Randomized controlled trial

Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour.

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This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear.
OBJECTIVES: To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN. SEARCH
METHODS: For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012. In addition, we searched online clinical trial registries for ongoing trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN.
DATA COLLECTION AND ANALYSIS: Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study.
MAIN RESULTS: We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens. AUTHORS’
CONCLUSIONS: CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.

Source: Cochrane database

Amantadine Accelerates Recovery from Post-Traumatic Disorders of Consciousness.

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The benefit rapidly disappeared after amantadine was stopped, leaving questions about its long-term effects.

Traumatic brain injury (TBI) often causes disorders of consciousness such as minimally conscious or vegetative states. Psychotropic medications are frequently used to promote alertness in these patients, but none has been evaluated in rigorous, randomized, clinical trials. Investigators have now performed a multicenter, placebo-controlled clinical trial of amantadine hydrochloride, an N-methyl-D-aspartate (NMDA) antagonist and indirect dopamine agonist, for this indication. The 184 patients enrolled were aged 16 to 65, receiving inpatient rehabilitation, and in a minimally conscious or vegetative state 4 to 16 weeks after sustaining a nonpenetrating TBI. The patients were randomized to 4 weeks of treatment with placebo or amantadine, titrated to as much as 200 mg twice daily at week 4. The primary outcome was the rate of change on the Disability Rating Scale (DRS), a validated 29-point scale commonly used in this population.

The average DRS score at baseline was 22 (the lowest score that still indicates a vegetative state). During treatment, patients receiving amantadine had significantly faster improvement in arousal and function, with scores declining by 0.24 points more per week on the DRS than the placebo group. However, the groups had similar DRS scores (approximately 18) when assessed 2 weeks after the end of treatment. There was no evidence of significant adverse effects from amantadine.

Comment: Besides dispelling the notion that TBI is too complex to be properly studied in randomized clinical trials, this study provides good evidence that amantadine accelerates recovery from severe TBI. The converging trajectories of the two groups’ DRS scores after treatment cessation suggest that, rather than promoting neuroregeneration, amantadine simply stimulates patients to regain consciousness faster. Still, that difference is no small benefit given the morbidity associated with immobility after brain injury. Although the short-term benefits may be modest and the long-term benefits remain unknown, this benign and inexpensive drug appears worthwhile for patients with post-traumatic disorders of consciousness.

Source: Journal Watch Neurology

 

 

 

 

 

 

 

Newer Oral Anticoagulants Associated with ‘Dramatic Increase’ in Bleeding After ACS .

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When used to prevent thrombotic events after an acute coronary syndrome, the newer oral anticoagulants (for example, apixaban, dabigatran, and rivaroxaban) are associated with increased rates of major bleeding that offset their antithrombotic benefit, according to an Archives of Internal Medicine meta-analysis.

Researchers examined seven randomized controlled trials comprising over 30,000 patients who were hospitalized with ACS and received antiplatelet therapy. Compared with placebo recipients, those on new-generation oral anticoagulants had “a dramatic increase in major bleeding events.” Significant (but moderate) reductions in the risks for stent thrombosis and other ischemic events were seen, but there was no significant effect on overall mortality.

An editorialist concludes that routine use of these drugs in patients with ACS “is unwarranted.”

Source: Archives of Internal Medicine

 

Acadesine Does Not Improve Outcomes of CABG.

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In a randomized trial, an adenosine-regulating agent had no apparent cardioprotective effect.

Despite advances in surgical technology, ischemia/reperfusion injury associated with coronary artery bypass grafting (CABG) remains an important cause of morbidity and mortality. To evaluate the protective effect of acadesine, an adenosine-regulating agent, investigators at 300 sites in 7 countries conducted a manufacturer-sponsored, randomized, double-blind, placebo-controlled trial involving intermediate- or high-risk patients undergoing nonemergent, on-pump CABG during 2009–2010. The primary composite endpoint was all-cause mortality, nonfatal stroke, or mechanical support for severe left ventricular dysfunction during CABG or 4 weeks of follow-up.

The trial was stopped for futility after enrollment of 30% of the projected study population. The final cohort included 2986 patients (median age, 66), most of whom were white men with hyperlipidemia, diabetes, and family history of cardiovascular disease. The primary-endpoint rate was 5.0% overall and did not differ significantly between the placebo and acadesine groups (5.0% and 5.1%, respectively), as demonstrated by a Kaplan-Meier curve. No between-group difference in the rate of any secondary endpoint reached or approached statistical significance, nor was any significant difference found among groups stratified by Society of Thoracic Surgeons risk quintile.

Comment: Although previous studies yielded promising findings, this well-designed trial failed to show any benefit of acadesine on outcomes in intermediate- or high-risk patients undergoing coronary artery bypass grafting. The rate of the primary endpoint, although lower than the 10% expected with placebo in this population, underscores the need for continued efforts to prevent ischemia/reperfusion injury during and after CABG.

Source: Journal Watch Cardiology