Antiplatelet drugs in cardiological practice: Established strategies and new developments

A common pathophysiological course in vascular diseases is an overwhelming activation and aggregation of blood platelets, which results in atherothrombosis. By causing the last decisive step of cerebral, coronary, or peripheral arterial ischemia thrombotic complications of atherosclerotic disease represent a major player in death cause statistics of most western countries. The development of novel therapies against platelet-dependent thrombosis and the concurrent improvement of existing therapeutic strategies thus is a paramount focus of pharmaceutical research. Currently, efficiency, dosing and indications of established antiplatelet substances are being re-evaluated, whilst new, so far unrecognized molecular targets for inhibition of platelet activity come up front. This not only allows for interesting new therapeutical options, but also widens our insight into the role platelets play in atherosclerosis in general. This article summarizes the relevant pathophysiology of platelet activation, presents current concepts in antiplatelet drug therapy, and highlights the role of platelets in vascular diseases apart from atherothrombosis

Effect of Growth Hormone (hGH) Replacement Therapy on Physical Work Capacity and Cardiac and Pulmonary Function in Patients with hGH Deficiency Acquired in Adulthood.

The effects of 6 months of replacement therapy with recombinant human GH (hGH) on physical work capacity and cardiac structure and function were investigated in 20 patients with hGH deficiency of adult onset in a double blind, placebo-controlled trial. The GH dose of 12.5 micrograms/kg BW was self-administered daily sc. Oxygen consumption (VO2), CO2 production, and ventilatory volumes were measured during exercise on a bicycle spiroergometer. M-Mode echocardiography was performed using standard techniques. The VO2 max data, expressed per kg BW (mL/min.kg BW) showed a significant increase from 23.2 +/- 2.4 to 30.0 +/- 2.3 (P < 0.01) in the hGH-treated group, whereas the VO2 max data, expressed per lean body mass (milliliters per min/kg lean body mass) did not change significantly in either group. Maximal O2 pulse (milliliters per beat) increased significantly from 15.2 +/- 5.6 to 19.6 +/- 3.3 mL/beat (P < 0.01), but remained constant in the placebo group. The maximal power output (watts +/- SE) increased significantly (P < 0.01) from 192.5 +/- 13.5 to 227.5 +/- 11.5 in the hGH-treated group, but remained constant in the placebo group. Cardiac structure (left ventricular posterior wall, interventricular septum thickness, left ventricular mass, left ventricular end-systolic dimension, and left ventricular end-diastolic dimension) as well as echocardiographically assessed cardiac function did not change significantly after 6 months of treatment in either group. We conclude that hGH replacement in hGH-deficient adults improves oxygen uptake and exercise capacity. These improvements in pulmonary parameters might be due to an increase in respiratory muscle strength and partly to the changes in muscle volume per se observed during hGH replacement therapy. Furthermore, an increased cardiac output might contribute to the improvement in exercise performance during hGH treatment. According to our data, hGH replacement therapy leads to an improvement of exercise capacity and maximal oxygen uptake, but has no significant effect on cardiac structure

Antioxidative vitamines for prevention of cardiovascular disease for patients after renal transplantation and patients with chronic renal failure

Introduction: The mortality from cardiovascular disease in patients with chronic renal failure is much higher than in the general population. In particular, patients with chronic renal failure with replacement therapies (dialysis patients and patients with renal transplantation) show both increased traditional risk factors and risk factors due to the dysfunction of the renal system. In combination with necessary medication for renal insufficiency oxidative stress is elevated. Progression of atherosclerosis is promoted due to increased oxidation of lipids and endothelium damage. This link between lipid oxidation and artherogenesis provides the rationale for the supposed beneficial effect of supplementation with antioxidative vitamins (vitamin A, C and E). Such an effect could not be demonstrated for patients with a history of cardiovascular disease and without kidney diseases. However, in high risk patients with chronic renal failure and renal replacement therapies this could be different. Objectives: The objective of this systematic literature review was to assess the clinical effectiveness and cost-effectiveness of supplementation with antioxidative vitamins A, C or E to reduce cardiovascular events in patients with chronic kidney diseases, dialysis-requiring patients and patients after a renal transplantation with or without cardiovascular diseases. Methods: A systematic literature review was conducted with documented search and selection of the literature, using a priori defined inclusion and exclusion criteria as well as a documented extraction and assessment of the literature according to the methods of evidence-based medicine. Results: 21 publications met the inclusion criteria for the evaluation of clinical effectiveness. No study could be identified for the economic evaluation. Two studies (four publications) analysed the effect of oral supplementation on the secondary prevention of clinical cardiovascular endpoints. Studies analysing the effect on patients without a history of cardiovascular disease could not be identified. 17 studies analysed the effect of oral supplementation or infusion with antioxidative vitamins or the supplementation with dialysis membranes coated with vitamin E on intermediate outcomes like oxidative stress or vessel parameters. The two randomized clinical trials analysing the effect of orally supplemented vitamin E on clinical endpoints in patients with mild-to-moderate renal insufficiency and for haemodialysis patients respectively reported different results. After 4.5 years supplementation with a daily dose of 400 IU vitamin E renal insufficiency patients showed neither a beneficial nor a harmful effect on a combined event rate of myocardial infarction, stroke or death by cardiovascular causes. The second study reported a 50% risk reduction (RR=0.46, 95%-KI: 0.27-0.78, p=0.014) on the combined event rate of fatal myocardial infarction, nonfatal myocardial infarction, stroke, peripheral vascular disease or unstable angina pectoris in the study arm with vitamin E-Supplementation of 800 IU daily. In 16 of 17 studies with intermediate endpoints the supplementation with vitamins was associated with a change of one or several of the examined endpoints in the expected direction. This means that the concentrations of the markers for oxidative stress decreased in the Vitamin E-group, the progression of aortic calcification (only one study) was reduced, the intima media thickness decreased and the lipid profile improved. No studies regarding costs or cost-effectiveness were identified. Discussion: A possible explanation for the different results in the two studies with clinical endpoints may be due to the different study populations with different risk profiles, to different dosage during the intervention or to variation by chance. Due to the absence of clinically meaningful endpoints, the relevance of studies analysing the effect of antioxidative vitamins on intermediate endpoints like oxidative stress markers is basically limited to show single intermediate steps of the postulated biological effect mechanisms by which a potentially preventive effect could possibly be mediated. The mainly unsatisfactory planning and reporting quality of the 17 identified studies and a possible "publication bias" are further limitations. Conclusion: The available evidence is not sufficient to support or to reject an effect of antioxidative vitamins on secondary prevention for cardiovascular disease for patients with chronic renal insufficiency or renal replacement therapy. There is a lack of randomized, placebo-controlled studies with a sufficient number of cases and clinical endpoints of cardiovascular disease, on the effect of antioxidative vitamins either orally applied or given by vitamin E-modified dialysers.No data are available about supplementation with antioxidative vitamins for primary prevention of cardiovascular disease. Therefore the current evidence does not allow to draw conclusions concerning this subject either. As opposed to patients with a history of cardiovascular disease without kidney diseases where there is enough evidence to exclude a beneficial effect on secondary prevention of cardiovascular disease for patients with chronic renal insufficiency and renal replacement therapy this question remains unanswered. Conclusions about costs and cost-effectiveness also cannot be drawn

Crucial role of local peroxynitrite formation in neutrophil-induced endothelial cell activation

Introduction and methods: The reaction of superoxide anions and NO not only results in a decreased availability of NO, but also leads to the formation of peroxynitrite, the role of which in the cardiovascular system is still discussed controversially. In cultured human endothelial cells, we studied whether there is a significant interaction between endothelial NO and neutrophil-derived superoxide anions in terms of endothelial peroxynitrite formation. We particularly studied whether a significantly higher redox-stress can be found in those endothelial cells directly adjacent to an activated neutrophil. Results: A considerable part of the 2,7-dihydrodichlorofluoresceine signal in endothelial cells was due to oxidation by peroxynitrite. Providing superoxide radicals by enzymatic source or by the neutrophil respiratory burst increased the fluorescence, which was attenuated by blockade of endothelial NO-synthase, suggesting that peroxynitrite was formed from neutrophil- or extracellular enzyme-derived superoxide and endothelial NO. Considerably higher fluorescence intensity was observed in endothelial cells in direct neighborhood to a neutrophil. This was particularly pronounced in the presence of a NO-donor and was accompanied by a strong activation of NF-κB and increased expression of E-selectin in these cells. Conclusion: Endothelial cells adjacent to neutrophils may have elevated levels of peroxynitrite that result in an increased expression of adhesion molecules. Such cells might represent a preferential site for adhesion and migration of additional neutrophils when simultaneously high concentrations of NO and neutrophil-derived superoxide are present

Measurement of fractional flow reserve to guide decisions for percutaneous coronary intervention

Background Coronary artery disease (CAD) is one of the leading causes of premature death in Germany. Percutaneous coronary interventions (PCI) are frequently performed in patients with angiographically intermediate stenoses. However, the necessity of PCI has not been proven for all patients. Pressure-based fractional flow reserve (FFR) is an invasive test that can be used to assess the functional significance of intermediate coronary stenoses in order to guide decisions on PCI. Objectives This health technology assessment (HTA) aims to evaluate (1) the diagnostic accuracy, (2) the risk-benefit trade-off and (3) the long-term cost-effectiveness of FFR measurement to guide the decision on PCI in patients with stable angina pectoris and intermediate coronary stenoses. Methods We performed a literature search in medical and HTA databases. We used the DIMDI instruments (DIMDI = Deutsches Institut für Medizinische Dokumentation und Information/German Institute for Medical Information and Documentation) to assess study quality and to extract and summarize the information in evidence tables. We performed a meta-analysis to calculate the pooled overall estimate for sensitivity and specificity of FFR with 95% confidence intervals (95% CI). Individual studies' case numbers were used as weights. The influence of single studies and important covariates on the results was tested in sensitivity analyses. We developed the German Coronary Artery Disease Outcome Model (German CADOM), a decision-analytic Markov model, to estimate the long-term effectiveness and cost-effectiveness of FFR measurement in the context of the German healthcare system. Results Our literature search identified twelve studies relevant to this HTA-report including ten diagnostic accuracy studies of FFR measurement, one randomized clinical trial (RCT) investigating the clinical benefits of this technique as well as one economic evaluation. Pooled estimates for sensitivity and specificity were 81.7% (95% CI: 77.0-85.7%) and 78.7% (95% CI: 74.3-82.7%). Sensitivity analyses indicated robust results. The RCT investigating the efficacy of an FFR-based treatment strategy provided evidence of the advantages of this strategy for patients with respect to freedom from angina and major adverse cardiac events. The published cost-effectiveness study demonstrates that the FFR-based strategy is cost-saving in the US context. Based on our own decision analysis for the German context, the FFR-based strategy improves (quality-adjusted) life-expectancy when compared to universal PCI and is cost-effective in the German healthcare context. This HTA is limited by the use of poor gold standards in several of the included diagnostic studies as well as the ongoing advance of technology and treatment options in interventional cardiology. Results of the decision analysis are limited by the necessary underlying assumptions and the uncertainty regarding long-term mortality reduction associated with PCI. Further research should focus on the acquisition of long-term data for disease progression in patients with and without functional coronary stenoses as well as the benefits and risks of PCI. Conclusions Based on actual evidence and our decision analysis, the use of FFR measurement to guide the decision on PCI should lead to better short- and long-term clinical outcomes in patients with stable angina and single-vessel disease without documented myocardial ischemia and it should provide a cost-effective use of resources in the German healthcare system. FFR measurement should be introduced in routine clinical practice. However, appropriate reimbursement strategies are necessary to avoid wrong incentives.Hintergrund Die koronare Herzkrankheit gehört zu den wichtigsten Mortalitätsursachen in Deutschland. Es wird zunehmend bezweifelt, ob alle der zahlreich durchgeführten perkutanen Koronarinterventionen (PCI) bei angiographisch mittelgradigen Stenosen medizinisch sinnvoll und notwendig sind. Für die Abwägung von medizinischem Nutzen, Risiko und Kosten zwischen PCI und medikamentöser Behandlung kann die druckbasierte Messung der koronaren fraktionierten Flussreserve (FFR) eine wichtige Entscheidungshilfe sein. Ziele Dieses Health Technology Assessment (HTA) dient der Bewertung (1) der diagnostischen Genauigkeit, (2) der Nutzen-Risiko-Abschätzung und (3) der Langzeitkosteneffektivität der FFR zur Indikationsstellung der PCI bei stabiler Angina pectoris und angiographisch mittelgradigen Stenosen. Methoden Es erfolgte eine Literaturrecherche in medizinischen und HTA-Datenbanken. Relevante Literaturstellen wurden mit Hilfe des DIMDI-Instrumentariums (DIMDI = Deutsches Institut für Medizinische Dokumentation und Information) auf Studienqualität geprüft, die Ergebnisse wurden systematisch beschrieben und in Evidenztabellen zusammenfassend dargestellt. Im Rahmen einer Metaanalyse wurden die gepoolten Schätzer für Sensitivität und Spezifität der FFR mit 95%-Konfidenzintervallen (95% KI) berechnet. Potenzielle Einflussfaktoren der Testgüte wurden in Sensitivitätsanalysen untersucht. Für die Bestimmung der klinischen und gesundheitsökonomischen Langzeitkonsequenzen der FFR-Messung im Kontext des deutschen Gesundheitssystems wurde ein entscheidungsanalytisches Markov-Modell entwickelt, das German Coronary Artery Disease Outcome Model (German CADOM). Ergebnisse Die Literaturrecherche ergab insgesamt zwölf relevante Studien: zehn Studien zur diagnostischen Testgüte von FFR, eine randomisierte klinische Studie (RCT) zum medizinischen Nutzen und eine gesundheitsökonomische Evaluation. Die gepoolte Sensitivität von FFR beträgt 81,7% (95% KI: 77,0-85,7%), die gepoolte Spezifität 78,7% (95% KI: 74,3-82,7%). Sensitivitätsanalysen deuten auf robuste Ergebnisse hin. Das RCT zum klinischen Nutzen einer FFR-basierten Behandlungsstrategie zeigt Vorteile für Patienten hinsichtlich Anginafreiheit und schwerwiegender kardialer Ereignisse. Die publizierte gesundheitsökonomische Evaluation deutet darauf hin, dass die FFR-Messung im US-amerikanischen Kontext kostensparend ist. Basierend auf den Ergebnissen des deutschen Entscheidungsmodells (German CADOM) führt die FFR-basierte Strategie zu einer höheren (qualitätsadjustierten) Lebenserwartung und ist im Kontext des deutschen Gesundheitssystems kosteneffektiv. Dieser HTA-Bericht ist limitiert durch die Verwendung eingeschränkter Goldstandards in einigen diagnostischen Studien sowie durch die fortwährende Weiterentwicklung von Technologie und Behandlungsmöglichkeiten in der interventionellen Kardiologie. Die Aussagen der Entscheidungsanalyse werden eingeschränkt durch die verwendeten Annahmen und Unsicherheit zur Wirksamkeit der PCI bezüglich Langzeitmortalität. Forschungsbedarf besteht in der Erhebung und Auswertung von Langzeitdaten zur Krankheitsprogression bei Patienten mit und ohne funktioneller Stenose sowie zu Nutzen und Risiken der PCI. Schlussfolgerungen und Empfehlungen Basierend auf der aktuellen Evidenz und der entscheidungsanalytischen Modellierung ist davon auszugehen, dass bei Patienten mit stabiler Angina pectoris und Eingefäßerkrankung ohne kardialen Ischämienachweis die FFR-Messung zur Indikationsstellung der PCI zu verbesserten kurz- und langfristigen klinischen Ergebnissen führt sowie einen kosteneffektiven Einsatz von Ressourcen im deutschen Gesundheitssystem darstellt. Ein breiterer Einsatz der FFR-Messung erscheint sinnvoll, erfordert jedoch die Vereinbarung angemessener Entgelte zur Vermeidung möglicher Fehlanreize und Fehlsteuerungen

Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial

In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcome compared with angiography-guided PCI for up to 2 years of follow-up. The aim in this study was to investigate whether the favourable clinical outcome with the FFR-guided PCI in the FAME study persisted over a 5-year follow-up

Relationship between cardiovascular risk factors and biomarkers with necrotic core and atheroma size: a serial intravascular ultrasound radiofrequency data analysis

We explored the impact of patient demographics, anthropometric measurements, cardiovascular risk factors, and soluble biomarkers on necrotic core and atheroma size in patients with coronary disease. The IBIS-2 trial enrolled 330 patients. In the multivariate analysis, at baseline, creatinine had a positive, whereas baseline mean lumen diameter and myeloperoxidase had a negative, independent association with percentage of necrotic core (PNC); while age, glomerular filtration rate <60, HbA1c, previous PCI or CABG and baseline % diameter stenosis were positively, and acute coronary syndromes (ACS) were negatively associated with baseline percentage atheroma volume (PAV). The variables associated with a decrease in PNC from baseline were darapladib, ACS and a large content of NC at baseline, while variables associated with an increase in PNC were previous stroke and % diameter stenosis at baseline. Those variables associated with a decrease in PAV from baseline were waist circumference, statin use, CD40L and baseline PAV, while the only variable associated with an increase in PAV was baseline diastolic blood pressure. Treatment with darapladib was associated with a decrease in necrotic core, but was not associated with a decrease in percentage atheroma volume. On the contrary, statin use was only associated with a decrease in percentage atheroma volume

Virtual histology

As a luminogram, coronary angiography provides a good overview of the coronary artery tree. Using quantitative coronary measurements, the degree of coronary obstruction can be determined. The limitation of coronary angiography is that it does not provide information on the arterial wall structure and therefore cannot assess the extent of atherosclerosis. Knowledge about adaptive coronary remodelling processes as compensatory enlargement of the coronary artery has focused diagnostic interest on the non‐stenotic lesions of the coronary tree. Intravascular ultrasound (IVUS) can reveal discrepancies between the extent of coronary atherosclerosis and angiography imaging by in vivo plaque imaging. Spectrum analysis of IVUS‐derived radiofrequency (RF) data enables a more detailed analysis of plaque composition and morphology. Preliminary in vitro studies correlated four histological plaque components with a specific spectrum analysis of the RF data. The different components (fibrous, fibrofatty, necrotic core and dense calcium) are colour coded. Coronary tissue maps were reconstructed from RF data using IVUS–Virtual Histology (VH IVUS) software (Real‐Time VH, Volcano Corporation, Rancho Cordova, California, USA). VH IVUS has the potential to detect high‐risk lesions and can provide new insights into the pathophysiology of coronary artery disease. VH IVUS allows the differentiation of different lesion types based on information derived from histopathology. The in vivo specific histological analysis of coronary atherosclerosis may allow better stratification of treatment of patients with coronary artery disease