Dániel Kehl

Use of New-Generation Oral Anticoagulant Agents in Patients Receiving Antiplatelet Therapy After an Acute Coronary Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND Despite receipt of dual antiplatelet therapy, patients after an acute coronary syndrome (ACS) remain at significant risk for thrombotic events. The role of orally activated Xa antagonist (anti-Xa) and direct thrombin inhibitors is debated in this setting. Our study objective was to evaluate the efficacy and safety of new-generation oral anticoagulant agents compared with placebo in patients receiving antiplatelet therapy after an ACS. METHODS Electronic databases were searched to identify prospective randomized placebo-controlled clinical trials that evaluated the effects of anti-Xa or direct thrombin inhibitors in patients receiving antiplatelet therapy after an ACS. Efficacy measures included stent thrombosis, overall mortality, and a composite end point of major ischemic events, while thrombolysis in myocardial infarction-defined major bleeding events were used as a safety end point. The net clinical benefit was calculated as the sum of composite ischemic events and major bleeding events. RESULTS For the period January 1, 2000, through December 31, 2011, we identified 7 prospective randomized placebo-controlled clinical trials that met the study criteria, involving 31 286 patients. Based on the pooled results, the use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an ACS was associated with a dramatic increase in major bleeding events (odds ratio, 3.03; 95% CI, 2.20-4.16; P < .001). Significant but moderate reductions in the risk for stent thrombosis or composite ischemic events were observed, without a significant effect on overall mortality. For the net clinical benefit, treatment with new-generation oral anticoagulant agents provided no advantage over placebo (odds ratio, 0.98; 95% CI, 0.90-1.06; P = .57). CONCLUSION The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS.

Complications after bladder augmentation or substitution in children: a prospective study of 86 patients.

Study Type – Therapy (case series)

Risk of Myocardial Infarction in Patients with Long-Term Non-Vitamin K Antagonist Oral Anticoagulant Treatment.

UNLABELLED The relative cardiovascular (CV) safety of oral anticoagulants continues to be debated, and in particular concerns for risk of myocardial infarction (MI) have been raised. We analyzed the risk of MI in patients treated long term with oral anticoagulants (vitamin K antagonists [VKA], direct thrombin inhibitors or activated X factor antagonist) for atrial fibrillation, deep vein thrombosis or pulmonary embolism using a network meta-analysis (NMA). METHODS Randomized, phase 3 trials comparing novel anticoagulants to VKA were searched. Information on study design and clinical outcomes was extracted. The primary end-point of the analysis was the occurrence of MI or acute coronary syndrome. A Bayesian multiple treatment analysis was performed using fixed-effect and random-effects modeling. RESULTS Twelve trials including 100,524 randomized patients were analyzed. The odds for MI in NMA were worse with dabigatran when compared to VKA, rivaroxaban, apixaban, and edoxaban (OR: 0.66 CI: 0.49-0.87; OR: 0.56 CI: 0.38-0.82, OR: 0.59 CI 0.40-0.88, and OR: 0.71 CI: 0.50-1.0, respectively).The posterior probability of being the first best choice of treatment was 53.5% for rivaroxaban, 33.8% for apixaban, 9.5% for ximelagatran, 2.0% for edoxaban, 1.2% for VKA, and 0.007% for dabigatran. CONCLUSIONS There is a considerable heterogeneity regarding CV safety among oral anticoagulants. Differences in risk of MI may influence the choice of treatment. Multiple treatment NMA found 29%-44% higher odds of MI with dabigatran supporting the concerns regarding its CV safety.

Meta-analysis of randomized trials on access site selection for percutaneous coronary intervention in ST-segment elevation myocardial infarction.

Introduction Superior outcomes with transradial (TRPCI) versus transfemoral coronary intervention (TFPCI) in the setting of acute ST-segment elevation myocardial infarction (STEMI) have been suggested by earlier studies. However, this effect was not evident in randomized controlled trials (RCTs), suggesting a possible allocation bias in observational studies. Since important studies with heterogeneous results regarding mortality have been published recently, we aimed to perform an updated review and meta-analysis on the safety and efficacy of TRPCI compared to TFPCI in the setting of STEMI. Material and methods Electronic databases were searched for relevant studies from January 1993 to November 2012. Outcome parameters of RCTs were pooled with the DerSimonian-Laird random-effects model. Results Twelve RCTs involving 5,124 patients were identified. According to the pooled analysis, TRPCI was associated with a significant reduction in major bleeding (odds ratio (OR): 0.52 (95% confidence interval (CI) 0.38–0.71, p < 0.0001)). The risk of mortality and major adverse events was significantly lower after TRPCI (OR = 0.58 (95% CI: 0.43–0.79), p = 0.0005 and OR = 0.67 (95% CI: 0.52–0.86), p = 0.002 respectively). Conclusions Robust data from randomized clinical studies indicate that TRPCI reduces both ischemic and bleeding complications in STEMI. These findings support the preferential use of radial access for primary PCI.

A cross-cultural study on perceived health-related quality of life in children and adolescents with type 1 diabetes mellitus

OBJECTIVE This study investigated whether culture can affect self- and proxy-reports of perceived diabetes-specific health-related quality of life of children and adolescents with type 1 diabetes when taking into account glycemic control, gender and age. METHODS A total of 416 patients aged between 8 and 18 years--84 (Greece), 135 (Hungary) and 197 (Kuwait)--and their parents completed the Pediatric Quality of Life Inventory 3.0. Diabetes Module. RESULTS Gender and age did not have any effect on perceived diabetes-specific health-related quality of life. Significant differences were detected among countries in self- and proxy-reports of diabetes-specific health-related quality of life when controlling for glycemic control. More specifically, Greek patients with type 1 diabetes and their parents reported significantly worse disease-specific health-related quality of life than their peers from Kuwait and Hungary. Moreover, culture affected the level of agreement between self- and proxy-reports with parents from Kuwait underestimating their childrens diabetes-specific health-related quality of life. CONCLUSION The impact of culture on self- and proxy-reports of diabetes-specific health-related quality of life warrants further investigation, since it might suggest the need for differential psychosocial treatment.

Impairment of Left Atrial Mechanics Is an Early Sign of Myocardial Involvement in Systemic Sclerosis

BACKGROUND Left ventricular (LV) diastolic dysfunction is common in systemic sclerosis (SSc). Less is known, however, about left atrial (LA) mechanics in this context. The aim of this study was to investigate the correlation between LV diastolic function and LA mechanics in SSc patients with the use of volumetric and 2-dimensional speckle tracking-derived strain techniques and to compare the results with those obtained in healthy subjects. METHODS AND RESULTS Seventy-two SSc patients and 30 healthy volunteers (H) were investigated. LV diastolic function was classified as normal (I), impaired relaxation (II), and pseudonormal pattern (III). LA reservoir (H: 51.8 ± 7.4%; I: 45.1 ± 8.1%; II: 42.2 ± 6.6%; III: 36.6 ± 7.3%; analysis of variance: P < .001) and contractile strain (H: 24.8 ± 4.9%; I: 18.2 ± 4.4%; II: 21.5 ± 2.8%; III: 16.8 ± 3.6%; P < .001) already showed significant worsening in SSc patients with preserved LV diastolic function compared with healthy subjects. LA conduit strain (H: 27.1 ± 4.6%; I: 26.9 ± 5.7%; II: 20.6 ± 6.1%; III: 19.5 ± 5.3%; P < .001) was preserved in this early phase. Further deterioration of reservoir strain was pronounced in the pseudonormal group only. LA contractile strain increased significantly in the impaired relaxation group and then decreased with the further worsening of the LV diastolic function. Regarding phasic volume indices, the differences between groups were not always statistically significant. CONCLUSION LA mechanics strongly reflects the changes in LV diastolic function in SSc. On the other hand, strain parameters of the LA reservoir and contractile function already show significant worsening in SSc patients with preserved LV diastolic function, suggesting that impairment of the LA mechanics is an early sign of myocardial involvement in SSc.

Pathfinding to an optimal strategy of revascularization in primary coronary intervention in patients with multivessel disease: a network meta-analysis of randomized trials

Abstract Objectives: In ST-segment elevation myocardial infarction (STEMI), current guidelines discourage treatment of the non-culprit lesions at the time of the primary intervention. Latest trials have challenged this strategy suggesting benefit of early complete revascularization. We performed a Bayesian multiple treatment network meta-analysis of randomized clinical trials (RCTs) in STEMI on culprit-only intervention (CO) versus different timing multivessel revascularization, including immediate (IM), same hospitalization (SH) or later staged (ST). Methods: Outcome parameters were pooled with a random-effects model. For multiple-treatment meta-analysis, a Bayesian Markov chain Monte Carlo method was used. Results: Eight RCTs involving 2077 patients were identified. ST and IM revascularization was associated with a decrease in major adverse cardiac events (MACEs) compared to culprit-only approach (risk ratio [RR]: 0.43 credible interval [CrI]: 0.22–0.77 and RR: 0.36 CrI: 0.24–0.54, respectively). IM was superior to SH (RR: 0.49 CrI: 0.29–0.80). With regards to myocardial infarction IM was superior to SH (RR: 0.18 CrI: 0.02–0.99). The posterior probability of being the best choice of treatment regarding the frequency of MACEs was 71.2% for IM, 28.5% for ST, 0.3% for SH and 0.05% for culprit-only approach. Conclusions: Results from RCTs indicate that immediate or staged revascularization of non-culprit lesions reduces major adverse events in patients after primary percutaneous coronary intervention. Differences in MACEs suggest superiority of the immediate or staged intervention; however, further randomized trials are needed to determine the optimal timing of revascularization of the non-culprit lesions.

Using risk difference as opposed to odds-ratio in meta-analysis. Response

We appreciate the interest of Messori and colleagues [1] in our recent meta-analysis published in the Journal. In the article, we concluded that intensifying antiplatelet therapy on the basis of platelet reactivity testing reduced cardiovascular mortality and stent thrombosis after PCI, without increasing the risk for major bleeding complications [2]. In their letter, the authors raise concerns regarding the methodology used in the meta-analysis, adding results of a post-hoc analysis using risk difference (RD) as opposed to odds ratio (OR). First of all, it should be declared that the choice of OR as an effect estimate in our meta-analysis is entirely appropriate and standard, also supported by the Cochrane collaboration and applied in several previously published impacting meta-analyses [3–6]. The preference of risk ratio (RR) and RD over OR originates from the less straightforward interpretation of the latter due to its mathematical definition that might lead to confusions if OR is misinterpreted as a RR. However, the non-equivalence of the RR and OR does not indicate that either is wrong; both are entirely valid ways of describing an intervention effect [3]. On the other hand, since OR has many advantageous features over RR or RD in statistical modeling and outcome analysis, OR and its timedependent equivalence, hazard ratio (HR) are the most frequently used effect estimates in clinical outcome analyses [3]. Likewise, using OR or HR in a meta-analysis is appropriate and has the advantage of keeping better contact between the original study results and that of the meta-analysis. Notably, the difference between OR and RR is larger in case of analyzing frequent outcomes in a study, but is ignorable in case of rare outcomes, such as in the case of our meta-analysis. Recalculating our findings by using RR as an effect estimate provided almost identical results to the originals, without any impact on statistical significance levels (Table 1). The difference between our results and the post-hoc analysis of Messori and colleagues does not originate from the fundamental differences between OR and RR, but comes from the fact that they estimated RD-s in an analysis including studies without any outcome event. In cases when the standard error cannot be computed from the available information (such as in studies without outcomes in both arms), the software performs a correction to the outcomes andproduces weighted RD values that suggest equivalence between study arms. However, this attempt is seriously questionable, because lack of events does notmeanequivalence. If no events are observed in both groups, the studyprovides no information about the relative probabilityof the event between study arms. Therefore, in such cases, the appropriate and generally applied approach is to use OR or RR as an effect estimate, and studies without events are omitted by the analysis [3]. In addition, since the included trials enrolled highly heterogeneous patient populations regarding the underlying risk for thrombotic and bleeding events, calculation of absolute risk differences (RD) instead of differences in relative event probabilities (OR or RR) is less appropriate and meaningful. However, we acknowledge that a clinical limitation to our meta-analysis was to include a large number of small studies with rare outcomes. Therefore, as highlighted in the limitation section, the exact numerical results of our meta-analysis should be interpreted cautiously as they might be subject to overestimation of treatment effect due to the small sample sizes and rare outcomes. Indeed, we believe that pooling outcome information from all the currently available, randomized, controlled clinical trials into a meta-analysis added significant novel findings to this scientific area justifying its clinical importance. In conclusion, based on the statistical analysis used, the results of our meta-analysis are valid to support the clinical benefits of intensified antiplatelet therapy based on platelet reactivity testing and the concerns of Messori and colleagues cannot be shared.

Comparison of hemorheological changes in patients after acute coronary events, intervention and ambulatory rehabilitation

During the past decades, our group have investigated the hemorheological parameters (HPs) of more than 1,000 patients with various forms of ischemic heart disease (IHD). Our data indicate that HPs are altered in patients with IHD and the extent of the alterations is in good correlation with the clinical severity of the disease. Our findings have also proven that HPs play a critical role in the pathogenesis of myocardial ischemia.The lack of regular exercise is an important cardiovascular risk factor. Regular physical activity - as part of the cardiovascular rehabilitation training program (CRP) - is recommended for the treatment of IHD and the prevention of first or further cardiovascular events. To estimate the beneficial hemorheological effects of CRP, compared to patients after a coronary event or intervention and not participating in CRP, the data of four of our prospective studies (three non-CRP and one CRP-participating) were evaluated.Hematocrit (Hct), plasma and whole blood viscosity (WBV), Hct/WBV ratio significantly (p < 0.05) increased in the non-CRP groups during the 6-12 months follow-up, while in the CRP group they significantly decreased (p < 0.05). Red blood cell aggregation decreased in a much greater manner in the CRP group.Our results indicate that CRP has beneficial hemorheological effects and is able to reverse the deterioration of HPs after coronary events or intervention.

Mortality after transradial approach in ST-segment elevation myocardial infarction. Do we see the forest for the trees?

hepatic dysfunction nutritional deficiencies (i.e., iron, vitamin B12, and folic acid), bone marrow dysfunction, inflammatory diseases, chronic systemic inflammation and use of any medications or could represent an integrative measure of all these pathological processes occurring during the progression of HF. In addition, the authors usedMDRD formula for GFR. However,MDRD formulamightmeasure higher GFR inyounger age groups compare to the Cockcroft-Gault equation, but it can measure lower GFR in older individuals comparisonwith Cockcroft-Gault equation [8]. For this reason, itmaybeuseful, and the result of the studymaybedifferent, if the authors had also used Cockcroft-Gault equation due to these factors. Additionally, not only RDW but also mean platelet volume, neutrophil lymphocyte ratio, CRP and uric acid are easy methods to evaluate the cardiovascular disease of the patients [9]. These markers might be useful in clinical practice [10]. Finally, it would be better if the authorsmight define howmuch time they specified onmeasuring RDW levels, because of the delaying blood sampling can cause abnormal results in RDW measurements. In conclusionwe hardly believe that thosefindings obtained from the current study will lead to further studies examining the relationship between RDW and HF. However, one should keep in mind that RDW itself alone without other inflammatory indicators may not give exact information to clinicians about the inflammatory status and prognostic indication of the patients. So, from that point of view we think that it should be evaluated accompanied with other serum inflammatory markers.