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Pharmacology in the News
Geriatric Times May/June 2003 Vol. IV Issue 3
Drug Displays Efficacy in Patients With Advanced AD
According to a study published in the April 3 New England Journal of Medicine, memantine showed efficacy in treating moderate-to-severe Alzheimer's disease (AD). The drug is the first of its kind to make daily activities easier to perform and to increase patients' cognitive skills. The results of the study indicated that it will improve patients' quality of life and significantly lower the amount of care required.
The 28-week, double-blind, parallel-group study examined 252 patients. Eligibility criteria consisted of a baseline Mini-Mental State Examination (MMSE) score between 3 and 14, a stage of 5 or 6 on the Global Deterioration Scale and a stage of 6a or greater on the Functional Assessment Staging instrument, which indicated significant dementia-related deficits in the ability to perform one or more basic activities of daily living. No study of any other anti-dementia drugs has been conducted on a cohort with the same severity of disease.
The patients administered memantine showed significant improvement in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev), the Functional Assessment Staging ratings and the Severe Impairment Battery. The treatment effects observed in cognition seemed to translate into improvements in behavior.
It has been estimated that caregivers of patients with moderate-to-severe AD provide 15 hours of care per day. The memantine-treated patients in the study spent statistically significantly less time with their caregivers than the placebo-treated group (difference between groups, 45.8 hours per month; p=0.01).
Memantine, approved for use in Europe, is currently under review by the U.S. Food and Drug Administration. If approved, it would be the first drug in the United States offering treatment for the most advanced cases of AD. Forest Laboratories, Inc. owns the license to produce memantine in the United Sates.
Several of the study authors reported receiving either lecture or consulting fees from companies with a stake in the success of the drug--JK
Dalteparin Approved for Elderly Patients
The U.S. Food and Drug Administration recently approved additional labeling information supporting the use of dalteparin sodium injection (Fragmin) in elderly patients. Dalteparin is indicated for the prevention of deep vein thrombosis in patients undergoing hip replacement surgery and at-risk patients undergoing abdominal surgery. It is also approved for the prevention of ischemic cardiac complications in patients with unstable angina and non-Q wave myocardial infarction when concurrently administered with aspirin.
According to Pharmacia Corporation, clinical studies involving 2,765 patients who were 65 or older and 897 patients who were 75 or older showed no overall differences in the safety of dalteparin when used in elderly patients. In addition, clinical studies have not shown any differences in its efficacy between older and younger patients.
More than half of total hip replacement surgeries are performed on patients 65 and older, a group who is at risk for unstable angina and myocardial infarction.
Incidence of hemorrhagic complications during treatment with dalteparin injection has been low. The most commonly reported side effect is hematoma at the injection site, although bleeding may increase with higher doses. As with all anticoagulants, dalteparin should be used with extreme caution in patients who have an increased risk of hemorrhage. Dalteparin may produce slight-to-moderate elevation of liver transaminases. Thrombocytopenia and other allergic reactions such as urticaria, anaphylaxis, pruritus, hair loss and skin necrosis may occur. Risks are higher in patients who have an indwelling catheter or are using additional medications affecting hemostasis such as non-steroidal anti-inflammatory drugs. Elderly patients may be more sensitive to the drug effects and may require a dosage reduction. Patients should also be frequently monitored for signs and symptoms of neurological impairment--AR
Adverse Events Found With Risperidone
Behavioral symptoms, which can include agitation, aggression, hallucinations and vocalizations, are common features in dementia; and such symptoms, rather than cognitive problems, are often the reason why caregivers place patients with dementia in nursing homes. Anti-psychotics have been the most frequently studied medications for the treatment of these behavioral symptoms; but the use of conventional antipsychotics has been limited by extrapyramidal symptoms, anticholinergic adverse effects, sedation and postural hypotension. The atypical antipsychotics are believed to offer a better risk:benefit ratio.
In an April 16 letter to health care providers, however, Janssen Pharmaceutica Products, L.P., announced that risperidone (Risperdal) prescribing information had been updated to reflect reports of cerebrovascular adverse events such as stroke and transient ischemic attack, including deaths, in elderly patients with dementia (mean age=85; range 73 to 97).
The update was based on results of four placebo-controlled trials of elderly patients with dementia-related psychosis (n=1230) who had been treated with risperidone. During the trials, researchers reported a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo.
In the letter to health care providers, Janssen cautioned that risperidone, like all other antipsychotics, is not indicated for the treatment of dementia.
To read the "Dear Healthcare Provider" letter and for full risperidone prescribing information please go to <www.fda.gov/medwatch/SAFETY/2003/safety03.htm#risper>--MB
New Options, Strategies for Treating Heart Disease
Presentations at the American College of Cardiology's (ACC) 52nd Annual Scientific Session show promise for further options and strategies for treating patients with heart disease.
Carl J. Pepine, M.D., presented the findings from INVEST (International Verapamil SR-Trandolapril Study), the second largest cardiovascular outcomes trial. The trial examined more than 22,000 high-risk patients from 15 countries to determine if verapamil (Calan, Isoptin) based treatment was equal to the gold standard ß-blocker therapy in the reduction of mortality, heart attacks or strokes. Verapamil, a non-dihydropyridine calcium channel blocker, was compared against the ß-blocker atenolol (Tenoretic, Tenormin) in a prospective study that used the Internet to enroll patients, collect data and distribute medications.
All patients had documented hypertension and coronary artery disease and were at least 50 years old (mean age=66); 52% of the patients were female. Treating physicians were allowed to augment verapamil with the agiotensin-converting enzyme inhibitor trandolapril (Mavik) or use the co-formulated tablet containing both verapamil SR and trandolapril, followed by the diuretic hydrochlorothiazide (Esidrix, Oretic) as needed. Patients receiving ß-blockers could also receive hydrochlorothiazide followed by trandolapril as needed. The addition of at least one medication was required in the majority of patients (70%) in the study.
Overall, more than 70% of patients reached the blood pressure target of <140/90 mmHg, compared to 51% of patients treated with hypertensive medications. Researchers also found that patients in the verapamil-treatment arm were 13% less likely to develop type 2 diabetes than were their counterparts in the ß-blocker group.
Also presented at the ACC meeting were findings from the recently completed SPORTIF 111 (Stroke Prevention Oral Thrombin Inhibitor in Atrial Fibrillation) trial of the investigational agent ximelagatran (Exanta) in treating cardiac patients at risk for stoke. Ximelagatran, set to be the first new fixed-dose anticoagulant since warfarin (Coumadin), is currently under study for approval in both Europe and the United States.
In the European trial of 3,407 patients, a fixed dose of 36 mg twice-daily ximelagatran compared favorably with dose-adjusted warfarin in preventing stroke and systemic embolic events in atrial fibrillation. Safety data further supported the use of this agent, with no significant difference between ximelagatran and warfarin in all cause mortality. The combined rates for major and minor bleeding were significantly lower for ximelagatran.
Professor Bertil Olsson, key investigator and professor of cardiology at University Hospital in Lund, Sweden, noted that in comparison with warfarin, "Treatment with Exanta is less complex as there is no need for coagulation monitoring, dose titration, dietary restrictions and it is not associated with serious side effects"--HAD
Levetiracetam Safe and Effective for Older Patients
Epilepsy is more common in elderly adults than it is in younger adults. Many of the estimated 61,000 new cases of epilepsy in patients older than 65 are due to conditions such as stroke, heart attack and Alzheimer's disease. This patient population is particularly sensitive to antiepileptic drug treatment due to both age-related physiological changes and concomitant diseases and treatments. However, results of a study presented in April at the American Academy of Neurology's 55th Annual Meeting showed levetiracetam (Keppra) to be not only highly effective, but also safe for reducing seizures in community dwelling seniors.
Investigators studied a subset of 78 patients enrolled in the KEEPER Trial. The majority of patients were female (61.5%), and the mean age was 73.5 years. Patients had experienced between three and 42 partial seizures (mean=3.3 per month) in the three months prior to study entry, despite taking one to two concomitant antiepileptic drugs. The most common drugs used were phenytoin (Dilantin), carbamazepine (Tegretol) and valproic acid (Depakene). The researchers added levetiracetam 1000 mg/day to patients' existing regimen. The dose was increased by 1000 mg/day at the end of weeks 2 and 4 unless the patient was seizure-free during the preceding two-week period. The dose then remained the same for 12 weeks.
Patients kept seizure diaries throughout the 16-week study. Investigators measured seizure frequency, incidence of adverse events and clinical impression rating (using the Global Evaluation Scale [GES] assessment).
Levetiracetam produced a median overall reduction in seizure frequency of 80.1%. According to GES assessment, 76.0% of patients showed marked, moderate or slight improvement. Analysis of responder rate showed 76.9% of patients were ≥50% responders, 56.9% were ≥75% responders, and 40.0% were 100% responders. The maximum daily dose of levetiracetam was 1000 mg in 52.6%, 2000 mg in 20.5% and 3000 mg in 19.2% of patients. Levetiracetam was well tolerated, with 42.3% of patients reporting one or more treatment-related adverse events. The most common adverse events included somnolence (16.7%) and dizziness (9%); 15 patients dropped out due to adverse events.
Investigators postulated that levetiracetam was safe and effective for this patient population due to its pharmacokinetic profile, which includes lack of hepatic metabolism, lack of renal excretion, linear pharmacokinetics, no protein binding and no known drug interactions--JH
ISHIB Releases New Treatment Guidelines
A consensus group composed of members of the International Society on Hypertension in Blacks (ISHIB) and leading medical experts recently published the first treatment guidelines for African-Americans with high blood pressure (Arch Intern Med 2003;163[5]:525-541). African-Americans are at higher risk than the general population for the negative consequences of hypertension.
The consensus group recommended physicians assess cardiovascular risk; set, achieve and maintain an appropriate blood pressure target; assist patients in implementing therapeutic lifestyle changes; and administer effective pharmacologic interventions early and persistently. The ISHIB suggests setting a target blood pressure of <130/80 mm Hg in patients with high blood pressure and complications such as diabetes, heart disease or kidney disorders; patients with uncomplicated high blood pressure should set a target of <140/90 mm Hg.
The consensus group discussed the Dietary Approaches to Stop Hypertension (DASH) study that highlights the importance of a diet rich in fruits, vegetables, fiber and low-fat dairy foods, including meat and poultry with reduced saturated and total fats. The DASH diet has been found to reduce hypertension in African-American patients, and the group recommended educating all patients--not just those with high blood pressure--on this heart healthy lifestyle intervention.
The group also found combination antihypertensive therapy (e.g., ß-blocker/diuretic, angiotensin-converting enzyme (ACE) inhibitor/diuretic, ACE inhibitor/calcium channel blocker or angiotensin II receptor blocker/diuretic) effective in lowering patients' blood pressure.
The consensus group emphasized, "Identifying an optimal management plan for each patient is the key element for successful blood pressure reduction"--RG
