Antiplatelet therapy in secondary stroke prevention.

Stroke is the third leading cause of death in the United States. Antiplatelet agents are the mainstays of ischaemic stroke prevention. The therapies recommended for initial therapy include aspirin (50 - 325 mg) daily, the combination of aspirin (25 mg) and extended-release dipyridamole (200 mg) b.i.d., or clopidogrel (75 mg) daily. Ticlopidine 250 mg b.i.d. is approved for stroke prevention but is no longer a first-line therapy. This article reviews the literature on antiplatelet agents for secondary stroke prevention.

Thrombolytic therapy for acute myocardial infarction.

Numerous factors must be considered when determining the formulary status of thrombolytic agents for the treatment of acute myocardial infarction. Defined treatment options, predicted outcomes, and the economic consequences of this disorder continue to evolve from clinical trials. Pharmacists have a major role in delivering patient care, with responsibility for evaluating, procuring, and monitoring thrombolytic agents and drug therapy in general. By participating in the development and implementation of treatment guidelines, evaluating economic and therapeutic outcomes, providing timely optimal drug therapy, and educating health care providers and the public, they contribute significantly to the health care team.

Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group.

BACKGROUND AND PURPOSE: Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. METHODS: We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. RESULTS: Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003). CONCLUSIONS: Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.

Strategies for the management of acute myocardial infarction: selecting patients for thrombolytic therapy.

Strategies for managing acute myocardial infarction (AMI), with a focus on thrombolytics, are reviewed. Revised guidelines published by the American College of Cardiology and the American Heart Association strongly recommend the use of thrombolytic therapy in carefully selected patients to promote reperfusion of ischemic myocardium. Thrombolytics reduce in-hospital mortality, and the mortality benefit is maintained for at least one year. Which patients are the best candidates for thrombolytics has been debated; variables that have been analyzed include infarct location, time after onset of symptoms, age, sex, blood pressure, and prior AMI. Clinicians should be thoroughly familiar with the absolute and relative contraindications to thrombolytic therapy to minimize potential hemorrhagic complications. The diagnosis of AMI should be clearly established. All patients should receive thrombolytic therapy if they arrive for treatment within 12 hours of the onset of symptoms of AMI and have appropriate ECG changes. Aspirin should be given to all patients, and beta-blockers should also be given if there are no contraindications. Heparin may be given as antithrombotic therapy in patients not receiving thrombolytics or as adjuvant therapy in those receiving thrombolytics. Other adjuvant treatments, notably angiotensin-converting-enzyme inhibitors, are used as indicated. Primary angioplasty may have a role in selected patients. Long-term interventions are intended to prevent recurrence of AMI. Thrombolytic therapy can substantially improve survival and function in patients with AMI, especially when it is given within six hours of the onset of symptoms.

Spironolactone-induced agranulocytosis.

OBJECTIVE: To report a case of agranulocytosis secondary to spironolactone in a patient with cryptogenic liver disease. CASE SUMMARY: A 58-year-old Hispanic woman with cryptogenic cirrhosis was admitted to University Hospital on October 31, 1995. Laboratory data revealed a leukocyte count of 1.0 x 10(3)/mm3 and an absolute neutrophil count (ANC) of 10 cells/mm3. Prior to treatment with spironolactone, the leukocyte count was 10.2 x 10(3)/mm3 and ANC 8400 cells/mm3. Agranulocytosis resolved 5 days following the discontinuation of spironolactone. Results from the bone marrow biopsies before and after treatment with spironolactone suggested that agranulocytosis was caused by the drug's toxic effect on the bone marrow. DISCUSSION: Drug-induced agranulocytosis is a serious adverse effect, occurring at a rate of approximately 6.2 cases per million persons each year. In addition to the case reported here, three other reports of agranulocytosis secondary to spironolactone have been published in the literature. Several factors have been identified that may increase a patient's risk for developing agranulocytosis, including increased age, hepatic or renal impairment, drug dosage and duration, and concurrent medications. CONCLUSIONS: Agranulocytosis secondary to spironolactone is a serious potential adverse effect. Patients with risk factors for developing this adverse effect should be closely monitored since early detection and discontinuation of spironolactone can improve prognosis.

Principles of drug administration in renal insufficiency.

Normal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use. Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLCR) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted. Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent. Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion. Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.

Ibutilide: a new class III antiarrhythmic agent.

Ibutilide fumarate is a new antiarrhythmic agent recently approved for the conversion of atrial flutter (AFl) and atrial fibrillation (AF) to normal sinus rhythm. A class III agent in the Vaughan Williams classification system, ibutilide prolongs cardiac repolarization by activating a slow inward, predominantly sodium current. An alternative or additive mechanism to prolong repolarization may be blockade of the outward delayed rectifier potassium rapid current. Ibutilide is administered intravenously, and approximately 40% of the drug in serum is protein bound. It is eliminated through hepatic metabolism by undefined enzyme systems, and it appears that none of the metabolites contributes significantly to antiarrhythmic activity. The elimination half-life of ibutilide ranges from 2-12 hours. When administered by 10-minute infusion, ibutilide 1 mg (approximately 0.015 mg/kg) resulted in conversion to sinus rhythm in 24-58% of patients with AFl and 20-32% with AF, compared with about 5% for placebo. Administering a second dose of 0.5-1 mg improved the overall response rates to approximately 75% and 45%, respectively. In randomized comparative trials, ibutilide was more effective than sotalol in converting AFl (70% vs 19%) and AF (44% vs 11%) and more effective than procainamide (76% vs 12% and 51% vs 20%, respectively). The time to conversion in most trials was usually 20-30 minutes. Nausea is the most common noncardiac adverse effect (< 2%). Nonsustained and sustained polymorphic ventricular tachycardia occurred in 2.7-6.7% and 1.7% of patients, respectively.

Strategies in the management of acute myocardial infarction.

Clinical trials continue to evaluate the pharmacologic management of myocardial infarction for benefits in mortality, degree of infarct artery patency, and frequency of reocclusion. The discovery of thrombus formation in the development of the myocardial infarction renewed interest in thrombolytic therapy. In appropriate candidates, timely administration of thrombolytics after myocardial infarction restores coronary artery patency, reduces myocardial ischemic damage, and improves left ventricular function. Adjunct therapy for thrombolysis typically includes aspirin, heparin, beta-blockers, nitroglycerin, and angiotensin-converting enzyme inhibitors, if not contraindicated. To reduce cardiac risk, postthrombolysis management generally includes aspirin. beta-blockers, and angiotensin-converting enzyme inhibitors together with efforts to reduce known cardiovascular risk factors.

Drug-related hospital admissions.

To describe the frequency and pattern of drug-related morbidity that results in hospital admission and the extent to which these admissions are avoidable, we prospectively reviewed the charts of 452 consecutive patients admitted to the intensive care unit or internal medicine service of a university-affiliated, county hospital. Of these, 73 (16.2%) were admitted due to drug-related morbidity. Forty patients (54.8%) experienced drug therapy failure, 24 (32.9%) had an adverse reaction, and 9 (12.3%) had overdoses. Thirty-six (49.3%) of these admissions were definitely avoidable. Compared with patients admitted for other reasons, these patients were more likely to report noncompliance with drug therapy (65.8% vs 15.7%, p < 0.0001) and were taking more drugs (p = 0.0037). We conclude that approximately half of drug-related hospital admissions are avoidable. Targeting patients taking several drugs and with a history of noncompliance may reduce this problem.

Preventing stroke in patients with nonrheumatic atrial fibrillation.

Published and ongoing studies of drug therapy for preventing stroke in patients with nonrheumatic atrial fibrillation (AF) are discussed, and updated recommendations are provided. Stroke is the most common complication of nonrheumatic AF; there are more than 75,000 such strokes each year in North America. Nonrheumatic AF increases the risk of stroke almost sixfold. Emboli from clots that form in the left atrium because of ineffective atrial contraction and turbulent blood flow may cause most of these strokes. The results of six randomized trials of antithrombotic therapy in patients with nonrheumatic AF are now available. In almost all of these trials, warfarin therapy significantly reduced the risk of stroke. One trial showed that aspirin significantly reduced the risk of stroke, but another trial did not support that finding. Ongoing trials are addressing the efficacy and risks of aspirin plus low-dose warfarin and very low intensity anticoagulation. Overall, the data suggest that patients who are younger than 75 years of age and who lack risk factors can be adequately protected against stroke with aspirin. Patients younger than 75 years who have risk factors but no contraindications to warfarin should receive warfarin. Patients older than 75 years appear to benefit from anticoagulation therapy, but this benefit is offset by the higher risk of bleeding complications. Lone AF is best managed with aspirin. Warfarin is superior to aspirin as a secondary intervention in patients with a recent thromboembolic event. Strategies for preventing stroke in patients with nonrheumatic atrial fibrillation continue to be refined.

Pharmacologic stress testing: experience with dipyridamole, adenosine, and dobutamine.

The use of pharmacologic stress testing for detecting and assessing ischemic heart disease (IHD) is reviewed. Methods of diagnosing IHD are designed to emulate conditions that increase myocardial oxygen demand in order to identify areas of ischemia and atherosclerotic lesions and to evaluate their functional or anatomical importance. Diagnostic methods can be divided into functional assessment with stress testing and anatomical assessment with coronary angiography. Physical stressors, such as exercise or atrial pacing, or pharmacologic stressors, such as vasodilators or beta-adrenergic-receptor agonists, can be used in stress testing. Electrocardiography, thallium planar scintigraphy, echocardiography, and other techniques are used to evaluate the response to stress testing. Unlike exercise stress testing, pharmacologic testing does not require physical exertion. Adenosine, dipyridamole, and dobutamine are the principal agents used in pharmacologic stress testing. Adenosine and dipyridamole mediate coronary artery vasodilation. Adenosine, a direct agonist, has a rapid onset and short duration of action. Dipyridamole, the only agent with approved labeling for use in stress testing, inhibits adenosine indirectly. Dobutamine increases cardiac output and heart rate as well as promoting coronary artery vasodilation. Clinical trials show that all three drugs can be used safely and effectively in patients after acute myocardial infarction or before vascular surgery and in individuals with risk factors for or symptoms of IHD. The sensitivity and specificity of pharmacologic stress testing for detecting IHD are at least as high as those of exercise testing. Minor adverse effects, including chest pain, headache, and facial flushing, are common, but major adverse effects are rare. Pharmacologic stress testing can be used in patients who cannot undergo exercise testing and offers a noninvasive alternative to coronary angiography.

Drug dosing in renal insufficiency.

Drug dosing in renal insufficiency needs to be individualized whenever possible to optimize therapeutic outcomes and to minimize toxicity. Although a number of published tables that provide dosing guidelines and nomograms exist to assist in dose modification, individualization of therapy should be based on pharmacokinetic principles whenever possible. The basis equations to estimate the pharmacokinetic parameters of clearance, volume of distribution, and half-life for intravenous drug administration of drugs with first-order kinetics are not difficult to understand and apply. Their use should be encouraged in patient care.

Phenformin-induced lactic acidosis: a forgotten adverse drug reaction.

OBJECTIVE: To document a case of severe metabolic and lactic acidosis secondary to phenformin. This adverse effect has almost been forgotten as 15 years have passed since its withdrawal from the US market. CASE SUMMARY: A 64-year-old man presented with a four-day history of left upper abdominal pain and a one-week history of constipation and diarrhea. His arterial blood gases were pH 6.7, pCO2 2.80 kPa, and pO2 12.00 kPa with 90% oxygen saturation on room air. Serum chemistries indicated an unmeasurable serum bicarbonate concentration, anion gap 52 mmol/L, lactate concentration 29.5 mmol/L, blood urea nitrogen 6.63 mmol/L, creatinine 229.84 mumol/L, and blood glucose 4.35 mmol/L. There were low levels of urine and serum ketones. In the emergency department, he required resuscitation for hypotension and bradycardia. His diagnosis was lactic and ketoacidosis secondary to phenformin. The patient was treated with NaCl 0.9%, sodium bicarbonate, insulin, and hemodialysis. Although he survived the initial insult of lactic and ketoacidosis, his hospital course was complicated and he died on hospital day 105. CONCLUSIONS: Treatment of lactic acidosis is difficult and challenging. The continued availability of phenformin in neighboring countries, and the renewed interest in biguanide therapy for treating diabetes mellitus make it an important diagnosis of exclusion in diabetic patients who present with severe acidosis. Metformin, another biguanide under investigation for the treatment of diabetes mellitus, is associated with a much lower incidence of lactic acidosis than is phenformin.

Pharmacotherapy specialty certification examination. IV. 1992 results and process modifications, including recertification. The 1992 Specialty Council on Pharmacotherapy, Board of Pharmaceutical Specialties.

Certification of pharmacotherapy specialists is proceeding smoothly. Modifications to the examination process, which include reapportioning domains, offering the examination at several sites, and establishing the recertification process, have occurred. The guidelines for petitioners and structure of specialization continue to receive the attention and interest of prospective candidates, pharmacy organizations, and the BPS. To date, 674 specialists have been certified in the approved specialties: 175 nuclear pharmacists, 236 nutrition pharmacists, and 263 pharmacotherapy specialists.