2 Minute Medicine Rewind May 2, 2016

Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy

Isotretinoin, a teratogen, is widely used in the treatment of cystic acne. While the risks of pregnancy during isotretinoin therapy are well known, levels of adherence with pregnancy prevention programs are unclear. In Canada, females must provide informed written consent and have negative results on two pregnancy tests before initiating isotretinoin, and use two reliable forms of contraception during treatment. In this retrospective cohort study, 59, 271 female patients age 12-48 years that had been dispensed 1 or more prescriptions for isotretinoin were followed up to evaluate the effectiveness of the Canadian pregnancy prevention program. This study was conducted using large administrative health datasets from 4 provinces. Researchers found that, on average, the rate of pregnancy was between 4-6 per 1000 female users of isotretinoin, with no evidence of changes in rates of pregnancy over the years studied (1996-2011). Interestingly, rates of pregnancy were highest in Ontario amongst women of lower socioeconomic status. In examining pregnancy-related outcomes during the treatment period plus 42 weeks, researchers recorded 1473 pregnancies, of which 118 (8.0%) resulted in live births, 1041 (70.7%) were medically aborted, and 290 (19.7%) were spontaneously lost. Of the 118 pregnancies that resulted in live births, 11 (9.3%) were identified as having congenital malformations. This study therefore shows that adherence to the current isotretinoin pregnancy prevention program in Canada has been poor.

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

Multiple myeloma treatment has significantly advanced over the last two decades with the introduction of immunooncology drugs and proteasome inhibitors. Various proteasome inhibitors have been studied to great effect in small early trials for multiple myeloma with minimal sied effects. In this multicenter, international, randomized control trial, 722 patients with relapsed or refractory multiple myeloma were randomized to either ixazomib (a novel proteasome inhibitor) or placebo with lenalidomide and dexamethasone. The investigators found that patients who received ixazomib had significantly longer progression-free survival (20.6 months vs. 14.7 months, HR 0.74, p = 0.01) For both regimens, there were good initial outcomes with 48% and 39% respectively of either complete response or very good partial response to chemotherapy. There was no statistically significant different in severe adverse side effects, which included neutropenia, thrombocytopenia and neuropathy, however there was more rash and gastrointestinal adverse side effects. This all oral regimen for treatment of multiple myeloma appears to be safe and lengthens progression-free survival in patients with refractory or relapsed multiple myeloma.

Effect of Dilute Apple Juice and Preferred Fluids vs Electrolyte Maintenance Solution on Treatment Failure Among Children With Mild Gastroenteritis: A Randomized Clinical Trial

Gastroenteritis is a common pediatric illness. Electrolyte maintenance solution is recommended in the treatment and prevention of dehydration whenever diarrhea occurs. However, the evidence supporting this approach emerged primarily from studies conducted in low- and middle-income countries, and therefore, similar findings may not arise in areas where significant dehydration is uncommon. In addition, electrolyte maintenance solution is relatively expensive, and challenges associated with electrolyte maintenance solution often result in intravenous (IV) rehydration when children are brought to the emergency department (ED) for care. Thus, there remains a need to improve oral rehydration success in children with minimal dehydration. In this randomized controlled trial, 647 children with gastroenteritis and minimal dehydration were randomized to consume either half-strength apple juice followed by their preferred fluids, or electrolyte maintenance solution to determine whether the former is non-inferior to electrolyte maintenance solution in children with mild gastroenteritis. Treatment failure occurred if a child required intravenous rehydration, subsequent care for the same episode of vomiting or diarrhea, had protracted symptoms, a 3% or greater weight loss or Clinical Dehydration Scale score of 5 or higher, or a physician requested to administer a solution necessitating treatment allocation crossover. Researchers found that the rate of treatment failure in the apple juice group was 16.7% compared to 25.0% in the electrolyte maintenance solution group (difference -8.3%, 97.5% CI -¥ to -2.0%; p<0.001 for inferiority, p=0.006 for superiority). In addition, fewer children administered apple juice and preferred fluids required intravenous rehydration compared to the electrolyte maintenance solution group (difference  -5.9%, 99% CI -10.5% to -2.0%). This study therefore shows that among children with mild gastroenteritis and minimal dehydration, initial oral hydration with dilute apple juice followed by their preferred fluids results in fewer treatment failures compared to electrolyte maintenance solution.

Breast cancer screening using tomosynthesis and digital mammography in dense and nondense breasts

Breast density is associated with reduced mammographic sensitivity and specificity. However, increased tumor size and worsened prognosis are associated with increased breast density, pointing to the need for supplemental screening for breast cancer in these women. In this retrospective cohort study, the results of 454, 850 examinations performed using digital mammography alone or digital mammography and tomosynthesis were compared to evaluate the differential screening performance of these two screening modalities as a function of breast density. Researchers found that recall rates per 1000 screens in non-dense breasts decreased from 90 to 79 (difference -12, 95% CI -14 to -9, p<0.001) and in dense breasts from 127 to 109 (difference -18, 95% CI-21 to -15, p<0.001) with the addition of tomosynthesis. With tomosynthesis, invasive cancer detection increased per 1000 screens in non-dense breasts (difference 0.9, 95% CI 0.4 to 1.5, p<0.001) and in dense breasts (difference 1.4, 95% CI 0.9 to 1.9, p<0.001). For subgroups of breast density, improvements in rates were greatest for women with scattered fibroglandular densities and heterogeneously dense breasts. This study therefore shows that the addition of tomosynthesis to digital mammography for screening is associated with an increase in cancer detection rate and a reduction in recall rate for women with both dense and non-dense breast tissue.

Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-hyperglycemic medications that work by slowing the inactivation of incretin hormones by DPP-4 enzyme. This results an increase and prolongation of incretin levels, which in turn, reduce fasting and postprandial glucose concentrations in a glucose-dependent manner. However, the cardiovascular safety of DPP-4 inhibitors has recently become a subject of debate due to conflicting findings from several large post-marketing trials. In the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) trial, a higher incidence of hospitalized heart failure (hHF) was seen compared to the placebo group. As patients with diabetes have a higher hHF, the use of these anti-hyperglycemic agents warrants further investigation in this patient population. In this retrospective cohort study, patients with type 2 diabetes initiating the use of a DPP-4 inhibitor, either saxagliptin (n = 78, 553) or sitagliptin (n = 298, 124), and new users of second-generation sulfonylureas, pioglitazone, or long-acting insulin products were followed up to assess the risk of hHF in patients using DPP-4 inhibitors. Researchers found that the risk for hHF was not higher with DPP-4 inhibitors compared to the other study drugs. In comparing the two DPP-4 inhibitors, saxagliptin was associated with a lower risk of hHF when compared to sitagliptin (HR 0.83, 95% CI 0.70 to 0.99). Saxagliptin was also associated with a decreased risk of hHF when compared to pioglitazone (HR 0.63, 95% CI 0.47 to 0.85), sulfonylureas (HR 0.69, 95% CI 0.54 to 0.87) and insulin (HR 0.61, 95% CI 0.50 to 0.73). Similar results were found for siptagliptin when compared to pioglitazone (HR 0.75, 95% CI 0.64 to 0.85), sulfonylureas (HR 0.86, 95% CI 0.77 to 0.95) and insulin (H5 0.71, 95% CI, 0.64 to 0.78). This study therefore shows that patients using DPP-4 inhibitors may not be at a higher risk for hHF compared to other anti-hyperglycemic agents.

Image: PD

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