Georg Wolff

Survival Benefits of Invasive Versus Conservative Strategies in Heart Failure in Patients With Reduced Ejection Fraction and Coronary Artery Disease: A Meta-Analysis.

Background— Heart failure with reduced ejection fraction caused by ischemic heart disease is associated with increased morbidity and mortality. It remains unclear whether revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) carries benefits or risks in this group of stable patients compared with medical treatment. Methods and Results— We performed a meta-analysis of available studies comparing different methods of revascularization (PCI or CABG) against each other or medical treatment in patients with coronary artery disease and left ventricular ejection fraction ⩽40%. The primary outcome was all-cause mortality; myocardial infarction, revascularization, and stroke were also analyzed. Twenty-one studies involving a total of 16 191 patients were included. Compared with medical treatment, there was a significant mortality reduction with CABG (hazard ratio, 0.66; 95% confidence interval, 0.61–0.72; P<0.001) and PCI (hazard ratio, 0.73; 95% confidence interval, 0.62–0.85; P<0.001). When compared with PCI, CABG still showed a survival benefit (hazard ratio, 0.82; 95% confidence interval, 0.75–0.90; P<0.001). Conclusions— The present meta-analysis indicates that revascularization strategies are superior to medical treatment in improving survival in patients with ischemic heart disease and reduced ejection fraction. Between the 2 revascularization strategies, CABG seems more favorable compared with PCI in this particular clinical setting.

From proprotein convertase subtilisin/kexin type 9 to its inhibition: state-of-the-art and clinical implications

Statins are recommended as first-line therapy for patients with hypercholesterolaemia. A sizable proportion of patients, however, does not reach therapeutic goals, is statin intolerant, or, despite optimal statin therapy, is at high risk of ischaemic events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in lipid metabolism and several comorbidities. Monoclonal antibodies targeting PCSK9 are a new lipid-lowering approach with the potential to improve clinical outcomes in patients with dyslipidaemia. In this review, we discuss current experimental and clinical evidence of the role of PCSK9 and its inhibition on lipid metabolism and several pathologic conditions with a focus on clinical outcomes. A state-of-the-art analysis of current clinical evidence and future directions on PCSK9 and its inhibition is provided.

Implantable cardioverter/defibrillators for primary prevention in dilated cardiomyopathy post-DANISH: an updated meta-analysis and systematic review of randomized controlled trials.

BackgroundSudden cardiac death (SCD) is frequent in patients with heart failure due to dilated cardiomyopathy (DCM). Implantable cardioverter/defibrillator (ICD) device therapy is currently used for primary prevention. However, publication of the DANISH trial has recently given reason for doubt, showing no significant improvement in all-cause mortality in comparison to contemporary medical therapy.MethodsWe performed a meta-analysis of all randomized controlled trials comparing ICD therapy to medical therapy (MT) for primary prevention in DCM. The primary outcome was all-cause mortality; secondary analyses were performed on sudden cardiac death, cardiovascular death and non-cardiac death.ResultsFive trials including a total of 2992 patients were included in the pooled analysis. Compared to contemporary medical treatment there was a significant mortality reduction with ICD device therapy [odds ratio (OR) 0.77, 95% confidence interval (CI) 0.64–0.93; p = 0.006]. SCD was decreased significantly (OR 0.43, CI 0.27–0.69; p = 0.0004), while cardiovascular death and non-cardiac death showed no differences. Sensitivity analyses showed no influence of amiodarone therapy on overall results. Analysis of MT details revealed the DANISH population to adhere the most to current guideline recommendations. In addition, it was the only study including a substantial amount of CRT devices (58%).ConclusionsOur meta-analysis of all available randomized evidence shows a survival benefit of ICD therapy for primary prevention in DCM. DANISH results suggest an attenuation of this ICD advantage when compared to contemporary medical and cardiac resynchronization therapy. Until larger trials have confirmed this finding, ICD therapy should remain the recommendation for primary prevention of SCD in DCM.

Patent foramen ovale closure or medical therapy for cryptogenic ischemic stroke: an updated meta-analysis of randomized controlled trials

BackgroundPrevious randomized controlled trials (RCT) failed to demonstrate benefits of patent foramen ovale (PFO) closure (PFO-C) over medical therapy (MT) for secondary prevention of cryptogenic ischemic stroke. Three recently published RCTs, however, turned out positive for PFO-C and warrant an updated meta-analysis.MethodsData from all available RCTs on PFO-C vs. MT for secondary prevention of cryptogenic ischemic stroke up until October 2017 were abstracted and analyzed in a comprehensive meta-analysis. Clinical efficacy outcomes were recurrent stroke, recurrent TIA, and their combination; safety outcomes were mortality, major bleeding, venous thromboembolism (VTE), and new-onset atrial fibrillation/flutter (NOAF).ResultsFive trials including a total of 3440 patients were included in the meta-analysis. PFO-C significantly reduced recurrent stroke [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.19–0.90; p = 0.03] and the combination of recurrent stroke + TIA (OR 0.53, CI 0.36–0.80; p = 0.002) compared to MT; recurrent TIA alone showed no differences (OR 0.77; CI 0.51–1.14; p = 0.19). NOAF was significantly more frequent after PFO-C (OR 5.75, CI 3.09–10.70; p < 0.00001). Mortality (OR 0.80, CI 0.39–1.67), major bleeding (OR 0.96, CI 0.48–1.92), and VTE (OR 2.45, CI 0.75–7.99) remained neutral. Trials with superior patient selection for PFO-C showed advantageous results compared to MT.ConclusionsPFO-C after cryptogenic ischemic stroke is safe and effective to reduce the risk of recurrent stroke and recurrent stroke + TIA, albeit with an increased risk for NOAF.

Red cell distribution width in anemic patients undergoing transcatheter aortic valve implantation

AIM To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI). METHODS In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patients characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables. RESULTS Mean age in our study population was 81 ± 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW > 14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure. CONCLUSION Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia.

Extracellular Adenosine Formation by Ecto-5'-Nucleotidase (CD73) Is No Essential Trigger for Early Phase Ischemic Preconditioning.

Background Adenosine is a powerful trigger for ischemic preconditioning (IPC). Myocardial ischemia induces intracellular and extracellular ATP degradation to adenosine, which then activates adenosine receptors and elicits cardioprotection. Conventionally extracellular adenosine formation by ecto-5’-nucleotidase (CD73) during ischemia was thought to be negligible compared to the massive intracellular production, but controversial reports in the past demand further evaluation. In this study we evaluated the relevance of ecto-5’-nucleotidase (CD73) for infarct size reduction by ischemic preconditioning in in vitro and in vivo mouse models of myocardial infarction, comparing CD73-/- and wild type (WT) mice. Methods and Results 3x5 minutes of IPC induced equal cardioprotection in isolated saline perfused hearts of wild type (WT) and CD73-/- mice, reducing control infarct sizes after 20 minutes of ischemia and 90 minutes of reperfusion from 46 ± 6.3% (WT) and 56.1 ± 7.6% (CD73-/-) to 26.8 ± 4.7% (WT) and 25.6 ± 4.7% (CD73-/-). Coronary venous adenosine levels measured after IPC stimuli by high-pressure liquid chromatography showed no differences between WT and CD73-/- hearts. Pharmacological preconditioning of WT hearts with adenosine, given at the measured venous concentration, was evenly cardioprotective as conventional IPC. In vivo, 4x5 minutes of IPC reduced control infarct sizes of 45.3 ± 8.9% (WT) and 40.5 ± 8% (CD73-/-) to 26.3 ± 8% (WT) and 22.6 ± 6.6% (CD73-/-) respectively, eliciting again equal cardioprotection. The extent of IPC-induced cardioprotection in male and female mice was identical. Conclusion The infarct size limiting effects of IPC in the mouse heart in vitro and in vivo are not significantly affected by genetic inactivation of CD73. The ecto-5’-nucleotidase derived extracellular formation of adenosine does not contribute substantially to adenosine’s well known cardioprotective effect in early phase ischemic preconditioning.

Non-vitamin K oral anticoagulants (NOAC) and the risk of myocardial infarction: Differences between factor IIa and factor Xa inhibition?

Abstract Guidelines already recommend non‐vitamin K oral anticoagulants (NOAC) over vitamin‐K antagonists (VKA) for stroke prevention in patients with atrial fibrillation. However, recommendations are lacking with respect to which NOAC to use. At the moment, NOACs may employ two different molecular mechanisms: Factor IIa inhibition (dabigatran) and factor Xa inhibition (apixaban, edoxaban, rivaroxaban). The focus of this review is to compare and contrast potential differences between factor IIa‐ and factor Xa inhibition with respect to risk of myocardial infarction and to detail underlying mechanisms.

Safety and efficacy of Tirofiban in STEMI-patients

BACKGROUND Tirofiban is recommended as bail out therapy in patients with ST-elevation myocardial infarction (STEMI). However, evidence regarding safety and efficacy of tirofiban is unclear. Tirofiban has been shown to improve ST-resolution, to decrease infarct size (IS) and to reduce incidence of major adverse cardiac and cerebrovascular events (MACCE). However, bleeding is enhanced in tirofiban treated patients. In this study, we aim to investigate efficacy and safety of Tirofiban in STEMI-patients. METHODS 610 STEMI patients were analyzed. MACCE (death, myocardial infarction [MI], stroke) and TIMI bleeding events were registered during hospital course and 12 month follow-up. RESULTS Tirofiban patients were slightly younger (tirofiban 63 ± 13 years vs. control 65 ± 14 years; p = 0.04). They had higher peak-high-sensitive troponin T [Hs-TnT] (tirofiban 6561 ± 11,065 vs. control 4594 ± 11,200, p-value = 0.047) and peak-creatine kinase [CK] (tirofiban 2742 ± 5097 vs. control 1416 ± 2160, p-value < 0.0001). Percutaneous coronary intervention (PCI) was more complex in tirofiban treated patients as radiation time (tirofiban 18 ± 15 vs. control 14 ± 13; p-value = 0.02) and use of contrast agent (tirofiban 240 ± 106 vs. control 209 ± 99; p-value = 0.01) was higher in tirofiban patients. However, there were no differences in MACCE (HR 0.877, 95% CI 0.62-1.25, p = 0.47) and bleeding (major: HR 1.494, 95% CI 0.65-3.44, p = 0.34; minor: HR 1.294, 95% CI 0.67-2.52, p = 0.45). CONCLUSION MACCE and bleeding events were similar. However, PCI was more complex and infarcts larger in tirofiban treated patients.

Antiplatelet effects of aspirin and clopidogrel after left atrial appendage (LAA) occluder implantation

BACKGROUND The optimal antithrombotic strategy after interventional left atrial appendage closure (LAAC) is controversial. Dual antiplatelet therapy with aspirin and clopidogrel is the most frequently used regiment. However, pharmacodynamic response to antiplatelet medication differs significantly between individuals. Therefore, we aimed to analyse pharmacodynamic response to aspirin and clopidogrel after LAAC. METHODS In this study, we included 129 patients undergoing interventional LAAC. Primary end point was pharmacodynamic response to antiplatelet medication. Platelet reactivity was measured by light transmittance aggregometry and vasodilator stimulated protein phosphorylation assay. Secondary endpoints were TIMI bleeding events and MACCE during hospital course and one-year follow-up. RESULTS Insufficient pharmacodynamic response (high on-treatment platelet reactivity - HTPR) to clopidogrel occurred in 67 patients (52%); HTPR to aspirin in 15 patients (12%); low on-treatment platelet reactivity - LTPR - to clopidogrel in 13 patients (10%). No occluder thrombosis or stroke occurred during one year follow-up. Pharmacodynamic response to antiplatelet medication was not associated with MACCE. However, the incidence of TIMI minor bleeding was increased in patients with LTPR to clopidogrel. CONCLUSIONS Impaired clopidogrel antiplatelet effects were very frequent in patients after LAAC. No stroke or occluder thrombosis occurred. Patients with LTPR to clopidogrel showed more minor bleeding events. Therefore, this hypothesis generating pilot study raises the question if clopidogrel early after LAAC is needed. This question should be addressed in large scale trials.

Perioperative aspirin therapy in non-cardiac surgery: A systematic review and meta-analysis of randomized controlled trials

Abstract Background Aspirin is a key element in prevention of cardiovascular and thromboembolic events. During non-cardiac surgery however, its balance of bleeding risks and benefits remains unclear. Methods A systematic review and meta-analysis of randomized controlled trials was performed. Online databases were screened for clinical trials randomizing aspirin to no aspirin therapy in non-cardiac surgery. Clinical outcomes of all-cause mortality and cardiovascular mortality, arterial ischemic events, venous thromboembolic events and bleeding events were separately evaluated. Results Seven RCTs comprising 28,302 patients were included. All-cause mortality (3.7% vs. 3.8%; odds ratio (OR) 0.97, CI 0.86–1.10) and cardiovascular mortality (2.0% vs. 2.1%, OR 0.92; CI 0.78–1.09) were not different in aspirin vs. no aspirin groups. Arterial ischemic events showed no differences, including myocardial infarction (2.5% (aspirin) vs. 2.5% (no aspirin)), cerebrovascular events (0.6% (aspirin) vs. 0.6% (no aspirin)) and peripheral arterial events (0.2% (aspirin) vs. 0.3% (no aspirin)). Aspirin significantly reduced the risk for venous thromboembolic events (VTE; 1.5% (aspirin) vs. 2.0% (no aspirin); OR 0.74, CI 0.59–0.94, p =0.02). Perioperative major bleeding was significantly more frequent in aspirin groups (4.4% vs. 3.7%; OR 1.18, CI 1.05 to 1.33, p =0.007). Conclusion Aspirin remained neutral with respect to overall survival, cardiovascular mortality and arterial ischemic events. It reduced venous thromboembolic events at the expense of perioperative major bleedings. Thus, this analysis supports recommendations against perioperative aspirin continuation/initiation in cardiovascular disease patients at intermediate risk, as well as recommendations of aspirin for VTE prophylaxis in orthopedic patients only.