Pharmacotherapy Update: What’s New About Old Medications (Part I)

Introduction Each year, new data are published regarding the safety and efficacy of currently available medications. Medications may be studied in a new population, in a different disease state, at a different dose, or in a head-to-head comparison with another medication. Results of these studies may impact patient care. Additionally, patients may be aware of clinical trial results through media coverage. Thus, health care providers should be attentive to clinical trials that impact the populations they treat. Data regarding pharmacotherapy are especially important for clinicians involved in the care of older adults, as many different drug treatments are utilized in the management of chronic medical conditions. Moreover, any new information regarding multiple uses of medications in this population is especially helpful. This article will summarize and discuss the impact of recently published data regarding the use of pharmacotherapy in older adults. Eleven clinical trials, divided by topic areas (cardiology, anticoagulation, urology, neurology, and women’s health), and three new drug interactions will be discussed. Drugs discussed include carvedilol, metoprolol, candesartan, warfarin, oxybutynin, tolterodine, finasteride, doxazosin, rofecoxib, naproxen sodium, galantamine, donepezil, vitamins B6, B12, and folate, conjugated estrogen, conjugated estrogen/medroxy progesterone acetate, rosiglitazone, gemfibrozil, paroxetine, and tamoxifen. Cardiology Clinical Trial: COMET. The Carvedilol Or Metoprolol European Trial (COMET), published in a July 2003 issue of The Lancet, compared two different beta-blockers for the treatment of systolic heart failure.¹ Prior to this study, it was known that beta-blockers could reduce mortality in patients with chronic heart failure due to systolic dysfunction, but it was not known if one beta-blocker offered more benefit over another. This double-blind trial enrolled 3029 European adults with a mean age of 62 years. The subjects had symptomatic systolic dysfunction (ejection fraction <35%) and were classified as New York Heart Association (NYHA) class II-IV (the majority as NYHA class II and III). Stable drug treatment with angiotensin-converting-enzyme (ACE) inhibitors and diuretics was required. At baseline, 60%, 11%, and 39% were taking digoxin, spironolactone, and aspirin, respectively. Subjects were randomized to one of two active treatment arms: carvedilol 3.125 mg titrated to 25 mg twice daily or immediate-release metoprolol 5 mg titrated to 50 mg twice daily. After a mean follow-up period of 4.8 years, the primary outcomes evaluated were all-cause mortality and a composite of all-cause mortality or all-cause hospital admission. A statistically significant 17% relative risk reduction (RRR) and a 5.6% absolute risk reduction (ARR) in all-cause mortality were found with carvedilol: hazard rate (HR) 0.83 (95% CI, 0.74-0.93; P = 0.0017). Thus, the number needed to treat (NNT) to prevent one outcome of all-cause mortality with carvedilol compared to metoprolol was 18 patients. Interestingly, no significant difference was found in the composite outcome of all-cause mortality or all-cause admission. A subgroup analysis also indicated the all-cause mortality reduction with carvedilol was statistically significant in those subjects 65 years of age or older and not significant in those under 65 years of age. When evaluating this study, it is important to consider some differences between the two treatment arms that may have impacted the results. First, carvedilol is an alpha-1 and nonselective beta-blocker, while metoprolol is a beta-1 selective blocker. Second, treatment doses of both drugs were planned to be equivalent in effect, but mean heart rate reductions were greater in the carvedilol arm (13.3 beats per minute with carvedilol and 11.7 beats per minute with metoprolol). Finally, an immediate-release formulation of metoprolol, not approved for the treatment of heart failure, was used in the study. The morbidity and mortality outcomes may have been different had the investigators compared carvedilol to extended-release metoprolol, which is approved for the treatment of systolic heart failure. COMET Conclusions and Clinical Impact. Carvedilol prolonged survival compared to generic, immediate-release metoprolol in systolic heart failure patients, but this effect was possibly due to metoprolol dosing. Appropriate patients will likely benefit from either drug therapy. Clinical Trial: CHARM-Added . The Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Added) trial, one of four clinical trials of the CHARM program, was published in a September 2003 issue of The Lancet.² The purpose of this study was to prospectively evaluate whether the angiotensin II-receptor blocker (ARB) candesartan could improve clinical outcomes compared to placebo when added to an ACE-inhibitor in patients with systolic heart failure. This double-blind trial enrolled 2548 European adults with a mean age of 64 years; approximately 19% were 75 years of age and older. Subjects had symptomatic systolic heart failure (ejection fraction <=40%) and had to be classified as NYHA class II-IV; 73% were in NYHA class III at baseline. ACE-inhibitor treatment was required for all patients; almost half were taking a beta-blocker, digoxin and aspirin; approximately 17% were also taking spironolactone. At baseline, the blood pressure was 125/75 mm Hg. Subjects were randomized to placebo or candesartan 4 mg titrated to 32 mg daily. After a median follow-up of 3.4 years, the primary outcome evaluated was a composite of cardiovascular death or heart failure admission. Several secondary outcomes (combinations of cardiovascular death, heart failure admission, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization) were also evaluated. Results showed a 15% RRR in the primary outcome with candesartan (unadjusted HR, 0.85; 95% CI, 0.75-0.96; P= 0.011) and a NNT of 23 patients to prevent one primary outcome compared to placebo. All secondary outcomes were also statistically significant and adjusting each hazard rate did not affect results. Significant differences in angioedema or hypotension were not seen when treatments were compared. However, in the candesartan group there was an overall low, but significantly higher number of subjects who had an increase in serum creatinine (7.8%) and hyperkalemia (3.4%). Blood pressure was also lowered significantly more in the candesartan group (4.6 mm Hg/3.0 mm Hg more compared to placebo). CHARM-Added Conclusions and Clinical Impact. Candesartan decreased cardiovascular death and heart failure admission in patients with systolic heart failure already receiving standard of care treatment. Although an expensive regimen, clinicians may utilize combination ARB/ACE inhibitor therapy to provide additional mortality and morbidity reduction, but will likely need to closely monitor potassium and serum creatinine. Anticoagulation Clinical Trial: ELATE. The Extended Low-intensity Anticoagulation for Thrombo-Embolism (ELATE) investigators published the results of their trial in an August 2003 issue of the New England Journal of Medicine.³ Currently, anticoagulation guidelines recommend that patients with a first idiopathic venous thromboembolism (VTE) and those with recurrent VTE be treated with at least 6 months of conventional-intensity warfarin therapy and with 12 months to lifetime of conventional-intensity warfarin therapy, respectively.⁴ In 2003, the results of the Prevention of REcurrent VENous Thromboembolism (PREVENT) study were reported.⁵ The results showed that low-intensity anticoagulation therapy significantly reduced the risk of recurrent VTE compared to placebo in patients with either one previous VTE or those with a history of recurrent VTE. This new data suggested that long-term anticoagulation should be recommended for all patients with a history of idiopathic VTE. However, the study did not clarify whether the long-term anticoagulation should be conventional-intensity or low-intensity. Hence, the purpose of the ELATE study was to determine if there was a difference between bleeding rates and recurrent VTE in subjects with a history of idiopathic VTE treated long term with low-intensity compared to conventional-intensity warfarin therapy. The ELATE study enrolled 738 adults with a mean age of 57 years (approximately 1/3 were elderly). Subjects were required to have completed at least 3 months of conventional-intensity anticoagulation therapy for an idiopathic VTE; 70% had a history of recurrent VTE. Subjects were randomized to double-blind low-intensity warfarin adjusted to an international normalized ratio (INR) goal of 1.5-1.9 or conventional-intensity warfarin adjusted to an INR goal of 2.0-3.0. After a mean follow-up period of 2.4 years, no difference in the primary outcome of major bleeding was found between the groups (HR, 1.2; 95% CI, 0.4-3.0; P = 0.76). However, a higher rate of major bleeding was found among those subjects 65 years and older and among those with a higher number of risk factors for bleeding. Recurrent VTE was significantly higher in the low-intensity group (HR, 2.8; 95% CI, 1.1-7.0; P = 0.03). In a subgroup analysis, subjects with a baseline history of recurrent VTE were found to have a significantly higher number of VTE events with low-intensity anticoagulation (HR, 6.7; 95% CI, 1.5-29.5); subjects with their first VTE had a similar number of recurrent events in both warfarin groups (HR, 0.8; 95% CI, 0.2-3.5), indicating that VTE results were driven by those with recurrent VTE at baseline. However, the study was powered to detect a difference in major bleeding rates. It is possible that the lack of difference in VTE events found in the subgroup analysis of subjects with their first VTE was due to inadequate power. ELATE Conclusions and Clinical Impact. Long-term conventional-intensity anticoagulation with warfarin did not increase major bleeding and was significantly better at reducing recurrent VTE in patients with a history of recurrent idiopathic VTE compared to low-intensity warfarin. However, results also indicate that after treating the acute event with conventional-intensity warfarin, clinicians can utilize long-term low-intensity anticoagulation for those patients presenting with their first idiopathic VTE and a high risk of bleeding. Urology Clinical Trial: Comparative Efficacy and Safety of Transdermal Oxybutynin and Oral Tolterodine versus Placebo in Previously Treated Patients with Urge and Mixed Urinary Incontinence. The purpose of this study, published in the August 2003 issue of Urology, was to compare two different administration routes and formulations of antimuscarinic therapy in the treatment of urinary incontinence (UI).⁶ Currently, patients with urge or mixed UI are usually treated with the drugs oxybutynin and tolterodine. Both drugs are available in oral immediate-release and extended-release formulations, but recently oxybutynin was also approved for use in the United States in a transdermal formulation. Since this formulation bypasses the gastrointestinal tract, it is likely that some side effects may be lower than when the drug is given orally. This trial enrolled 361 adults with a mean age of approximately 63 years who were previously treated for urge or mixed UI (50% with oxybutynin and 47% with tolterodine). Subjects were randomized in a double-blind fashion to one of three treatments: oxybutynin patch 3.9 mg/day applied twice weekly, tolterodine LA 4 mg once daily, or placebo. Subjects received at least one placebo formulation (patch or oral), so that both routes of administration were blinded. At the end of 12 weeks, subjects were evaluated for four outcomes: change in daily number of incontinence episodes, average daily urinary frequency, average urinary void volume, and quality of life (QOL) changes. Compared to placebo, both transdermal oxybutynin and tolterodine LA caused a significantly greater reduction in the number of daily incontinence episodes (-2.1; -2.9; P= 0.0137; -3.2; P = 0.0011, respectively). Mean decreases in daily urinary frequency for placebo, transdermal oxybutynin, and tolterodine LA were -1.4, -1.9, and -2.2 (P= 0.0025 for tolterodine LA compared to placebo), respectively. Both drugs significantly increased mean urinary void volumes and QOL scores compared to placebo. When adverse events were evaluated, most were of mild to moderate severity. Transdermal oxybutynin caused the most site reactions compared to tolterodine LA and placebo (26% of patients vs 5.7% and 6.8%, respectively). Dry mouth and constipation were highest in the tolterodine group: 7.3% and 5.7%, respectively, compared with 4.1% and 3.3% in the oxybutynin group. Because this patient population was comprised of subjects who had previously tolerated antimuscarinic therapy, adverse events were likely lower than they would be in the general population. Further statistical evaluation of adverse events was not reported. Oxybutynin/Tolterodine/Placebo Conclusions and Clinical Impact. Both transdermal oxybutynin and tolterodine LA were effective in reducing symptoms of UI in previously treated patients compared to placebo. However, side effects differed: transdermal oxybutynin caused more site reactions, while tolterodine LA caused slightly more dry mouth and constipation. Antimuscarinic therapy for UI patients can be guided based on adverse-effect profiles. 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