Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Scant data is available on the efficacy and safety of adding ezetimibe to high-intensity statin therapy for early and rapid reduction of low-density lipoprotein cholesterol (LDL-C) within 4-12 weeks of an acute-event in acute coronary syndrome (ACS). We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving patients with ACS receiving ezetimibe in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in LDL-C levels post-ACS. Secondary outcomes were to evaluate alterations in other lipid parameters and adverse events. RESULTS: From initially screened 4561 articles, data from 11 studies (20,291 patients) were analyzed. Compared to controls, patients receiving ezetimibe had significantly lower LDL-C at 7-days [MD -19.55 mg/dl(95 %CI:-36.46 to -2.63);P = 0.02;I2 = 91 %], 1-month [MD-24.67 mg/dl (95 %CI:-34.59 to -14.76);P < 0.001;I2 = 81 %], 3-months [MD -18.01 mg/dl(95 %CI:-24.11 to -11.90);P < 0.001;I2 = 92 %] and 10-12 months [MD -16.90 mg/dl (95 % CI: -17.67 to -16.12); P < 0.001; I2 = 0 %] of treatment. Compared to controls, patients receiving ezetimibe had significantly lower total cholesterol at 7-days [MD-21.05 mg/dl(95 %CI:-26.73 to -15.37);P < 0.001;I2 = 0 %], 1-month [MD-25.56 mg/dl(95 %CI:-38.29 to -12.83);P < 0.001;I2 = 85 %], 3-months [MD-22.54 mg/dl(95 %CI:-36.90 to -8.19);P = 0.002;I2 = 22 %] and 12-months [MD-19.68 mg/dl(95 %CI:-20.78 to -18.59);P < 0.001;I2 = 0 %] of treatment. Death from any cause, ACS and non-fatal stroke [OR0.89(95 %CI:0.83-0.96);P = 0.002;I2 = 0 %], non-fatal myocardial infarction [OR0.86(95 %CI:0.79-0.94);P = 0.001;I2 = 0 %] and ischemic stroke [OR0.80(95 %CI:0.68-0.94);P = 0.009;I2 = 0 %] was significantly reduced in patients receiving ezetimibe. CONCLUSION: Addition of ezetimibe to high-intensity statin therapy at the time of ACS event is associated with significantly better cholesterol reduction at day-7,1-month, 3- months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events post an index event of ACS. CONCISE SUMMARY OF FINDINGS: Addition of ezetimibe to high-intensity statin therapy at the time of acute coronary syndrome (ACS) index event is associated with significantly better low density lipoprotein cholesterol and total cholesterol reduction at day-7, 1-month, 3-months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events (death from any cause, major ACS, non-fatal stroke, non-fatal myocardial infarction, and ischemic stroke) post an index event of ACS.

Efficacy and safety of luseogliflozin in improving glycaemic and non-glycaemic outcomes in type-2 diabetes: A meta-analysis.

BACKGROUND & AIMS: No meta-analysis is available analysing the role of luseogliflozin in type-2 diabetes. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving diabetes patients receiving luseogliflozin in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in glucose, blood pressure, weight, lipids, and adverse events. RESULTS: From initially screened 151 articles, data from 10 RCTs involving 1304 patients was analysed. Individuals receiving luseogliflozin 2.5 mg/d had a significantly lower HbA1c [MD -0.76% (95% CI: 1.01 to -0.51); P < 0.01; I2 = 83%], fasting glucose [MD -26.69 mg/dl (95% CI: 35.41 to -17.96); P < 0.01; I2 = 80%], systolic blood pressure [MD -4.19 mm Hg (95% CI: 6.31 to -2.07); P < 0.01; I2 = 0%], body-weight [MD -1.61 kg (95% CI: 3.14 to -0.08); P = 0.04; I2 = 0%], triglycerides PCG [MD -12.60 mg/dl (95% CI: 24.25 to -0.95); P = 0.03; I2 = 0%], uric acid [MD -0.48 mg/dl (95% CI: 0.73 to -0.23); P < 0.01; I2 = 49%] and alanine aminotransferase [MD -4.11 IU/L (95% CI: 6.12 to -2.10); P < 0.01; I2 = 0%] compared to placebo. Occurrence of treatment-emergent adverse-events [RR 0.93 (95% CI: 0.72-1.20); P = 0.58; I2 = 0%], severe adverse-events [RR 1.19 (95% CI: 0.40-3.55); P = 0.76; I2 = 0%], hypoglycaemia [RR 1.56 (95% CI: 0.85-2.85); P = 0.15; I2 = 0%] and genital infections [RR 1.42 (95% CI: 0.48-4.18); P = 0.53; I2 = 0%] were not increased with luseogliflozin. Cardiovascular outcome trials are lacking and are urgently required. CONCLUSION: Luseogliflozin has good glycaemic and non-glycaemic benefits similar to other SGLT2 inhibitors and is well tolerated.

Treatment outcomes of graded dose of empagliflozin in type-2 diabetes: A real world study.

Background: Costs are important cause of therapeutic noncompliance in type-2 diabetes mellitus (T2DM). Half-tablet empagliflozin (EMPA)-25 mg has lowest monthly cost among all EMPA preparations; data is unavailable on efficacy of half EMPA-25. This study compared real world weight loss and glycaemic outcomes of 10 mg versus 12.5 mg versus 25 mg of EMPA. Methods: Data, retrospectively captured from records of 2 different centresfor patients > 35 years-age having T2DM on EMPA as part of standard pharmacotherapy for T2DM, having > 6 months follow-up data available was analysed. Patients were in 3-groups depending on EMPA dosage: Group 1 on EMPA 10 mg/day (1-tablet EMPA-10), Group-2 on EMPA 12.5 mg/day (half-tablet EMPA-25), and Group 3 on EMPA 25 mg/day (1-tablet EMPA-25). Primary endpoints were glycaemic efficacy and weight-loss. Results: Of 3601 records screened, data from 599 patients (184, 239 and 176 in Group-1, 2 and 3 respectively) was analysed. All 3 groups were comparable with regards to sex, blood pressure, haemoglobin, renal function, medications use. Group-3 were significantly older, had longest diabetes duration, highest HbA1c and lowest body mass index. Glycaemic efficacy was comparable among groups (ΔHbA1c Groups 1-3: -0.9 (-1.9 - 0.0), -1.0 (-1.8 - 0.5) and - 1.0 (-1.5 - 0.22], respectively; P = 0.363). Patients on EMPA 12.5 or 25 mg/d had significantly higher total (-1.4 [-3.0 -0.2] vs. -0.3 [-2.4 - 1.32] kg; P = 0.028) and percent weight-loss (-1.75% [-4.15 - 0.26] vs. -0.44% [-3.11 - 1.39]; P = 0.039), and significantly higherfraction achieving HbA1c < 5.7% (12% vs. 0; P = 0.021), compared to EMPA-10. Conclusion: Half EMPA-25 is the most cost effective way of using EMPA in clinical practice.

Résumé Contexte: Les coûts sont une cause importante de non-conformité thérapeutique dans le diabète sucré de type 2 (DT2). Empagliflozine demi-comprimé (EMPA) -25 mg a le coût mensuel le plus bas parmi toutes les préparations EMPA; les données ne sont pas disponibles sur l'efficacité de la moitié de l'EMPA-25. Cette étude a comparé le monde réel perte de poids et résultats glycémiques de 10 mg contre 12,5 mg contre 25 mg d'EMPA. Méthodes: Données, capturées rétrospectivement à partir d'enregistrements de 2 centres différents pour les patients de plus de 35 ans ayant un DT2 sous AEM dans le cadre de la pharmacothérapie standard pour le DT2, ayant> 6 mois les données de suivi disponibles ont été analysées. Les patients étaient répartis en 3 groupes en fonction de la posologie d'EMPA: Groupe 1 sous EMPA 10 mg / jour (1 comprimé d'EMPA-10), Groupe-2 sur EMPA 12,5 mg / jour (demi-comprimé EMPA-25) et groupe 3 sur EMPA 25 mg / jour (1 comprimé EMPA-25). Les critères d'évaluation principaux étaient glycémiques efficacité et perte de poids. Résultats: sur 3601 enregistrements examinés, les données de 599 patients (184, 239 et 176 dans les groupes 1, 2 et 3 respectivement) étaient analysé. Les 3 groupes étaient comparables en ce qui concerne le sexe, la pression artérielle, l'hémoglobine, la fonction rénale et l'utilisation de médicaments. Groupe-3 étaient significativement plus âgé, avait la plus longue durée de diabète, le plus haut taux d'HbA1c et le plus bas indice de masse corporelle L'efficacité glycémique était comparable entre groupes (ΔHbA1c Groupes 1 à 3: −0,9 (−1,9 - 0,0), −1,0 (−1,8 - 0,5) et - 1,0 (−1,5 - 0,22], respectivement; P = 0,363). Patients sous EMPA 12,5 ou 25 mg / j avaient un total significativement plus élevé (−1,4 [−3,0 ­0,2] contre −0,3 [−2,4 - 1,32] kg; P = 0,028) et un pourcentage de perte de poids (−1,75% [−4,15 - 0,26] contre −0,44% [−3,11 - 1,39]; P = 0,039), et une fraction significativement plus élevée atteignant un taux d'HbA1c <5,7% (12% contre 0; P = 0,021), par rapport à EMPA-10. Conclusion: HalfEMPA-25 est le moyen le plus rentable d'utiliser EMPA dans la pratique clinique. Mots-clés: Diabésité, inversion du diabète, empagliflozine, euglycémie, perte de poids.

Efficacy and Safety of Once Weekly Thyroxine as Compared to Daily Thyroxine in Managing Primary Hypothyroidism: A Systematic Review and Meta-Analysis.

AIMS: No meta-analysis is available which has holistically analyzed efficacy and safety of once weekly thyroxine (OWT) vs. standard daily therapy (SDT) with regards to managing primary hypothyroidism. We undertook this meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched for clinical trials involving hypothyroid patients receiving OWT in intervention arm, and SDT in control arm. Primary outcome was to evaluate changes in serum thyroid stimulating hormone. Secondary outcomes were to evaluate alterations in total tetra-iodothyronine (TT4), total tri-iodothyronine (TT3), free T4 (FT4), free T3 (FT4), heart rate (HR), cardiac function, symptomatology, and adverse events. RESULTS: From initially screened 159 studies, data from four trials involving 294 patients were analyzed. Patients of OWT had significantly higher thyroid stimulating hormone (TSH) [mean difference (MD) +1.85 mU/L (95% confidence interval, CI: 0.95-2.75); P < 0.01; I 2 = 63%], comparable TT4 [MD -0.87 mcg/dl (95% CI: -2.98-1.24); P = 0.42; I 2 = 65%], and significantly lower TT3 [MD -15.7 ng/dl (95% CI: -29.9-1.51); P = 0.03; I 2 = 90%], following 6-weeks therapy. TT4 [MD 3.05 mcg/dl (95% CI: 1.44-4.66); P < 0.01], and FT4 [MD 0.56 ng/dl (95% CI: 0.04-1.08); P = 0.03; I 2 = 66%] were significantly higher 2 h after thyroxine intake, in people on OWT compared to SDT. TT4 levels were significantly higher 4 h after thyroxine intake in OWT as compared to SDT [MD 0.70 ng/dl (95% CI: 0.52-0.88); P < 0.01]. Following 4-8 h of intake of thyroxine, isovolumetric contraction time [MD 3.62 ms (95% CI: 1.93-5.31); P < 0.01; I 2 = 0%] and aortic ejection time/pre-ejection period ratio [MD 0.01 (95% CI: 0.00-0.02); P = 0.02; I 2 = 0%], were significantly higher in people on OWT as compared to SDT. CONCLUSION: OWT is associated with less efficient control of hypothyroidism at 6 weeks and may be associated with supraphysiologic elevation of thyroid hormone levels along with transient echocardiographic changes in some patients following 2-4 h of thyroxine intake.

Current Perspective on Use of NOAC in Clinical Practice in India.

Oral vitamin K antagonists (VKA) such as warfarin have been the mainstay of therapy for stroke prevention in patients with non valvular atrial fibrillation (NVAF) while low-molecular-weight heparin, fondaparinux and adjusted-dose warfarin or aspirin have been routinely used for thromboembolism (VTE) prophylaxis in patients undergoing total hip or knee replacement. However, VKAs are associated with considerable limitations, including increased risk of bleeding and narrow therapeutic window. Novel oral anticoagulants (NOACs, now referred as Non Vit K dependent oral anticoagulants), including the direct thrombin inhibitor dabigatran and direct Factor Xa inhibitors such as rivaroxaban and apixaban are now approved alternatives to warfarin for prophylaxis of stroke and systemic embolic events (SEE) in patients with NVAF and treatment and prophylaxis of VTE. The efficacy and safety of NOACs have been proven in several clinical trials. The advantages offered by NOACs such as rapid onset and termination of action, predictable anticoagulant effect, less frequent laboratory monitoring make them promising alternatives to warfarin. However, clinicians in India seek more information over the practical aspects that require due consideration to ensure proper use of these drugs. The article addresses some crucial aspects of NOAC therapy such as measurement of anticoagulant effects, transition between different agents, ensuring drug intake compliance, dealing with dosing errors, management of bleeding complications etc based on the guidance offered by the European Heart Rhythm Association in 2013.

Fondaparinux in Acute Coronary Syndromes.

Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Anticoagulant-associated adverse events like heparin-induced thrombocytopenia, bleeding complications and need of close monitoring of anticoagulation led to focus on developing agents causing anticoagulation without affecting primary haemostasis. Fondaparinux, a new-age synthetic anticoagulant, acts by inhibiting factor Xa. It is simple to administer and has low inter and intra-subject variability. Moreover, there is no risk of significant drug interactions and no need for monitoring the platelet count. Efficacy of fondaparinux has been studied in various disorders including prevention of venous thromboembolism in major orthopaedic surgery, abdominal surgery and acutely ill medical patients, treatment of venous thromboembolism, non-ST-elevation acute coronary syndromes and ST-elevation acute myocardial infarction. This article covers the review of fondaparinux and its practical advantages mainly in the management of ACS including non-ST-elevation acute coronary syndromes and ST-elevation acute myocardial infarction.

Use of fetal echocardiography for characterization of fetal cardiac structure in women with normal pregnancies and gestational diabetes mellitus.

OBJECTIVES: To assess fetal cardiac structure and function and to evaluate the efficacy of routine fetal echocardiography for detection of fetal cardiac abnormalities in women with normal pregnancies and those with gestational diabetes mellitus. METHODS: In this prospective study, we studied fetal cardiac structure and function in 294 uncomplicated singleton pregnancies and 302 pregnancies complicated by gestational diabetes. Fetal echocardiography (2-dimensional sonography and pulsed wave Doppler imaging) was used to assess functional parameters and to detect any cardiac structural abnormality. Data from clinical and echocardiographic evaluations of neonates at birth and 3 months were obtained to confirm the antenatal findings. RESULTS: The mean maternal age ± SD was 28.9 ± 5.0 years in the diabetes group and was comparable to that of women with normal pregnancies. The mean hemoglobin A1c value was 6.3%, and the mean body mass index was 28.0 kg/m(2). The systolic function as assessed by the ejection fraction increased significantly in the diabetes group compared to the normal pregnancy group independent of glycemic control (P < .001). The pulsed wave parameters (early diastolic peak flow velocity and early-to-late diastolic peak flow velocity ratio) were significantly different between the groups (P < .001). The interventricular septum and fetal ventricular wall thicknesses were significantly increased in the presence of gestational diabetes (P < .001). No major fetal cardiac structural anomaly was detected in either group. On follow-up after delivery, all neonates were assessed clinically and by transthoracic echocardiography to rule out congenital defects. CONCLUSIONS: In our study, significant increases in the interventricular septum and ventricular wall thicknesses were detected in the presence of gestational diabetes mellitus. Interestingly, none of the neonates of pregnant women with gestational diabetes were found to have echocardiographic evidence of congenital heart disease.

Role of homocysteine & MTHFR C677T gene polymorphism as risk factors for coronary artery disease in young Indians.

BACKGROUND & OBJECTIVES: Hyperhomocysteinaemia (HCA) either due to mutation of MTHFR gene or deficiency of vitamin B 12 and folic acid, has been reported as a risk factor for coronary artery disease (CAD). The present study was aimed to determine plasma homocysteine (Hcy) levels and to evaluate MTHFR C677T gene polymorphism as risk factors for CAD, and to study the role of Hcy in conjunction with a few other risk factors of CAD in young Indians. The effect of vitamin B12 and folic acid supplements on the raised plasma Hcy levels in patients of CAD was also assessed. METHODS: The present study included 199 consecutive angiography confirmed CAD patients, <45 yr of age, without any other known pro- coagulant state and 200 age- and sex-matched healthy controls. Fasting blood samples were collected in EDTA and plasma Hcy was estimated by ELISA test and the MTHFR C677T polymorphism detection was carried out by PCR-RFLP method. RESULTS: Significant difference (P<0.001) was found between mean fasting levels of plasma Hcy in cases (22.14 ± 10.62 µmol/l) and controls (17.38 ± 8.46 µmol/l) with an Odds ratio as 1.93 (95% CI, 1.27-2.94). Levels of cholesterol, LDL, and triglycerides were significantly (P<0.001) higher in cases compared with controls. INTERPRETATION & CONCLUSIONS: Our study showed significant correlation between hyperhomocysteinaemia and coronary artery disease. Multivariate analysis by logistic regression of the various risk factors of CAD, found high levels of Hcy, cholesterol, LDL and low levels of HDL and smoking as independent predictors of CAD when all other factors were controlled. Significant post-treatment decrease found in HCA was easily modifiable by vitamin intervention irrespective to their CT or TT genotype of C677T MTHFR gene. Further studies to look at the plasma levels of folate and cobalamines and their association with Hcy are required to be done.

Thrombosuction for procedural acute thrombosis during high-risk carotid angioplasty--a case report.

Carotid endarterectomy in the presence of an occluded contralateral artery is associated with a high risk of perioperative stroke. Carotid stenting with neuroprotection devices has emerged as a safe procedure for revascularization in this circumstance. We performed high-risk carotid angioplasty in a patient with a history of recurrent transient ischemic attacks and 90% stenosis of left internal carotid artery with other occluded cerebral vessels. The final follow-up angiogram revealed thrombotic obstruction of the stent without any evidence of vasospasm, stent deformation or dissection. Direct thrombosuction was performed with the guiding sheath. Multiple suction passes yielded complete restoration of vascular patency and intracranial flows. A control angiogram performed 10 days later revealed no residual stenosis or thrombus. Thrombosuction using a guiding sheath leads to rapid revascularization in a patient with acute carotid stent thrombosis.

A comparative study of restenosis rates in bare metal and drug-eluting stents.

BACKGROUND: Various studies have been performed throughout the world on the rate of restenosis using bare metal stents (BMS) and drug-eluting stents (DES). The prohibitive costs associated with DES generally dictate the type of stent used, especially in developing countries. Therefore, there was a need for a study to assess the effect of various risk factors on restenosis in BMS and DES in the Indian context. A study was performed in the premier institution of the Indian Armed Forces, the Army Hospital (Research and Referral), New Delhi, India, under the aegis of the Indian Council of Medical Research (New Delhi). The profile of patients in the armed forces is inherently diverse in terms of demography, ethnicity, genetics, etc, which reflects the diverse and varied nature of the population in India. METHODS AND RESULTS: A total of 130 patients were included in the present study. Follow-up after stent implantation was scheduled for six to nine months following the procedure to assess symptoms, drug compliance, and treadmill test and coronary angiography results, and to ascertain the incidence of restenosis. However, only 80 patients returned for follow-up and, therefore, the final analysis was based on these patients. They were segregated into BMS (n=41) and DES (n=39) groups. Restenosis occurred in 29 patients (36.3%). Nine of 39 patients with DES (23.1%) and 20 of 41 patients with BMS (48.8%) developed restenosis. There was a statistically significant relationship between restenosis and female sex, clinical presentation before intervention and at the time of follow-up evaluation (unstable angina), hypertension, positive stress test and compliance with medical therapy (P<0.05). No statistically significant relationship was observed between restenosis and age, diabetes, smoking, obesity and diet (P>0.05). CONCLUSIONS: DES appear to reduce the restenosis rate and clinical end points, and appear to be more cost effective than BMS. Patient-related factors (eg, sex, hypertension and unstable angina) are important variables that affect the restenosis rate. Noninvasive stress testing had high positive and negative predictive values. Therefore, based on the present study, noninvasive stress testing is suggested before routine angiography at follow-up, which will reduce the need for repeat coronary angiography.

N-terminal pro-BNP plasma levels before and after percutaneous transvenous mitral commissurotomy for mitral stenosis.

In this study, we investigated the change in N-terminal pro-brain natriuretic peptide (NT-pro-BNP) plasma levels among 44 consecutive patients with mitral stenosis, 10 min before and 24 h after undergoing percutaneous transvenous mitral commissurotomy (PTMC). The procedure was successful in all patients and a significant decline was noted in NT-pro-BNP levels. Reduction of NT-pro-BNP was more marked in patients in sinus rhythm as compared to those with atrial fibrillation. In conclusion, serial measurement of plasma NT-pro-BNP levels might be a useful noninvasive method for documenting the success of PTMC among patients in sinus rhythm.

Mahaim automatic accelerated rhythm: a marker of successful radiofrequency ablation.

BACKGROUND: Mahaim pathways are characterized by the presence of an accessory pathway potential-the 'M' potential, at the tricuspid annulus. M potential is a very useful guide during radiofrequency ablation of Mahaim pathway. During ablation, an accelerated rhythm with ORS morphology, identical to fully pre-excited QRS complex is observed, and has been labeled as Mahaim automatic rhythm. We analyzed this rhythm during radiofrequency ablation of these pathways. METHODS AND RESULTS: Eighteen patients with Mahaim accessory pathways were taken up for electrophysiology study and radiofrequency ablation. Tricuspid annulus was mapped for 'M' potentials and targeted for ablation. Duration of ablation and number of ablation attempts were guided by Mahaim automatic rhythm during ablation. Mahaim tachycardia was inducible in all. 'M' potentials were recorded in 15/18 patients. Radiofrequency energy was delivered at the site where Mahaim accelerated rhythm was noticed and was continued till abolition of the rhythm. This resulted in long-term success. In 3 patients, M potentials were not recordable, and in them other methods including 3-dimensional electroanatomical mapping was also not successful. CONCLUSIONS: 'M' potential-guided radiofrequency ablation is a useful technique. Presence of Mahaim automatic rhythm and its abolition during ablation is associated with long-term success of the procedure.