Interpreting measures of treatment effect in cancer clinical trials.
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The efficacy of a new cancer regimen is usually assessed by analyzing outcomes such as tumor response and overall survival. Many publications summarizing results of cancer clinical trials report measures such as odds ratios and hazard ratios, as these are the estimators of treatment effect obtained from regression models used to analyze the data. However, these measures are sometimes misinterpreted, as they are not necessarily familiar to many readers. The most common mistake is to interpret both measures as relative risks, an interpretation that can lead to an incorrect impression of the impact of the treatment on response and survival. (+info)
Home-based intervention in congestive heart failure: long-term implications on readmission and survival.
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BACKGROUND: It is not known to what extent initially observed benefits of postdischarge programs of care for patients with chronic congestive heart failure (CHF) in respect to event-free survival, readmissions, and healthcare costs persist in the long term. Methods and Results- We prospectively studied the long-term effects of a multidisciplinary home-based intervention (HBI) in a cohort of CHF patients randomly allocated to either to HBI (n=149) or usual care (n=148). During a median of 4.2 years of follow-up, there were significantly fewer primary end points (unplanned readmission or death) in the HBI versus usual care group: a mean of 0.21 versus 0.37 primary events per patient per month (P<0.01). Median event-free survival was more prolonged in the HBI than usual care group (7 versus 3 months; P<0.01). Fewer HBI patients died (56% versus 65%; P=0.06) and had more prolonged survival (a median of 40 versus 22 months; P<0.05) compared with usual care. Assignment to HBI was both an independent predictor of event-free survival (RR 0.70; P<0.01) and survival alone (RR 0.72; P<0.05). Overall, HBI patients had 78 fewer unplanned readmissions compared with usual care (0.17 versus 0.29 readmissions per patient per month; P<0.05). The median cost of these readmissions was $A325 versus $A660/month per HBI and usual care patient (P<0.01). CONCLUSIONS: The beneficial effects of HBI in reducing frequency of unplanned readmissions in CHF patients persist in the long term and are associated with prolongation of survival. (+info)
Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study.
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BACKGROUND: Despite the use of heparin, aspirin, and other antiplatelet agents, acute coronary syndrome patients without ST-segment elevation remain at risk of cardiovascular thrombotic events. Given the role of inflammation in the pathogenesis of arterial thrombosis, we tested the hypothesis that the combination of meloxicam, a preferential COX-2 inhibitor, and heparin and aspirin would be superior to heparin and aspirin alone. METHODS AND RESULTS: In an open-label, randomized, prospective, single-blind pilot study, patients with acute coronary syndromes without ST-segment elevation were randomized to aspirin and heparin treatment (n=60) or aspirin, heparin, and meloxicam (n=60) during coronary care unit stay. Patients then received aspirin or aspirin plus meloxicam for 30 days. During the coronary care unit stay, the primary outcomes variable of recurrent angina, myocardial infarction, or death was significantly lower in the patients receiving meloxicam (15.0% versus 38.3%, P=0.007). The second composite variable (coronary revascularization procedures, myocardial infarction, and death) was also significantly lower in meloxicam-treated patients (10.0% versus 26.7%, P=0.034). At 90 days, the primary end point remained significantly lower in the meloxicam group (21.7% versus 48.3%, P=0.004), as did the secondary end point (13.3% versus 33.3%, P=0.015) and the need for revascularization alone (11.7% versus 30.0%, P=0.025). No adverse complications associated with the meloxicam treatment were observed. CONCLUSIONS: Meloxicam with heparin and aspirin was associated with significant reductions in adverse outcomes in acute coronary syndrome patients without ST-segment elevation. Additional larger trials are required to confirm the findings of this pilot study. (+info)
Cytotoxic and antiviral activities of Colombian medicinal plant extracts of the Euphorbia genus.
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Forty-seven plant extracts of 10 species of the genus Euphorbia (Euphorbiaceae) used by Colombian traditional healers for the treatment of ulcers, cancers, tumors, warts, and other diseases, were tested in vitro for their potential antitumour (antiproliferative and cytotoxic) and antiherpetic activity. To evaluate the capacity of the extracts to inhibit the lytic activity of herpes simplex virus type 2 (HSV-2) and the reduction of viability of infected or uninfected cell cultures, the end-point titration technique (EPTT) and the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] colorimetric assay were used, respectively. The therapeutic index of the positive extracts for the antiviral activity was determined by calculating the ratio CC50 (50% cytotoxic concentration) over IC50 (50% inhibitory concentration of the viral effect). Five of the 47 extracts (11%) representing 3 out of 10 Euphorbia species (30%) exhibited antiherpetic action; the highest activity was found in the leaf/stem water-methanol extracts from E. cotinifolia and E. tirucalli. The therapeutic indexes of these two plant species were > 7.1; these extracts exhibited no cytotoxicity. Six extracts (13%) representing 4 plant species (40%) showed cytotoxic activity. The highest cytotoxicity was found in the dichloromethane extract obtained from E. cotinifolia leaves and the CC50 values for the most susceptible cell lines, HEp-2 and CHO, were 35.1 and 18.1 microgram/ml, respectively. (+info)
Comparison of visual and spectrophotometric methods of broth microdilution MIC end point determination and evaluation of a sterol quantitation method for in vitro susceptibility testing of fluconazole and itraconazole against trailing and nontrailing Candida isolates.
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Visual determination of MIC end points for azole antifungal agents can be complicated by the trailing growth phenomenon. To determine the incidence of trailing growth, we performed testing of in vitro susceptibility to fluconazole and itraconazole using the National Committee for Clinical Laboratory Standards broth microdilution M27-A reference procedure and 944 bloodstream isolates of seven Candida spp., obtained through active population-based surveillance between 1998 and 2000. Of 429 C. albicans isolates, 78 (18.2%) showed trailing growth at 48 h in tests with fluconazole, and 70 (16.3%) showed trailing in tests with itraconazole. Of 118 C. tropicalis isolates, 70 (59.3%) showed trailing growth in tests with fluconazole, and 35 (29.7%) showed trailing in tests with itraconazole. Trailing growth was not observed with any of the other five Candida spp. tested (C. dubliniensis, C. glabrata, C. krusei, C. lusitaniae, and C. parapsilosis). To confirm whether or not isolates that showed trailing growth in fluconazole and/or itraconazole were resistant in vitro to these agents, all isolates that showed trailing growth were retested by the sterol quantitation method, which measures cellular ergosterol content rather than growth inhibition after exposure to azoles. By this method, none of the trailing isolates was resistant in vitro to fluconazole or itraconazole. For both agents, a 24-h visual end point or a spectrophotometric end point of 50% reduction in growth relative to the growth control after 24 or 48 h of incubation correlated most closely with the result of sterol quantitation. Our results indicate that MIC results determined by either of these end point rules may be more predictive of in vivo outcome for isolates that give unclear visual end points at 48 h due to trailing growth. (+info)
Effects of coronary stenting on vessel patency and long-term clinical outcome after percutaneous coronary revascularization in diabetic patients.
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OBJECTIVES: We sought to compare coronary stent implantation with balloon angioplasty (BA), in a diabetic population, in terms of the six-month angiographic outcome and four-year clinical events. BACKGROUND: Diabetic patients have a poor angiographic and clinical outcome after standard coronary BA. To date, it is still unclear whether stent implantation may improve this outcome. METHODS: We investigated this issue by individual matching of 314 diabetic patients treated with either coronary stenting or standard BA. These two groups were derived from a population of consecutive diabetic patients (1993 to 1996). Matching criteria were gender, anti-diabetic regimen, stenosis location, reference diameter, and minimal luminal diameter (+/-0.4 mm). One lesion per patient was considered for matching. RESULTS: Baseline characteristics were similar between the two groups of 157 patients. At six months, the rates of restenosis (27% vs. 62%; p < 0.0001) and occlusion (4% vs. 13%; p < 0.005) were lower in the stent group than in the BA group. This was associated with a significant decrease in ejection fraction at six months in the BA group (p = 0.02) while, during the same period, no change was observed in the stent group (p = NS). Subgroup analysis demonstrated that angiographic benefit was consistent among the subgroups. At four years, the combined clinical end point of cardiac death and non-fatal myocardial infarction was lower in the stent group (14.8% vs. 26.0%; p = 0.02), as was the need for repeat revascularization (35.4% vs. 52.1%; p = 0.001). CONCLUSIONS: In a population of diabetic patients, coronary stent implantation was associated with a highly beneficial effect on the six-month angiographic outcome and four-year clinical events compared with standard BA. (+info)
Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions.
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BACKGROUND: Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored. Summary of Review- In part 1, we review key challenges and complexities in translational stroke research by focusing on the "disconnect" in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often been limited by inappropriately long time windows, insufficient statistical power, insensitive outcome measures, inclusion of protocol violators, failure to target specific stroke subtypes, and failure to target the ischemic penumbra. In part 2, we explore new concepts in ischemic pathophysiology that should encourage us also to think beyond the hyperacute phase of ischemia and consider the design of trials that use multiagent therapy and exploit the capacity of the brain for neuroplasticity and repair. CONCLUSIONS: By recognizing the strengths and limitations of animal models of stroke and the shortcomings of previous clinical trials, we hope to move translational research forward for the development of new therapies for the acute and subacute stages after stroke. (+info)
Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).
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BACKGROUND: Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. METHODS AND RESULTS: We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment--was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P=0.187)--a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P=0.024) and a 6% lower risk of death (P=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P=0.012). CONCLUSION: Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study. (+info)