Antonio Addis

Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: Evidence from a meta-analysis

BACKGROUND Rates of patient adherence (compliance) to pharmacotherapy range from <5% to >90%. Negative determinants include multiple daily dosing (MDD), chronic duration, and asymptomatic disease. Reports suggest that once-daily (QD) dosing may improve adherence, but their findings are inconclusive. OBJECTIVE The purpose of this study was to compare the rates of adherence with QD, twice-daily (BID), and MDD antihypertensive drug regimens. METHODS MEDLINE, Embase, and International Pharmaceutical Abstracts databases were searched to identify comparative trials of patient adherence to antihypertensive medication in solid, oral formulations. Data were combined using a random-effects meta-analytic model. RESULTS Eight studies involving a total of 11,485 observations were included (1,830 for QD dosing, 4405 for BID dosing, 4147 for dosing >2 times daily [>BID], and 9655 for MDD), in which the primary objective was to assess adherence. The average adherence rate for QD dosing (91.4%, SD = 2.2%) was significantly higher (Z = 4.46, P < 0.001) than for MDD (83.2%, SD = 3.5%). This rate was also significantly higher (Z = 2.22, P = 0.026) than for BID dosing (92.7% [SD = 2.3%] vs 87.1% [SD = 2.9%]). The difference in adherence rates between BID dosing (90.8%, SD = 4.7%) and >BID dosing (86.3%, SD = 6.7%) was not significant (Z = 1.82, P = 0.069). CONCLUSIONS The results of this meta-analysis demonstrate that with antihypertensive medications, QD dosing regimens are associated with higher rates of adherence than either BID or MDD regimens.

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.

Abstract Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. Design Meta-analysis. Setting: Studies from 1966 to present. Subjects: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. Interventions:Data extraction and quality assessment were done independently and in duplicate. Main outcome measures: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. Results:Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1.35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). Conclusions:Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.

Fetal effects of cocaine: an updated meta-analysis.

BACKGROUND A very large number of women in the reproductive age group consume cocaine, leading to grave concerns regarding the long term health of millions of children after in utero exposure. The results of controlled studies have been contradictory, leading to confusion, and, possible, misinformation and misperception of teratogenic risk. OBJECTIVE To systematically review available data on pregnancy outcome when the mother consumed cocaine. METHODS A meta-analysis of all epidemiologic studies based on a priori criteria was conducted. Comparisons of adverse events in subgroups of exposed vs. unexposed children were performed. Analyses were based on several exposure groups: mainly cocaine, cocaine plus polydrug, polydrug but no cocaine, and drug free. RESULTS Thirty three studies met our inclusion criteria. For all end points of interest (rates of major malformations, low birth weight, prematurity, placental abruption, premature rupture of membrane [PROM], and mean birth weight, length and head circumference), cocaine-exposed infants had higher risks than children of women not exposed to any drug. However, most of these adverse effects were nullified when cocaine exposed children were compared to children exposed to polydrug but no cocaine. Only the risk of placental abruption and premature rupture of membranes were statistically associated with cocaine use itself. CONCLUSIONS Many of the perinatal adverse effects commonly attributed to cocaine may be caused by the multiple confounders that can occur in a cocaine using mother. Only the risk for placental abruption and PROM could be statistically related to cocaine. For other adverse effects, additional studies will be needed to ensure adequate statistical power.

Prenatal exposure to misoprostol and vascular disruption defects: A case-control study

Prenatal exposure to misoprostol has been associated with Moebius and limb defects. Vascular disruption has been proposed as the mechanism for these teratogenic effects. The present study is a multicenter, case-control study that was designed to compare the frequency of prenatal misoprostol use between mothers of Brazilian children diagnosed with vascular disruption defects and matched control mothers of children diagnosed with other types of defects. A total of 93 cases and 279 controls were recruited in eight participating centers. Prenatal exposure was identified in 32 infants diagnosed with vascular disruption defects (34.4%) compared with only 12 (4.3%) in the control group (P<0.0000001). Our data suggest that prenatal exposure to misoprostol is associated to the occurrence of vascular disruption defects in the newborns.

Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies.

BACKGROUND This study was designed to examine whether there is an increased risk for major malformations following the use of fluoxetine during the first trimester of pregnancy. METHODS Published and unpublished reports were identified through computerized and manual searches of bibliographical databases, reference lists from primary articles, and letters to editors, agencies, foundations and content experts. Meta-analysis was undertaken of prospective controlled and uncontrolled studies on the use of fluoxetine during first trimester of pregnancy. RESULTS The pooled relative risk and 95% confidence interval for major malformations does not suggest an association between the use of fluoxetine during the first trimester and an increased risk of major malformations. Combination of controlled and uncontrolled studies shows a weighted risk of 26% (95% CI 1-4.2%). The summary odds ratio from the two controlled studies (OR = 1.33, 95% CI 0.49-3.58) was not significant. Homogeneity testing shows that the effect sizes are similar throughout all studies. Power analysis indicates that 26 controlled studies of similar size, would be required, to reverse this finding. CONCLUSIONS The use of fluoxetine during the first trimester of pregnancy is not associated with measurable teratogenic effects in human.

Risk classification systems for drug use during pregnancy: are they a reliable source of information?

AbstractBackground: In several countries, risk classification systems have been set up to summarise the sparse data on drug safety during pregnancy. However, these have resulted in ambiguous statements that are often difficult to interpret and use with accuracy when counselling patients on drug use in pregnancy. Objectives: The objective of this study was to compare and analyse the consistency between and the criteria for risk classification for medications used during pregnancy included in 3 widely used international risk classification systems. All 3 systems use categories based on risk factors to summarise the degree to which available clinical information has ruled out the risk to unborn offspring, balanced against the drug’s potential benefit to the patient. Methods: Drugs included in the risk classification systems from the US Food and Drug Administration (FDA), the Australian Drug Evaluation Committee (ADEC) and the Swedish Catalogue of Approved Drugs (FASS), were reviewed and compared on basis of the risk factor category to which they had been assigned. Agreement between the systems was calculated as the number of drugs common to all 3 and assigned to the same risk factor category. In addition, evidence on teratogenicity and adverse effects during pregnancy was retrieved using a MEDLINE search (from 1966 up to 1998) for common drugs classified as teratogenic. Results: Differences in the allocation of drugs to different risk factor categories were found. Risk factor category allocation for 645 drugs classified by the FDA, 446 classified by ADEC and 527 classified by FASS was compared. Only 61 (26%) of the 236 drugs common to all 3 systems were placed in the same risk factor category. Analysis of studies on the safety of common drugs during pregnancy of drugs classified as X by the FDA indicated that the variability in category allocation was not only attributable to the different definitions for the categories, but also depended on how the available scientific literature was handled. Conclusions: Differences in category allocation for the same drug can be a source of great confusion among users of the classification systems as well as for those who require information regarding risk for drug use during pregnancy, and may limit the usefulness and reliability of risk classification systems.

A Multicentre Prospective Controlled Study to Determine the Safety of Trazodone and Nefazodone Use during Pregnancy

Objectives: Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. Methods: Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby Results: We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. Conclusion: Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.

The safety of omeprazole during pregnancy: A multicenter prospective controlled study

OBJECTIVES Our purpose was to determine whether omeprazole use during pregnancy is associated with an increased risk of malformations, spontaneous abortions, decreased birth weight, or perinatal complications. STUDY DESIGN In a multicenter, prospective controlled study, pregnant women exposed to omeprazole during gestation were matched with controls exposed to nonteratogens and with disease-paired controls who used histamine blockers for similar indications. The primary end point was the incidence of major malformations. RESULTS One hundred thirteen pregnant women were exposed to omeprazole during pregnancy. Rates of major malformations in the omeprazole group (4%) did not differ from controls exposed to nonteratogens (2%) (P = .68, relative risk = 1.94, 95% confidence interval 0.36 to 10.36) and disease-paired controls (2.8%). Birth weight, gestational age at delivery, preterm deliveries, and neonatal complications were comparable among the three groups. CONCLUSIONS No association was found between exposure to omeprazole during the period of organogenesis and increased risk for major malformations. Exposure throughout pregnancy is not associated with increased risk of spontaneous abortions, decreased birth weight, or perinatal complications.

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1).

AbstractObjective: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L1 or, using meta-analysis of the literature. Methods: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after ≥3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg · l−1) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg · kg−1 · day−1, which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: ≤50 mg · kg−1 · day−1 and ≥75 mg · kg−1 · day−1. Results: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4–36 months) with 66.4 mg · kg−1 · day−1 (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg · l−1 was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving ≥75 mg · kg−1 · day−1 over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (≤50 mg · kg−1 · day−1) were included, the success rate was 45.1%. Conclusion: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses ≥75 mg · kg−1 · day−1, most patients had a decrease in ferritine concentration.

PHARMACOECONOMIC ANALYSIS OF VENLAFAXINE IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

We conducted a cost-effectiveness analysis of acute major depressive disorder (MDD) using serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine), selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, sertraline, paroxetine), or tricyclic antidepressants (TCAs; amitriptyline, imipramine, desipramine, nortriptyline). A decision-tree model over 6 months was constructed using an expert panel. The analytic perspective was that of the Ontario Ministry of Health as payor for all direct costs, which were derived from standard lists and included the cost of the drug as well as those for medical care, laboratory services, hospitalisation and managing adverse events. Success and dropout rates were determined from a meta-analysis of published randomised controlled trials. Medline, Embase, and International Pharmaceutical Abstracts were searched from 1984 to 1996, as were references from retrieved articles and reviews. Inpatients and outpatients were analysed separately. SSRIs were used as backup therapy for patients receiving venlafaxine and TCAs, and SNRIs were used as backup therapy for patients receiving SSRIs. Pharmacoeconomic outcomes were expected cost per success, expected cost per symptom free day (SFD), and incremental cost per success and per SFD. The meta-analysis identified 56 treatment arms from 36 randomised controlled trials involving 2953 patients (2380 outpatients and 573 inpatients). SNRIs had the highest success rates. The respective costs (in 1996