Hydroxychloroquine (HCQ) Treatment for Hospitalized Patients with COVID- 19.

OBJECTIVE: Studies have indicated that hydroxychloroquine (HCQ) exerts antiviral effects against SARS-CoV-2 in vitro. However, trials regarding its effects on patients are very controversial. This study aims to evaluate the efficacy of (HCQ) in the treatment of hospitalized patients with COVID-19. METHODS: We prospectively enrolled 260 patients hospitalized for COVID-19 in Heart and Brain Center of Excellence- Pleven, Bulgaria, for the period from November 6 to December 28, 2020. This study is not randomized, which we compensated for with Propensity Score Matching. Patients in the HCQ group were given HCQ 200 mg 3 times a day (600mg daily) for the duration of their hospitalization plus conventional treatment, while those in the control group were given conventional treatment only. The primary endpoints were transferred to the intensive care unit, needed for mechanical ventilation, and in-hospital death. RESULTS: Of the 260 COVID-19 patients, 178 (68.5%) were male and the mean age was of 63.78 ± 12.45 years, with the most prevalent comorbidity hypertension (68.5%). We had two subgroups: treated with HCQ and conventional treatment (128 patients) and treated with conventional treatment only (132 patients). In the primary analysis, patients in the HCQ group presented with fewer comorbidities and were younger than the group without HCQ. Patients treated with HCQ demonstrated a significant benefit in the primary endpoints compared to those without HCQ, namely, transferred to ICU - 20 (20,8%) vs. 41 (36.9%), p=0.011, need for mechanical ventilation 13 (13.4%) vs. 33 (28.2%), p=0.009 and in-hospital death 14 (10.9%) vs. 35 (26.5%), p=0,001, respectively. We repeated this analysis with PSM, where 70 matched pairs were identified. Regarding the primary endpoints, we found again a statistically significant difference between the groups. Comparing transferring to ICU, better outcomes were presented in the HCQ group: 8 (17.4%) vs. 27 (44.3%), with p= 0.003. Besides, a smaller proportion of the patients needed mechanical ventilation: 6 (12.8%), compared to the control group, 23 (35.4%), p= 0.007. Notably, patients from the HCQ group died during hospitalization: 8 (11.4%) in comparison with 19 (27.1%) from the control group, p= 0.018. CONCLUSION: Patients treated with HCQ demonstrated a significant benefit in the primary endpoints in our study, namely, transfer to the intensive care unit, need for mechanical ventilation, and in-hospital death. HCQ improves prognosis in hospitalized patients with COVID-19.

Network meta-analysis of efficacy and safety of chlorthalidone and hydrochlorothiazide in hypertensive patients.

Hypertension is a chronic condition leading to increased stress on the heart and blood vessels, a critical risk factor for clinically significant events such as myocardial infarction heart failure, stroke and death. Chlorthalidone and hydrochlorothiazide are first-line antihypertensive agents for most patients with hypertension. The aim of our meta-analysis was to compare the efficacy and safety of both therapies in patients with hypertension. Searches of electronic databases PubMed, MEDLINE, Scopus, PsycInfo and eLIBRARY.ru, were performed. We used network meta-analysis to combine direct and indirect evidence. Forest plots and closed loops depict estimated results from studies included in our meta-analysis. Of 1289 identified sources, only 37 were included in our meta-analysis. Our analysis has demonstrated a slight superiority for chlorthalidone regarding SBP and not statistically significant differences regarding DBP. Simultaneously, hydrochlorothiazide seems to be a safer choice of therapy, as evidenced by the levels of serum potassium. The two diuretics can be used interchangeably.

EQ-5D-5L Bulgarian population norms.

OBJECTIVES: The present study aimed to provide normative data for the EQ-5D-5L questionnaire in Bulgaria, based on a nationally representative sample. METHODS: Random sampling was used. In September 2018, a total of 1005 respondents (aged 18-89 years) completed the self-administered paper-based EQ-5D-5L questionnaire, including a visual analogue scale (EQ VAS). Health state utility index scores were derived using the directly measured Polish value set. RESULTS: The study sample was representative of the general Bulgarian population in terms of age, sex, geographical region, educational level, social and professional status. Mean EQ-5D-5L and EQ VAS values decreased from 0.986 and 89.7 (age group 18-24 years) to 0.789 and 53.6 (age group ≥ 75 years), respectively. Perfect health (the "11,111" health state) was reported by half of the population (50.1%), more often by men than women (55.8% vs 44.9%). The most frequently reported complaints characterised pain/discomfort dimension (39.1%), followed by anxiety/depression (34.5%). Although the least commonly reported health limitations concerned the self-care dimension, their frequency (13.6%) was the highest among the seventeen identified EQ-5D-5L population norm studies. The mean severity index score for the whole study sample was 6.96. EQ-5D-5L index was higher in respondents from lower age groups and with a higher average income per household member. CONCLUSIONS: Bulgarian population norms, which were developed for the descriptive part of the EQ-5D-5L and EQ VAS, can be used as reference values. The availability of such normative data should encourage the use of the EQ-5D-5L questionnaire in health-related quality-of-life studies in Bulgaria.

Combining angiotensin receptor blockers with chlorthalidone or hydrochlorothiazide - which is the better alternative? A meta-analysis.

BACKGROUND: Hypertension is a disease with significant clinical and socio-economic consequences. The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. Diuretics have proven useful for the prevention of cardiovascular complications in addition to a long history of safety and efficacy. The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension. METHODS: A comprehensive literature search was conducted through electronic databases PubMed, MEDLINE, Scopus, PsyInfo, Cochrane, eLIBRARY.ru, http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu in July 2020 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. Changes in systolic and diastolic blood pressure (BP) expressed as a weighted mean difference (WMD) were our primary outcomes. The random-effects method was chosen as the primary analysis and results were presented with a 95% confidence interval (CI). Sensitivity analysis was performed and bias was assessed. RESULTS: Our search returned 2745 titles. Of them, 51 full-text articles remained to be subjected to assessment. Comparisons of ARB/HCTZ versus ARB showed changes in BP of -6.89 (-8.09, -5.69) mmHg for systolic BP and - 3.67 (-4.15, -3.19) mmHg for diastolic BP. For the ARB/CTLD versus ARB/HCTZ comparison changes were - 6.30 (-7.30, -5.29) mmHg for systolic BP and - 3.57 (-4.17, 2.98) mmHg for diastolic BP. CONCLUSION: Our analysis suggests a small but significant favor for CTLD in blood pressure control when compared to HCTZ. We believe it should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB although further research is required.

Insights into antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine affecting the new SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia with an unusual outbreak in Wuhan, China, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is currently no licensed antiviral treatment available to prevent human CoV infection. The widespread clinical use and existing knowledge on antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine in the treatment of previous epidemic diseases, namely, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), may be helpful in the combat with novel SARS-CoV-2 infection. Recent clinical evidence didn't confirm the beneficial role of lopinavir/ritonavir and chloroquine/hydroxychloroquine for COVID-19 patients and their use was reassessed. We provide an overview of the current evidence into the mechanisms of action of these available drugs which are repurposed for treatment of the new virus. Available data identifies remdesivir as an adenosine analogue that can target the RNA-dependent RNA polymerase and block viral RNA synthesis. It has been a promising antiviral drug against a wide array of RNA viruses. 3CLpro is a major CoV protease that cleaves the large replicase polyproteins during viral replication and can be targeted by the protease inhibitor lopinavir/ritonavir but the clinical effects are controversial. Chloroquine/Hydroxychloroquine could impair the replication of SARSCoV-2 by multiple mechanisms and their immunomodulatory properties could ameliorate clinical manifestations that are mediated by immune reactions of the host although its beneficial effects are under question and need to be proven at the clinical level. Existing in vitro and in vivo evidence delineate the molecular mechanisms of these drugs in CoV-infected cells. Numerous studies demonstrated the ability of remdesivir to inhibit SARS-CoV-2 replication but future research would be needed to understand the exact mode of action of lopinavir/ritonavir and chloroquine/hydroxychloroquine in SARS-CoV-2 infected cells and to use this knowledge in the treatment of the current COVID-19.

Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis.

Hypertension is a complex syndrome of multiple hemodynamic, neuroendocrine, and metabolic abnormalities. The goals of treatment in hypertension are to optimally control high blood pressure and to reduce associated cardiovascular morbidity and mortality using the most suitable therapy available. Hydrochlorothiazide (HCTZ) and chlorthalidone (CTLD) are with proven hypertensive effects. The topic of our meta-analysis is to compare the efficacy of HCTZ and CTLD therapy in patient with hypertension. A search of electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru was performed. We chose the random-effects method for the analysis and depicted the results as forest plots. Sensitivity analyses were performed in order to evaluate the degree of significance of each study. Of the 1289 identified sources, only nine trials directly compared HCTZ and CTLD and were included in the meta-analysis. Changes in SBP lead to WMD (95% CI) equal to -3.26 mmHg showing a slight but statistically significant prevalence of CTLD. Results from analyzed studies referring to DBP lead to WMD (95% CI) equal to -2.41 mmHg, which is also statistically significant. During our analysis, we found that there were not enough studies presenting enough data on the effect of CTLD and HCTZ on levels of serum potassium and serum sodium. Our meta-analysis has demonstrated a slight superiority for CTLD regarding blood pressure control. At the same time, the two medications do not show significant differences in their safety profile.

Comparative effectiveness of pan-genotypic therapies for the treatment of patients with hepatitis C virus infection in Bulgaria.

Hepatitis C virus (HCV) is a positive-stranded RNA virus which belongs to the family of Flaviviridae, predominantly infecting liver hepatocytes. HCV infection is a major cause for morbidity worldwide. Aim: The primary objective was to evaluate the comparative effectiveness of pan-genotypic therapies for the treatment of patients with HCV infection in Bulgaria. Materials & methods: The databases MEDLINE, EMBASE, Cochrane Library, PubMed and clinicaltrials.gov were searched to identify studies evaluating the therapeutic efficacy of sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for the treatment of HCV patients. Results: The range of sustained virologic response rates among all genotypes achieved after therapy with sofosbuvir/velpatasvir/voxilaprevir was 92-100% (8-week therapy) in treatment-naive patients and 99-100% (12-week therapy) in experienced patients. The range of sustained virologic response rates with glecaprevir/pibrentasvir was 91-100% (12-week therapy) and 97-100% (12-week therapy) with sofosbuvir/velpatasvir. Conclusion: Sofosbuvir/velpatasvir/voxilaprevir is a noninferior therapy offering a simple and short-term treatment regimen with high efficacy, favorable safety profile and good tolerability.

ALK Mutation Status in EGFR-negative Non-small-cell Lung Cancer Patients in Bulgaria.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement mutation are found to be 3-13%. AIM: To evaluate the prevalence of ALK mutations in EGFR-negative NSCLC patients in Bulgaria. MATERIALS AND METHODS: One hundred and thirty-two patients with EGFR-negative NSCLC were examined for ALK mutation analysis between January and June 2016. Data were obtained from patients' register of four major oncological hospitals in Bulgaria. RESULTS: Data were available for 124 (93.9%) patients, tumor mass was insufficient for analysis in 8 (6.1%) patients. Most of the patients were with adenocarcinoma (82 patients, 62.1%); 11 patients (8.3%) were with squamous histology and 2 patients (1.5%) were with other type of NSCLC. Histology data were missing in 37 patients (28.0%). ALK mutation was confirmed in 5 patients (3.8%), 119 (90.2%) patients had ALK wild type. ALK positive patients were with adenocarcinoma (n=3), squamous cell carcinoma (n=1) and other type (n=1) NSCLC. All ALK mutations were observed in never smokers (n=3) and former smokers (n=2). CONCLUSION: The present study is the first of this kind in Bulgaria - it investigates the prevalence of ALK mutation rate in EGFR-negative NSCLC patients, which was found to be 3.8%. The presence of EGFR, ALK or other driver mutations is a prerequisite for targeted therapy and thus needs to be accurately assessed in NSCLC.

Bosutinib: Valuable therapeutic option for the Bulgarian market.

AIM OF STUDY: This review aims to highlight that bosutinib represents a valuable alternative for patients already treated unsuccessfully with one or more other tyrosine kinase inhibitors (TKIs). Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm associated with a specific genetic abnormality resulting in a fusion protein with an active tyrosine kinase region. Therefore, TKIs were developed as a suitable treatment option. METHODS: Full-text articles, abstracts, and meta-analysis comparing the efficacy and safety of the five TKIs were included in the review. Efficacy of these enhanced therapies is estimated on the basis of achievement of a complete cytogenetic response (CCyR) and this outcome is an important goal as a surrogate marker for improved survival. RESULTS: Bosutinib's efficacy is comparable to that of imatinib in the first-line setting and with dasatinib and nilotinib as second-line therapy, while its safety profile is distinctly different. Most therapeutic guidelines for CML recommend an initiation of therapy with imatinib and application of dasatinib and nilotinib as subsequent lines. CONCLUSION: Bosutinib is generally not recommended despite its demonstrated efficacy and manageable toxicity. However, resistance, intolerance, specific mutations, as well as disease progression are often the reasons for the lack of sufficient response to therapy registered by the lower rates or complete absence of CCyR. Treatment options are limited for these patients.

Pioglitazone Therapy and Fractures: Systematic Review and Meta- Analysis.

INTRODUCTION: Thiazolidinediones are a group of synthetic medications used in type 2 diabetes treatment. Among available thiazolidinediones, pioglitazone is gaining increased attention due to its lower cardiovascular risk in type 2 diabetes mellitus sufferers and seems a promising future therapy. Accumulating evidence suggests that diabetic patients may exert bone fractures due to such treatments. Simultaneously, the female population is thought to be at greater risk. Still, the safety outcomes of pioglitazone treatment especially in terms of fractures are questionable and need to be clarified. METHODS: We searched MEDLINE, Scopus, PsyInfo, eLIBRARY.ru electronic databases and clinical trial registries for studies reporting an association between pioglitazone and bone fractures in type 2 diabetes mellitus patients published before Feb 15, 2016. Among 1536 sources that were initially identified, six studies including 3172 patients proved relevant for further analysis. RESULT: Pooled analysis of the included studies demonstrated that after treatment with pioglitazone patients with type 2 diabetes mellitus had no significant increase in fracture risk [odds ratio (OR): 1.18, 95% confidence interval (CI): 0.82 to 1.71, p=0.38] compared to other antidiabetic drugs or placebo. Additionally, no association was found between the risk of fractures and pioglitazone therapy duration. The gender of the patients involved was not relevant to the risk of fractures, too. CONCLUSION: Pioglitazone treatment in diabetic patients does not increase the incidence of bone fractures. Moreover, there is no significant association between patients' fractures, their gender and the period of exposure to pioglitazone. Additional longitudinal studies need to be undertaken to obtain more detailed information on bone fragility and pioglitazone therapy.

Effects of pioglitazone therapy on blood parameters, weight and BMI: a meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most common diseases worldwide and insulin insufficiency and insulin resistance are two main metabolic issues connected with it. The dyslipidemia associated with insulin resistance and T2DM is characterized by higher triglycerides (TGs), higher very-low-density lipoprotein cholesterol and lower apo A1. Pioglitazone, a member of the thiazolidinedione class, with a proven antihyperglycemic effect, is known to positively influence insulin sensitivity and ß-cell function and to have the potential to alter the lipid profile. METHODS: The aim of our meta-analysis is to summarize and determine the influence of pioglitazone on the glycemic profile and lipoprotein metabolism as well as on weight and BMI in order to highlight the benefit of pioglitazone therapy in patients with T2DM. A comprehensive literature search was conducted through the electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru (from 2000 until February 2016) to identify studies that investigate the effect of pioglitazone on the glycemic and lipid profile and on the weight and BMI. We chose the random-effects method as the primary analysis. Forest plots depict estimated results from the studies included in the analysis and funnel plots are used to evaluate publication bias. Sensitivity analyses were performed in order to evaluate the degree of influence of the consequent elimination of each individual study on the final result. RESULTS: Of the 1536 identified sources only 15 randomised trials were included in the meta-analysis. Pioglitazone treatment was associated with improvement in the glycemic profile. It reduced FPG levels by a mean of 1.1-2 mmol/l and HbA1c by a mean of 0.9-1.3%. Our results reaffirmed the hypothesis that pioglitazone has a positive influence on the lipid profile of T2DM patients with increase in TC and HDL, no significant changes in LDL and notable decrease in TGs. Results also showed that pioglitazone therapy led to increase in both weight and BMI (WMD 1.755, 95% CI 0.674 to 2.837 and 1.145, 95% CI 0.389 to 1.901 respectively). CONCLUSION: Our results prove that the PPAR γ agonist pioglitazone has the potential to be beneficial to patients with T2DM.

Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis.

People with type 2 diabetes are at increased risk of bladder cancer. Pioglitazone is said to increase it further, although published evidence is mixed. We conducted a meta-analysis to determine if any link between the use of pioglitazone and an increased risk of bladder cancer can be found. A comprehensive literature search was conducted through electronic databases as well as registries for data of clinical trials to identify studies that investigate the effect of pioglitazone on bladder cancer in diabetic patients. We used the risk ratio (RR) and the hazard ratio (HR) provided by the studies to illustrate the risk of occurrence of bladder cancer in the experimental group compared to that in the control group. Fourteen studies using RR and 12 studies using HR were included in the analysis. The overall RR was 1.13 with 95% CI (0.96-1.33) with low heterogeneity among the studies using RR, suggesting that no connection exists between use of pioglitazone and the risk of bladder malignancy. The summary HR was 1.07 (0.96-1.18) allowing us to affirm that there is no link between long-term use of pioglitazone and bladder cancer. Our results support the hypothesis of no difference in the incidence of bladder cancer among the pioglitazone group and the nonuser group. Our conclusion is that the explanation of hypothetically increased risk of bladder malignancy should be attributed to other factors. FUNDING: Tchaikapharma High Quality Medicines Inc.

Comparative analysis of therapeutic efficiency and costs (experience in Bulgaria) of oral antidiabetic therapies based on glitazones and gliptins.

Type 2 diabetes mellitus is a serious, chronic, progressive and widespread disease. Metformin is the most commonly prescribed initial therapy, but combination with other antidiabetic agents usually becomes necessary due to the progression of the disease. Pioglitazone is recommended as a second-line therapy because of its strong antihyperglycemic effect and its ability to reduce insulin resistance. Treatment with pioglitazone is associated with a significantly lower risk of cardiovascular complications and hypoglycemia, while simultaneously improving the lipid profile and the symptomatic and histological changes in the liver. Gliptins (sitagliptin and vildagliptin) are a new class of oral antidiabetic drugs which reduce glycated hemoglobin by a different mechanism. Although the efficacy of sitagliptin and vildagliptin is close to that of pioglitazone, the lack of long-term safety data and the higher price question their predominant use. The objective of this review is to highlight the advantages of mono- and combination therapy with pioglitazone in comparison with gliptins and to underline the inconsistencies in the medicinal and reimbursement policy in Bulgaria.

Pharmacotherapeutic recommendations for application of target oncological drug therapies for treatment of breast cancer in Bulgaria - therapeutic efficacy and cost effectiveness.

PURPOSE: The purpose of this study was to determine the direct costs of targeted cancer therapies for the treatment of breast cancer, calculating the effectiveness of the additional costs (ICER) and the cost of life years gained (LYG), using data from randomized clinical trials cited in the summary of product characteristics (SPC) of medicinal products approved for use under the centralized procedure. METHODS: Data from the SPC and clinical trials was analyzed. ICER and LYG of the medicinal therapies were compared using data from Phase III clinical trials cited in the Summary of product characteristics. The perspective of the payer was adopted. RESULTS: The SPCs of five drugs were analyzed. Targeted therapies were compared to placebo or to best supportive care (BSC) in some of them, while in others monoclonal antibodies (mAbs) and tyrosine kinase inhibitors were compared to existing drug therapies. Cost-effectiveness of each therapy was calculated. The value of ICER was between 56 470 Bulgarian Levs/LYG and 879 480 Bulgarian Levs/LYG. CONCLUSION: The current pharmacotherapeutic recommendations for targeted therapies for the treatment of breast cancer are based on evidence of therapeutic efficacy and cost effectiveness. Their application in therapeutic practice in Bulgaria is necessary to ensure patient access to effective therapies within the limited public funds.

Decrease in acute coronary syndrome mortality in Pleven district: implementation of scientific evidence into everyday practice.

Cardiovascular mortality in Bulgaria has increased for the last 25 years, contrary to the rest of the EU countries. One of the reasons is high in-hospital mortality due to acute myocardial infarction. The Bulgarian Cardiac Institute has established a modern cardiac hospital with a catheterization laboratory (cathlab) in the Medical University in Pleven, which helps it decrease acute coronary syndrome (ACS) mortality, taking all the necessary steps according to the guidelines of the European Society of Cardiology (ESC).

Medical doctors' opinion of healthcare reforms in Bulgaria.

At the time of the ongoing organizational changes in healthcare, the medical professionals' opinions regarding the reforms are the most critical since, as medical professionals, they are the main participants in the healthcare reforms. In this article the opinion of 1015 medical doctors is given regarding their awareness of the aims and essence of the reform, their level of preparedness and willingness to support and implement the process, their perception of patient-doctor relationships and public health system change, the financial resources, payment of medical work and the overall satisfaction with the reform.

The misuse of clinical paths as an instrument for funding inpatient care in Bulgaria.

Clinical paths in Bulgaria are used not as a method for quality assessment, but as an instrument to fund hospitals. Their use and incompleteness cause limited access of all Bulgarian citizens to the international treatment guidelines. That way quality of treatment worsens and mortality increases. The Bulgarian system of regulated medical guidelines by all therapeutic and surgical lines still suffers many deficiencies. The National Health Insurance Fund should use the system of clinical paths for quality control as well.