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

Continued from previous page Clinical Trial: PCPT . The Prostate Cancer Prevention Trial (PCPT) was published in a July 2003 issue of the New England Journal of Medicine.⁷ Currently, no medical therapies are effective for the prevention of prostate cancer. The purpose of this study was to determine whether long-term treatment with the 5-a-reductase inhibitor finasteride could reduce the prevalence of prostate cancer in healthy men. The study enrolled 18,882 men 55 years of age or older (38% >=65 years of age) with a normal digital rectal exam, a prostatespecific antigen (PSA) concentration less than 3.0 ng/mL, and an American Urological Association (AUA) symptom score less than 20. Subjects were randomized to double-blind therapy with placebo or finasteride 5 mg once daily. The study was stopped 15 months early by the data and safety monitoring committee based on evidence that the study objective had been met. After a follow-up of 7 years, the primary outcome evaluated was prevalence of prostate cancer by prostate biopsy. Results were published for the 86.3% of men who had completed 7 years of the study; however, approximately 25% of the men in the study refused an end-of-study prostate biopsy. Thus, the overall number included in the final analyses was 9060. At study termination, finasteride significantly reduced the prevalence of prostate cancer by 25% compared to placebo. In the finasteride group, 18.4% of men were diagnosed with cancer compared with 24.4% in the placebo group (RRR, 24.8%; 95% CI, 18.6-30.6%; P<0.001). However, 6.4% of those in the finasteride group were diagnosed with high-grade cancer (Gleason score 7-10) compared to only 5.1% in the placebo group (relative risk, 1.27; 95% CI, 1.07-1.50; P = 0.005). Hence, the NNT to prevent one case of prostate cancer with finasteride was 17 patients, while the number needed to harm one patient with high-grade cancer was 77 patients. Adverse effects also differed between groups: those in the finasteride group had significantly more erectile dysfunction, loss of libido, gynecomastia, and reduced ejaculate volume compared to those in the placebo group, who had significantly more urinary urgency, urinary frequency, urinary retention, urinary tract infections, and prostatitis (P<0.001 for all comparisons). PCPT Conclusions and Clinical Impact. Seven years of finasteride 5 mg per day significantly reduced prostate cancer but at the cost of increased high-grade cancer and sexual side effects. Application of this data in clinical practice will need to be on a patient-specific basis after a provider–patient discussion of risks and benefits of therapy. Clinical Trial: MTOPS. The Medical Therapy Of Prostatic Symptoms (MTOPS) study was published in a December 2003 issue of the New England Journal of Medicine.⁸ Prior to this study, short-term combined drug therapy was not shown to be superior to single-drug therapy in reducing urinary symptoms of benign prostatic hyperplasia (BPH). Thus, the purpose of this study was to evaluate whether long-term therapy with an alpha-blocker, a 5-a-reductase inhibitor, or the combination would delay or prevent clinical progression of BPH. The double-blind study enrolled 3047 men age 50 years and older (mean age, 63 years) with BPH and an AUA symptom score of 8-30. At baseline, the mean AUA score was 17 out of 35 total points and the mean prostate volume was 36 mL. Subjects were randomized to one of four treatment arms: placebo, doxazosin 1 mg titrated up to 4-8 mg at bedtime, finasteride 5 mg at bedtime, or the combination of doxazosin and finasteride. After a mean follow-up period of 4.5 years, the primary outcome evaluated was overall clinical progression of BPH, defined as a first occurrence of an increase of four points in AUA score over baseline, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or UI. The majority (78%) of clinical progression events reported was due to an increase in AUA score. All active drug treatments significantly reduced clinical progression of BPH compared to placebo. Finasteride, doxazosin, and combination therapy reduced the primary outcome by 34% (95% CI, 14-50%; P = 0.002), 39% (95% CI, 20-53%; P < 0.001), and 66% (95% CI, 54-76%; P < 0.001), respectively. Combination therapy also significantly reduced the primary outcome compared to doxazosin and finasteride treatment alone (P < 0.001 for each comparison). Reported numbers needed to treat to prevent one event of overall clinical progression were 13.7 for doxazosin, 15.0 for finasteride, and 8.4 for combination therapy. When only those with a baseline prostate volume greater than 40 mL were evaluated, the numbers needed to treat decreased to 7.2 with finasteride and 4.9 with combination therapy. The most common events were dizziness, postural hypotension, and asthenia with doxazosin and erectile dysfunction, decreased libido, and abnormal ejaculation with finasteride. Subjects treated with combination therapy reported adverse events similar to both drug therapies in addition to peripheral edema and dyspnea. However, discontinuation rates were lower in the combination therapy group: 18% compared to 27% in the doxazosin group, and 24% in the finasteride group. MTOPS Conclusions and Clinical Impact. Contrary to previous data, long-term combination therapy with doxazosin and finasteride was well tolerated and significantly reduced the clinical progression of BPH compared to either drug alone. Combination therapy may be a good choice for some patients presenting with BPH, especially those with a prostate volume greater than 40 mL. Neurology Clinical Trial: Effects of Rofecoxib or Naproxen versus Placebo on Alzheimer’s Disease Progression: A Randomized Controlled Trial The purpose of this study, published in a June 2003 issue of JAMA, was to determine whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) could prevent cognitive decline in subjects with mild-to-moderate Alzheimer’s disease (AD).⁹ The study enrolled 351 adults (mean age, 74 years) with mild-to-moderate AD. Sixty-eight percent of subjects were being treated for their dementia with stable doses of acetylcholinesterase inhibitors (AChEIs). Subjects were randomized in a double-blind fashion to one of three treatments: placebo, rofecoxib 25 mg once daily, or naproxen sodium 220 mg twice daily. At 1 year, the primary outcome evaluated was the change in Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score. No difference was found in the ADAS-Cog score change between placebo (-5.7), naproxen (-5.8), and rofecoxib (-7.6). Interestingly, compared to placebo, the rofecoxib group showed a trend toward greater cognitive decline (P = 0.09). Adverse events were significantly higher in the active treatment groups compared to the placebo group: increased fatigue (P = 0.05) and new cases of hypertension (P = 0.004) with rofecoxib and new cases of hypertension with naproxen (P = 0.03). NSAIDs in AD Conclusions and Clinical Impact. Separate 1-year treatments of rofecoxib 25 mg per day and low-dose naproxen did not slow cognitive decline in patients with mild-to-moderate AD, and both treatments caused side effects. NSAIDs of any type should not be recommended for the sole purpose of preventing AD decline. Clinical Trial: A Long-Term Comparison of Galantamine and Donepezil in the Treatment of Alzheimer’s Disease. This purpose of this study, published in a 2003 issue of Drugs & Aging, was to compare the efficacy and safety of galantamine and donepezil in patients with AD.¹⁰ Currently, four AChEIs are approved for use in the United States: tacrine, donepezil, rivastigmine, and galantamine. However, no long-term, prospective, double-blinded clinical trials have compared one therapy to another. Treatment utilizing these agents is frequently guided by provider preference, adverse event profiles, and drug cost. This study enrolled 182 United Kingdom adults (mean age, 74 years) living at home with caregiver access, a diagnosis of probable AD, and a Mini-Mental State Examination (MMSE) score of 9-18 (mean, 15). The study was rater-blinded and subjects were randomized to either galantamine titrated from 4 to 12 mg twice daily or donepezil titrated from 5 to 10 mg daily. Overall, approximately 70% of the subjects completed the study on the maximum dose of both drugs (24 mg galantamine and 10 mg donepezil). At the end of 1 year, subjects were evaluated for the primary outcome of change in the Bristol Activities of Daily Living (BrADL) scale and for the secondary outcomes MMSE, ADAS-Cog/11, Neuropsychiatric Inventory (NPI), and the Screen for Caregiver Burden (SCGB). The study was adequately powered to detect a difference in the primary outcome. No difference between treatments was found in the primary outcome of BrADL score change or in the secondary outcomes ADAS-Cog/11, MMSE, and NPI. Adverse drug events (nausea, agitation, vomiting, headache, and falls) were higher in the galantamine group compared to the donepezil group. However, it was not reported whether these differences were statistically significant. Galantamine versus Donepezil in AD Conclusions and Clinical Impact. In this small study of patients with mostly moderate dementia treated with galantamine or donepezil for 1 year, no statistically significant differences in outcomes were found. It is unlikely this study will have any effect on the current practice of prescribing AChEI therapy in patients with AD. Clinical Trial: VISP. The Vitamin Intervention for Stroke Prevention (VISP) trial was published in a February 2004 issue of JAMA.¹¹ Prior to this study, case-control data supported the hypothesis that patients with premature peripheral and cerebrovascular disease have higher levels of homocysteine. Thus, the purpose of this study was to determine if high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12) would decrease homocysteine levels to reduce recurrent stroke compared to low doses of the vitamins. The study enrolled 3680 subjects (59% >=65 years of age) with a past history of nondisabling ischemic stroke within the last 120 days and a total homocysteine level >=25th percentile for the North American stroke population. Subjects were randomized in a double-blind fashion to a low-dose vitamin group (200 µg B6, 6 µg B12, and 20 µg folate) or a high-dose vitamin group (25 mg B6, 400 µg B12, and 2.5 mg folate). After a mean follow-up of 1.7 years, the primary outcome evaluated was recurrent cerebral infarction and secondary outcomes evaluated were coronary heart disease (CHD) events and death. Concentrations of total homocysteine decreased more in the high-dose vitamin group (mean reduction, 2 µmol/L greater than low-dose group). However, no significant differences were found in any outcome measured. Moreover, when outcomes were combined and when subgroups were analyzed, no significant differences were found. VISP Conclusions and Clinical Impact. Moderate reduction of total homocysteine from vitamin B6, B12, and folate supplementation in patients with ischemic strokes had no effect on vascular outcomes at 2 years. Further exploration of this hypothesis in longer trials with different populations may be warranted. Women’s Health Clinical Trial: WHIMS. The Women’s Health Initiative Memory Study (WHIMS) was published in a May 2003 issue of JAMA.¹² Prior to this study, mixed findings suggested that estrogen therapy may or may not have a role in preventing dementia in postmenopausal women. Thus, the purpose of this study was to evaluate the effects of conjugated estrogen/progestin on cognitive function in a large, well-designed randomized controlled trial. This study enrolled 4532 women from the Women’s Health Initiative (WHI) Study who were postmenopausal and at least 65 years of age. Overall, most of the women were between the ages of 65-69 (47%), while 36% were age 70-74, and 18% were age 75 years and older. Subjects were randomized to double-blind treatment with placebo or conjugated estrogen/medroxyprogesterone acetate 0.625/2.5 mg once daily. Because the WHI study was stopped early due to increased health risks in the hormone therapy arm, early examination of the WHIMS data was required. After a follow-up of 5 years, the primary and secondary outcomes evaluated were incidence of probable dementia and incidence of mild cognitive impairment, respectively. The rate of women diagnosed with probable dementia in the hormone replacement group was twice that of the placebo group (40 cases compared to 21 in the placebo group; HR, 2.05; 95% CI, 1.21-3.48; P = 0.01). No significant difference was found between groups in mild cognitive impairment (HR, 1.07; 95% CI, 0.74-1.55; P = 0.72). To put these results in perspective, it is interesting to compare the established risks associated with conjugated estrogen/progestin therapy. Although the WHI study results included all subjects over age 50, the results show that compared to placebo, eight additional invasive breast cancer events, seven additional CHD events, and eight additional pulmonary emboli events will occur per 10,000 women taking estrogen/progestin therapy over 1 year.¹³ Most women are now aware of these highly publicized risks. However, women may be unaware of the much higher risk found in the WHIMS results: 23 additional cases of probable dementia will occur per 10,000 women taking estrogen/progestin therapy over 1 year. WHIMS Conclusions and Clinical Impact. Four years of estrogen/progestin therapy in healthy, postmenopausal elderly women significantly increased the risk of probable dementia more than placebo, adding to negative hormone replacement data. Women should not be prescribed hormone replacement therapy for the prevention of dementia, and may want to consider discontinuing long-term hormone replacement therapy based on the increased risk of probable dementia. Clinical Trial: WHI-Estrogen Only Trial. The second trial of the core WHI clinical trials was published in an April 2004 issue of JAMA.¹⁴ The purpose of this study was to examine the risks and benefits of long-term conjugated estrogen monotherapy in postmenopausal women. The double-blind study enrolled 10,739 postmenopausal women who had undergone hysterectomy and were between the ages of 50-79 (mean age, 64 years). Subjects were randomized to placebo or conjugated estrogen 0.625 mg once daily. After a mean follow-up of 7 years, the National Institutes of Health stopped the study approximately 2 years early. The primary outcomes evaluated were CHD rate and invasive breast cancer. Secondary outcomes evaluated were rates of fracture, stroke, VTE, colorectal cancer, and an overall global index. Both nominal and adjusted confidence intervals were reported for the results of the study. Based on nominal confidence intervals, conjugated estrogen therapy significantly increased the risk of stroke by 39% compared to placebo (HR, 1.39; 95% CI, 1.10-1.77; P = 0.007), but significantly decreased the risk of fracture by 30% (HR, 0.70; 95% CI, 0.63-0.79; P < 0.001). Based on adjusted confidence intervals, only fracture risk remained statistically significant (HR, 0.70; 95% CI, 0.59-0.83; P < 0.001). Other outcome differences were not statistically significant. Interestingly, the risks associated with estrogen-only therapy appear lower than the risks associated with estrogen/progestin therapy as reported from the first WHI study. For every 10,000 women treated over 1 year with conjugated estrogen compared to placebo, there would be five less CHD events, seven less invasive breast cancer events, 12 more strokes, 56 less fractures, and one more colorectal cancer event. WHI-Estrogen Only Trial Conclusions and Clinical Impact. Conjugated estrogen in postmenopausal women with a history of hysterectomy reduced fractures but significantly increased risk of stroke compared to placebo. Long-term therapy for disease prevention should be discouraged. Drug Interactions Rosiglitazone and Gemfibrozil A study of 10 patients in the October 2003 issue of Diabetologia indicates that gemfibrozil increases concentrations of rosiglitazone.¹⁵ This interaction is thought to be due to cytochrome P450 2C8 inhibition by gemfibrozil. This inhibition of metabolism increases rosiglitazone concentrations, which can increase adverse events from rosiglitazone and potentiate hypoglycemia in patients also taking a sulfonylurea or insulin. Clinically, this drug combination and interaction is likely to occur in patients with type 2 diabetes and hypertriglyceridemia. To manage this interaction, gemfibrozil can be replaced with fenofibrate, as it does not inhibit cytochrome P450 2C8. If both drugs need to be continued, rosiglitazone doses should be decreased by at least 50% and patients should be monitored for adverse events. Providers should also be aware that this drug interaction may also occur with gemfibrozil and pioglitazone. Warfarin and Cranberry Juice A September 2003 issue of Current Problems in Pharmacovigilance reported a new drug interaction between warfarin and cranberry juice.¹⁶ The cause of this interaction is unknown, but it is possibly due to antioxidant-induced inhibition of warfarin metabolism through the cytochrome P450 system. In the five cases reported, four patients had elevated INR measurements. The onset of the increased INR is unknown, but in one patient it occurred at 6 weeks. That same patient died from bleeding after his INR increased to greater than 50. To manage this interaction, patients taking warfarin should be discouraged from drinking cranberry juice. If they insist on drinking it, patients should be counseled to maintain consistency with the brand, quantity, and number of drinks per day, and a decrease in warfarin dose may be required. Paroxetine and Tamoxifen A report in the December 2003 issue of the Journal of the National Cancer Institute discussed a new drug interaction between paroxetine and tamoxifen.¹⁷ Tamoxifen is utilized in the long-term treatment of hormone-dependent breast cancer and causes hot flashes as a side effect. Patients taking tamoxifen who get hot flashes often utilize second-line treatments (ie, paroxetine, fluoxetine, venlafaxine, gabapentin, and clonidine) for their hot flashes because they cannot utilize estrogen therapy. Thus, it is conceivable that patients may be treated concomitantly with tamoxifen and paroxetine. Once ingested, tamoxifen is metabolized to active metabolites, which likely account for its efficacy. The cytochrome P450 2D6 pathway in the liver, which paroxetine inhibits, is one mechanism by which active metabolites are produced. Consequently, it is possible that paroxetine may reduce the effectiveness of tamoxifen. No cases of tamoxifen failure were included in this report. However, to prevent this situation, patients should avoid this drug combination. If hot flashes occur, gabapentin or clonidine can be utilized safely in combination with tamoxifen. Conclusions As the population of older adults increases, so will the number of drugs available to treat medical conditions. Moreover, data regarding currently available drugs continues to increase. Knowledge of new clinical information about drug therapies is important for health care practitioners treating older adults. This review provides a summary of clinical trial data and newly recognized drug interactions published in the last year that relate to the treatment of older adults. A summary table is provided as a quick reference tool for clinicians, who can utilize this information to continue, discontinue, or alter drug therapies in their clinical practice. Dr. Linnebur received an unrestricted educational grant in 2002 from Pzifer, Inc. for the research project, “Evaluation of treatment length with acetylcholinesterase inhibitors in demented patients in a university geriatric outpatient clinic.”