Mortality rate in patients with chronic myeloid leukemia in chronic phase treated with frontline second generation tyrosine kinase inhibitors: a retrospective analysis by the monitoring registries of the Italian Medicines Agency (AIFA).

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0-29 years, stable around 2% for the intervals 30-44 years and 45-59 years, and 1.4% for the interval 60-74 years; interestingly this rate is reduced for patients aged 75 years and more as compared to the general population (- 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74 years.

Real-World Effectiveness of PCSK9 Inhibitors in Reducing LDL-C in Patients With Familial Hypercholesterolemia in Italy: A Retrospective Cohort Study Based on the AIFA Monitoring Registries.

Background Information on the real-world use of proprotein convertase subtilisin kexin 9 inhibitors (PCKS9is) in familial hypercholesterolemia are limited. We evaluated the pattern of prescription and the long-term efficacy of alirocumab and evolocumab in Italian patients with familial hypercholesterolemia in clinical practice. Methods and Results The data set for analysis was extracted from the PCKS9i Italian Medicines Agency (AIFA) registry and included 2484 patients with heterozygous familial hypercholesterolemia (HeFH) and 62 patients with homozygous familial hypercholesterolemia (HoFH) who were prescribed PCKS9is from February 2017 to December 2021. As the follow-up schedules were not prespecified and could vary, persistence and adherence as well as low-density lipoprotein cholesterol (LDL-C) changes during 2 years of treatment were analyzed in a final cohort of 1299 patients with familial hypercholesterolemia. At baseline, 53.8% of patients with HeFH and 69.4% of patients with HoFH were receiving maximally tolerated lipid-lowering therapies, while 45.9% of patients with HeFH and 30.7% of patients with HoFH reported statin intolerance; mean LDL-C was 197.7±52.3 mg/dL in HeFH and 252.0±106.2 mg/dL in HoFH. The 6-month persistence and adherence to therapy were >85%, and LDL-C reduction reached 58.6% (to 79.7 mg/dL) in HeFH and 57.6% (to 95.1 mg/dL) in HoFH after 24 months of treatment. The European Atherosclerosis Society/European Society of Cardiology LDL-C goals were achieved in 43.3% of patients with HeFH and 37.5% of patients with HoFH. Conclusions PCKS9i prescribed to patients with familial hypercholesterolemia in clinical practice showed LDL-C-lowering efficacy similar to that observed in controlled trials. However, 2 of 5 HeFH cases and 2 of 6 HoFH cases achieved the recommended LDL-C goals. The full achievement of European Atherosclerosis Society/European Society of Cardiology LDL-C goals should require a lower threshold for PCKS9i initiation and a combination of multiple therapies.

Mortality in SARS-CoV-2 Hospitalized Patients Treated with Remdesivir: A Nationwide, Registry-Based Study in Italy.

Remdesivir is the first drug approved for treatment of COVID-19 but current evidence for recommending its use for the treatment of moderate-to-severe disease is still controversial among clinical guidelines. We performed a nationwide, registry-based study including all Italian hospitalized patients with COVID-19 treated with remdesivir to assess the impact of major confounders on crude 15-day and 29-day mortality. Mortality was calculated using the Kaplan-Meier estimator and the Cox proportional-hazards model was applied to analyze the risks by patient's baseline features. In total, 16,462 patients treated with remdesivir from 29 October 2020 to 17 December 2020 were entered in the study. Crude 15-day and 29-day mortality were 7.1% (95% CI, 6.7-7.5%) and 11.7% (95% CI, 11.2-12.2%), respectively. Being treated within two days of admission reduced the risk of death by about 40% (HR 1.4, 95% CI, 1.2-1.6). Results from the largest cohort of remdesivir-treated patients suggests that mortality in SARS-CoV-2 hospitalized patients is substantially influenced by the days between SARS-CoV-2 diagnosis and drug prescription. Current recommendations and future clinical trials for remdesivir alone or in combination should carefully consider the target population and timing for best efficacy of treatment.

Impact of the COVID-19 pandemic on prescription of sacubitril/valsartan in Italy.

AIMS: The present study sought to examine the effect of the COVID-19 pandemic and lockdown measures on the prescription of sacubitril/valsartan in patients with heart failure (HF) in Italy. METHODS AND RESULTS: Data from Italian Medicines Agency (AIFA) monitoring registries were analysed. The sacubitril/valsartan monitoring registry is based on 6-month prescriptions. A monthly aggregation on new activations throughout the observational period was computed. From March to December 2020, the initiation of new HF patients on sacubitril/valsartan decreased by nearly 40% with prescriptions dropping to values similar to 2018 when the registry was still operated off-line. A slight increase in prescriptions was observed after the lockdown measures were lifted, but prescriptions remained constantly below the pre-lockdown period. CONCLUSION: A marked and worrisome decline during the COVID-19 pandemic in the activation of a life-saving treatment such as sacubitril/valsartan was observed. This decline was clearly linked to the lockdown measures instated to counteract the COVID-19 pandemic. Upcoming studies should analyse the occurrence of new cases of HF as well as the severity of patients admitted to hospitals and their mortality compared to pre-pandemic levels.

How many chronic myeloid leukemia patients who started a frontline second-generation tyrosine kinase inhibitor have to switch to a second-line treatment? A retrospective analysis from the monitoring registries of the italian medicines agency (AIFA).

The frequency of patients who switch to a second-line therapy from a frontline second-generation (2gen) tyrosine kinase inhibitor (TKI) such as dasatinib and nilotinib, is still substantially unknown. We retrospectively investigated a large series of chronic phase chronic myeloid leukemia (CP-CML) patients initially treated with 2gen TKIs monitored through the Italian Medicines Agency (AIFA Agenzia Italiana del farmaco) registries. Overall, 2420 patients were analyzed over a period of 6 years. One hundred and fifty-seven patients (16.3%) treated with dasatinib and 164 treated with nilotinib (11.3%) have switched to another drug, with an overall frequency of 13.2%. In the dasatinib cohort, 39.4% of patients changed treatment for failure and 36.3% for intolerance as compared to 45.7% and 27.4% respectively in the nilotinib cohort. Overall, the median time to switch due to resistance was 293 days, whereas it was 317 days in case of intolerance. Resistance was observed mainly in younger male patients with high-risk features, while intolerance was not related to any baseline parameter. After resistance/intolerance to nilotinib, the majority of patients switched to dasatinib (53.8%) whereas in case of frontline dasatinib to ponatinib (43.2%). To the best of our knowledge these data provide the first report on the frequency of discontinuation of frontline 2gen TKIs and on the main causes and pattern of choice to a second-line therapy in the real-life setting.

The loss of entropy circadian rhythm in sinusal R-R intervals of type 1 diabetic pregnant women suggests an indeterministic chaos in cardiac pacing (minimum delirium cordis syndrome). A newly identifiable type of silent cardiac dysautonomia?

OBJECTIVE: The scope of this study is to detect whether or not the entropy (E) circadian rhythm (CR) is maintained preserved in sinusal R-R intervals (SRRI), its loss being the expression of a transition to an indeterministic chaos in heart rate variability (HRV). METHODS: The E of SRRI was estimated in 14 type I diabetic pregnant women (DPW) in the first trimester of an apparently uncomplicated gestation (7 patients - mean age = 30.3 +/- 4.1 y - without clinical and laboratory evidence of cardiac autonomic neuropathy, and 7 patients - mean age = 30.7 +/- 3.6 y - with positive tests for a cardiac dysautonomia). The E CR was studied via the single cosinor method, and summarized via the population-mean cosinor method. RESULTS: The E CR was found not to be preserved in both the investigated type I DPW, despite the occurrence of the SRRI CR. CONCLUSIONS: The loss of the E CR confirms that in type I DPW there is a transition to an indeterministic disorder in HRV due to the lack of an autocorrelated periodic chaos in cardiac pacing. Such an unphysiological neurovegetative regulation suggests a new silent cardiac dysautonomic syndrome, that we intend to call "minimum delirium cordis syndrome" (MDCS). Can the MDCS be regarded as a condition of cardiovascular risk? To answer this question, it seems justified to suggest that the study of the E CR should be added to the routine tests that are presently applied to clinical analysis of the Holter ECG, being the classic tests of linear analysis not methodologically suitable for detecting the indeterministic chaos of the MDCS.

Twenty-four-hour blood pressure monitoring in normoalbuminuric normotensive type 1 diabetic women during pregnancy.

UNLABELLED: We monitored blood pressure (BP) for a 24-h period in type 1 diabetic women at each trimester of pregnancy (10-13, 20-22, and 30-33 weeks of gestation) to identify early alterations of BP profile in pregnancies complicated by hypertension. PATIENTS AND METHODS: We prospectively studied 71 type 1 diabetic pregnant women and 48 nondiabetic pregnant women (homogeneous by age and pre-pregnancy BMI) consecutively recruited at 10+/-2 weeks of pregnancy in the space of 2 years (1999-2000). They were all normotensive (<130/80 mm Hg) and normoalbuminuric (AER<20 microg/min) at entry to the study. STATISTICS: Analysis of variance (ANOVA) and simple regression and chi(2) were applied as appropriate by an Apple software program (Stat View). RESULTS: In diabetic women, we recorded higher levels of diastolic BP (even if within a normal range) at each time point; diabetic vs. nondiabetic women: first trim daytime diastolic BP: 71.35+/-8.75 vs. 67.7+/-9.7, P=.01; second trim nighttime diastolic BP: 62.15+/-6.45 vs. 58.05+/-6.7, P=.05; third trim nighttime diastolic BP: 66.03+/-8.72 vs. 60.7+/-6.5, P=.01. Among diabetics, those who later developed pregnancy-induced hypertension (36.6%) showed significantly higher values of BP at the first and third trimester compared to those who remained normotensive. In the two groups, there were no differences in age and pre-pregnancy BMI by contrast of diabetes duration (hypertensive vs. normotensive, 19.18+/-7.3 vs. 14.35+/-9.1 years, P=.03) and age of diagnosis (hypertensive vs. normotensive, 9.6+/-5.5 vs. 14.7+/-8.6 years, P=.01). Positive correlation was found between fasting blood glucose and diastolic BP at each trimester of pregnancy.

Comparison of Insulin Lispro Protamine Suspension with NPH Insulin in Pregnant Women with Type 2 and Gestational Diabetes Mellitus: Maternal and Perinatal Outcomes.

Insulin therapy is still the gold standard in diabetic pregnancy. Insulin lispro protamine suspension is an available basal insulin analogue. Aim. To study pregnancy outcomes of women with type 2 and gestational diabetes mellitus when insulin lispro protamine suspension or human NPH insulin was added to medical nutrition therapy and/or short-acting insulin. Methods. In this retrospective study, for maternal outcome we recorded time and mode of delivery, hypertension, glycaemic control (fasting blood glucose and HbA1c), hypoglycemias, weight increase, and insulin need. For neonatal outcome birth weight and weight class, congenital malformations was recorded and main neonatal complications. Two-tail Student's t-test and chi-square test were performed when applicable; significant P < 0.05. Results. Eighty-nine pregnant women (25 with type 2 diabetes and 64 with gestational diabetes mellitus; 53 under insulin lispro protamine suspension and 36 under human NPH insulin) were recruited. Maternal and neonatal outcomes were quite similar between the two therapeutic approaches; however, insulin need was higher in NPH. At the end of pregnancy, eight women with gestational diabetes continued to use only basal insulin analogue. Conclusions. Pregnancy outcome in type 2 and gestational diabetes mellitus with insulin lispro protamine suspension was similar to that with NPH insulin, except for a lower insulin requirement.

Continuous glucose monitoring during breastfeeding in women with recent gestational diabetes mellitus.

AIMS: This study monitored blood glucose profiles in normotolerant breastfeeding women, with and without previous gestational diabetes, in real life in order to identify normal blood glucose fluctuations during breastfeeding. SUBJECTS AND METHODS: Two groups were studied: (1) 18 women with recent gestational diabetes mellitus but normotolerant postpartum (pGDM-N group) and (2) 15 women normotolerant both during pregnancy and postpartum (pN-N group). All participants underwent continuous glucose monitoring during which they recorded their main daily activities and three standardized events: "suckling," "meal," and "meal and suckling." Other than these three events, these women were essentially on an "ad lib" diet. Data were expressed as median and SD values. Student's t test and Fisher's test were used to compare mean, variances, and percentages. Differences were significant with P<0.05. Clustering analysis was used to determine the normal range of glucose values. RESULTS: The two groups were matched for age, follow-up duration, and monitoring measurements but not for body mass index. Blood glucose levels and variances were higher in the pGDM-N group, particularly during daytime and the three standardized events, and were not related to body mass index. Suckling had no direct effect on glucose profile during both the non-fed and the fed state. Blood glucose levels that best represent the normal breastfeeding population were between 50 and 126 mg/dL (from 2.8 to 7.0 mmol/L). CONCLUSIONS: Three months after delivery, normotolerant women with recent gestational diabetes had higher daily blood glucose levels than women who were always normotolerant, with no direct effect of suckling. The blood glucose profiles of healthy subjects could be representative of the normal range of the population during breastfeeding.

Hypertension in diabetic pregnancy: impact and long-term outlook.

Hypertensive disorders in pregnancy can be chronic, pregestational or just diagnosed before the 20th week, or newly diagnosed in the second half of pregnancy. Any type of hypertension is more frequent in diabetic pregnancies with a different distribution among different types of diabetes. Most of the evidence is for pre-eclampsia associated with a marked increase in primary caesarean section, preterm birth and more need for neonatal intensive care. Different risk factors and pregnancy outcomes would support the hypothesis that pre-eclampsia and gestational hypertension might be largely separate entities, but this position is not unanimously accepted. Chronic hypertension increases with age and duration of diabetes, predicting increased rates of prematurity and neonatal morbidity, especially when associated with superimposed pre-eclampsia. Long-term consequences are observed in women whose pregnancy was complicated by hypertension such as chronic hypertension and cardiovascular diseases.