Publications by authors named "Ioannis Doundoulakis"

45 Publications

Atrial High-Rate Episodes in Patients with Devices Without a History of Atrial Fibrillation: a Systematic Review and Meta-analysis.

Cardiovasc Drugs Ther 2021 Jun 5. Epub 2021 Jun 5.

First Department of Cardiology, University of Athens Medical School, Athens, Greece.

Purpose: Atrial high-rate episodes (AHREs) recorded with cardiac implantable electronic devices (CIEDs) have been associated with the development of clinical atrial fibrillation (AF) and increase in stroke and death risk. We sought to perform a systematic review with a meta-analysis to evaluate the prevalence of AHREs detected by CIEDs, their association with stroke risk, development of clinical AF, and mortality among patients without a documented history of AF.

Methods: We searched several databases, ClinicalTrials.gov, references of reviews, and meeting abstract books without any language restrictions up to 9 September 2020. We studied patients with CIEDs in whom AHREs were detected. Exclusion criterion was AF history. Our primary outcome was the risk of ischemic stroke in patients with AHREs.

Results: We deemed eligible eight studies for the meta-analysis enrolling a total of 4322 patients with CIED and without a documented AF history. The overall AHRE incidence ratio was estimated to be 17.56 (95% CI, 8.61 to 35.79) cases per 100 person-years. Evidence of moderate certainty suggests that patients with documented AHREs were 4.45 times (95% CI 2.87-6.91) more likely to develop clinical AF. Evidence of low confidence suggests that AHREs were associated with a 1.90-fold increased stroke risk (95% CI 1.19-3.05). AHREs were not associated with a statistically significant increased mortality risk.

Conclusion: The present systematic review and meta-analysis demonstrated that among patients without a documented history of AF, the detection of AHREs by CIEDs was associated with significant increased risk of clinical AF and stroke.

Registration Number (doi): Available in https://doi.org/10.17605/OSF.IO/ZRF6M .
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http://dx.doi.org/10.1007/s10557-021-07209-8DOI Listing
June 2021

Cardiovascular Disease Risk Prediction Models and Scores.

Curr Pharm Des 2021 ;27(10):1231

Department of Cardiology, AHEPA University Hospital Aristotle University of Thessaloniki, School of Medicine, Faculty of Health Sciences, St. Kyriakidi Str 1, 54636, Thessaloniki, Greece.

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http://dx.doi.org/10.2174/138161282710210324104510DOI Listing
January 2021

Haemodynamic effects of PAH-targeted therapies in pulmonary hypertension due to lung disease: A systematic review and meta-analysis.

Pulm Pharmacol Ther 2021 Jun 9;68:102036. Epub 2021 May 9.

Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece. Electronic address:

Background: Pulmonary hypertension (PH) is a negative predictor in patients with lung disease and/or hypoxia (group 3 PH). Current guidelines do not endorse the use of targeted therapies for pulmonary arterial hypertension (PAH) in patients with group 3 PH, due to lack of strong evidence. However, a variety of studies have examined the effect of PAH-targeted therapies in group 3 PH with mixed methods and conflicting results.

Objective: To evaluate the effect of PAH-targeted therapies on haemodynamic parameters as assessed by right heart catheterization in patients with group 3 PH.

Methods: Search strategy included PubMed and CENTRAL databases for randomized controlled trials from inception until Jan 30, 2020. We hand searched review articles, clinical trial registries and reference lists of retrieved articles. The primary outcome was the effect of PAH-targeted therapies on haemodynamic parameters [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI) and right atrial pressure (RAP)] in patients with group 3 PH, while secondary outcomes were 6-min walking distance (6MWD), brain natriuretic peptide (BNP) and quality of life (QoL).

Results: Five studies with a total of 140 patients were included. PAH-targeted therapies improved significantly mPAP [mean difference (MD) -4.02 mmHg, 95% CI -7.95;-0.09], and PVR [standardized mean difference (SMD) -0.29, 95% CI -0.50;-0.07], but not CI (SMD 0.23, 95% CI -0.23; 0.70) or RAP (MD 0.26 mmHg, 95% CI -18.75; 19.27). PAH-targeted therapies significantly increased the 6MWD by 38.5 m (95% CI 17.6; 59.4), while they did not manage to improve QoL (SMD -3.42, 95% CI -14.74; 7.91) or BNP values. There was no effect of oxygenation by the PAH-targeted therapies compared to placebo.

Conclusion: PAH-targeted therapies slightly improved mPAP and PVR in group 3 PH, without affecting CI. Larger RCTs targeted in specific subpopulations are needed to extract more robust conclusions.

Protocol Registration: Open Science Framework 10.17605/OSF.IO/56FDW.
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http://dx.doi.org/10.1016/j.pupt.2021.102036DOI Listing
June 2021

Syncope associated with supraventricular tachycardia: Diagnostic role of implantable loop recorders.

Ann Noninvasive Electrocardiol 2021 May 6:e12850. Epub 2021 May 6.

First Department of Cardiology, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Syncope represents a relatively uncommon symptom of supraventricular tachycardia (SVT). It is likely that an impaired autonomic vasomotor response to the hemodynamic stress of tachycardia is the determinant of hemodynamic changes leading to cerebral hypoperfusion and syncope. In this regard, tilt-table test may detect abnormalities in the autonomic nervous function and predict the occurrence of syncope during SVT. Electrophysiology studies may reproduce the SVT, distinguish it from other life-threatening ventricular tachyarrhythmias, and exclude other causes of syncope. Not infrequently mixed syncope mechanisms are revealed during the above diagnostic workup raising doubts about the operating mechanism in the clinical setting. In such cases of uncertainty, an implantable loop recorder, providing long-term cardiac monitoring, may play a pivotal role in the establishment of the diagnosis, confirming the association of an arrhythmic event with the symptom. Herein, we present four such cases with recurrent unexplained syncope finally attributed to paroxysmal SVT guiding them to a potentially radical treatment through radiofrequency catheter ablation.
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http://dx.doi.org/10.1111/anec.12850DOI Listing
May 2021

Evaluation of subclinical cardiac damage in biopsy-proven nonalcoholic fatty liver disease: a systematic review and meta-analysis.

Ann Gastroenterol 2021 5;34(3):424-430. Epub 2021 Feb 5.

Department of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki (Artemis Christina Oikonomidou, Ioannis Doundoulakis, Theodoros Dardavessis, Michail Chourdakis).

Background: Data on the association of nonalcoholic fatty liver disease (NAFLD) with subclinical cardiac damage are scanty. We performed a systematic review to provide comprehensive information on subclinical cardiac alterations among NAFLD subjects.

Methods: PubMed and the Cochrane Library were searched to identify studies comparing subclinical cardiac damage between NAFLD and healthy adults. We also searched PROSPERO to check for any similar meta-analysis in progress in order to avoid duplication with our study. Conference abstracts and the reference lists of relevant studies and systematic reviews were perused. The Newcastle-Ottawa quality assessment scale for case-control and cohort studies were used to assess study quality.

Results: Seven studies were finally included in the meta-analysis (1 cross sectional and 6 case-control), with a total of 602 individuals (362 patients with NAFLD). Epicardial fat thickness were statistically significantly higher in patients with NAFLD than in controls (mean difference [MD] 1.17, 95% confidence interval [CI] 0.45-1.89, =89%). Global longitudinal strain was lower in NAFLD, to a statistically significant degree (MD -3.17, 95%CI -5.09 to -1.24, =89%). However, significant heterogeneity of the findings was observed.

Conclusions: Our findings indicate that NAFLD is related to subclinical cardiac damage. Further studies with a larger number of biopsy-proven NAFLD patients are needed to confirm this finding. Preventive and therapeutic interventions early in the course of the disease might decrease morbidity in this high-risk patient group.
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http://dx.doi.org/10.20524/aog.2021.0594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079885PMC
February 2021

Effects of Major Antihypertensive Drug Classes on Erectile Function: a Network Meta-analysis.

Cardiovasc Drugs Ther 2021 May 4. Epub 2021 May 4.

Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Purpose: To determine the effect of major antihypertensive classes on erectile function (EF) in patients with or at high risk of cardiovascular disease.

Methods: We performed a systematic review and frequentist network meta-analysis of randomized controlled trials assessing the effect of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and thiazide diuretics on EF compared to each other and to placebo (PROSPERO: CRD42020189529). Similarly, we performed a network meta-analysis to explore the effect of different β-blockers on erectile function (nebivolol, other vasodilating and non-vasodilating β-blockers, placebo). Records were identified through search of PubMed, Cochrane Library, and Scopus databases and sources of grey literature until September 2020.

Results: We included 25 studies (7784 patients) in the qualitative and 16 studies in the quantitative synthesis. The risk of bias was concerning or high in the majority of studies, and inconsistency was also high. No significant differences in EF were demonstrated in the pairwise comparisons between major antihypertensive classes. Similarly, when placebo was set as the reference treatment group, no treatment strategy yielded significant effects on EF. In the β-blockers analysis, nebivolol contributed a beneficial effect on EF only when compared to non-vasodilatory β-blockers (OR 2.92, 95%CI 1.3-6.5) and not when compared to placebo (OR 2.87, 95%CI 0.75-11.04) or to other vasodilatory β-blockers (OR 2.15, 95%CI 0.6-7.77).

Conclusion: All antihypertensive medication classes seem to exert neutral or insignificant effects on EF. Further high-quality studies are needed to better explore the effects of antihypertensive medication on EF.
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http://dx.doi.org/10.1007/s10557-021-07197-9DOI Listing
May 2021

American, European and international hypertension guidelines: Time to shake hands?

Int J Cardiol Hypertens 2021 Mar 17;8:100075. Epub 2020 Dec 17.

3rd Department of Internal Medicine, Aristotle University, Hypertension, Hypertension-24h Ambulatory Blood Pressure Monitoring Center, Papageorgiou Hospital, Thessaloniki, Greece.

Background: Following evidence-based medicine through guidelines is the first step to successfully treat hypertension and prevent cardiovascular outcomes.

Methods: This study compares the recommendations of the most recent American College of Cardiology (ACC)/American Heart Association (AHA), European Society of Cardiology (ESC)/European Society of Hypertension (ESH) blood pressure and International Society of Hypertension (ISH) focusing on prevalent contrasts among guidelines on when, how and in whom start the treatment, which is a major health implications of guidelines.

Results: The three guidelines disagree for the cut-off values in the definition of hypertension. Due to the different cut-off values of BP at the definition of hypertension, a patient may be misclassified to one of the four phenotypes of BP from office and out of office measurements, based to which guidelines are followed by the physicians. In addition to this, each society propose different risk score to evaluate the cardiovascular risk in patients with hypertension.

Conclusion: These differences cause a confusion not only to the general practitioners, but also the hypertension experts about the correct approach. The poor agreement between guidelines and diagnostic tools implies a huge number of patients remained unknown whether they should receive treatment.
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http://dx.doi.org/10.1016/j.ijchy.2020.100075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803036PMC
March 2021

Incident atrial fibrillation in patients with differentiated thyroid cancer: a meta-analysis.

Endocr Relat Cancer 2021 Apr 29;28(5):325-335. Epub 2021 Apr 29.

Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece.

Differentiated thyroid cancer (DTC) represents the most common form of thyroid neoplasms and is becoming increasingly prevalent. Evidence suggests a possible relationship between DTC diagnosis and subsequent atrial fibrillation (AF). If confirmed, this may present an alarming health risk (AF) in an otherwise condition with a relatively good prognosis (DTC). The aim of this systematic review and meta-analysis is to provide for the first time a pooled estimate of AF incidence in DTC patients in comparison to healthy controls. A detailed search in electronic databases, clinical trial registries and grey literature was performed to identify studies reporting the incidence of AF in DTC patients. Newcastle-Ottawa quality assessment scale was used to assess study quality. We used a random effects (RE) generalized linear mixed model (GLMM) in pooling of individual studies and also calculated a prediction interval for the estimate of a new study. Six observational studies met the eligibility criteria, which included totally 187,754 patients with DTC and 199,770 healthy controls. The median follow-up period was 4.3 to 18.8 years; the incidence rate of AF was 4.86 (95% CI, 3.29 to 7.17, I2 = 96%) cases per 1000 person-years, while the incidence rate ratio was 1.54 (95% CI, 1.44 to 1.65, I2 = 0%, 95% PI, 1.33 to 1.78).This is the first meta-analysis to confirm that patients with DTC are at a high risk for developing AF, which may be attributed to a state of iatrogenic hyperthyroidism due to long-term thyrotropin suppression therapy.
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http://dx.doi.org/10.1530/ERC-20-0496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111325PMC
April 2021

Permanent pacemaker implantation in unexplained syncope patients with borderline sinus bradycardia and electrophysiology study-proven sinus node disease.

J Arrhythm 2021 Feb 22;37(1):189-195. Epub 2020 Nov 22.

First Department of Cardiology National and Kapodistrian University "Hippokration" Hospital Athens Greece.

Background: Significant sinus bradycardia (SB) in the context of sinus node dysfunction (SND) has been associated with neurological symptoms. The objective was to evaluate the effect of permanent pacing on the incidence of syncope in patients with rather mild degrees of SB, unexplained syncope, and "positive" invasive electrophysiologic testing.

Methods: This was an observational study based on a prospective registry of 122 consecutive mild SB patients (61.90 ± 18.28 years, 61.5% male, 57.88 ± 7.73 bpm) presenting with recurrent unexplained pre and syncope attacks admitted to our hospital for invasive electrophysiology study (EPS). Τhe implantation of a permanent antibradycardia pacemaker (ABP) was offered to all patients according to the results of the EPS. Eighty patients received the ABP, while 42 denied.

Results: The mean of reported syncope episodes was 2.23 ± 1.29 (or presyncope 2.36 ± 1.20) in the last 12 months before they were referred for a combined EP guided diagnostic and therapeutic approach. Over a mean follow-up of approximately 4 years (50.39 ± 32.40 months), the primary outcome event (syncope) occurred in 18 of 122 patients (14.8%), 6 of 80 (7.5%) in the ABP group as compared to 12 of 42 (28.6%) in the no pacemaker group ( = .002).

Conclusions: Among patients with mild degree of SB and a history of unexplained syncope, a set of positivity criteria for the presence of EPS defined SND after differentiating reflex syncope, identifies a subset of patients who will benefit from permanent pacing.
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http://dx.doi.org/10.1002/joa3.12460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896452PMC
February 2021

Τhe European and American guidelines in the detection of hypertension phenotypes: The no-deal under the light of clinical practice.

Eur J Prev Cardiol 2020 Jul 2. Epub 2020 Jul 2.

3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece.

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http://dx.doi.org/10.1177/2047487320935559DOI Listing
July 2020

Cardio-protective Effects of Glucagon-like Peptide-1 Receptor Agonists: An Overview of Systematic Reviews and Publication Overlap.

Curr Pharm Des 2021 ;27(8):1068-1079

1st Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a new antihyperglycemic class with the demonstrated advantage of reducing major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM), atherosclerotic cardiovascular disease, or high cardiovascular risk.

Objective: Τo summarize the evidence of systematic reviews (SRs) that assess MACE (cardiovascular mortality, nonfatal myocardial infarction, and stroke) and hospitalizations for heart failure in GLP-1RAs-treated patients and to evaluate possible overlap in pertinent SRs.

Methods: We performed a comprehensive search via MEDLINE, Cochrane Library, and PROSPERO databases up to February 23, 2020, for SRs examining cardiovascular outcomes of GLP-1RAs in T2DM patients. Three independent authors extracted data and assessed the methodological quality of the included SRs using the ROBIS tool.

Results: We found 37 SRs - published between 2009 and 2020 in English - of which 35 collected data only from randomized clinical trials while two from observational studies as well. The methodological quality of the 37 SRs ranged from low to high, while only 3 have evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach. All the included SRs showed cardiovascular safety of GLP-1RAs while the latest ones demonstrated a reduction in composite MACE endpoint as well as its every individual component and heart failure hospitalizations.

Conclusion: In the first overview of SRs about cardiovascular outcomes of GLP-1RAs, they proved favorable effects on reducing cardiovascular events in T2DM patients. There are, however, many overlapping reviews based on relatively few cardiovascular outcomes trials.
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http://dx.doi.org/10.2174/1381612827666210119103153DOI Listing
May 2021

Impact of Silymarin in individuals with nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Nutrition 2021 03 25;83:111092. Epub 2020 Nov 25.

Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address:

Objectives: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting a significant proportion of the general population. Recently, randomized clinical trials have been conducted examining the efficacy of silymarin in individuals with NAFLD, with conflicting results. The aim of this meta-analysis was to evaluate the efficacy of silymarin in the treatment of NAFLD by examining changes in liver biochemistry, body mass index, and liver histology.

Methods: We searched major electronic databases PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, as well as gray-literature sources, up to June 2020 for randomized clinical trials examining the efficacy of treatment with silymarin in individuals with NAFLD compared to placebo. The primary outcomes were changes in the mean values of transaminases (alanine aminotransferase and aspartate aminotransferase). Secondary outcomes included changes in body mass index and liver histology. Quality analysis was performed with the risk-of-bias tool 2.0. We synthesized results using weighted mean differences for continuous outcomes, along with 95% confidence intervals.

Results: In the meta-analysis, eight randomized clinical trials were included. A cutoff level of 0.05 was considered to provide statistically significant results. Silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss.

Conclusions: Silymarin seems to be effective in reducing transaminase levels in individuals with NAFLD. Despite the statistical benefits, we call attention to potential flaws related to the quality of the included studies. Further well-designed studies should be carried out to examine whether this reduction in transaminase levels corresponds to histologic improvement.
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http://dx.doi.org/10.1016/j.nut.2020.111092DOI Listing
March 2021

Pharmacologic Cardioversion in Patients with Paroxysmal Atrial Fibrillation: A Network Meta-Analysis.

Cardiovasc Drugs Ther 2021 Apr 5;35(2):293-308. Epub 2021 Jan 5.

Athens Heart Center, Athens Medical Center, Distomou 5-7, 15125, Athens, Greece.

Purpose: We sought to indirectly compare and rank antiarrhythmic agents focusing exclusively on adults with paroxysmal atrial fibrillation in order to identify the most effective for pharmacologic cardioversion over different time settings (4 h as primary, and 12, 24 h as secondary outcomes).

Methods: We searched several databases from inception to March 2020 without language restrictions, ClinicalTrials.gov, references of reviews, and meeting abstract material. We included randomized controlled trials of patients with AF lasting ≤7 days comparing either two or more intravenous (i.v.) or oral (p.o.) pharmacologic cardioversion agents or an agent against placebo. For each outcome, we performed network meta-analysis based on the frequentist approach.

Results: Forty-one trials (6013 patients) were included in our systematic review. Moderate confidence evidence suggests that i.v. vernakalant and flecainide have the highest conversion rate within 4 h, possibly allowing discharge from the emergency department and reducing hospital admissions. Intravenous and p.o. formulations of class IC antiarrhythmics (flecainide more so than propafenone) are superior regarding conversion rates within 12 h, while amiodarone efficacy is exhibited in a delayed fashion (within 24 h), especially if ranolazine is added.

Conclusion: Our network meta-analysis identified with sufficient power and consistency the most effective antiarrhythmics for pharmacologic cardioversion over different time settings, with vernakalant and flecainide exhibiting a safer and more efficacious profile toward faster cardioversion.
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http://dx.doi.org/10.1007/s10557-020-07127-1DOI Listing
April 2021

Atrial conduction time associated predictors of recurrent atrial fibrillation.

Int J Cardiovasc Imaging 2021 Apr 3;37(4):1267-1277. Epub 2021 Jan 3.

First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi str 1, 54636, Thessaloniki, Greece.

Identifying patients at high risk of atrial fibrillation (AF) recurrence remains challenging. This study aimed to evaluate total atrial conduction time (TACT) and left atrial (LA) asynchrony as predictors of AF recurrence. Consecutive patients after the first AF episode, terminated either spontaneously or with cardioversion, underwent transthoracic echocardiography. TACT, estimated by the time delay between the onset of P-wave and the peak A'-wave on the Tissue Doppler Imaging (PA-TDI duration), atrial volumetric and functional parameters, and biatrial strain were assessed. We calculated mean PA-TDI-the average of PA-TDI measurements in all left atrial (LA) walls-and the difference between the longest and the shortest PA interval (DLS) and the standard deviation of 4 PA intervals (SD4) to assess the LA global remodeling and asynchrony, respectively. The primary endpoint was AF recurrence. Patients with recurrent AF had significantly prolonged PA-TDI intervals in each LA wall-and thus mean PA-TDI-than those without recurrence (mean PA-TDI: 157.4 ± 17.9 vs. 110.2 ± 7.7 ms, p < 0.001). At univariate analysis, LA maximum volume index, total LA emptying fraction, right atrial maximum volume index, PA-TDI, DLS, and SD4 were predictors of AF recurrence. At multivariable analysis, PA-TDI intervals in all LA walls remained strong predictors with mean PA-TDI (odds ratio 1.04; 95% confidence interval 1.03-1.06) having an optimal cutoff of 125.8 ms in receiver operator characteristics curve analysis providing 98% sensitivity and 100% specificity for AF recurrence (area under the curve = 0.989). PA-TDI was an independent predictor of AF recurrence and outperformed established echocardiographic parameters.
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http://dx.doi.org/10.1007/s10554-020-02113-yDOI Listing
April 2021

Comparative Analysis of Risk Stratification Scores in Atrial Fibrillation.

Curr Pharm Des 2021 ;27(10):1298-1310

First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: Atrial Fibrillation (AF) has become a major global health concern and is associated with an increased risk of poor outcomes. Identifying risk factors in patients with AF can be challenging, given the high burden of comorbidities in these patients. Risk stratification schemes appear to facilitate accurate prediction of outcomes and assist therapeutic management decisions.

Objective: To summarize current evidence on risk stratification scores for patients with AF.

Results: Traditional risk models rely heavily on demographics and comorbidities, while newer tools have been gradually focusing on novel biomarkers and diagnostic imaging to facilitate more personalized risk assessment. Several studies have been conducted to compare existing risk schemes and identify specific patient populations in which the prognostic ability of each scheme excels. However, current guidelines do not appear to encourage the implementation of risk models in clinical practice, as they have not incorporated new ones in their recommendations for the management of patients with AF for almost a decade.

Conclusion: Further work is warranted to analyze new reliable risk stratification schemes and optimally implement them into routine clinical life.
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http://dx.doi.org/10.2174/1381612826666201210113328DOI Listing
January 2021

Risk Models and Scores of Cardiovascular Disease in Patients with Diabetes Mellitus.

Curr Pharm Des 2021 ;27(10):1245-1253

Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece.

Diabetes mellitus (DM) is an established risk factor for atherosclerotic cardiovascular disease (CVD), and patients with DM are at a two to four-fold higher cardiovascular risk, including myocardial infraction, unstable angina, stroke, and heart failure. All of the above have arisen interest in CVD preventive strategies by the use of non-invasive methods, such as risk scores. The most common approach is to consider DM as a CVD equivalent and, therefore, to treat patients with DM in a similar way to those who required secondary CVD prevention. However, this approach has been disputed as all patients with DM do not have the same risk for CVD, and since other potentially important factors within the context of DM, such as DM duration, presence of albuminuria, and comorbidities, should be taken into consideration. Thus, the second and third approach is the application of risk models that were either developed initially for the general population or designed specifically for patients with DM, respectively. This review summarizes the evidence and implications for clinical practice regarding these scores. Up to date, several models that can be applied to the diabetic population have been proposed. However, only a few meet the minimum requirement of adequate external validation. In addition, moderate discrimination and poor calibration, which might lead to inaccurate risk estimations in populations with different characteristics, have been reported. Therefore, future research is needed before recommending a specific risk model for universal clinical practice in the management of diabetes.
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http://dx.doi.org/10.2174/1381612826666201210112743DOI Listing
January 2021

Lipoprotein(a) Reduction With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic Review and Meta-analysis.

J Cardiovasc Pharmacol 2021 Mar;77(3):397-407

Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Abstract: Lipoprotein(a) [Lp(a)] is a cardiovascular factor, for which there is no approved specific lowering treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to have lowering effects on Lp(a). Aim of this systematic review is to synthesize the current literature and quantify the effects of PCSK9 inhibitors on the serum Lp(a) levels in human subjects. Double-blind, phase 2 or 3, randomized-controlled trials comparing PCSK9 inhibitors (alirocumab or evolocumab) to placebo and/or ezetimibe and/or other lipid-lowering therapy were deemed eligible for inclusion. We searched MEDLINE (via PubMed), CENTRAL, Scopus, and Web of Science as of 17 June 2020. Quality assessment was performed using the Revised Cochrane risk-of-bias tool for randomized trials. Forty-three studies were identified (64,107 patients randomized) and 41 studies were included in the quantitative analysis. PCSK9 inhibitors reduced Lp(a) levels by -26.7% (95% CI, -29.5% to -23.9%) with a significant heterogeneity within studies. There was significant difference in Lp(a) change from baseline according to comparator (placebo: mean -27.9%; 95% CI, -31.1% to -24.6% vs. ezetimibe: mean, -22.2%; 95% CI, -27.2% to -17.2%; P = 0.04) and duration of treatment (≤12 weeks: mean, -30.9%; 95% CI, -34.7% to -27.1% vs. >12 weeks: mean, -21.9%; 95% CI, -25.2% to -18.6%; P < 0.01). Meta-regression analysis showed that only the mean percentage change from baseline low-density lipoprotein cholesterol due to the intervention is significantly associated with the effect size difference (P < 0.0001). PCSK9 inhibitors reduced low-density lipoprotein cholesterol by -54% (95% CI -57.6% to -50.6%). There is substantial efficacy of the currently approved PCSK9 inhibitors in the lowering of Lp(a) levels. Dedicated randomized controlled trials are needed to establish the benefit of this intervention.
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http://dx.doi.org/10.1097/FJC.0000000000000963DOI Listing
March 2021

Venous thromboembolism in the era of COVID-19.

Phlebology 2021 Mar 10;36(2):91-99. Epub 2020 Sep 10.

Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, USA.

Coronavirus disease 2019 (COVID-19) does not only affect the respiratory system but appears to be a systemic disease. Venous thromboembolism is a common manifestation in hospitalized patients with COVID-19 with a reported incidence that is significantly higher compared to other acute viral infections. The pathophysiology mechanisms have not been fully explored and autopsy studies might enhance our understanding on this topic. Microthrombi formation occurs mainly in the pulmonary vasculature but can also occur in other organs. The high inflammatory burden related to COVID-19 seems to be associated with the coexisting coagulopathy. Concomitant manifestations of COVID-19, such as severe pneumonia, which has similar clinical presentation with pulmonary embolism (PE), and barriers related to strict isolation protocols are the two main reasons why PE diagnosis might be more challenging in patients with COVID-19. Medical societies have published guidance reports suggesting the administration of prophylactic anticoagulant therapy in hospitalized patients with COVID-19, but several questions regarding the optimal acute and long-term treatment of these patients remain unanswered.
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http://dx.doi.org/10.1177/0268355520955083DOI Listing
March 2021

Association of anticoagulant-related bleeding events with cancer detection in atrial fibrillation: A systematic review and meta-analysis.

Hellenic J Cardiol 2020 Nov 24. Epub 2020 Nov 24.

First Department of Cardiology, AHEPA University Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece. Electronic address:

Background: A bleeding episode may herald cancer in the general population. Oral anticoagulants (OACs), the mainstay treatment for atrial fibrillation (AF), are known to increase the risk of bleeding, and may thus promote an earlier diagnosis of cancer. Data regarding the association of bleeding episodes with cancer in patients with AF on OACs are scarce.

Methods: In this systematic review and meta-analysis, we searched electronic databases (Medline, Scopus, and Central) and gray literature sources for studies of patients with nonvalvular AF under any OAC, from inception until 14 October 2020. The primary outcome was the association of bleeding occurrences with the detection of cancer. A subgroup analysis was performed according to OAC type [NOAC (non-vitamin K oral anticoagulant) versus VKA (vitamin K antagonist)].

Results: Overall, 4 studies were included, accounting for a total of 144,362 patients with AF receiving OAC. During follow-up, 816 (0.57%) cases of cancer were confirmed. The presence of a bleeding event, either major or minor, was associated with a higher risk for cancer detection (odds ratio [OR] 8.79, 95% confidence interval [CI] 4.98-15.51, and I 85%). Heterogeneity was explained after studies were stratified by the type of OAC (NOACs: OR 6.12, 95% CI 4.47-8.37, I 0%, VKAs: OR 15.16, 95% CI 12.61-18.23, and I 0%).

Conclusion: The detection of a bleeding event could be an alerting sign of cancer in patients with AF on OACs, particularly in patients receiving VKAs. REGISTRATION NUMBER (DOI): available in https://doi.org/10.17605/OSF.IO/3948R, DOI: 10.17605/OSF.IO/3948R.
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http://dx.doi.org/10.1016/j.hjc.2020.11.007DOI Listing
November 2020

Signal-averaged electrocardiogram findings among right ventricular arrhythmogenic cardiomyopathy (ARVC) patients: Do they have a place in ARVC management?

Int J Cardiol 2021 01 8;322:175. Epub 2020 Oct 8.

First Department of Cardiology, National and Kapodistrian University of Athens, Hippokrateion Hospital, 114 Vasilissis Sofias avenue, Attica, Athens 11527, Greece.

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http://dx.doi.org/10.1016/j.ijcard.2020.10.007DOI Listing
January 2021

Arrhythmic risk stratification in heart failure mid-range ejection fraction patients with a non-invasive guiding to programmed ventricular stimulation two-step approach.

J Arrhythm 2020 Oct 2;36(5):890-898. Epub 2020 Aug 2.

First Department of Cardiology and Electrophysiology Laboratory Hippokration General Hospital National and Kapodistrian University of Athens School of Medicine Athens Greece.

Background: Although some post myocardial infarction (post-MI) and dilated cardiomyopathy (DCM) patients with mid-range ejection fraction heart failure (HFmrEF/40%-49%) face an increased risk for arrhythmic sudden cardiac death (SCD), current guidelines do not recommend an implantable cardiac defibrilator (ICD). We risk stratified hospitalized HFmrEF patients for SCD with a combined non-invasive risk factors (NIRFs) guiding to programmed ventricular stimulation (PVS) two-step approach.

Methods: Forty-eight patients (male = 83%, age = 64 ± 14 years, LVEF = 45 ± 5%, CAD = 69%, DCM = 31%) underwent a NIRFs screening first-step with electrocardiogram (ECG), SAECG, Echocardiography and 24-hour ambulatory ECG (AECG). Thirty-two patients with presence of one of three NIRFs (SAECG ≥ 2 positive criteria for late potentials, ventricular premature beats ≥ 240/24 hours, and non-sustained ventricular tachycardia [VT] episode ≥ 1/24 hours) were further investigated with PVS. Patients were classified as either low risk (Group 1, n = 16, NIRFs-), moderate risk (Group 2, n = 18, NIRFs+/PVS-), and high risk (Group 3, n = 14, NIRFs+/PVS+). All in Group 3 received an ICD.

Results: After 41 ± 18 months, 9 of 48 patients, experienced the major arrhythmic event (MAE) endpoint (clinical VT/fibrillation = 3, appropriate ICD activation = 6). The endpoint occurred more frequently in Group 3 (7/14, 50%) than in Groups 1 and 2 (2/34, 5.8%). Logistic regression model adjusted for PVS, age, and LVEF revealed that PVS was an independent MAE predictor (OR: 21.152, 95% CI: 2.618-170.887,  = .004). Kaplan-Meier curves diverged significantly (log rank,  < .001) while PVS negative predictive value was 94%.

Conclusions: In hospitalized HFmrEF post-MI and DCM patients, a NIRFs guiding to PVS two-step approach efficiently detected the subgroup at increased risk for MAE.
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http://dx.doi.org/10.1002/joa3.12416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532265PMC
October 2020

Rationale and design of a prospective, observational, multicentre study on the safety and efficacy of apixaban for the prevention of thromboembolism in adults with congenital heart disease and atrial arrhythmias: the PROTECT-AR study.

BMJ Open 2020 09 22;10(9):e038012. Epub 2020 Sep 22.

Cardiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece

Introduction: The risk for stroke in adults with congenital heart disease (ACHD) is increased, especially in the setting of commonly ensuing atrial arrhythmias (AA), namely atrial fibrillation, atrial flutter or intra-atrial re-entrant tachycardia. Data are limited regarding treatment with non-vitamin K oral anticoagulants in long-term studies involving patients with ACHD and AA.

Methods And Analysis: PReventiOn of ThromboEmbolism in Adults with Congenital HearΤ disease and Atrial aRrhythmias is a prospective, multicenter, single-arm, non-interventional cohort study designed to investigate the safety and efficacy of apixaban for the prevention of thromboembolism in ACHD with AA in a 'real-world' setting. Eligible patients will be evaluated by the means of available registries and clinical counter. The study aims to accumulate approximately 500 patient-years of exposure to apixaban as part of routine care. Enrolment will take place at four ACHD centres in Greece. The first patient was enrolled in July 2019. The primary efficacy endpoint is a composite of stroke, systemic or pulmonary embolism and intracardiac thrombosis. The primary safety endpoint is major bleeding, according to the International Society on Thrombosis and Haemostasis bleeding criteria.

Ethics And Dissemination: The study protocol has been approved by the institutional review board/independent ethics committee at each site prior to study commencement. All patients will provide written informed consent. Results will be disseminated at scientific meetings and published in peer-reviewed journals.

Trial Registration Number: NCT03854149; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-038012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509965PMC
September 2020

Systematic review with meta-analysis: The effect of vitamin E supplementation in adult patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Feb 10;36(2):311-319. Epub 2020 Sep 10.

Laboratory of Hygiene, Social and Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background And Aim: Νon-alcoholic fatty liver disease (NAFLD) is estimated to be the most common cause of end-stage liver disease in the next years. Vitamin E has shown beneficial effects as a possible "scavenger" of oxidative stress products, which play a major role in pathogenesis of the disease. The purpose of the present meta-analysis is to investigate the effects of vitamin E supplementation in biochemical and histological parameters in adult patients with NAFLD.

Methods: Literature search was performed in major electronic databases (MEDLINE, CENTRAL, and Embase) up to June 2020 for randomized clinical trials, which examined vitamin E versus placebo treatment in adults with NAFLD. Changes in liver enzymes were considered as primary outcomes while changes in histological, biochemical, and metabolic parameters as secondary. Quality of evidence was assessed through risk of bias according to the Cochrane risk of bias tool.

Results: Eight studies were included in qualitative analysis and seven in quantitative analysis. Vitamin E reduced the values of liver enzymes compared with placebo (-7.37 IU/L, 95% confidence interval: -10.11 to -4.64 for alanine aminotransferase, and -5.71 IU/L, 95% confidence interval: -9.49 to -1.93 for aspartate aminotransferase). Additionally, vitamin E improved statistically significantly liver pathology in every individual histological parameter as well as low-density lipoprotein cholesterol, fasting blood glucose, and serum leptin values.

Conclusions: Vitamin E can improve biochemical and histological characteristics of NAFLD patients, especially of non-alcoholic steatohepatitis patients. The results indicate that vitamin E could be a promising choice and be considered as a treatment option in patients with NAFLD.
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http://dx.doi.org/10.1111/jgh.15221DOI Listing
February 2021

Estimated arterial stiffness and prediction of vascular aging: The rising of a new era.

Curr Pharm Des 2020 07 28. Epub 2020 Jul 28.

Hypertension Center, 3rd Department of Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki. Greece.

Arterial stiffness has been associated with cardiovascular events and correlated with cardiovascular risk factors. In the new guidelines of the European Society of Hypertension, the evaluation of arterial stiffness, and specifically carotid-femoral pulse wave velocity (c-f PWV), was taken into account for the detailed screening of the hypertensive population. Despite the importance of arterial stiffness as a target organ damage, the measurement is time-consuming, not practical, needs expensive equipment and experienced staff. For all these reasons, c-f PWV is not recommended for the everyday clinical practice and its currently use is restricted for research purpose. The importance of arterial properties in clinical practice and cardiovascular prevention is well known. Hence, the estimation of arterial stiffness and vascular health based on parameters that affect arterial stiffness, but without the use of a machine, is a new promising field. Furthermore, the relationship between age-related MRI abnormalities as well as ultrafast ultrasound with vascular effect gives a new promise for future vascular aging assessment.
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http://dx.doi.org/10.2174/1381612826666200728150637DOI Listing
July 2020

Τhe European and American guidelines in the detection of hypertension phenotypes: The no-deal under the light of clinical practice.

Eur J Prev Cardiol 2020 Jul 1:2047487320935559. Epub 2020 Jul 1.

3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Greece.

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http://dx.doi.org/10.1177/2047487320935559DOI Listing
July 2020

Non-Vitamin K Oral Anticoagulants in Adults with Congenital Heart Disease: A Systematic Review

J Clin Med 2020 06 9;9(6). Epub 2020 Jun 9.

First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, 54 636 Thessaloniki, Greece.

Adults with congenital heart disease (ACHD) experience more thromboembolic complications than the general population. We systematically searched and critically appraised all studies on the safety and efficacy of non-vitamin-K oral anticoagulants (NOACs) in adult patients with various forms of congenital heart disease. PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were used, with duplicate extraction of data and risk of bias assessment. The Newcastle-Ottawa quality assessment scale was used to assess study quality. Three studies fulfilled the inclusion criteria and were analyzed. The total number of participants was 766, with a total follow-up of 923 patient-years. The majority of patients (77%) received a NOAC for atrial arrhythmias, while the remainder were prescribed NOACs for secondary (19%) or primary (4%) thromboprophylaxis. The annual rate of thromboembolic and major bleeding events was low: 0.98% (95% CI: 0.51-1.86) and 1.74% (95% CI: 0.86-3.49) respectively. In Fontan patients, the annual rate of thromboembolic and major bleeding events was 3.13% (95% CI: 1.18-8.03) and 3.17% (95% CI: 0.15-41.39) respectively. NOACs appear safe and effective in ACHD without mechanical prostheses. Additional studies are, however, needed to confirm their efficacy in complex ACHD, especially those with a Fontan-type circulation.
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http://dx.doi.org/10.3390/jcm9061794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356004PMC
June 2020

Masked and white coat hypertension, the double trouble of large arteries: A systematic review and meta-analysis.

J Clin Hypertens (Greenwich) 2020 05 1;22(5):802-811. Epub 2020 May 1.

Third Department of Internal Medicine, Hypertension-24h ABPM ESH Center of Excellence, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Arterial damage of large arteries, addressed as c-f PWV, is recognized as independent predictor for future cardiovascular disease. The aim of this study was to systematically investigate the association of the four hypertension phenotypes with carotid-femoral pulse wave velocity (c-f PWV), in untreated patients. PubMed and Cochrane Library were searched to identify studies comparing c-f PWV levels between normotensives, sustained hypertensives, white-coat hypertensives (WCH), and masked hypertensives (MH). Meta-analysis was performed to compare the difference c-f PWV levels between these groups. Newcastle-Ottawa quality assessment scale for cross-sectional studies was used to assess study quality. MH and WCH patients had significantly increased c-f PWV values compared to the normotensive groups (d = 0.96 m/s, 95% CI: 0.49-1.42; I2 = 85%, P < .01 for MH and d = 0.85 m/s, 95% CI: 0.48-1.22; I2 = 89%, for WCH). Moreover, the sustained hypertensive population was found to have significantly increased values of c-f PWV compared to MH (d = -0.70 m/s, 95% CI: -0.87 to -0.54; I2 = 12%, P = .33) but not compared to WCH population (d = -0.75 m/s, 95% CI: -1.52-0.02; I  = 96%,). Finally, there was no significant difference between MH and WCH population (d = 0.06 m/s, 95% CI: -1.04 to 1.15; I  = 96%,). MH and WCH population may have increased values of c-f PWV compared to the normotensive group. These results demonstrate that these phenotypes are not clinically innocent, in the untreated population.
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http://dx.doi.org/10.1111/jch.13876DOI Listing
May 2020

Non-Vitamin K Antagonist Oral Anticoagulants in Pulmonary Embolism: An Overview of Systematic Reviews.

Curr Pharm Des 2020 ;26(23):2686-2691

First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background: Anticoagulation in patients with pulmonary embolism.

Objective: To identify how non-vitamin K antagonist oral anticoagulants are associated with multiple outcomes in patients with pulmonary embolism.

Methods: We performed a systematic search of systematic reviews via multiple electronic databases from inception to August 19th, 2019, without language restriction. Two authors independently extracted data and assessed the methodological quality of the included systematic reviews using the ROBIS tool.

Results: We found twelve systematic reviews. Eleven SRs collected their data from randomized clinical trials and one from observational studies. All the included studies were published between 2014 and 2019 in English. The methodological quality of the 12 systematic reviews was low to high. None of the systematic reviews, which are included in our overview of systematic reviews, has evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach.

Conclusion: This is the first effort to summarize evidence about non-vitamin K antagonist oral anticoagulants in an overview of systematic reviews focusing exclusively on patients with pulmonary embolism. The evidence suggests that the non-vitamin K antagonist oral anticoagulants seem to be more effective and safer than a dualdrug approach with LMWH- VKA.
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http://dx.doi.org/10.2174/1381612826666200506114450DOI Listing
January 2021

The flipside of hydralazine in pregnancy: A systematic review and meta-analysis.

Pregnancy Hypertens 2020 Jan 21;19:177-186. Epub 2020 Jan 21.

3(rd) Department of Internal Medicine, Aristotle University of Thessaloniki, Hypertension-24h Ambulatory Blood Pressure Monitoring Center, Papageorgiou General Hospital, Thessaloniki, Greece. Electronic address:

The present systematic review and meta-analysis investigated the effects of hydralazine compared with other antihypertensive drugs in maternal, perinatal and neonatal outcomes of pregnant women with hypertensive disorders. Twenty studies with 1283 participants were included. Of them, 626 received hydralazine and 657 other antihypertensive treatments, such as labetalol, nifedipine, ketanserin, diazoxide, urapidil, isradipine and epoprostenol. Women receiving hydralazine had higher heart rate (WMD: 13.4, 95%CI: 0.1 to 26.8 beats/min), increased number of adverse effects (RR: 1.21, 95%CI: 1.01 to 1.45) and gave birth to neonates of lower birthweight (WMD: 13.4, 95%CI: 0.1 to 26.8 beats/min) compared with other antihypertensive treatments at the end of follow-up. When studies, which used antihypertensive agents that are no longer indicated for hypertension in pregnancy, were excluded in the sensitivity analyses, hydralazine found not to have a statistically significant difference compared with labetalol and nifedipine regarding the reduction of maternal blood pressure (WMD: 1.72, 95%CI: -1.47 to 4.9 mmHg for systolic, WMD: 0.26, 95%CI: -1.75 to 2.28 mmHg for diastolic), maternal heart rate (WMD: 13.56, 95%CI: -5.62 to 32.74 beats/min), low birthweight (WMD: -88.62, 95%CI: -243.24 to 66 beats/min) and adverse events (RR: 1.19, 95%CI: 0.99 to 1.43). Hydralazine seems not to be inferior compared to labetalol and nifedipine for safety and efficacy.
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http://dx.doi.org/10.1016/j.preghy.2020.01.011DOI Listing
January 2020

The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date.

Drug Des Devel Ther 2019 22;13:2985-2996. Epub 2019 Aug 22.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.
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http://dx.doi.org/10.2147/DDDT.S166765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709822PMC
April 2020