Cost-Utility analysis of tissue plasminogen activator therapy for acute ischaemic stroke: a Canadian healthcare perspective.

BACKGROUND: There are over 40000 ischaemic strokes annually in Canada, which result in significant morbidity, mortality and burden to the healthcare system. A recent, large clinical trial has evaluated tissue plasminogen activator (t-PA) intravenously for the treatment of acute ischaemic stroke with promising outcomes but with an increased risk of symptomatic intracranial haemorrhage. OBJECTIVE: To compare clinical and economic outcomes of intravenous t-PA therapy (0.9 mg/kg, to a maximum of 90 mg, initiated within 3 hours of stroke onset) versus no t-PA for acute ischaemic stroke based on the outcomes achieved in the National Institute of Neurological Disorders and Stroke (NINDS) trial. DESIGN: A Markov model depicting the natural lifetime course after an initial acute ischaemic stroke. On the basis of this model, a simulated trial compared no t-PA with t-PA. PATIENTS: A hypothetical cohort of 1000 patients with acute ischaemic stroke. STUDY PERSPECTIVE: Canadian healthcare system. OUTCOME MEASURES: Total acute stroke and post-stroke treatment costs and cumulative quality-adjusted life-years (QALYs). RESULTS: For a hypothetical cohort of 1000 patients, the estimated lifetime stroke costs were 103100000 Canadian dollars (SCan) [1999 values) in the t-PA arm ($Can103100 per patient) compared with SCan106900000 in the no t-PA arm ($Can106900 per patient), yielding a lifetime cost difference of $Can3800000 in favour of t-PA versus no t-PA (SCan3800 per patient). In the hypothetical cohort, t-PA treatment resulted in 13 130 QALYs versus 9670 QALYs with no t-PA treatment. This translated into a net benefit of 3460 additional QALYs per 1000 patients (3.46 QALYs per patient). No treatment, outcome or economic variables influenced the model outcome. CONCLUSION: From the standpoint of cost effectiveness, treatment of acute ischaemic stroke with intravenous t-PA is an economically attractive strategy.

Pulmonary effects of low dose amiodarone: a review of the risks and recommendations for surveillance.

Previous studies have reported an incidence of amiodarone-induced pulmonary toxicity (AIPT) of 5% to 10% with high doses of amiodarone (greater than 400 mg daily). A lower rate of 1.6% is recorded from combined placebo controlled, double-blind trials involving 3439 patients receiving daily amiodarone doses of 400 mg or less. Although the rate of diagnosis of AIPT appears to be lower than previously reported, it is still considerable, and its consequences are potentially fatal if undiagnosed. Before amiodarone is initiated, baseline chest x-ray (CXR) and pulmonary function tests should be performed. Although follow-up surveillance with CXR at three- to six-month intervals has been recommended, pulmonary toxicity can develop rapidly, and radiographic abnormalities may not precede clinical toxicity. Repeat lung function testing should be reserved for patients who develop new symptoms or CXR findings. Patient self-reporting of symptoms and regular clinical evaluation are likely the easiest and most useful strategies for prompt detection of AIPT.

Amiodarone-induced pulmonary toxicity.

Amiodarone-induced pulmonary toxicity (AIPT) is one of the most serious adverse effects of amiodarone therapy and can be fatal. Therefore, vigilant monitoring is advised. Baseline chest radiograph and pulmonary function tests and follow-up chest films at 3-month intervals are advocated. However, since abnormalities on these two examinations do not always precede symptoms, patient self-reports of respiratory symptoms appear to be the best method for early detection of AIPT.

Outpatient self-management of warfarin therapy: a pilot study.

Self-testing and adjusting of warfarin dosages by patients is an evolving strategy for management of oral anticoagulation. We performed this open, prospective, 3-month pilot study to assess the feasibility of conducting a large, randomized trial comparing self-managed with physician-managed anticoagulation. Ten competent patients with planned anticoagulation for at least 3 months were provided education on warfarin therapy and trained to use an individualized warfarin nomogram. International normalized ratios (INRs) were determined weekly for 12 weeks and reported with warfarin dosages to the investigator for the first 8 weeks only. Eight patients elected to use a home monitor (ProTime) to measure INRs. Patients maintained 76.5% (range 50-91.7%) of INRs within the target range. In 119 dosage adjustment decisions, there were only 3 errors (2.5%). No bleeding or thrombotic complications occurred. To confirm concordance, initial and final INRs were measured concurrently by the ProTime monitor and laboratory. The mean absolute difference for 16 paired INR determinations was 0.33 (range 0.02-0.9). All patients expressed satisfaction and a desire to continue with self-management. This pilot study provides support for conducting a prospective, large-scale, randomized trial.

Cost-effectiveness analysis of abciximab: a Canadian hospital perspective.

OBJECTIVE: To assess the cost-effectiveness of abciximab therapy versus traditional practice in high-risk patients receiving percutaneous transluminal coronary angioplasty (PTCA) from a Canadian hospital perspective. DESIGN: A predictive decision analytic model using published clinical and economic evaluations, as well as costs of medical care in Canada. SUBJECTS: High-risk PTCA patients as defined by the Evaluation of c7E3 for Prevention of Ischemic Complications trial and the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina trial. INTERVENTIONS: Two treatment strategies were compared: (1) abciximab 0.25 mg/kg intravenous bolus 10 minutes prior to PTCA followed by abciximab 10 micrograms/min intravenous infusion for 12 hours after the procedure, and (2) no abciximab adjunctive therapy at the time of PTCA. Both treatment strategies were combined with intravenous heparin up to 100 units/kg bolus pre-PTCA followed by bolus doses for 1 hour after PTCA per the protocol. Cumulative outcomes were considered up to 6 months after initial PTCA. RESULTS: At 6 months, 29% of the patients in the abciximab treatment arm compared with 33% in the no abciximab arm achieved one of the primary events. The most common adverse event experienced was major bleeding at 4% in the abciximab treatment arm versus 1.6% in the no abciximab arm. The average cost per patient for each strategy was $3261 Can ($1 Can = $0.686 US) (abciximab arm) versus $2073 Can (no abciximab arm), resulting in an incremental cost-effectiveness ratio of $29,700 Can per event-free patient. In univariate sensitivity analyses, the only controllable factor that changed the results of the cost-effectiveness outcome was the cost of abciximab. CONCLUSIONS: Although the use of abciximab as an adjunct to PTCA results in a reduction in event rates in high-risk patients compared with traditional treatment, there is an increased cost associated with this strategy.

The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines.

The English-language literature was systematically reviewed to clarify the role of combination antithrombotic therapy with warfarin and acetylsalicylic acid (ASA) versus monotherapy with either agent, including data from several recently published trials. Sixteen published studies with evaluable efficacy and/or safety data were identified. For patients with prosthetic heart valves at high risk of thromboembolism, combined warfarin and ASA therapy may be beneficial compared with warfarin alone. Combination therapy may also be used for primary prevention in patients at high risk for ischemic heart disease, although the expected benefits are small. Evidence does not support the use of combined antithrombotic therapy in patients with established ischemic heart disease, ischemic stroke, coronary artery bypass grafts or atrial fibrillation. Combination therapy is associated with an increased risk of minor and major bleeding. The highest dose of ASA that can be recommended in combination with warfarin is 100 mg daily.

Is oral sotalol effective in converting atrial fibrillation to sinus rhythm?

d,l-Sotalol is a noncardioselective beta-blocker that has class III antiarrhythmic activity. It is often used to convert atrial fibrillation (AF) to normal sinus rhythm. Since class III agents increase action potential duration and refractoriness in atrial tissue without affecting conduction, they are theoretically considered ideal agents for the treatment of reentrant arrhythmias such as AF. We reviewed the literature evaluating the efficacy of sotalol for restoring sinus rhythm in patients with acute or chronic AF. Articles indexed on MEDLINE (1966-1996) and referenced articles not identified by MEDLINE that compared sotalol with placebo or another antiarrhythmic agent were included. Sotalol was significantly inferior to quinidine in converting AF of recent onset (< 48 hrs) to sinus rhythm. In patients with duration of AF of more than 48 hours, sotalol was significantly less effective than quinidine and comparable with placebo. Conversion rates for sotalol in all studies combined ranged from 8-49%. Published studies do not support the drug for conversion of AF to sinus rhythm. Larger well-designed studies are required to evaluate its efficacy and optimum dosage for this indication. Until further data are available, pharmacologic cardioversion with traditional class I antiarrhythmic agents may be preferable as they are effective particularly for recent-onset AF.

Oral propafenone for rapid conversion of recent onset atrial fibrillation--a review.

OBJECTIVE: To review comparative studies evaluating oral propafenone for restoring sinus rhythm in recent onset atrial fibrillation. DATA SOURCES: A MEDLINE search of the English-language literature (1966 to 1996) along with any referenced articles not identified by MEDLINE. STUDY SELECTION: Because intravenous propafenone is not marketed in Canada, only studies evaluating oral propafenone were included. Studies were selected if they compared oral propafenone with placebo or other antiarrhythmic agents for converting recent onset atrial fibrillation to normal sinus rhythm. DATA SYNTHESIS: Propafenone is often used as a first-line agent for pharmacological cardioversion of atrial fibrillation. In earlier studies, the efficacy of propafenone in restoring sinus rhythm was reported to be low with conversion rates of 6% to 62%. Many of these studies were noncomparative and often included patients with refractory, chronic atrial fibrillation or employed suboptimal doses of propafenone. More recently propafenone has been evaluated in the treatment of recent onset atrial fibrillation by using a single 600 mg oral loading dose. Success rates of 76% at 8 h and 83% at 12 h following the loading dose are reported. The incidence of atrial flutter during active treatment was similar to that with placebo, with the majority exhibiting 2:1 or greater atrioventricular conduction ratios and heart rates 150 beats/min or less. CONCLUSIONS: A single 600 mg oral dose of propafenone is highly effective at restoring sinus rhythm in patients with acute onset atrial fibrillation with few adverse effects. The small studies reviewed cannot lead to definitive conclusions about the safety of propafenone without prior administration of agents for rate control.

Unstable angina associated with sertraline.

An 81-year-old woman reported with chest pain occurring shortly after initiating treatment with sertraline. She had no prior history of cardiovascular disease. She developed nausea and malaise 4 h after her first dose, which resulted in avoidance of further treatment. After voluntarily reinitiating sertraline 10 days later, she again developed nausea and malaise but persisted with treatment. On the second day, her gastrointestinal symptoms were accompanied by crushing retrosternal chest pain radiating to both arms and resolving spontaneously after 10 mins. Following the third dose of sertraline, the patient experienced severe and persistent crushing retrosternal chest pain radiating to both arms. She was hospitalized with a diagnosis of unstable angina and treated with acetylsalicylic acid, intravenous heparin and nitroglycerin. The temporal relationship of chest pain onset following ingestion of sertraline is strongly suggestive of an adverse medication effect.

Increasing GPI-anchored protein harvest concentrations from suspension and porous microcarrier CHO cell cultures.

Chinese hamster ovary (CHO) cells expressing the human melanoma tumour antigen, p97, were used to develop a controlled release process for the production of recombinant glycosyl-phosphatidylinositol (GPI) anchored proteins. The cells were cultured either in suspension or immobilized on porous microcarriers and p97 was selectively cleaved from the cell surface by the bacterial enzyme, phosphatidylinositol-phospholipase C (PI-PLC). The kinetics of p97 cleavage from the cell surface by PI-PLC was shown to be approximated by Michaelis-Menten kinetics. The recovered p97 concentrations were increased by reusing the PI-PLC enzyme solution to harvest multiple batches of cells. A convenient PI-PLC assay was developed to monitor the harvesting process and to determine the stability of PI-PLC under harvesting conditions. Although the Pl-PLC was stable under harvesting conditions, it rapidly adsorbed to the cell surface and was depleted from the reused enzyme solution. In order to maintain PI-PLC activity, it was necessary to add fresh PI-PLC to the reused enzyme solution before harvesting a fresh batch of cells. The maximum p97 concentration that could be obtained from harvesting CHO cells cultured on porous microcarriers was limited by the dilution effects of sample removal, adding fresh PI-PLC and liquid associated with settled microcarriers. A model was developed that adequately predicted the p97 concentration after each harvest and the maximum p97 concentration that could be achieved by this harvesting method. The dilution effects were minimized by harvesting from centrifuged suspension culture cells and the harvested p97 concentration was increased by over sixfold to 0.64 mg/mL.

Comparison of a weight-based heparin nomogram with traditional heparin dosing to achieve therapeutic anticoagulation.

Optimum anticoagulation with heparin within the first 24 hours of a thrombotic event is critical in preventing a recurrence. We believed that traditional nonweight-based heparin dosing at our institution resulted in delayed anticoagulation. A weight-based heparin nomogram was therefore created and compared to traditional heparin dosing in patients with a diagnosis of acute deep vein thrombosis or pulmonary embolism. Fifty historical control patients were compared to 50 consecutive patients treated prospectively using the weight-based nomogram. The primary outcome assessed was time to achieve therapeutic anticoagulation, defined as an activated partial thromboplastin time (aPTT) of 46-70 seconds (1.5-2.5 times the control aPTT). The weight-based nomogram achieved an aPTT above the therapeutic threshold more rapidly than the control group (10.7 hrs nomogram vs 33.3 hrs control group, p < 0.004). Similarly, the proportion of patients who exceeded the therapeutic threshold at the first aPTT measurement, at 24 hours, and at 48 hours was significantly higher in the nomogram group. There was no difference in the frequency of bleeding complications or recurrent thrombotic events between the two groups. The initial nomogram was revised for patients weighing more than 80 kg owing to a greater frequency of excessive anticoagulation in these patients. Subsequent analysis of 29 patients using the modified nomogram revealed sustained efficacy and a reduced number of supratherapeutic aPTTs. We concluded that a weight-based heparin nomogram is superior to traditional therapy in achieving rapid therapeutic anticoagulation without an increase in adverse outcomes.