly, inappropriate prescribing, prescriptions, prevalence, Beers criteria, health outcomes and Europe. Results and discussion: Prescription of potentially inappropriate medications to older people is highly prevalent in the United States and Europe, ranging from 12% in community-dwelling elderly to 40% in nursing home residents. Inappropriate prescribing is associated with adverse drug events. Limited data exists on health outcomes from use of inappropriate medications. There are no prospective randomized controlled studies that test the tangible clinical benefit to patients of using drug utilization review tools. Existing drug utilization review tools have been designed on the basis of North American and Received 17 October 2006, Accepted 2 November 2006 Correspondence: D. O Mahony, Department of Geriatric Medicine, Cork University Hospital, Wilton, Cork, Ireland. Tel.: ; fax: ; omahoney@shb.ie Canadian drug formularies and may not be appropriate for use in European countries because of the differences in national drug formularies and prescribing attitudes. Conclusion: Given the high prevalence of inappropriate prescribing despite the widespread use of drug-utilization review tools, prospective randomized controlled trials are necessary to identify useful interventions. Drug utilization review tools should be designed on the basis of a country s national drug formulary and should be evidence based. Keywords: Beers criteria, elderly, health outcomes, inappropriate prescribing, prescriptions, prevalence INTRODUCTION Inappropriate prescribing encompasses the use of medicines that introduce a significant risk of an adverse drug-related event where there is evidence for an equally or more effective but lower-risk alternative therapy available for treating the same condition. Inappropriate prescribing also includes the use of medicines at a higher frequency and for longer than clinically indicated, the use of multiple medicines that have recognized drug drug interactions and drug disease interactions, and importantly, the under-use of beneficial medicines that are clinically indicated but not prescribed for ageist or irrational reasons. People over the age of 65 years have a higher prevalence of chronic illness, disability and dependency than those <65 years. They are more likely to be on medication than younger people. They are often taking several drugs at once to treat concomitant disease processes. A recent survey of 2590 non-institutionalized older adults in the United States showed an increased usage of all medications with advancing age, the highest prevalence of drug use being in women 65 years of age and Ó 2007 The authors. Journal compilation Ó 2007 Blackwell Publishing Ltd 113

2 114 P. Gallagher et al. older with 12% taking 10 or more medications and 23% taking at least five prescribed drug therapies (1). Everitt and Avorn (2) found that elderly women took, on average, 5Æ7 prescription drugs and 3Æ2 non-prescription drugs concurrently. In most industrialized nations older people consume three times as many prescription medications as younger people and purchase 70% of non-prescription medications (3). In the United States, 12Æ5% of the population is over 65 years of age but consume 32% of all prescription medications and account for 25% of drug expenditure and 30% of total national healthcare expenditure (4 6). In Ireland, people over the age of 65 years comprise 11Æ13% of the population but consume 47% of all prescription medications (7). In Europe, people over 65 years of age consume on average 2Æ3 times the amount of health care than do those <65 years of age (8). These figures indicate that older people are the greatest consumers of medications and healthcare resources in developed countries. Population demographics are changing worldwide, with life expectancy and the proportions of older persons increasing. It is reasonable to assume that as more drugs become available and longevity continues to increase, the consumption of prescription drugs by older people will increase further and the incidence of potentially inappropriate prescribing will grow. CHALLENGES IN PRESCRIBING FOR OLDER PEOPLE Older people are a heterogenous group, often with multiple concomitant illnesses and multiple prescriptions. Prescribing for older people is challenging as any new medication must be considered in the context of altered pharmacokinetics (drug absorption, distribution, metabolism and excretion), altered pharmacodynamics (physiological effects of the drug) and age-related changes in body composition and physiology. With ageing, there is a decrease in lean body mass and total body water with a relative increase in total body fat (9). Such changes lead to a decreased volume of distribution for hydrophilic drugs such as lithium, ethanol and digoxin where unadjusted dosing can result in higher plasma concentrations, thus increasing the potential for adverse effects. Conversely, lipid soluble drugs such as long-acting benzodiazepines have an increased volume of distribution, thereby delaying their maximal effects and resulting in accumulation with continued use. There is a reduction in hepatic mass and blood flow with ageing (10). Drugs such as beta-blockers, nitrates and tricyclic anti-depressants that have a first pass effect in the liver may have a higher bioavailability in older people and thus be effective at lower doses. Cytochrome P450 oxidation declines with ageing (11, 12) and drug drug interactions involving these enzymes are important to recognize. Excretion is altered as a result of agerelated changes in renal structure (9). Larger drug storage reservoirs and decreased clearance prolong drug half-lives and lead to increased plasma drug concentrations in older people. If serum albumin is decreased there will be an increase in the active unbound drug concentration for highly proteinbound drugs such as phenytoin, theophylline, warfarin and digoxin. Ageing is also associated with changes in the end-organ responsiveness to drugs at receptor or post-receptor level. There is decreased sensitivity to beta-receptors along with a possible decreased clinical response to beta-blockers and beta-agonists (13, 14). Increased sensitivity to drugs such as opiates and warfarin is common (15, 16). Changes in patient medical status over time can cause medications that have been used chronically to become unsafe or ineffective. Particular care must be taken in determining drug dosages when prescribing for older adults. POLYPHARMACY The use of several drugs concomitantly is justified in the treatment of multiple chronic diseases. However, polypharmacy is known to dramatically increase the risk of adverse drug reactions (ADRs), drug drug and drug disease interactions (17 22). It has been claimed that patients taking two drugs face a 13% risk of adverse drug interactions, rising to 38% when taking four drugs and to 82% if seven or more drugs are given simultaneously (23). With polypharmacy, duplicative prescribing within the same drug class is prevalent and unrecognized drug adverse-effects are often treated with more drugs thus leading to prescribing cascades, e.g. using levodopa to treat the Parkinsonian adverseeffects of neuroleptic medications. Polypharmacy

3 Inappropriate prescribing in the elderly 115 also makes compliance with medications more challenging. Non-compliance with prescribed medications can result in sub-optimal therapeutic effectiveness and can have major clinical consequences (24, 25). If the existence of non-compliance is not recognized, the physician may increase the dose of the initial medication or add a second agent, increasing both the risk and the cost of treatment. ADVERSE DRUG REACTIONS Adverse drug reactions can be difficult to detect in older patients because they often exhibit non-specific symptoms such as lethargy, confusion, lightheadedness, falls, constipation and depression (26, 27). ADRs can lead to extra physician visits, hospitalizations, injury, deterioration of body functioning and even death (3, 25, 28 34). Drug-related hospitalizations account for 2Æ4 6Æ7% of all medical admissions in the general population; the proportion is much higher for older patients (22, 35 37). The ADR rate in older people is at least three times that of the general population. Bero et al. (38) found that 20% of re-admissions to hospital in a geriatric population of 706 patients were drug related. Seventy-five per cent of these admissions could have been prevented had medications been used properly (38). Col et al. (25) estimated that 17% of elderly patients in hospital were admitted as a result of non-compliance with medications or ADRs. A recent meta-analysis of 39 studies found an in-hospital incidence of ADRs of 6Æ7% and an incidence of fatal ADRs of 0Æ3%, making fatal ADRs amongst the six leading causes of death in the USA (36). ADRs in community based older patients may be as high as 30%. They are a major cause of hospitalization in the older patient and may account for as much as 20 30% of hospital admissions in this age group (33). A 1997 study of ADRs found that 35% of ambulatory older adults experienced an ADR and 29% required healthcare services (physician, emergency department, or hospitalization) for the ADR (26). Cooper (39) found that almost two-thirds of nursing home residents experienced ADRs over a 4-year period, with one in seven of these resulting in hospitalization. These figures indicate the magnitude of the morbidity and resource utilization associated with adverse drug events in the elderly. Several studies have suggested that inappropriate prescription drug use is a principal cause of ADRs (33, 40). A Swedish population-based study of 785 community-dwelling people over the age of 75 years found that inappropriate drug use was common, with a prevalence of 18Æ6% (40). Over 3 years of follow up, inappropriate drug use was associated with increased risk of at least one acute hospitalization in community-living elderly, after adjustment for age, sex, education, co-morbidity, dependency in activities of daily living and smoking (40). DRUG UTILIZATION REVIEW TOOLS One way to identify potentially inappropriate prescriptions in older adults is to use validated screening tools that incorporate explicit prescribing indicators. There are two principal validated screening tools cited in the literature Beers Criteria (41 43) and Improved Prescribing in the Elderly Tool (IPET) (44), which is based on McLeod s 1997 criteria (45). These tools list medications that have a high potential for adverse effects in older people and recommend alternatives with lower risk. BEERS CRITERIA In 1991 Beers et al. (41) published the first set of explicit criteria for determining inappropriate medication use in nursing home residents. A modified Delphi technique was employed to derive consensus opinion on prescribing indicators from a panel of 13 experts in geriatric medicine, long-term care, geriatric and psychogeriatric pharmacology and pharmacoepidemiology. The expert panel produced a list of 30 medications to be avoided in nursing home residents regardless of diagnoses, dose and frequency of medication use. This list incorporated certain psychotropic medications, antihypertensives, oral hypoglycaemic agents, nonsteroidal anti-inflammatory drugs and analgesic agents. In 1994, Stuck et al. (46) modified Beers 1991 criteria to study inappropriate drug use in community dwelling older persons as the original criteria were intended solely for nursing home residents. The modified list contained most of the same drugs as the original, with the exception of methyldopa and propranolol.

4 116 P. Gallagher et al. Beers 1991 criteria, and the modified 1994 version, have been used to assess inappropriateness of prescribing for the elderly in a number of studies. A review of such studies by Aparasu and Mort (47) in 2000 found the prevalence rate of inappropriate drug use varied from 14% in community-dwelling elderly to 40Æ3% in nursing home residents. Despite differences in study populations and methodology, the review highlighted some consistent patterns of use of inappropriate medications across different healthcare settings. The most frequently prescribed inappropriate medications using Beers 1991 criteria were long-acting benzodiazepines, dipyridamole, propoxyphene and amitriptyline. The risk of being prescribed an inappropriate medication increased with the number of medications prescribed on multivariate analyses. Some of the univariate analyses suggested other risk factors for receiving an inappropriate medication, including being female and being aged over 80 years (47). Wilcox et al. (48) conducted a large retrospective epidemiological study using the modified Beers 1991 criteria and concluded that 6 million older Americans were exposed to possible inappropriate medication use. In 1997, Beers (42) published a revised and more comprehensive set of explicit criteria for potentially inappropriate drug use in ambulatory people aged 65 years and over. The revised criteria were designed to be applicable to all elderly people regardless of their place of residence (community or nursing home) or level of frailty. A modified Delphi consensus method of validation enabled a panel of six experts to classify potentially inappropriate drugs into three categories: (i) drugs that generally should be avoided in older adults, (ii) drugs that exceed a maximum recommended daily dose and (iii) drugs to be avoided in combination with specific co-morbidity. The 1997 criteria were further revised by Zhan et al. (49) in 2001 to include the use of certain drugs in certain clinical situations, e.g. chlordiazepoxide in acute alcohol withdrawal, amitriptyline in low dose for neuropathic pain. Several large-scale epidemiological studies have used Beers 1997 criteria to estimate the prevalence of inappropriate drug prescribing in various populations across different care settings (49 57). In 2000, Liu et al. published a literature review which examined 11 such studies (58). The majority were retrospective cross-sectional studies of medical insurance databases or surveys, which, by their nature, rarely contained information on drug dosage or patient disease conditions. Therefore, only a subset of Beers 1997 criteria could be applied to these studies to assess inappropriateness of prescriptions. This subset comprised the list of medications that should be absolutely avoided irrespective of disease condition or medication dose. The prevalence rate of inappropriate prescribing ranged from 21Æ3% in community-dwelling persons over 65 years of age to 40% in nursing home residents, figures similar to those studies using the 1991 criteria. This suggests that nursing home residents are more vulnerable than other elderly groups when it comes to receiving inappropriate drugs. Other risk factors for inappropriate prescribing included polypharmacy, female sex and poor health status. However, although the prevalence of inappropriate prescribing identified by these studies in the United States is high, the retrospective design of these epidemiological studies fails to capture instances of drug drug interactions, drug disease interactions, errors in drug frequency and drug dosage regimens as well as instances of omission of clinically indicated medications. Beers Criteria were updated in 2002, again validated by a consensus technique (43). Medications were added to the general list of inappropriate medications, e.g. nitrofurantoin, doxazosin and amiodarone. Fifteen medications and medication classes were removed from the 1997 list, e.g. the use of beta-blockers (with exception of propranolol) in those with COPD, asthma, peripheral vascular disease and syncope or falls. The comorbidity list was also revised to include new diagnoses such as depression, Parkinsons disease and cognitive impairment and incontinence. However, the updated criteria do not identify all important causes of potentially inappropriate prescribing (e.g. drug drug interactions are not included). Controversy exists over some of the medications that are considered to be potentially inappropriate by Beers criteria, e.g. amitriptyline a tricyclic antidepressant that is useful in a broad range of pain syndromes. The criteria only deal with the prescribing of inappropriate medications and not with the under-prescribing of clinically indicated drugs and other drug management issues.

5 Inappropriate prescribing in the elderly 117 IMPROVED PRESCRIBING IN THE ELDERLY TOOL The IPET was first published in 2000 (44). It represented an attempt to update McLeod s previously published inappropriate prescribing criteria (45) whilst presenting a workable shortlist of the more common inappropriate prescription instances in routine clinical practice. However, IPET is deficient. It is not based on physiological systems. Its criteria are not comprehensive enough, there are only 14 cited situations to be avoided. IPET is heavily weighted towards cardiovascular, psychotropic and non-steroidal anti-inflammatory drug use. Many drug categories are under-represented. IPET has clear-cut errors, principally the avoidance of beta-blockers in heart failure and avoidance of benzodiazepines with long half-lives under any circumstances. There are no published prospective randomized studies in which IPET or Beers have demonstrated clear-cut benefit as an intervention with respect to morbidity, composite health resource utilization or mortality. POTENTIALLY INAPPROPRIATE PRESCRIBING IN EUROPE Beers criteria and McLeod s criteria were developed in the United States and Canada respectively, on the basis of those countries national drug formularies. European-specific criteria for potentially inappropriate medication use have not yet been developed, primarily because of significant differences in national drug formularies. However, a number of European studies have adopted Beers and McLeod criteria to investigate the prevalence of potentially inappropriate medication use by older people in Europe and to determine the risk factors for receiving such prescriptions (22, 59 61). A population-based survey in Finland estimated the prevalence rate of inappropriate prescribing at 12Æ5% (60). A study of hospitalized elderly people in Italy found the prevalence rate of potentially inappropriate medication to be 14Æ6% using Beers 1997 criteria (22). In this Italian study, age and cognitive impairment were associated with less inappropriate drug use, whereas a direct relationship was observed for a number of drugs used during hospital stay and Charlson co-morbidity index (22). These studies showed a somewhat lower prevalence of inappropriate medication use in Europe than in the United States. However, because of different study populations, time horizons and methodologies these studies have little comparability. Van Der Hooft et al. (62) studied the computerbased records of a group of 150 general practitioners in the Netherlands from 1997 to Using Beers 1997 and 2002 criteria this study found that the most frequently prescribed inappropriate drugs were nitrofurantoin, long-acting benzodiazepines, amitriptyline, promethazine and cimetidine. Conventional NSAIDs in persons with a history of gastric/duodenal ulcer were the most frequently prescribed contra-indicated drugs. The 1-year risk of receiving at least one inappropriate drug prescription for older people living in the Netherlands ranged between 16Æ8% and 18Æ5% according to the 1997 criteria and between 19Æ1% and 20% according to the updated 2002 criteria (62). A large, retrospective, cross-sectional study combined Beers 1997 and 2002 criteria and McLeod s 1997 criteria to determine the prevalence of potentially inappropriate medication use in 2707 patients receiving home-care in 8 European countries (61). Using all three sets of prescribing criteria in combination, 19Æ8% of these patients received at least one inappropriate medication. There were significant differences in the prevalence rates of inappropriate medication use between countries in Eastern Europe (41Æ1% Czech republic) and Western Europe (mean 15Æ8%, ranging from 5Æ8% in Denmark to 26Æ5% in Italy). Potentially inappropriate medication use was associated with polypharmacy, anxiolytic drug use, depression and poor economic situation. The odds of potentially inappropriate medication use were significantly increased with the number of associated factors. Those aged 85 years and older, and those living alone, were less likely to receive a potentially inappropriate prescription. The research group also applied Beers 1997 criteria in isolation to the data and found that the prevalence of potentially inappropriate medication use was generally <11%. When compared with epidemiological studies in the United States using Beers 1997 criteria, the prevalence rate of inappropriate prescribing for European countries is remarkably lower than that in the United States (22, 59 61). Differences in drug

6 118 P. Gallagher et al. policy and pharmaceutical marketing among countries may have a great impact on the extent of inappropriate drug prescribing. The low rate of potentially inappropriate prescribing in Denmark despite high rates of polypharmacy is likely related to drug utilization review provided by the National Institute of Health with feedback to individual physicians (63). In the UK, clinical pharmacists auditing and implementation of guidelines has contributed to lower prevalence of inappropriate medication use (64). In the European study where Beers 1997 and 2002 criteria were combined with McLeod s criteria for potentially inappropriate prescribing the authors reported that nearly half of the medications from the combined list were not approved in most European countries (61). The percentage of drugs on the list of inappropriate medications that were approved in European countries was 31Æ6% in Norway, 48Æ1% in the Netherlands, 50Æ6% in Iceland, 51Æ9% in Denmark, 55Æ7% in Finland and UK, and 70Æ9% in Italy. Similarly, drugs that may be inappropriate for older persons may be marketed in Europe and not included in the Beers list, because they are not marketed in the USA. Considering this, the extent of inappropriate drug prescribing observed in European studies using American and Canadian criteria might be an under-representation of the problem. Conversely, the Beers list may not be complete enough to adequately assess inappropriate drug prescribing in Europe. This raises the question of whether criteria for potentially inappropriate prescribing in North America are suitable for a European population where differences in drug formularies and prescribing attitudes are different not only from America but also vary from one country to another within Europe. OUTCOME STUDIES OF DRUG UTILIZATION REVIEW TOOLS Beers criteria have become established as a standardized tool for pharmacological research. However, they have mainly been used to examine prevalence and trends in the prescribing of potentially inappropriate medications to older people. Few studies have addressed the associations between inappropriate drug use and patient health outcome measures. A study of patients at an emergency department found that those receiving inappropriate drugs at or during admission had significantly poorer quality of life in terms of physical function and pain in the 3-month follow up period compared with those not receiving inappropriate drugs (50). No association was found between potentially inappropriate prescription and death or return visits to the emergency department (50). Fick et al., in a retrospective study of a Medicare Managed care population, identified changes in healthcare costs and utilization resulting from inappropriate drug use. After controlling for gender, co-morbidity and total number of prescriptions, patients receiving inappropriate drugs were found to use more healthcare services, including hospital inpatient and outpatient visits, emergency department visits and general practitioner visits (54). A study of 3372 elderly nursing home residents in the United States showed that certain patterns of exposure to inappropriate drugs were associated with higher risk of subsequent hospitalization and death (65). Those who received any potentially inappropriate medication had greater odds of being hospitalized and at greater risk of death in the following month than those not receiving a potentially inappropriate medication. Residents with potentially inappropriate medication exposure for two consecutive months were also at increased risk of hospitalization. Residents with intermittent potentially inappropriate medication exposures were at greater risk of death compared with those with no potentially inappropriate medication exposure. These studies were based on local populations or healthcare settings, which limited the generalizability of their results. Existing literature offers little evidence of how inappropriate drug use would affect patient health outcomes. There is an absence of prospective randomized controlled trials that test the tangible clinical benefit to patients and health resource utilization of using such prescribing criteria. Few studies provide the empirical evidence for the adverse effect of inappropriate medication use on health outcomes at a national level. CONCLUSION It is clear from the published literature that potentially inappropriate prescribing is highly prevalent. Beers criteria and IPET have been widely referenced in the literature yet have not

7 Inappropriate prescribing in the elderly 119 made their way into mainstream clinical practice. What is required is a workable, systematic, evidence-based, easily applicable list of prescribing indicators that would capture most commonly used, but potentially inappropriate medications, common drug drug interactions and drug disease interactions as well as medications that are clinically indicated, e.g. the use of warfarin in patients with atrial fibrillation. A drug utilization review tool should not replace clinical judgement but should provide guidance as to appropriateness of therapy in common clinical situations. Drug utilization review tools should be designed on the basis of a country s national drug formulary and should be evidenced based. More older people should be participating in clinical trials to broaden the evidence based upon which drug utilization review tools can be developed. A screening tool by definition must be shown to improve outcome. There is a need for randomized control trials to test the true benefit to patients of screening their medications in terms of morbidity and mortality, and also in terms of health resource utilization. Comparing outcomes could provide useful information as to what extent these criteria are relevant in clinical practice and how they influence the prognosis of older patients. It is also clear from reviewing the literature that the incidence of potentially inappropriate medication prescribing is not decreasing. The training of medical students and doctors, as well as pharmacists and nursing staff in appropriate pharmacotherapy for the elderly is paramount for drug utilization screening tools to be a success. Other aspects of medication care such as under-prescribing, drug monitoring and documentation should be used in a complementary way with explicit criteria to improve drug prescribing in this vulnerable group. REFERENCES 1. Kaufman DW, Kelly JP, Rosenberg L et al. (2002) Recent patterns of medication use in the ambulatory adult population of the United States: The Slone Survey. JAMA, 287, Everitt DE, Avorn J (1986) Drug prescribing for the elderly. Archives of Internal Medicine, 146, Christchilles EA, Foley DJ, Wallace RB et al. (1992) Use of medications by persons 65 and over: data from the established populations for epidemiologic studies of the elderly. Journal of Gerontology, 47, Arnett RH III, Blank LA, Brown AP et al. (1990) National Health Expenditures Office of National Cost Estimates. Health Care Financing Review, 11, Gupta S, Rappaport HM, Bennett LT (1996) Inappropriate drug prescribing and related outcomes for elderly Medicaid beneficiaries residing in nursing homes. Clinical Therapeutics, 18, Golden AG, Preston RA, Barnett SD et al. (1999) Inappropriate prescribing in homebound older adults. Journal of the American Geriatrics Society, 47, Barry M (2002) Drug Expenditure in Ireland IMJ, 95, O Connor K, O Mahony D (2003) Drugs and ageing. In: Liston R, Mulkerrin EC, eds. Medicine for older patients: cases and practice. Dublin, Ireland: Eireann Healthcare Publications, Meyer BR (2003) Clinical pharmacology and ageing. In: Grimley Evans J, Franklin Williams T, Lynn Beattie B, Michael J-P, Wilcock G, eds. Oxford textbook of geriatric medicine, 2nd edn. Oxford: Oxford University Press, Woodhouse KW, Ewynne HA (1988) Age related changes in liver size and hepatic blood flow: the influence of drug metabolism in the elderly. Clinical Pharmacokinetics, 15, Hunt CM, Westerkam WR, Stave GM et al. (1992) Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. Mechanisms of Ageing and Development, 64, Hunt CM, Westerkam WR, Stave GM (1992) Effect of age and gender on the activity of human hepatic CYP3A. Biochemical Pharmacology, 44, Vestal RE, Wood AJJ, Shand DG (1988) Adrenoreceptor status and cardiovascular function in ageing. Journal of Hypertension, 6(Suppl. 1), S59 S Vestal RE, Wood AJJ, Shand DG (1979) Reduced beta adrenoceptor sensitivity in the elderly. Clinical Pharmacology and therapeutics, 26, Gage BF, Fihn SD, White RH (2000) Management and dosing of warfarin therapy. American Journal of Medicine, 109, Beers MH, Berkow R eds (2000) Clinical Pharmacology. The Merck manual of geriatrics, 3rd edn. White house Station, NJ: Merck Research Laboratories, Holbrook AM, Pareira JA, Labiris R et al. (2005) Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine, 165, 1095.

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