Canadian Trial Research Articles

UKPACE: to die, or not to die ... Is that the question?

Publication of the United Kingdom Pacing and Cardiovascular Events (UKPACE) trial in 20051 brings to three the number of important randomized clinical trials that call into question what formerly had seemed to be a bullet-proof principle of modern cardiac pacemaker therapy, namely the apparent desirability of maintaining a normal atrioventricular (AV) timing relationship. Indeed, as a group, UKPACE and two earlier North American trials [the Canadian Trial of Physiological Pacing (CTOPP) and the Mode Selection Trial (MOST) in sinus node dysfunction (SND)]2,3 may influence physicians and health insurers to advocate, based on a mortality cost-effectiveness basis, for a return to the predominance of single-chamber ventricular pacing. However, before turning back the clock, the messages delivered by these studies warrant careful examination. CTOPP and MOST compared outcomes during dual-chamber and single-chamber ventricular pacing in over 4500 patients with AV block and/or SND and reported no overall difference in mortality or stroke. However, more than two-thirds of the patients enrolled in these two trials were paced for treatment of SND, a condition in which the frequency of pacing may vary widely from patient to patient, and death is a less relevant endpoint than is preventing syncope, reducing thromboembolic risk or improving exercise tolerance. UKPACE, the most recently published of the three major clinical trials noted earlier, randomized cardiac pacemaker treatment candidates ≥70 years of age with AV block between dual- ( n =1012) and single-chamber devices ( n =1009), and further subdivided the single-chamber population into two groups: fixed-rate ventricular pacing ( n =504), and rate-modulated single-chamber pacing ( n =505). The resulting three subgroups proved to be reasonably comparable in terms of age, gender, New York Heart Association (NYHA) functional class, AV conduction disease, symptoms, co-morbidities, and medications. Further, a high pacing ‘burden’ was anticipated in all patients by virtue of …

The Effect of Preoperative Radiotherapy and Reconstructive Surgery on Wound Complications after Resection of Extremity Soft-Tissue Sarcomas

Major wound complications (MWCs) are frequent after preoperative radiotherapy (RT) for extremity soft-tissue sarcoma (STS). We examined the rate of MWCs at a single institution with readily available reconstructive surgery. The medical records of consecutively treated extremity STS patients treated with preoperative external-beam RT and surgical resection from June 1996 through February 2003 were reviewed. Patients underwent RT (median 50 Gy), followed by resection 4-8 weeks later. Patients believed to be at higher risk for MWC underwent wound closure by the reconstructive surgery service (RSS). MWCs included secondary operation, invasive procedure, hospital readmission, or persistent deep packing or dressing changes. A total of 173 patients underwent preoperative RT. Median age was 54 years; 51% were female; 80% had lower extremity STS. Wound closure was performed by the primary surgeon in 91 cases (53%). The RSS performed wound closure in the remaining 82 patients (47%). One or more MWCs occurred in 55 patients (32%). Wound complications were more likely in patients with lower extremity (49/138, 36%) than upper extremity (6/35, 17%) STS (P = 0.03). Among patients with lower-risk wounds closed by the primary surgical team, 29 (32%) experienced MWC, whereas in the higher-risk patients closed by the RSS, MWC occurred in 26 (32%). MWCs are frequent after preoperative RT and occur more commonly in patients with lower extremity tumors. The MWC rate observed in a single-institution setting was comparable to that observed in the preoperative therapy arm of a multicenter Canadian trial. Patients believed to be at higher risk for MWCs undergoing RSS closure have MWC rates comparable to those with lower-risk wounds closed by the primary team.

AB15-6: Body mass index predicts recurrence of atrial fibrillation: Insights from the Canadian Trial of Atrial Fibrillation (CTAF)

AB15-6: Body mass index predicts recurrence of atrial fibrillation: Insights from the Canadian Trial of Atrial Fibrillation (CTAF)

Policy makers ignoring science and scientists ignoring policy: the medical ethical challenges of heroin treatment

A decade of research in Switzerland, The Netherlands, Germany, and Spain now constitutes a massive body of work supporting the use of heroin treatment for the most difficult patients addicted to opiates. These trials concur on this method's safety and efficacy and are now serving as a prelude to the institution of heroin treatment in clinical practice throughout Europe.While the different sampling and research protocols for heroin treatment in these studies were important to the academic claims about specific results and conclusions that could be drawn from each study, the overall outcomes were quite clear – and uniformly positive. They all find that the use of prescribed pharmaceutical heroin does exactly what it is intended to do: it reaches a treatment refractory group of addicts by engaging them in a positive healthcare relationship with a physician, it reduces their criminal activity, improves their health status, and increases their social tenure through more stable housing, employment, and contact with family.The Canadian trial (NAOMI), now underway for over a year, but not yet completed, now faces a dilemma about what to do with its patients who have successfully completed 12 months of heroin and must be withdrawn from heroin and transferred to other treatments in accordance with the research protocol approved by Government of Canada, federal granting body and host institutions. The problem is that the principal criterion for acceptance to NAOMI was their history of repeated failure in these very same treatment programs to which they will now be referred.The existence of the results from abroad (some of which were not yet available when NAOMI was designed and initiated) now raises a very important question for Canada: is it ethical to continue to prohibit the medical use of heroin treatment that has already been shown to be feasible and effective in numerous medical studies throughout the world? And while this is being worked out, is it acceptable to require patients who have been successfully treated with heroin in Canada, to be forced to move back to less effective treatments (treatments that failed to be efficacious in the past)?This essay discusses this dilemma and places it in the broader context of ethics, science, and health policy. It makes the case for continuation of the current successful patients in heroin treatment and the institution of heroin treatment to all Canadian patients living with active addictions who qualify.

Design and Rationale for a Randomized, Controlled Trial of Interpersonal Psychotherapy and Citalopram for Depression in Coronary Artery Disease (CREATE)

Recognition that depression is associated with increased morbidity and mortality in coronary artery disease (CAD) patients has augmented the need for evidence-based treatment guidelines. This article presents the design of a multisite, Canadian trial of the efficacy, safety, and tolerability of interpersonal psychotherapy (IPT), an empirically supported, depression-focused therapy, and the selective serotonin reuptake inhibitor citalopram, alone or in combination, in the treatment of major depression in CAD patients. Two hundred eighty stable CAD patients with a current major depressive episode of at least 4 weeks' duration, based on the Structured Clinical Interview for Depression (SCID), and who have a baseline score >19 on a centralized, telephone-administered, 24-item Hamilton Depression Rating Scale (HAM-D) will be randomly assigned to receive 12 weekly IPT sessions or 12 weekly sessions of standardized clinical management (CM). Patients are also randomly assigned to receive 20 to 40 mg per day of citalopram or pill-placebo. This results in a 2-by-2 factorial design with four groups: IPT plus pill-placebo, IPT plus citalopram, CM plus pill-placebo, and CM plus citalopram. This permits the evaluation of both IPT and citalopram. Blinded, centralized, 24-item, HAM-D telephone ratings constitute the primary outcome variable. The self-report Beck Depression Inventory-II is the secondary outcome. Analyses will involve the intent-to-treat principle with last observation carried forward for incomplete assessments. Not applicable. The results of this trial will contribute to the development of evidence-based clinical guidelines for managing depression in the context of CAD.

Omeprazole vs. Ranitidine for Dyspepsia

Several therapeutic options exist for patients with Helicobacter pylori–negative dyspepsia. In this primary care–based randomized Canadian trial, 512

Cost-effectiveness of physiologic pacing: Results of the Canadian Health Economic Assessment of Physiologic Pacing

The purpose of this study was to determine the cost-effectiveness of physiologic pacemakers. The Canadian Trial of Physiologic Pacing (CTOPP) was a large randomized trial that evaluated the efficacy of physiologic pacing compared with ventricular pacing. CTOPP also included a prospective cost-effectiveness substudy. Resource usage and costs were collected from a subset of 472 patients (of 1,094) who received a physiologic pacemaker and 586 (of 1,474) who received a ventricular pacemaker. Costs included initial pacemaker implantation and all health care follow-up costs over a follow-up of 5.2 years. Costs are reported in 2004 Canadian dollars (1 Canadian dollar = 0.76 US dollars), with adjustments for censoring. Incremental cost-effectiveness was estimated as the ratio of the difference (treatment-control) in mean cost to the difference in life expectancy (mean survival), with costs and effects discounted at 3% per year. Over a mean follow-up of 3.1 years, physiologic pacing was associated with a gain of 0.01 life-years. This benefit increases to 0.25 life-years in the subgroup of patients with an intrinsic (unpaced) heart rate < or =60 bpm. Physiologic pacing was more expensive than ventricular (16,833 Canadian dollars vs 13,857 US dollars), largely because of the increased cost of dual-chamber devices. Among all substudy patients, the incremental cost-effectiveness of physiologic pacing is 297,600 Canadian dollars per life-year gained; however, this value falls to 16,343 Canadian dollars in patients with an intrinsic heart rate >60. In the short term, a strategy of routine implantation of physiologic pacemakers is not cost-effective by currently accepted standards. The selective use of these devices in patients likely to be pacemaker dependent appears to be cost-effective. Further studies with longer follow-up and which consider the benefit of reducing nonfatal cardiac events would be valuable.

Use of Physiologic Pacing After the Canadian Trial of Physiologic Pacing

The Canadian trial of physiologic pacing (CTOPP), published in 2000, demonstrated a reduction in atrial fibrillation (AF), stroke and death with preservation of atrioventricular synchrony, though only the lower rate of AF was statistically significant. The purpose of this study was to determine the effect of CTOPP on pacing mode selection in our region. The British Columbia Cardiac Registry contains prospectively entered data covering a population of 4 millions (M) and 17 implanting centers. It was examined for mode selection trends from 1997 to 2002. At examination, there were data on 22,446 pulse generators (PG) and 29,898 leads. New implant rates per M population were 1997:473; 1998:456; 1999:505; 2000:513; 2001:486; 2002:510. PG replacements also increased, resulting in a total implant rate of 667 PG per M in 2002. Over the 6-year period, DDD use decreased from 321 to 306, but DDDR use, more than doubled from 317 to 750 PG/year. VVI use steadily decreased from 741 to 410 PG/year, while VVIR use increased more modestly from 1997 to 1999, then remained stable. During the 6-year period bracketing CTOPP, use of modes maintaining AV synchrony increased by over 32%, to 53% of PG implanted in 2002. Our PG implant rate was much higher than expected from prior retrospective surveys, and similar to rates in Belgium, France, and Germany. CTOPP did not decrease our use of physiologic pacing but, instead, was associated with a brief pause, then progressively increased in both academic and community centers. Patients' need and widely accepted standards of care proved more important in clinical decision making than the results of a flawed randomized trial.

The Cross-Examiner's Tactics: What the Expert Witness Should Know

In my book, Financial Litigation: Quantifying Business Damages and Values,1 I provide a comprehensive list of suggestions (do’s and don’ts) for the business valuator when giving expert testimony in the witness box, both in examination-in-chief and in cross-examination. This lengthy “checklist” was developed from both personal experience and working with eminent Canadian and American trial lawyers. I believe it may be of interest to aspiring (and even experienced) expert witnesses to obtain a view from “behind the scenes” and to see what rules and maxims have been established for the trial attorneys themselves. Just as we expert witnesses have our own “do’s and don’ts” checklist, so does the litigation lawyer cross-examining you. Crossexamination is such an important part of the trial process that entire books have been devoted to the subject. In this article, I have taken material from the writings of two Canadian and two American legal authorities: Former Supreme Court of Canada Justice John Sopinka (when he was a practicing trial lawyer) in The Trial of An Action and Ontario District Court Judge Roger Salhany in Cross-Examination: The Art of The Advocate . The American authors are Peter Brown in The Art of Questioning and the nineteenth-century trial lawyer, Francis Wellman, in his classic, The Art of Cross-Examination. My comments consist of a potpourri of the rules, or maxims, given by these renowned trial lawyers to their fellow attorneys. I hope they will provide insight as to what goes on in the mind of the cross-examiner and where he or she is “coming from,” and why. Needless to say, these rules are by no means exhaustive. Those specifically relating to criminal trials are not referred to, unless they are common to civil and commercial matters. Whenever expert evidence is involved, I have included the relevant maxims. Sopinka, in his book The Trial of An Action, gives several pages of advice (as an attorney) to trial lawyers in preparing a witness for cross-examination, and suggested: “In order to further neutralize the terror generated by the witness box the witness should be given a preview of the cross-examination. When the witness is a main witness and will be subjected to a searching cross-examination, it is often productive to plan the examination which is expected from opponent’s counsel and subject the witness to it ... . “Apart from being given a preview of the examination there are a number of ‘good pieces of advice’ about behavior from which a witness can profit ... . Don’t fence with the cross-examiner. Don’t lose your composure. ... no matter how much you dislike the cross-examiner treat him with respect. All of this will help to create a favorable impression on the tribunal.” Those of us who have already testified as a valuation expert appreciate that the foregoing instructions are those typically suggested by counsel preparing the expert for cross-examination. Sopinka notes that a witness’ evidence can be contradicted or impeached by (a) previous inconsistent statements, (b) other evidence, (c) contradiction in the witness’ own evidence or inherent improbabilities therein, or (d) attacking his or her memory, power of observation and credibility. As regards the expert (as opposed to the fact-witness), he makes the following suggestions to fellow counsel: • To cross-examine effectively, it is necessary to be schooled by an equally competent expert. • The object is to flaw him/her so that your expert is preferred. • The easiest way of discrediting the opinion is to refute a basic assumed or found fact, which may be done in cross-examination or by other evidence. • If a basic assumed fact cannot be refuted, attack the theory of the expert [presumably relying upon counsel’s own expert].

Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis

Sublingual swallow immunotherapy has been increasingly recognized as a safe and efficacious alternative to parenteral specific immunotherapy. To determine the safety and efficacy of sublingual swallow immunotherapy ragweed allergen extract for rhinoconjunctivitis treatment starting just before and continuing through the ragweed pollen season. This randomized, double-blind, placebo-controlled study was performed in children and adults with a documented history of allergic rhinoconjunctivitis during ragweed season at 9 Canadian allergy centers. Active treatment was standardized extract of ragweed allergen administered as sublingual swallow drops at increasing doses starting shortly before the pollen season and maintenance doses continued daily during the season. Primary efficacy variables were symptom and medication scores, and secondary variables included global evaluation of efficacy and immunologic measurements. Eighty-three patients were included in the safety analysis; 76 patients were included in the intent-to-treat analysis. Nine placebo recipients and 1 treatment recipient withdrew for lack of efficacy (P = .004). Nine patients in the treatment group withdrew because of adverse events, none serious (P = .003). Investigator evaluation of efficacy showed that significantly more patients improved and fewer deteriorated in the treatment group vs the placebo group (P = .047). Ragweed IgE and IgG4 levels increased significantly in treatment recipients vs placebo users (P < .001). Sneezing and nasal pruritus approached significant improvement in the treatment group vs the placebo group (P = .09 and .06, respectively). Quebec City experienced low pollen counts. Excluding Quebec City, significant improvement was seen for these 2 symptoms (P = .04). Sublingual swallow immunotherapy seems to be safe and efficacious for ragweed rhinoconjunctivitis even when started immediately before the ragweed pollen season.

Canadian trial of physiologic pacing. effects of physiologic pacing during long-term follow-up

Canadian trial of physiologic pacing. effects of physiologic pacing during long-term follow-up

An update on clinical trials in pacing: is dual chamber pacing better?

As pacemaker technology has increased in complexity and now offers a variety of additional capabilities, there is uncertainty as to which pacing mode offers more benefit-dual-chamber or single-chamber. Two large-scale randomized trials, the Canadian Trial of Physiologic Pacing and the Mode Selection Trial, demonstrated that dual-chamber pacing does not reduce the incidence of stroke or improve survival when compared with ventricular pacing. However, dual-chamber pacing does reduce the incidence of atrial fibrillation and in patients with sinus node dysfunction, reduces heart failure symptoms when compared with ventricular pacing. The modest results of these trials were unexpected when viewed in the context of the very favorable retrospective studies. A rethinking of the physiology of cardiac pacing has led to the concept that although atrioventricular synchrony supports an improvement in cardiac output and ventricular pressures, these favorable hemodynamics may be attenuated by ventricular dyssynchrony from right ventricular apical pacing. In patients with a reduced ejection fraction, this dyssynchrony may be especially detrimental. Two trials (DANPACE and SAVE-PACE) are currently underway that will clarify the clinical significance of reducing forced ventricular desynchronization. The results of these trials may direct pacemaker physicians away from the right ventricular apical lead toward a new imperative of atrioventricular and right ventricular-left ventricular synchrony.

Relationships between pacing mode and quality of life: evidence from randomized clinical trials.

Although mode-dependent differences in mortality are for the moment unproven, establishing a health-related quality of life difference between assigned pacing modes would be useful. Such a difference, if one exists, should be >or=0.5 standard deviation units among scales using validated instruments to have significant clinical meaning. Two large data sets, the Canadian Trial of Physiological Pacing (CTOPP) and the Mode Selection Trial (MOST) both similar in design, largely failed to clearly establish such a significant difference. Another trial the Pacemaker Selection in the Elderly (PASE) did suggest that for sinus node disease, DDD-R pacing may lead to an improvement in quality of life mainly early post implant. Two other large trials, UK-PACE and DANPACE have yet to present quality of life related results. All published data have established that restoration of chronotropic competence by pacing leads to improvements in quality of life that are significant. In CTOPP an attempt to quantify a mode-dependent difference for a pacemaker syndrome suggested that the prevalence and clinical importance of pacemaker syndrome may be exaggerated. The relative ease of crossover from VVI-R to DDD, by device upgrade in CTOPP or by programming in MOST, may explain the 2.9% vs. 31% crossover rates seen in CTOPP vs. MOST respectively. Trials to date may have had a mode dependent difference undermined by possible adverse effects from right ventricular apical sites of pacing. Future trial data; DANPACE, sinus node disease AAI-R vs. DDD-R and PAVE, post AVJ ablation VVI-R vs. VVI-CRT, will asses in more detail the role of site of pacing as a factor in determining mode dependent outcomes in pacing.

Cost evaluation of rhythm control methods for atrial fibrillation: evidence from CTAF.

Atrial fibrillation (AF) is a highly prevalent arrhythmia that is difficult to treat and generates important health care costs. One consideration in the selection of various therapeutic options is the cost of a given treatment compared to that of alternatives. The Canadian Trial of Atrial Fibrillation (CTAF) evaluated the effectiveness of sinus rhythm maintenance with amiodarone compared to propafenone or sotalol in a prospective, randomized fashion. A subsequent CTAF substudy of the medical costs associated with amiodarone vs. propafenone/sotalol found that amiodarone decreased AF-related costs. This paper reviews the results of the CTAF cost-analysis substudy in the context of other analyses in the literature of the cost effectiveness of amiodarone in AF. The costs associated with amiodarone therapy are no greater than for other sinus rhythm maintenance drugs, and for some cost categories and some patient subgroups are likely to be less, despite amiodarone's greater therapeutic efficacy. However, additional considerations are important in evaluating the clinical place of amiodarone, including its adverse effect and pharmacokinetic profile. As well, the results of recent randomized clinical trials have highlighted the limitations of sinus rhythm maintenance as a primary therapeutic objective in AF. The decision about whether and at what point to use amiodarone in a given patient requires a careful analysis of the individual case, in terms of symptomatology during AF, the response to previous treatment regimes, and risk factors for various forms of adverse drug reactions.

Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trials

In managing atrial fibrillation (AF), the main therapeutic strategies include rate control, termination of the arrhythmia, and the prevention of recurrences and thromboembolic events. Safety and efficacy considerations are important in optimizing the choice of an antiarrhythmic drug for the treatment of AF. Recently approved antiarrhythmics, such as dofetilide, and promising investigational drugs, such as azimilide and dronedarone, may change the treatment landscape for AF. For medical conversion of recent-onset AF, class IC antiarrhythmic drugs, administered as an oral bolus, have been demonstrated to be the most efficacious pharmacologic conversion agents. Intravenous ibutilide and oral dofetilide both have efficacies superior to placebo in controlled trials for converting persistent AF. Comparative trials in paroxysmal AF have demonstrated that flecainide, propafenone, quinidine, and sotalol are equally effective in preventing recurrences of AF. Amiodarone has been demonstrated to be more efficacious than propafenone or sotalol in the Canadian Trial of Atrial Fibrillation. In persistent AF, twice-daily dofetilide has been shown to be as or more effective than low-dose sotalol given twice daily for the maintenance of sinus rhythm in patients with AF. Trials have demonstrated that subjective adverse effects are less frequent with class IC drugs, sotalol, and dofetilide compared with such drugs as quinidine. In patients without structural heart disease, flecainide, propafenone, and d,l-sotalol are the initial drugs of choice, given their reasonable efficacy, low incidence of subjective side effects, and lack of significant end-organ toxicity. Treating AF in patients with left ventricular dysfunction can be difficult because of associated electrophysiologic derangements, potential proarrhythmic concerns, and negative inotropic effects of antiarrhythmics. Some data exist suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can prevent AF either by preventing atrial dilation and stretch-induced arrhythmias or by blocking the renin-angiotensin system. In post–myocardial infarction patients, d,l-sotalol, dofetilide, and amiodarone—and in congestive heart failure patients, amiodarone and dofetilide—have demonstrated neutral effects on survival in controlled trials. In the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT), amiodarone lowered the frequency of AF development and improved left ventricular ejection fraction over time. In CHF-STAT, there was lower mortality in patients who converted from AF to sinus rhythm. Dofetilide decreased rehospitalization for congestive heart failure in the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) trials. Neutral effects on survival and favorable hemodynamics have positioned amiodarone and dofetilide as the antiarrhythmics of choice in patients with left ventricular dysfunction. In post–myocardial infarction patients, sotalol is an additional agent to consider for treatment of AF in this setting.

Effect of pacing mode on health-related quality of life in the Canadian Trial of Physiologic Pacing

Background Both “physiologic” (dual-chamber or atrial only) or ventricular-pacing-only permanent pacemakers provide chronotropic competence, with unknown health-related quality of life (QOL) differences between these options. The QOL studies within the Canadian Trial of Physiologic Pacing were performed to assess whether QOL differences exist in patients randomized to these 2 pacing modes. Methods Two QOL protocols were performed: 1) a substudy of 269 patients with detailed QOL measures (The Medical Outcomes Study, Short-Form [SF-36], the Pacemaker Syndrome Scale, an activity scale, and a pacemaker-specific scale) at baseline and 6 months after implantation; and 2) a parent study assessment of QOL in 1721 patients with a 12-item QOL instrument package (SF-6, “ladder of life,” and pacemaker syndrome scale) given 6 months after implantation only. Results In the substudy, pacing was associated with an average significant ( P < .05) 0.36 SD unit improvement in QOL across all domains (SF-36: 38 ± 9 to 41 ± 11 for physical scores, 47 ± 11 to 52 ± 9 for mental health scores, both P < .001). Similar improvements were seen with the pacemaker-specific scales. There were no significant differences in the absolute or relative improvement in QOL between assigned pacing modes. The parent study similarly showed no differences in QOL between pacing modalities. Presyncope occurred in 31% of patients in the physiological pacing group, compared with 38% of the patients in the ventricular pacing group ( P < .01). No other symptoms were different between the 2 groups. Pacemaker dependency, defined as an escape heart rate <50 beats per minute, did not influence the lack of difference in QOL scores between the 2 assigned pacing modes. Conclusion In this largest randomized assessment of QOL in patients with pacemakers, with the instruments used, there was no significant health-related QOL difference seen between “physiologic” pacing and ventricular pacing. (Am Heart J 2003;145:430-7.)

The Palliative Benefit of Irinotecan in 5-Fluorouracil—Refractory Colorectal Cancer: Its Prospective Evaluation by a Multicenter Canadian Trial

Most patients with colorectal cancer (CRC) who have failed initial 5-fluorouracil (5-FU) chemotherapy have worsening of disease-related symptoms (DRS) and quality of life (QOL). Irinotecan has a reported response rate of 10%–20% in such patients. The aim of this phase II trial was to prospectively determine the palliative benefit of irinotecan utilizing DRS as primary endpoints of response. Patients had advanced CRC refractory to 5-FU with at least 1 DRS defined as (1) Karnofsky performance status (KPS) 60%–80%, (2) baseline analgesic use ≥ 10 mg morphine/day (or equivalent), or (3) disease-related pain score > 1 cm on a 10-cm linear analogue self-assessment (LASA) scale. Patients received irinotecan 125 mg/m 2 weekly for 4 weeks on an every-6-weeks schedule. The primary endpoint was palliative response defined as ≥ 50% decrease in pain score or analgesic usage, or 10% increase in KPS, from baseline for 4 weeks. QOL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionaire Core 30 (EORTC QLQ-C30) version 2 instrument. A total of 65 patients were entered onto the study. Median baseline parameters were KPS 70%, analgesic score 11 mg/day, and pain score 2.4 cm. A palliative response was achieved in 27 patients (42%), improvement in pain score predominated. LASA and EORTC QLQ-C30 instruments showed parallel changes in DRS. The radiological response rate was 11% (complete responses and partial responses, n = 46); 23 patients achieved stable disease. Median overall survival was 7.2 months. Irinotecan provides a rate of palliative benefit higher than the radiological response rate. Patient-oriented palliative endpoints can be useful in assessing the benefit of agents in early-phase clinical trials.

Management of Acute Proximal Deep Vein Thrombosis: Pharmacoeconomic Evaluation of Outpatient Treatment With Enoxaparin vs Inpatient Treatment With Unfractionated Heparin

A landmark Canadian randomized controlled clinical trial compared treatment of acute proximal vein thrombosis via low-molecular-weight heparin (LMWH) [enoxaparin] administered primarily at home with IV unfractionated heparin (UH) in the hospital. Results demonstrated equivalent safety and efficacy for home care with enoxaparin with a reduction in cost. Our objective was to validate these findings in the routine practice setting of a US health maintenance organization. Retrospective analysis of medical and administrative records of health-plan members meeting inclusion-exclusion criteria of the Canadian trial during the period from 1995 to 1998. Staff-model health maintenance organization serving New Mexico. Persons presenting as outpatients from 1995 to 1996 or from 1997 to 1998 with acute, proximal deep vein thrombosis (DVT) diagnosed by duplex ultrasonography. Initial anticoagulant therapy of IV UH administered in the hospital (from 1995 to 1996 group, n = 64) or subcutaneous LMWH (enoxaparin) administered primarily at home (from 1997 to 1998 group, n = 65), followed by warfarin therapy. No statistically significant differences were observed in the number of recurrent venous thromboembolic events (p = 0.36) or bleeding events (p = 1.0). Mean +/- SD cost per patient was 9,347 dollars +/- 8,469 in the enoxaparin group compared with 11,930 dollars +/- 10,892 in the UH group, a difference of - 2,583 dollars (95% bootstrap-adjusted asymmetrical confidence interval, - 6,147 dollars, + 650 dollars). Retrospective replication of the Canadian study in a US routine (managed) care setting found similar clinical and economic outcomes. Treatment of acute proximal DVT with enoxaparin in a primarily outpatient setting can be accomplished safely and yields savings through avoidance or minimization of inpatient stays.

Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation

Background The impact of atrial fibrillation (AF) and its treatment on health-related quality of life (QOL) is not well understood. We assessed QOL in patients with symptomatic AF participating in the Canadian Trial of Atrial Fibrillation. Methods Self-report QOL questionnaires including the Short-Form-36 (SF-36), symptom checklist (SCL) and AF Severity Scale (AFSS) were completed at baseline and 3, and 12 months after randomization. Results The study group was aged 65 ± 10 years and 59% were male. By design, 50% of patients were randomized to amiodarone (n = 132), 25% to sotalol (n = 66), and 25% to propafenone (n = 66). Most patients had normal left ventricular function (89%). Physical (41.9 ± 9.3 to 43.7 ± 9.2, P =.001) and mental health (47.5 ± 10.5 to 49.0 ± 9.8, P =.023) summary measures from the SF-36 improved significantly from baseline to 3 months. Arrhythmia symptom frequency and severity (SCL) also improved markedly from baseline to 3 months (symptom frequency 20.4 ± 9.4 to 16.2 ± 9.5 and symptom severity 16.7 ± 8.2 to 12.9 ± 7.4, both P <.001). QOL improvements were not significantly different among the groups randomized to amiodarone, sotalol, or propafenone. However, patients with no symptomatic recurrences of AF had higher scores at 3 months on measures of global well-being than those with recurrences in the first 3 months (7.4 ± 1.8 vs 6.9 ± 1.8, P <.05). There were no significant QOL changes from the 3 to 12 month assessment. Conclusion In patients with symptomatic AF, QOL improves after treatment, independent of the specific drug used for treatment. This is especially true for patients in whom treatment prevents AF recurrence. (Am Heart J 2002;143:984-90.)

The Attack on Breast Cancer Screening

The Attack on Breast Cancer Screening