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Safe and Effective Drug Therapy in Older Adults

Posted on: Wednesday, 9 February 2005, 03:00 CST

The 35 million Americans aged 65 or older are a heterogeneous group, ranging from independently living older adults who have "successfully" aged with few comorbid conditions to the 1.6 million frail elderly nursing home residents.1

The last two decades have witnessed advances in drug therapy for the treatment and prevention of chronic diseases associated with aging. As death rates have declined, the prevalence of chronic diseases and the need for safe and effective drug therapy in the elderly has increased.

NEW DRUGS AND THE ELDERLY

An adage advises that one should not be the first person to prescribe a new drug, nor the last to abandon an old drug. This remains a fundamental principle in safe and effective prescribing in the elderly. Basic questions of safety, efficacy and value continue to challenge clinicians when new medications are introduced. Further, balancing the potential additive benefit against the extra expense compared to established medications can be difficult when an individual and society have limited resources. Also, pharmaceutical promotion traditionally highlights the possible advantages of a new medication while the potential for side effects and drug interactions remains inadequately defined in the elderly.

In 2003, the Food and Drug Administration (PDA) approved 18 new drug entities." With few exceptions for medications such as memantine that are used primarily in older adults with moderate-to- severe Alzheimer's disease, most new drugs for chronic conditions continue to be studied primarily in middle-aged, relatively healthy populations with few concomitant chronic diseases or medications. Although data are presented on the use of new drugs in "the elderly", these individuals are between the ages of 65 and 74, and rarely have multiple comorbid conditions such as heart failure or chronic renal failure. Despite this, many older adults with multiple coexisting conditions are among the first patients to receive a new drug in clinical practice.

The true safety profile of a new drug in the elderly frequently emerges only after its widespread use and remains dependent on voluntary reports to the PDA's MedWatch program (http://www.fda.gov/ medwatch/). Metformin is a classic example. The drug had been used in Europe for many years prior to its US approval. Metformin was considered to be essentially free of lactic acidosis that had prompted the removal of its predecessor, phenformin, from the US market in the 1970s. However, lactic acidosis was quickly recognized to be a significant adverse drug reaction in the elderly who commonly have multiple risk factors for its development including renal insufficiency and heart failure.

One of the best examples of the dilemma in using new drugs in the elderly is with the selective cyclo-oxygenase (COX)-2 inhibitors such as rofecoxib and celecoxib. Nonsteroidal anti-inflammatory drugs (NSAID) have been recognized for many years to cause adverse gastrointestinal (GI) effects ranging from dyspepsia to acute bleeding and death. The risk of serious GI complications from traditional NSAID varies from 7.3 per 1000 patient years in osteoarthritis to 13 per 1000 patient years in rheumatoid arthritis.3 The mortality rate from NSAID-induced GI complications has been estimated to be 0.22% yearly.3 Advanced age is consistently identified as a major risk factor, and the risk may increase linearly with age.

Celecoxib and rofecoxib quickly became among the most commonly prescribed medications, generating $3.05 billion and $2.5 billion, respectively, in global sales in 2002.4 A common perception continues to be that their safety is much better in the elderly. However, the actual overall safety profile of COX-2 inhibitors, compared to traditional NSAIDs, has remained controversial, in part based on two large studies including the Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.5,6

The CLASS trial enrolled 8059 patients with osteoarthritis or rheumatoid ardiritis, with 39% of participants 65 years of age or older and 12% were 75 years of age or older.5 Patients received celecoxib 400 mg twice daily, ibuprofen 800 mg 3 times/day, or dtclofenac 75 mg twice daily. The use of aspirin in a dose of 325 mg/ day or less was permitted for cardiovascular and cerebrovascular prophylaxis with 20% of participants using aspirin. The primaiy outcome measure was the annualized incidence of ulcer complications including gastric or duodenal perforation, gastric outlet obstruction and upper GI bleeding. The use of celecoxib and the traditional NSAID resulted in the occurrence of the primary outcome measure in 0.76% and 1.45%, respectively, of treated patients. This difference was not statistically significant. When the primary outcome measure was combined with symptomatic ulcers, the use of celecoxib and the traditional NSAID was associated with 2.08% and 3.54%, respectively. Among individuals using low-dose aspirin, celecoxib did not decrease the risk of either die primaiy or secondary outcome measure compared to ibuprofen or diclofenac.

This study is controversial. Significant concern was raised when it was reported that only 6-month data was released when more information was available and had been reported to the FDA. Although presented as one study, data from CLASS came from two studies including a 12-month comparison between celecoxib and diclofenac and a 16-month comparison to ibuprofen. Based on the CLASS findings, the FDA indicated that celecoxib does not offer major advantages in terms of GI safety, although it stated that the concomitant use of aspirin may have masked the benefit from celecoxib.

The VIGOR trial randomized 8076 patients (mean age, 58 years) with rheumatoid arthritis to receive rofecoxib 50 mg/day or naproxen 500 mg twice daily.5'6 The median duration of the study was 9 months. The use of low-dose aspirin was not permitted, and corticosteroids were used by over 50% of individuals enrolled in the study. The primary outcome measure was serious complications including perforation or obstruction, upper GI bleeding and symptomatic gasti'oduodenal ulcers. The relative risk of developing a perforation, obstruction and severe upper GI bleeding was 0.6 (95% CI 0.2,0.8) for participants receiving rofecoxib. Although greater GI safety was demonstrated, rofecoxib was associated with a higher risk of myocardial infarction. In individuals for whom prophylaxis with aspirin was indicated, the risk of a myocardial infarction was 0.1 % in the naproxen group compared to 0.4% with rofecoxib. In the absence of significant cardiovascular disease, the risk was 0.1% and 0.2% for naproxen and rofecoxib, respectively. Based on the findings of VIGOR, the FDA approved labeling changes to indicate a lower risk of serious CiI complications compared to naproxen. New warnings were added concerning the increased risk of cardiovascular events with rofecoxib.

Several points concerning the VIGOR trial deserve particular emphasis. First, individuals for whom cardiovascular prophylaxis with aspirin was indicated were permitted entry into this study and, as a result, did not receive aspirin. Second, the causes of the cardiovascular effects with rofecoxib are unknown. Initially, the finding was explained on die basis that naproxen has antiplatelet effects not possessed by rofecoxib due to its COX-2 selectivity. However, this explanation has been challenged on the basis that the potential benefit reported with naproxen was too great and is inconsistent with the overall benefit from antiplatelet agents such as aspirin reported by the AntithromboticTrialists' Collaboration. A meta-analysis using data from VIGOR and CLASS, as well as two smaller rofecoxib studies, indicated that the risk of cardiovascular events was 2.38 (95% CI 1.39 - 4.0) for rofecoxib compared to naproxen. The report also indicated that the annualized risk of developing a myocardial infarction with rofecoxib and celecoxib was significantly higher compared to the placebo group in the meta- analysis.7

How should these studies be applied in order to provide evidence- based care of older patients? Rofecoxib may offer advantages in terms of a lower risk of upper GI bleeding in individuals not taking aspirin, but this benefit may be overshadowed by a potentially increased risk of cardiovascular events that are under-recognized. Further, it is unknown if die GI benefit of rofecoxib persists in patients who are taking low-dose aspirin. This is critical for older adults many of whom will have concomitant cardiovascular disease or significant risk factors. Finally, the potential benefit of COX-2 inhibitors in older adults at high risk of serious GI complications remains unknown as neither study included these individuals. (Note: Rofecoxib was withdrawn from the market in September 2004 and the safety of the other COX-2 inhibitors is under review by rhe FDA due to additional new concerns in December 2004.)

MEDICATION COSTS

Medication costs remain a barrier for many older adults. The interim Medicare prescription cards, introduced in the summer of 2004, have yielded savings to people with low incomes, but its benefits have not been sufficiently worthwhile to encourage a majority of middle-income Medicare enrollees to sign up. Also, enrollees found the plans confusing.

Regardless of the final Medicare prescription drug benefit, at least some medication costs \can be controlled by more reflective prescription practices by clinicians. For example, the use of prescription esomeprazole (Nexium) over generic omeprazole (Prilosec) is one example of unnecessary medication costs. Esomeprazole is an optical isomer of omeprazole and provides similar safety and efficacy, yet may cost between $80 and $100 more per month. As always, the most basic issue in controlling costs should always be whether or not a drug is even needed for a problem.

THE PRESCRIBING CASCADE

Polypharmacy has been defined as "the administration of many drugs at the same time". A discussion of prescribing issues in the elderly traditionally emphasizes the problem of "polypharmacy". However, based on the evidence from major clinical trials, the provision of quality care to a 75 year old patient with hypertension, type 2 diabetes mellitus and a prior myocardial infarction would encourage 2 drugs each for blood pressure and glucose control, a statin and at least aspirin or another antiplatelet agent, easily reaching a total of 6 drugs for a single patient.

Instead of simply considering the number of drugs, a better approach is to recognize the "prescribing cascade" in which a side effect from a first drug is misinterpreted as a new illness.8 A common example of the prescribing cascade is the iatrogenic increase in blood pressure that occurs with both NSAID and COX-2 inhibitors. Several case-control studies have documented the increased likelihood of initiating antihypertensive therapy after the starting anti-inflammatory therapy. Although not always feasible, a better approach is to reconsider the original need for NSAID or COX-2 inhibitor, trying instead to use acetaminophen, glucosamine or nonpharmacologic therapies for osteoarthritis.

CLINICAL TRIALS

Five to seven years ago, a common clinical question would have been to consider the risks and benefits of a therapy such as lovastatin in a 75-year-old man. During the last decade, more older adults have been enrolled in major clinical trials including, for example, studies using statins for the primary and secondary prevention of coronary heart disease. Now, however, the question is increasingly whether or not a therapy such as a statin or other drug has any value in an 85 or 95-year-old person.

In addition to the inclusion of elderly in clinical trials, an increasing number of studies address questions critical in providing evidence-based care to older adults. Landmark studies such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study challenge "conventional" practice and assumptions.910 As an example, doxazosin has traditionally been advocated as a preferred therapy for the management of hypertension in elderly men who have concomitant benign prostatic hypertrophy. In ALLHAT, the doxazosin arm of the study was terminated prematurely in February 2000, because me drug was associated with a 25% increase in cardiovascular disease due to a doubling of the risk of heart failure.9 The excess risk of heart failure was not due to the presence of a higher blood pressure among participants receiving doxazosin compared to chlorthalidone. Fortunately, a recent report has demonstrated that these results have diffused into practice relatively rapidly with the use of alpha- blockers declining by approximately 26%.11

In addition, the AFFIRM trial has demonstrated that rhythm control in patients with atrial fibrillation did not improve survival compared with anticoagulation alone and was associated with more hospitalizations and adverse drug reactions in patients who were asymptomatic or had only mild symptoms compared to the rate control group.10 Most importantly, AFFIRM identified that most strokes occur in patients who had either not received warfarin or who had a sub-therapeutic anticoagulation.

PREVENTION AND THE ELDERLY

The safe and effective use of drug therapy for the management of chronic diseases in older adults begins with prevention. Efforts to prevent complications from chronic diseases using proven pharmacotherapy continue to be underutilized in older adults. The use of aspirin for secondary cardiovascular prevention, angiotensin- converting enzyme inhibitors for heart failure, warfarin for atrial fibrillation, bisphosphonates and other therapies for postmenopausal osteoporosis and corticostcroid-induced osteoporosis and b-blockers following myocardial infarction are often under-prescribed in the elderly. Further, patient and family education can reduce the risk of adverse drug reactions (and interactions) and facilitate earlier recognition of drug-related toxicities.

COMPUTER DRUG INFORMATION

Hand-held technology including personal digital assistants (PDAs) provides convenient access to quality drug information to clinicians. However, the primary caution is to remember that the "geriatric dose" in a PDA is based on very healthy older adults in clinical trials. Odier major advances in technology such as electronic prescribing particularly when linked to an electronic medical record may reduce the potential for medication-related prescribing errors.

Also, over half of older Americans have used the Internet for health and medical information. (Almost a third of individuals over 65 years have computer access; 15% have an Internet connection in the home). In a national survey from the Pew Commission, 47% indicated that information from the Internet affected personal decisions about their treatment. Unfortunately, little information exists regarding the clinical outcomes associated with older adults using health-related information from the Internet. In the Pew Commission study of older adults, 52% of users who visited healdi sites thought that "almost all" or "most" of the information on the Internet was credible. Individuals with less formal education indicated greater credibility of health-related website information. 12 In order to help consumers find quality health information on the Internet, the College of Pharmacy at the University of Rhode Island developed a web portal (www.uri.edu/e-health and www.uri.edu/ e- salud) with over 400 consumer websites that have been evaluated.

SUMMARY

The last two decides have witnessed the introduction of major advances in drug therapy for many chronic diseases. Despite an increasing number of therapeutic choices, basic challenges remain when using new drugs in the elderly. It is essential: 1) to consider whether a new drug is truly safer, more effective or worth the extra expense compared to established medications, 2) to monitor patients for drug related toxicities, and 3.) to avoid polypharmacy and the prescribing cascade.

INSTEAD OF SIMPLY CONSIDERING THE NUMBER OF DRUGS, A BETTER APPROACH IS TO RECOGNIZE THE "PRESCRIBING CASCADE" IN WHICH A SIDE EFFECT FROM A FIRST DRUG IS MISINTERPRETED AS A NEW ILLNESS.

REFERENCES

1. Administration on Aging. Aging into the 21st century. National Aging Information Center. http://www.aoa.gov/prof/Statistics/ future_growth/aging21/demography, asp. Accessed March 30, 2004.

2. US Food and Drug Administration. Approvals of FDA-regulated products, http:// www.accessdata.fda.gov/scripts/cder/ drugsatfda/ Accessed March 30, 2004.

3. Singh G, Triadafilopoulus G. Epidemiology of NSAID-induced GI complications. J Rheumatol 1999;26(Suppl): 18-24.

4. Pharm Exec 50. Scllars AJ, editor, 4th ed., Pharm Exec 2003 March:42-52.

5. Silverstein FE, Faich G, Goldstein JL, et al Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-55.

6. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. NEJM 2000:343:1520-8.

7. Mukherjec D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954- 9.

8. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: The prescribing cascade. BMJ 1997:315:1096-9.

9. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981- 97.

10. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. NEJM 2002;347:1825-33.

11. Stafford RS, Furberg CD, Finkelstein SN, et al. Impact of clinical trial results on national trends in alpha-blocker prescribing, 1996-2002. JAMA 2004:291:54-62.

12. Fox S, Rainie L, Horrigan }, et al. The online health care revolution: How the Web helps Americans take better care of themselves. Pew Internet & American Life Project http:// www.pewinternet.org/rcports/pdfs/ PIP_Health_Report.pdf Accessed 3/ 30/04.

ANNE L. HUME, PHARM.D., FCCP, BCPS

Anne L. Hume, PharmD, FCCP RCPS, is Professor of Pharmacy, University of Rhode Island, on the faculty, Rhode Island Geriatric Education Center, and Adjunct Professor of Family Medicine, Brown Medical School.

CORRESPONDENCE:

Anne L. Hume, PharmD, FCCP, BCPS

Phone:(401)874-2734

Fax:(401)874-2717

e-mail: alhumeril@aol.com

Copyright Rhode Island Medical Society Jan 2005

Source: Medicine and Health Rhode Island

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