Clinical utility of dabigatran in United Arab Emirates: A pharmacovigilance study

Objectives:

To provide early data regarding clinical utility of dabigatran in Al-Ain, United Arab Emirates (UAE).

Methods:

This was an ethics approved retrospective cross sectional study. We retrieved a total of 76 patients who were using dabigatran from September to December 2014 in the Cardiology Clinic at Al-Ain Hospital, Al-Ain, UAE. The primary analysis was designed to test the frequency of bleeding events (rate) with dabigatran 75, 110, and 150 mg.

Results:

The mean age ± standard deviation of cohort was 67.9 ± 1.5 years (range; 29-98 years), composed of males (52.6%) with mean age of 66.3 ± 1.7 years, and females (47.4%) with mean age of 69.6 ± 1.1 years. The highest age group was those between 61-80 years (60.5%). Most comprised the age strata of ≤75 years (73.7%). The main indication for dabigatran use was atrial fibrillation. The rate of bleeding with dabigatran was 18/76 (23.7%), and melena was the leading cause of bleeding 8/76 (10.7%). The hospitalization rate was 67.1%, dabigatran withdrawal rate was 0.01%, and mortality rate was 6.5%. The cohort had exhibited incidences of minor bleeding with one fatal major bleeding, high co-morbidities, admission, and readmission, which was not directly linked to dabigatran. We did not identify any relation of death due to dabigatran.

Conclusion:

Dabigatran is a suitable alternative to warfarin obviating the need for repetitive international normalized ratio monitoring, however, it may need plasma drug monitoring.Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects 1-1.5% of population worldwide.1 Atrial fibrillation prevalence increases with age, and rises from 0.7% in those between 55-59 years to 17.8% in those ≥85 years. Nearly 85% of patients with AF are aged >65 years old.2 The lifetime risk for the development of AF as demonstrated in the Framingham study was one in 4 for men and women aged ≥40 years,3 which pose certain concerns in countries with aging populations.4,5 In addition to this, hospitalization related to AF is alarmingly increasing.6 The risk of stroke in patients with AF is 5 folds, and systemic thromboembolism is 3 folds.7,8 Banerjee, et al9 has deployed stroke prevention score in patients with AF, however, the predictive value is of less magnitude. The European Society of Cardiology set estimation of stroke risk in patients with AF as per CHA₂DS₂-VASc score to determine the recommendation for initiating an oral anticoagulant,10 whereas in patients with CHA₂DS₂-VASc ≥2, HAS-BLED score can be used to assess the risk of bleeding, and commencement of anticoagulant.11Warfarin (vitamin K antagonist [VKA]) has proven efficacy in reducing the risk of stroke in patients with AF, however, it poses high bleeding incidences, emergency hospitalizations, unpredictable therapeutic effect, and multiple international normalized ratio (INR) tests leading to many limitations in its clinical utility.12 Novel oral anticoagulants (NOACs) are proved as effective anticoagulants in prevention of stroke in patients with AF. Novel oral anticoagulants were preferred in non-valvular AF, and do not require coagulation monitoring, however, strict adherence to approved indication is highly warranted.13 Dabigatran (Pradaxa^®), a competitive inhibitor of thrombin was approved in October 2010 by the United States of America Food and Drug Administration to reduce the risk of stroke, and systemic embolism in patients with non-valvular AF.14 A systematic review incorporated 6 economic reviews from diverse healthcare systems (USA, Canada, and United Kingdom) utilizing different economic models. It has suggested the benefit of dabigatran in patients with high-risk of stroke, high-risk of intra-cerebral hemorrhage, or suboptimal use of warfarin. The review outlined concerns on tolerability of dabigatran, adherence issues, and adverse consequences.15In comparison with warfarin, dabigatran 150 mg has shown low rates of stroke, and systemic embolism (dabigatran p<0.001 for superiority). However, both drugs exhibited comparable rates of major hemorrhage.16-18 Greater fatal, and non fatal bleeding events were reported with dabigatran than warfarin.19,20 A recent (2015) retrospective Medicare data analysis study20 on dabigatran’s safety highlighted that the incidence of bleeding was higher than with warfarin (33% versus 27%), major bleeding (9% versus 6%), and gastrointestinal bleeding (17% versus 10%). Intracranial hemorrhage occurred more often with warfarin than dabigatran (1.8% versus 0.6%).20 It has been documented that risks of major bleeding from dabigatran is high for patients with chronic kidney disease, and in African Americans.20 The Randomized Evaluation of Long-term Anticoagulant Therapy: Dabigatran versus warfarin-RE-LY studies18 have showed similar risk of bleeding with warfarin versus dabigatran in patients with non-valvular AF. This dictated the importance of age sub-group analysis in studies. In real clinical practice, patients from different countries may have more co-morbid conditions than those in the RE-LY study.21 The current available data around bleeding incidences from dabigatran is relevant to populations with diverse characteristics. Revealing the clinical utility of dabigatran in our Emirati population may demonstrate different perspectives. Therefore, we intend to provide early data around the clinical utility of dabigatran in United Arab Emirates (UAE) Emirati population.     

Preoperative duplex ultrasound parameters predicting male fertility after successful varicocelectomy

Objectives:

To assess duplex ultrasound (DUS) parameters, and predicti the outcome of varicocele ligation in male infertility.

Methods:

This retrospective and follow up study was conducted at Dr. Sulaiman Al Habib Hospital, AlQassim, Saudi Arabia between January 2011 and December 2012. Eighty-two patients were selected, who presented with clinical/subclinical varicocele and male infertility. All these patients had DUS of the scrotum and underwent for low ligation varicocelectomy. These patients were followed for a period of 12-24 months after surgery for the occurrence of paternity. We reviewed pre-operative scrotal DUS of these 82 patients for the testicular size and volume, pampiniform veins caliber and duration of reflux in the dilated veins at rest, and after valsalva maneuver. These DUS parameters were correlated with the postoperative paternity rate.

Results:

Postoperative paternity was achieved in 18 patients (31.6%) with normal-sized testes, and in 3 patients (12%) with small size testes. The positive paternity rate was higher (38.5%) in patients with clinically detected varicocele, compared with only 16.7% of patients with subclinical varicocele (detected by ultrasound only). In addition, postoperative paternity was significantly higher in patients with bilateral varicocele (70.6%), with shunt-type varicocele (71.4%), and patients with a permanent grade of venous reflux (62.5%).

Conclusion:

Selection of patients for the successful paternity after varicocele repair depends mainly on DUS parameters, which includes normal size testicles with shunt type of bilateral varicocele and continuous reflux.Varicocele is defined as dilatation of the pampiniform venous plexus draining the testes. It is much more common on the left side compared with the right side, owing to long length of left testicular vein, the acute angle of insertion of left testicular vein into the left renal vein, lack of effective anti-reflux valves, which may transmit the high pressure of renal vein, making left testicular vein more vulnerable to varicocele.1,2 Varicocele is the most frequently identified male factor for infertility, present in up to 40% of cases. Long duration persistent varicocele is associated with adverse effects on sperm count, sperm motility and morphology, decrease testicular size, abnormal testosterone hormone level and decrease pregnancy rates.3-5 Scrotal physical examination is the preferred method for the diagnosis of varicocele. The Dubin grading system classifies the varicocele into 3 grades. Grade 1: varicocele is visible and palpable at rest; Grade 2: varicocele is palpable, but not visible; and Grade 3: varicocele is palpable only during valsalva maneuver. Duplex ultrasound (DUS) allows accurate diagnosis of varicoceles, even subclinical varicocele, which is not apparent on physical examination. Duplex ultrasound is performed at rest and during Valsalva maneuver.6,7 The scrotal vessels are assessed for the degree of dilatation, augmentation and direction of flow during Valsalva and duration of reflux. In this way, CDU is helpful to select the patient for varicocele repair.8-11 Many studies following varicocelectomy have reported approximately 66-70% improvement in semen parameters and 40-60% of patients have increased conception rates.12-15 Although, the outcome and prognosis after varicocelectomy are still controversial, and there are many preoperative parameters that determine the probability of success of the operation.16-18 There is a great need for research to improve preoperative selection of patients with varicocele. This study was carried out to assess the DUS (DUS includes grey scale ultrasound and color doppler ultrasound) parameters including the testicular size, degree of varicocele, type, and duration of reflux that could predict the outcome of varicocele repair in terms of paternity.     

Onset of ovulation after menarche in girls: a longitudinal study

INTRODUCTION: Hypothalamic-pituitary axis maturity has been believed to be the rate-limiting step in the development of ovulatory menstrual cycles. We hypothesized that, given current nutritional conditions, hypothalamic-pituitary axis maturation would be relatively rapid in menarcheal girls. METHODS: Daily urine and menstrual records were collected for 2 yr each from 10 girls aged 11-13 yr at study entry. Urinary excretion of LH, FSH, estradiol (E1c), and progesterone (Pdg) metabolites was measured using established ELISAs. An objective algorithm detected rises of LH, FSH, E1c, and Pdg consistent with follicular maturation and/or ovulation. RESULTS: Nine of 10 girls enrolled into the study experienced the onset of menarche prior to or during the 2-yr collection period. LH and FSH surges, as well as small amplitude Pdg increments, were observed prior to menarche. Regular, ovulatory-appearing cycles with LH surges and gradually increasing and more sustained Pdg rises were observed over time after menarche, although duration of Pdg elevations remained shorter than in adult women (8.9 +/- 1.0 vs. 12.1 +/- 0.8 d, P = 0.043). E1c levels leading to LH/FSH surges were lower in perimenarcheal girls than adult controls, and bleeding episodes did not uniformly correlate with hormone patterns. Progressive increases in FSH and Pdg, but not LH or E1c, were observed in association with menarche. CONCLUSION: Mature hormone patterns are established within several months of and even prior to menarche in normal-weight perimenarcheal girls. Factors determining menstrual bleeding in perimenarcheal girls may not be solely dependent on reproductive hormones or the neuroendocrine axis.     

Incidence and Outcomes of Pneumonia in Patients With Heart Failure

BackgroundThe incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).ObjectivesThis study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.MethodsThe authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro–B-type natriuretic peptide).ResultsIn PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).ConclusionsThe incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711)     

Gene expression of IQGAPs and Ras families in an experimental mouse model for hepatocellular carcinoma: a mechanistic study of cancer progression

IQGAPs genes play critical role in either induction or suppression of cancer and its progression, however the relationship between Ras genes and these genes are still unclear. In this study, we tried to understand the mechanistic action of IQGAPs genes and its correlation with Ras genes in mouse hepatic cancer model. The genetic expressions of IQGAP1, IQGAP2, IQGAP3, Hras, Kras, Nras, Mras, Caspase3, and BAX were followed in both hepatocellular carcinoma and normal liver cells of Balbc mice. Genotoxic agent diethylnitrosamine (DEN)-induced hepatic cancer model was induced in male mice and recorded the occurrence of hepatocellular carcinoma by morphological and histological changes in the liver. It was observed that mRNA expressions of IQGAP1, Hras, Kras, Nras, Mras, Caspase3, and BAX genes were highly elevated in hepatocellular carcinoma cells when compared with normal liver cells, additionally their expressions increased by concentrating the dose of DEN. While, the expressions of IQGAP2 and IQGAP3 were significantly decreased in hepatocellular carcinoma cells when compared with normal liver cells, as well as their expressions decreased more with increasing the dose of DEN. It was concluded from this study that IQGAP1 has a strong signaling relationship with Ras genes in induction of cancer and it is considered as a key gene for induction or suppression of the hepatocellular carcinoma.     

Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%‐8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long‐term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis‐related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow‐up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow‐up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow‐up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942‐2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407‐3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333‐1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.     

Willingness score obtained after a short CPAP trial predicts CPAP use at 1 year

Purpose

To predict continuous positive airway pressure (CPAP) adherence at 1 year.

Methods

We followed consecutive OSA patients scheduled for CPAP initiation for 1 year. Patients completed a self-efficacy questionnaire (5 = low, 25 = high score) before CPAP initiation. After CPAP initiation, we enquired about patients’ satisfaction in CPAP trial and their eagerness and willingness to continue CPAP therapy (0 = unsatisfied, uneager, or refused CPAP; 100 = satisfied, eager, or willing to continue CPAP treatment).

Results

Of the 580 patients we followed, 377 continued CPAP therapy beyond 1 year. A low willingness score (<50) was expressed by 77 patients but only 7 of them used CPAP >4 h daily at 1 year, yielding a specificity of 97 % in predicting CPAP failure. At 1 year, patients with a self-efficacy score >20, expressed prior to CPAP initiation, used CPAP more often than the patients with a score <20 (average use 4.4?±?2.2 h vs. 3.7?±?2.3 h, p?<?0.001).

Conclusions

A low score of willingness to continue CPAP therapy after a short trial predicts CPAP failure and poor CPAP adherence at 1 year.