MedDRA (Medical Dictionary tor Regulatory Activities) is a standardised medical terminology, published by the International Council for Harmonisation, used in particular for coding cases of adverse effects in clinical st...MedDRA (Medical Dictionary tor Regulatory Activities) is a standardised medical terminology, published by the International Council for Harmonisation, used in particular for coding cases of adverse effects in clinical study reports and pharmacovigilance databases, and to facilitate searches in these databases. MedDRA has a 5-level, hierarchical structure. Some levels are used to code adverse effects, and the others are designed to group together related terms for database searches. The links between these terms are hierarchical and complex. In addition to searches for terms, broad or narrow searches of MedDRA-coded databases can be performed using predefined "standardised Med-DRA queries", of which about a hundred are available in early 2016. A French study on 4 adverse effects recorded in France's national pharma- covigilance database showed that the effectiveness of MedDRA and stan- dardised MedDRA queries is highly variable, depending on the adverse effect examined. In some cases, less than half of the cases retrieved were relevant. A study on the adverse effects most frequently reported in clinical trials of 10 randomly selected drugs showed that a given adverse effect could be described using between 4 and several hundred different codes. One risk of fragmenting the reporting of adverse effects across multiple terms is that their true frequency will be underestimated. The development of a harmonised international terminology is a worth-while endeavour. But the complexity of MedDRA and its poorly evaluated performance make it susceptible to manipulation, errors of interpretation and bias. This applies in particular to the adverse effect statistics in the clinical study reports of clinical trials. The evaluation of the effectiveness of MedDRA as a tool for identifying and quantifying the adverse effects of new drugs must continue. For healthcare professionals, the limitations of MedDRA are one more reason to recognise that the known adverse effects of drugs, and their quantification, tend to be underestimated.
In a randomized trial in elderly women living at home who had fallen during the previous year, regular exercise reduced the incidence of falls resulting in injury. Routine vitamin D supplementation did not.In a randomized trial in elderly women living at home who had fallen during the previous year, regular exercise reduced the incidence of falls resulting in injury. Routine vitamin D supplementation did not.
After an acute coronary syndrome, the 6-year results of the "IMPROVE-IT" randomized trial showed a 1.6% reduction in the number of nonfatal myocardial infarctions with the ezetimibe + simvastatin combination compared wit...After an acute coronary syndrome, the 6-year results of the "IMPROVE-IT" randomized trial showed a 1.6% reduction in the number of nonfatal myocardial infarctions with the ezetimibe + simvastatin combination compared with simvastatin alone, but no reduction in mortality.
The results of two large epidemiological studies on the association between domperidone and ventricular arrhythmia or sudden cardiac death were published in 2015; one study was conducted in Taiwan and the other in the Un...The results of two large epidemiological studies on the association between domperidone and ventricular arrhythmia or sudden cardiac death were published in 2015; one study was conducted in Taiwan and the other in the United Kingdom. They also examined metoclopramide. Both studies demonstrated an increased risk of sudden cardiac death and ventricular arrhythmia with metoclopramide, similar to the risk associated with domperidone. The results concerning domperidone were consistent with those of previous studies. In particular, they showed that the risk was higher with doses greater than 30 mg per day or with concomitant use of inhibitors of the cytochrome P450 isoenzyme CYP3A4, which reduce domperidone clearance. In practice, metoclopramide has a marginal role in patient care, with minor efficacy. Domperidone should not be used at all; its efficacy at the approved dose, beyond a placebo effect, is uncertain.
In four trials including a total of more than 3000 patients, dulaglutide reduced the HbA1c concentration as effectively as other GLP-1 analogues when added to other hypoglycaemic drugs. The long elimination half-life of...In four trials including a total of more than 3000 patients, dulaglutide reduced the HbA1c concentration as effectively as other GLP-1 analogues when added to other hypoglycaemic drugs. The long elimination half-life of dulaglutide can make management of adverse effects and drug interactions more difficult. More data are needed on possible cardiac adverse effects.
In three comparative trials in a total of about 25,000 patients requiring coronary angioplasty, IV cangrelor was not more effective in reducing mortality than oral clopidogrel, and it only improved cardiovascular morbidi...In three comparative trials in a total of about 25,000 patients requiring coronary angioplasty, IV cangrelor was not more effective in reducing mortality than oral clopidogrel, and it only improved cardiovascular morbidity in a biased trial. Cangrelor can provoke bleeding, kidney failure and dyspnea.
In a placebo-controlled trial in 374 men, prucalopride was only effective in a minority of cases, as previously observed in women. In addition to its cardiovascular harms, there is evidence that prucalopride may cause de...In a placebo-controlled trial in 374 men, prucalopride was only effective in a minority of cases, as previously observed in women. In addition to its cardiovascular harms, there is evidence that prucalopride may cause depression and suicidal ideation.
In an unblinded trial in 452 patients with persistent, recurrent or metastatic cervical cancer, adding bevacizumab to other cytotoxic drugs prolonged median survival by 4 months, but adverse effects were often severe and...In an unblinded trial in 452 patients with persistent, recurrent or metastatic cervical cancer, adding bevacizumab to other cytotoxic drugs prolonged median survival by 4 months, but adverse effects were often severe and sometimes fatal. Tailored symptomatic care is also a valid option.
The only available trial, a non-comparative study with 63 patients, failed to determine the efficacy of ibrutinib. In contrast, adverse effects are numerous and sometimes severe, including haematological disorders. Furth...The only available trial, a non-comparative study with 63 patients, failed to determine the efficacy of ibrutinib. In contrast, adverse effects are numerous and sometimes severe, including haematological disorders. Further evaluation of ibrutinib in this setting is necessary.
Patients with polycythaemia vera, a myeloproliferative syndrome, are at increased risk of thrombotic events. Marrow fibrosis and transformation to acute leukaemia can also occur after several years. Treatment is based on...Patients with polycythaemia vera, a myeloproliferative syndrome, are at increased risk of thrombotic events. Marrow fibrosis and transformation to acute leukaemia can also occur after several years. Treatment is based on phlebotomy and aspirin at low (antiplatelet) doses, sometimes combined with hydroxycarbamide, a cytotoxic drug. Various other drugs are available if hydroxycarbamide fails or is poorly tolerated, but there is no consensus treatment. Ruxolitinib inhibits Janus tyrosine kinases, which are involved, among other roles, in haematopoiesis. Ruxolitinib has been authorised in the European Union for patients with polycythaemia vera in whom hydroxycarbamide has failed or is poorly tolerated. Clinical evaluation of ruxolitinib in this setting is based on a randomised, unblinded trial versus treatment chosen by the investigators, in 222 patients treated for 32 weeks. Hydroxycarbamide was chosen in 59% of cases, even though the patients had unacceptable adverse effects or an inadequate response to the drug. The efficacy of the investigators' other treatment choices was uncertain. Phlebotomy was less frequent in the ruxofitinib group than in the control group. The adverse effects of ruxotitinib in this situation are poorly documented, due to inadequate long-term assessment. In the short term, ruxolitinib causes anaemia and thrombocytopenia, as well as bleeding, potentially severe infections, headache, sensory disturbances, and weight gain. It is also likely to share the serious adverse effects of other immunosuppressants. Ruxolitinib is mainly metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP2C9, creating a risk of multiple drug interactions. Ruxolitinib showed embryofetal toxicity in animal studies. Virtually no data are available in pregnant women. In practice, available data on the harm-benefit balance of ruxolitinib fail to show that this drug represents a tangible advance for patients with polycythaemia vera, as compared with other drugs used when hydroxycarbamide is unsuitable.