Managing polypharmacy issues

Cardiology Review® Online, September 2004, Volume 21, Issue 9

Nannette M. Berensen, PharmD • C. Wayne Weart, PharmD

From the Department of Pharmacy and Clinical Sciences and the Department of Family Medicine, Medical University of South Carolina, Charleston, South Carolina

In 2000, there were 35 million people aged 65 years or older living in the United States, a 12% increase compared with data from 1990.1 Those who reach age 65 can expect to live another 15 to 19 years.1 As a group, the elderly purchase and consume more prescription and over-the-counter (OTC) medicines than any other age group.2,3 This is not surprising, considering that elderly people take an average of four to five medications at any given time. The effects of aging make this age group particularly vulnerable to adverse drug events.4,5 Mannesse and colleagues found that one in six older patients admitted to a general medicine floor had an adverse drug reaction, and 25% had serious drug reactions.6 Polypharmacy, therefore, assumes increasing importance in the day-to-day management of this population.

Major polypharmacy generally refers to using five or more medications concurrently; the term also applies to any medication regimen that contains any unnecessary medications.7-9 The potential consequences of polypharmacy include adverse drug reactions, drug interactions, medication errors, decreased medication adherence, increased costs, and increased consumption of health care services.

Polypharmacy should not be confused with justifiable augmentation therapy, for example, adding a diuretic to a patient’s beta-blocking agent regimen if blood pressure is not controlled. Using multiple medications that have different and complementary mechanisms is deemed necessary and advocated in various treatment guidelines, such as for congestive heart failure (five medications), the treatment of Helicobacter pylori (three medications), and type 2 diabetes (two or more antidiabetic agents).10-12

Contributing factors

Information overload without meaningful education. Direct-to-consumer pharmaceutical advertising in print, on television, and on the Internet is unprecedented. It is common for patients to request medications by name during office visits. Fueling this behavior are the patients’ strong beliefs that medications make people well and are indeed necessary. Although many patient education databases, textbooks, and company-sponsored educational materials are available, most patients appear to have no better understanding of their medication regimens today than they did 20 years ago. This is probably because most physicians and pharmacists do an inadequate job of explaining medication regimens. Moreover, patients are often not educated frequently enough

to ensure proper medication use.

To test this point, ask 10 patients with asthma to demonstrate their metered-dose inhaler technique.

Incomplete assessments, responses, and documentation. Incomplete history taking or incomplete documentation in the medical record by health care professionals, especially regarding changes in dosage, medication schedules, or medication discontinuations, contributes to polypharmacy. It is essential to specifically ask the patient if other practitioners have evaluated them since their last visit and to determine if they are taking additional medications or have had their regimen otherwise altered.

Poor adherence to and lack of persistence with medication regimens also contributes to poly-

pharmacy. Consider a patient with asthma who was prescribed the AdvairDiskus® 100/50 (a combination of 100 µg of fluticasone and 50 µg of salmeterol) and an albuterol inhaler for rescue. At her 6-month follow-up visit, the patient reports that she is still having frequent exacerbations. The physician decides to prescribe the AdvairDiskus® 250/50, twice daily, and calls in the prescription by phone to the patient’s pharmacy. On consulting with the pharmacist, the physician learns that the patient had only refilled the Advair- Diskus® 100/50 once in the last 6 months, but refilled her albuterol inhaler 22 times during the same period.

Patients may also provide incomplete responses when asked about their medication use. If patients are not properly educated about their medications to begin with, it is unlikely that they will be good historians. Many patients believe that OTC medications, vitamins, and herbal preparations are harmless and, therefore, they do not mention these products. Prescribers are encouraged to specifically solicit this information in a supportive manner when taking a medication history. Although a prescriber may not want the patient to use certain OTC or herbal preparations for valid clinical reasons, patients need to feel comfortable discussing this type of information with their physicians.

Pharmacy-order entry data provide limited information and are no substitute for a face-to-face medication history. These data may reveal information about prescriptions filled at a specific location only and afford little information regarding efficacy, tolerability, or safety. They also do not allow the clinician to determine if a patient is taking the medications as the prescribers intended. Unintended polypharmacy may result from prescribers using trade or brand names for combination products; hence, the prescriber may be unaware of all the active ingredients contained in the preparation.

Automatic therapeutic substitution programs. It is increasingly common for health care organizations to use automatic therapeutic substitution (ATS) programs. These programs provide authorization for phar-macists to substitute a formulary

medication in place of an ordered nonformulary medication without having to contact the prescriber. ATS protocols have been deemed to be therapeutically equivalent and have been sanctioned by the organization’s medication use governing body (eg, the pharmacy and therapeutics committee). Although ATS programs are intended to minimize nonformulary use, inadequate patient or caregiver education may result in unintended therapeutic duplication, further contributing to polypharmacy. Consider the following scenario. A patient is admitted to a hospital that uses ATS protocols for various medication classes (eg, proton pump inhibitors, angiotensin-converting enzyme [ACE] inhibitors). Before admission, the patient was taking lansoprazole and enalapril. Based on the institution’s ATS protocols, pantoprazole is substituted for lansoprazole and benazepril is substituted for enalapril during the patient’s hospitalization. A few days later, the patient is discharged with prescriptions for pantoprazole and benazepril. One week later, the patient is admitted to the emergency department. His wife states that he had been complain-

ing of dizziness and had fainted when getting up from the breakfast table. When questioned about his medications, she says that he had been taking lansoprazole, enalapril, pantoprazole, and benazepril. It is essential that patients and caregiv-ers receive adequate discharge and medication counseling to prevent this situation from occurring.

Aging. As part of the normal aging process, people experience changes in organ function. After age 40, for example, creatinine clearance dereases by about 6.5 mL/min per decade based on 1.73 m2 body surface area.13 Normal aging also results in decreased hepatic and biliary function and changes in pharmacodynamics; for many medications, there appears to be an increase in the sensitivity of receptors.6 These age-related changes, often complicated by other comorbidities, set the stage for problems with polypharmacy. Prescribers may find the revised Beers Criteria for Potentially Inappropriate Medication Use in Older Adults helpful in deciding which medications to avoid altogether and which to avoid based on a patient’s concomitant diseases or conditions.14

Drug—drug interactions. Drug–

drug interactions may have a pharmacokinetic or pharmacodynamic basis. A pharmacokinetic interaction results when the effect of one medication alters the absorption, distri-bution, metabolism, or elimination

of another. Of interest, changes in protein binding attributed to age generally do not significantly affect drug disposition.15 A pharmacodynamic interaction may result when the synergism or antagonism of one agent exhibits a pharmacologic effect that would not be expected with either drug alone. Malone and colleagues conducted a cross-sectional evaluation to create a list of clinically important drug—drug interactions commonly encountered in the ambulatory and community pharmacy settings.16 An expert panel that consisted of two physicians, two pharmacists, and a drug-interactions expert systemically reviewed standard drug interaction references and primary literature, and developed a list of 25 drug–drug interactions that are clinically important.

More medications available. At present, there are over 10,000 prescription medications available in the United States, and that number is rising.17 According to a recent survey by the Pharmaceutical Research and Manufacturers Association, pharmaceutical and biotechnology companies have more than 800 medicines in development to better manage diseases common in the elderly, including Alzheimer’s disease, arthritis, cancer, heart disease, osteoporosis, Parkinson’s disease, and stroke.18 In addition, there are more than 100,000 OTC products currently marketed, encompassing about 800 active ingredients and more than 80 therapeutic categories.17

Compliance/adherence/persistence. Col and colleagues reported that as many as 11.4% of hospital admissions are attributed to poor medication compliance.19 Medication adherence following hospitalization is also of concern. A study evaluating this issue in 50 patients recently discharged from a hospital showed that, within 2 weeks of discharge, more than 20% of patients had deviated from the prescribed regimen.20 Regimen complexity appeared to be a factor affecting compliance. Fewer than 25% of the patients knew the names and purposes of their medications, and 70% could not state one side effect that their medications might cause. More recently, Barat and colleagues evaluated data from 348 patients who were aged 75 years.21 Although they reported that 60% of patients knew the indication for at least 75% of their medications, only 21% understood the consequences of omitting a drug or dose. Perhaps more concerning, the data showed that only 4% of patients had any knowledge of adverse effects.

Practical advice for avoiding problems

Patient education. To achieve optimal outcomes, patients must understand their disease states and medications. Patient education is critical to achieving this goal. Health care professionals should assume that patients have not been adequately educated unless they can prove otherwise. Until clear delineation for the responsibility of patient education is achieved, this assumption is in the patient’s best interest.

Patients who are elderly, cognitively impaired, mentally ill, blind, deaf, aphasic, or do not speak English may require additional efforts regarding patient education. Several aids can be used to facilitate patient understanding and improve medication adherence. Prefilled pillboxes make it easier for elderly patients to take the right medications at the right times. Pillboxes are easy to handle and do not require a high degree of manual dexterity. Most pharmacists are willing to fill pillboxes for their patients. Caution must be taken to prevent unintentional ingestion, because these devices usually do not have poison-prevention closures.

Charts detailing the purpose, dose, schedule, and common side effects of each medication can be created and posted on the patient’s refrigerator to serve as a daily reinforcement of the patient’s regimen. Instructions on what to do if the patient experiences an adverse effect and information on what to do if a dose is missed should be included. Additionally, patients and health care providers benefit from patients having an up-to-date medication list. The provider should review this at every patient encounter. Patients need to be instructed to always bring their lists of medications or a bag containing all of the medications they are currently taking, or both, to each health care appointment. Medication pamphlets used during a patient counseling session, if they are written appropriately, may be a useful future reference for the patient.

Clinical strategies. Several approaches can help avoid the use of multiple drugs and minimize their side effects, especially in the elderly.

• Use nonpharmacologic therapy first. To illustrate this concept, consider the conditions of insomnia and gastroesophageal reflux disease. Insomnia is a symptom, not a disease. Treating the underlying cause, such as anxiety, depression, gastroesophageal re-flux disease, diabetes mellitus, congestive heart failure, or pain, will generally eliminate insomnia. The physician needs to ensure that good sleep hygiene has been adequately tried. Patients suffering from gastroesophageal reflux disease should be instructed to raise the head of their bed

or to use a wedge pillow. Patients should also be advised to avoid lying down within 3 hours after

a meal.

• Select medications that do not have active metabolites. For example, if a benzodiazepine is indicated, choose lorazepam, oxazepam, or temazepam instead of diazepam. In general, avoid prescribing agents that have long half-lives. A physician wishing to prescribe chlorpropamide for a 72-year-old patient with type 2 diabetes with an estimated creatinine clearance of 50 mL/min should reevaluate this choice. Chlorpropamide has a terminal half-life of about 36 hours, is eliminated 100% renally, may cause dilutional hyponatremia, and can result in prolonged hypoglycemia. Furthermore, a decreased glomerular filtration rate may prolong the half-life to more than 72 hours. In contrast, glipizide has a terminal half-life of approximately 2 to 4 hours, is eliminated 80% renally, and has no active metabolites. It also has a lower risk of weight gain and hypoglycemia compared with other sulfonylureas.

• Keep medication regimens simple. Regimen complexity is a major factor in compliance. Although decreasing the number of medications is not always possible, the scheduling of those medications can usually be arranged to result in fewer administration times per day. When appropriate, consider prescribing combination products. If you have a patient who is taking 10 mg of enalapril and 25 mg of hydrochlorothiazide, consider prescribing Vaseretic® 10-25. There are many generic combination products available. In addition to reducing the patient’s pill burden, this will also eliminate an insurance copayment.

• Give medications an adequate trial before increasing doses, changing agents, or adding drugs to the regimen. For example, if you initiate treatment with a selective serotonin reuptake inhibitor for a patient suffering from depression, 4 to 6 weeks are needed to see the maximum effect of therapy.

• Eliminate any medication that does not have a current therapeutic indication. For example, continuing to prescribe a histamine2 antagonist when the patient is on a proton pump inhibitor is not rational prescribing.

• Be aware of multiple-ingredient preparations, especially those sold over the counter. It is not uncommon for cold and flu preparations to have four or five active ingredients. Consider a patient with osteoarthritis who is taking 1 g acetaminophen four times daily and develops a cold. While grocery shopping she purchases a cold and cough flu medication. She begins taking one packet every 6 hours for the next 5 days. Each packet of this product contains 650 mg of acetaminophen,

4 mg of chlorpheniramine maleate, 20 mg of dextromethorphan hydrobromide, and 60 mg pseudoephedrine hydrochloride. By using this cold preparation, the patient unknowingly ingests well above the maximum daily dose of acetaminophen.

• When possible, avoid treating adverse drug events with additional medications because the masking of side effects that may occur with additional agents perpetuates polypharmacy. Switching medications may be the best option. For example, rather than adding a stimulant laxative to the regimen of a patient who develops constipation while taking verapamil for hypertension, consider changing to diltiazem. Diltiazem is equally effective in controlling blood pressure and heart rate but has much less constipation associated with it.

• Partner with pharmacists who want to meet your drug information needs. Encourage them to keep you informed about your patients who they suspect are not adhering to their regimens, especially when nonadherence is caused by a patient’s inability to afford what you have prescribed. Pharmacists can also provide patients with intensive counseling regarding disease states and medications to reinforce or supplement the information that

the physician has provided. In addition, pharmacists play a pivotal role in informing patients about and assisting patients with medication assistance programs. Pharmacists can also help patients with compliance aids, including pillboxes or medication scheduling charts.

• Use a drug information center when the need for information

is complex. Drug information centers are designed and staffed to assist physicians, pharmacists, and nurses in managing patients’ pharmacotherapy regimens. Many centers provide services to practicing health care professionals free of charge. A listing of the major drug information centers can be found in the 2004 Physicians’ Desk Reference and Drug Topics Redbook.

Indications for polypharmacy

Polypharmacy is a complex issue because underprescribing can be as problematic as overprescribing.22-24 A recent study by Higashi and colleagues further supports this point.25 These investigators evaluated 43 quality indicators spanning four pharmacologic care domains in vulnerable elderly patients from two managed care organizations: (1) prescribing indicated medications; (2) avoiding inappropriate medications; (3) education, continuity, and documentation; and (4) medication monitoring. Of the 475 vulnerable patients identified, 372 had medical records that could be abstracted. In this study, the term vulnerable elders was defined as persons at least 65 years of age who were at increased risk of death or functional decline. The pass rate for avoiding inappropriate medications was favorable

at 97% (95% confidence interval

[CI], 96%—98%). In contrast, the pass rates in the other domains were as follows: prescribing indicated medication, 50% (95% CI, 45%–55%); education, continuity, and documentation, 81% (95% CI, 79%–84%); and medication monitoring, 64% (95% CI, 60%–68%).

When treating patients with chronic diseases or comorbidities, polypharmacy may be required to achieve optimal outcomes. Consider the case of a 66-year-old woman with type 2 diabetes, hyperlipidemia (total cholesterol, 150 mg/dL), and hypertension.26 In combination with diet and exercise, it is likely this patient will require two or more agents to achieve the goals of glycemic control (fasting blood glucose level between 80 and 100 mg/dL, A1C level below 6%; 1- to 2-hour postprandial glucose level below 180 mg/dL, and a bedtime glucose concentration between 100 and 140 mg/dL). The patient should receive an ACE inhibitor or an angioten-

sin-II receptor antagonist to prevent diabetic nephropathy. The patient may also require a second or third agent to reach the recommended goal blood pressure of less than 130/80 mm Hg. To reduce the risk of cardiovascular events based on this patient’s baseline total cholesterol concentration, it would also be appropriate to treat her with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to achieve a low-density lipoprotein (LDL) cholesterol reduction of approximately 30% regardless of baseline LDL. The patient would also be taking 81 to 162 mg of aspirin daily. To treat this common triad of conditions according to current guidelines, seven medications are needed.26

Helping patients afford their medications

Patients frequently express concern regarding their inability to afford medications. This is particularly true for regimens consisting of multiple agents. Physicians are encouraged to be mindful of medication cost at the time of prescribing. Generic preparations should be used whenever available. With the new Medicare-approved drug discount card, patients are likely to be more confused than ever. Physicians can play a significant role in teaching patients or their caregivers how to get the greatest value in health care. By calling 1-800-Medicare or by logging on to, providers, patients, and their caregivers can compare approved providers and enrollment fees and can obtain cost quotes for a 30-day supply of their medications.27 The table shows 5 of 34 discount programs available for 10 mg of atorvastatin daily and the pharmacies within a 3.5-mile radius of the zip code 29466. Although patients can only enroll in one Medicare-approved drug discount card plan, it is important for them to know that they may also use their non—Medicare-approved discount cards (eg, Together Rx, Pfizer Share Card, or Lilly Cares Card).

Costs associated with polypharmacy

Reviewing the costs associated with adverse drug reactions assists in understanding the costs associated with polypharmacy, which is a risk factor for adverse drug reactions.5,28 In the outpatient population, adverse drug reactions of all severity have been reported to occur in 32% of patients.5 Medication-related morbidity and mortality in this setting is estimated to cost $76.6 billion annually.29 In a meta-analysis, Lazarou and colleagues estimated that 6.7% of inpatients experience serious adverse drug reactions.30 Annual costs attributed to adverse drug reactions in hospitalized and nursing home patients have been calculated to be $20 billion and $4 billion, respectively.31,32


Poor medication management resulting in polypharmacy has significant resource implications for the health care, social, and private sectors. Although the issue is complex, solutions are not beyond reach. There is little doubt that medications allow patients to live longer, healthier, and more productive lives. The goal is not to eliminate polypharmacy but rather to achieve balanced and rational prescribing to optimize patient outcomes.