Prescrire international
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Prescrire international · Apr 2007
Comparative StudySertindole: new drug. Another "atypical" neuroleptic; QT prolongation.
(1) The first-line drug for the treatment of schizophrenic disorders is a neuroleptic such as haloperidol. Amisulpride may be preferable when haloperidol causes unacceptable neurological reactions. Overall, the risk-benefit balance of more recent, so-called atypical neuroleptics is no better. (2) Sertindole, a neuroleptic, was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. ⋯ However, it causes weight gain. Sertindole also has alpha blocking properties, which can cause postural hypotension and reduce ejaculate volume; it also has atropinic effects (constipation, dry mouth, etc.). (5) Sertindole provokes a dose-dependent increase in the QT interval more frequently than haloperidol in comparative trials, and apparently more frequently than other 'atypical' neuroleptics such as risperidone and olanzapine. Sertindole has been suspected of increasing cardiovascular mortality but this has not been established. (6) Sertindole is metabolised by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4, hence a high risk of pharmacokinetic interactions. (7) In practice, when haloperidol has to be withdrawn because of adverse effects, especially neurological reactions, it is better to continue to resort to amisulpride, for example, with close monitoring of adverse effects, rather than expose patients to the potential dangers of sertindole.
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Prescrire international · Apr 2007
Comparative StudyIvabradine: new drug. Best avoided in stable angina.
(1) The first-line symptomatic treatment for stable angina is a betablocker such as atenolol. Some calcium channel blockers such as verapamil, and the potassium channel agonist amlodipine, are second-line alternatives. Long-acting nitrate derivatives have poorly documented efficacy but can be used as adjuvants or as third-line treatments. (2) Ivabradine is derived from verapamil but appears to have a different mechanism of action, mainly lowering the heart rate. ⋯ Three double-blind randomised controlled trials lasting 3 to 4 months, based on surrogate exercise endpoints, failed to show that ivabradine was any more effective than atenolol or amlodipine, or even more effective than placebo in patients already treated with amlodipine. (4) In two one-year double-blind randomised controlled trials comparing ivabradine with atenolol or amlodipine in a total of 704 patients, ivabradine was no more effective than the comparators in preventing angina attacks. (5) In head-to-head comparisons, serious coronary events were significantly more frequent with ivabradine than with atenolol (3.8% versus 1.5%). Severe arrhythmias were also more frequent with ivabradine than with atenolol (1.3% versus 0.7%) or amlodipine (0.6% versus 0.2%). (6) Ivabradine provokes phosphenes (flashing lights, etc.) in about 17% of patients in the short term. Information is inadequate to assess possible risks of retinal toxicity in the long term. (7) Ivabradine is metabolised by cytochrome P450 isoenzyme CYP 3A4; there is therefore a potentially high risk of pharmacokinetic interactions. (8) In practice, for long-term preventive treatment of angina it is better to avoid ivabradine and to use better-documented treatments: preferably a betablocker, or, if a betablocker cannot be used, verapamil or amlodipine.
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Non metastatic prostate cancer: avoid over-interpretation of flawed clinical trial evidence.
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Prescrire international · Feb 2007
Comparative StudyDrotrecogin alfa: a second look. More clinical trials in severe sepsis: mostly negative results.
(1) The initial evaluation of drotrecogin alfa in the treatment of severe sepsis did not convincingly demonstrate the therapeutic potential of this recombinant form of activated protein C. It mainly included one study (PROWESS), a double-blind placebo-controlled trial, involving 1690 patients with sepsis of varying severities. In this trial, drotrecogin alfa seemed to reduce the overall mortality rate at 28 days from 31% to 25%. ⋯ There was no evidence of a reduction in mortality with drotrecogin alfa (overall mortality rate 18%). (5) A paediatric placebo-controlled trial was interrupted after 477 children had been enrolled, because drotrecogin alfa was ineffective and caused severe bleeding. (6) Data from ongoing comparative and non comparative studies confirm the increased risk of severe bleeding during drotrecogin alfa therapy, affecting about 7% of patients. (7) In practice, despite trials involving thousands of patients, there are still no firmly identified patient subgroups in which drotrecogin alfa is clearly beneficial. In contrast, the increased bleeding risk is well documented. Drotrecogin alfa should not be routinely used in the management of patients with severe sepsis.