European guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Non-isotopic RNase cleavage assay for mutation detection in MEFV, the gene responsible for familial Mediterranean fever, in a cohort of Greek patients

Background: The MEFV gene is responsible for familial Mediterranean fever (FMF). Several disease associated mutations have been identified. The range of genetic variation in MEFV in Greek patients has not been determined. Objective: To describe a method that facilitates the routine screening of the entire coding sequence of MEFV (excluding exon 1). Methods: The non-isotopic RNase cleavage assay (NIRCA) was optimised and used as a first step screening method to screen exons 2 to 10 of MEFV. Exons 2 and 10 were analysed separately at DNA level, while exons 3 to 9 were analysed together at cDNA level. The sample group consisted of 26 FMF patients diagnosed using established clinical criteria, six asymptomatic relatives, 12 patients with atypical clinical manifestations, nine patients suffering from various inflammatory diseases, and three normal individuals. All were analysed by NIRCA for mutations in the MEFV gene and direct sequencing was applied subsequently to confirm the results. Results: MEFV mutations were identified in 25 of 26 typical FMF patients and in two of 12 patients with atypical manifestations. NIRCA results were in concordance with sequencing findings in all sequences analysed, suggesting that the method is highly reliable in this disease. Sixteen alterations of MEFV were identified (eight missense mutations and eight single nucleotide polymorphisms). Conclusions: NIRCA can be used for rapid screening of the coding sequence of the MEFV gene in patients suspected of suffering from FMF

Hepatitis C virus survival curve analysis in naïve patients treated with PegInterferon α-2b plus ribavirin. A randomized controlled trial for induction with high doses of PegInterferon and predictability of sustained viral response from early virologic data

Aim. To evaluate the significance of induction with high doses of pegylated interferon α-2b (Peg-IFNα-2b) and the predictability of sustained virologic response (SVR) in naïve patients with chronic hepatitis C. Methods. 188 consecutive naïve patients with chronic hepatitis C were enrolled in a randomised controlled clinical trial. Patients were randomised to receive either Peg-IFNα-2b 3.0 mcg/kg QW x 12 weeks followed by 1.5 mcg/kg QW x 36 weeks plus 800-1200 mg ribavirin (Arm A) or Peg-IFNα-2b 1.5 mcg/kg QW x 48 weeks plus 800-1200 mg ribavirin (Arm B). HCV-RNA was obtained at 0, 4, 8, 12, 16, 24, 48 and 72 weeks. Differences between schemes were evaluated by Kaplan-Meier curves. Predictability of SVR was assessed by two-way contingency table analysis and ROC curve analysis. Results. From 176 patients, 75 had genotype 1, 15 genotype 2, 75 genotype 3 and 11 genotype 4. No statistical significance emerged in HCV-RNA positivity, side effects and withdrawals between schemes. Patients with genotype 1 achieved lower SVR (46.6%) in comparison to patients with genotypes 2/3 (94.1%, p<0.001) and 4 (90.9%, p=0.002). The most appropriate time for estimation of SVR for genotype 1 is week 8 (accuracy=0.84, AUC=0.90) while predictability increases with time in genotypes 2/3, reaching maximum accuracy=0.93 and AUC=0.76 at week 16. Conclusion. Induction with high doses of Peg-IFNα-2b does not preclude better outcome and rapid virologic response at 4 weeks of treatment sufficiently predicts SVR. These findings might be useful in an attempt to gain supportive evidence for decision making in difficult-to-treat patients

Patients with Acute Coronary Syndrome are at High Risk Prior to the Event and Lipid Management is Underachieved Pre- and Post-Hospitalization

Background: Current European Guidelines suggest the use of cardiovascular risk categories and also recommend using high-intensity statins for patients with acute coronary syndromes (ACS). Objective: We examined the risk of ACS patients prior to the event, as well as the overall use and intensity of statins. Methods: We enrolled 687 ACS patients (mean age 63 years, 78% males). Low-density lipoprotein cholesterol (LDL-C) levels upon admission were used to assess attainment of LDL-C targets. Patients were categorized as very high, high, moderate and low risk based on their prior to admission cardiovascular (CV) risk. We examined statin use and dosage intensity among patients discharged from the hospital. Patients were followed for a median period of 189 days. Results: The majority of the patients (n=371, 54%) were at very high CV risk prior to admission, while 101 patients were at high risk (15%), 147 (21%) moderate risk and 68 (10%) low risk. Interestingly, LDL-C target attainment decreased as the risk increased (p&lt;0.001). The majority (96%) of patients received statins at discharge; however, most of them (60.4%) received low/moderate intensity statins and just 35.9% received the suggested by the Guidelines high-intensity dose of statins. At follow-up, the rate of patients at high-intensity dose of statins remained similar (34.8%); 6% received no statins at all at follow-up. Conclusion: According to our study, the majority of ACS patients are already at high risk prior to their admission. Further, LDL-C targets are underachieved prior to the event and high-intensity statins are underutilized in ACS patients at, and post-discharge