Cardiovascular & Haematological Disorders - Drug Targets - Volume 14, Issue 3, 2014

A paradigm shift is occurring in the way nephrologists evaluate patients with progressive chronic kidney disease for initiation of maintenance renal replacement therapy. Serum creatinine and serum creatinine-based equations used to calculate an estimated glomerular filtration rate (eGFR) are not accurate approximations of renal function at low levels. Further complicating matters is a trend toward early initiation of dialysis, once considered beneficial since patients had better outcomes if they started dialysis before the onset of protein malnutrition. But recent data, including results of a large randomized controlled trial, suggest no benefit and possibly increased risk of death with early initiation of dialysis. This review will examine the data and where the field stands in deciding when to initiate dialysis.

The development of simultaneous decompensation in cardiac and renal function is a common phenomenon in patients with congestive heart failure. Termed the cardiorenal syndrome (CRS), this joint deterioration in cardiac output and renal filtration is the result of a complex interplay of hemodynamic and neurohormonal factors. Recently, endothelial dysfunction, inflammation and uremia have been recognized as contributors to the crosstalk responsible for the development of CRS. Management strategies for the treatment of CRS involve correction of hemodynamic derangements and regulation of neurohormonal pathways. Future therapies may target more newly recognized components of CRS pathophysiologic development.

Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. This review provides a comprehensive overview of the possible risk factors for early atherosclerosis in children with CKD. Endothelial dysfunction, a precursor of atherosclerosis, starts early in renal disease, as indicated by increased carotid artery intima media thickness, carotid arterial wall stiffness, impaired flow mediated dilatation, and coronary artery calcification, which are frequently present in children with CKD. Many risk factors for atherosclerosis, such as hypertension, dyslipidemia, renal bone disease, hyperhomocysteinemia, and uremia-related cardiovascular risk factors are associated with CKD. All of these risk factors are modifiable and optimal clinical management can delay or prevent cardiovascular disease. Another strategy to decrease the risk of premature cardiac disease and death in children with CKD is to slow the progression of renal disease.

Cardiovascular (CV) disease is the most common cause of mortality among kidney transplant candidates on the waiting-list and after kidney transplantation. The mechanisms of cardiovascular disease burden after transplant are multifactorial and the risk is largely determined by pre-transplant factors including CV disease and dialysis duration. Current pre-transplant cardiac evaluation protocols have proven to be inconsistent in predicting adverse cardiovascular outcome post-transplant. However, multiple biomarkers have been recognized as predictors of all-cause mortality and cardiovascular events including graft function, hemoglobin, homocysteine, C - reactive protein among others. Of these, elevation in the biomarker cardiac troponin T appears to be a significant predictor of cardiovascular events and mortality among wait-listed kidney transplant candidates and after transplantation. The relationship between CV risk reduction, normalization of cardiac troponin T levels and restoration of renal function after kidney transplant is complex but opens opportunities for the use of cardiac troponin T and other cardiovascular biomarkers as important endpoints of clinical interventions in kidney transplant recipients.

One quarter of all hemodialysis patients will succumb to sudden cardiac death (SCD), a rate far exceeding that observed in the general population. A high prevalence of atherosclerotic coronary artery disease amongst patients with end-stage kidney disease (ESKD) partly explains this exaggerated risk. However, uremia and dialysis related factors are also of critical importance. Interventions aimed at preventing SCD have been inadequately studied in patients with ESKD. Data extrapolated from non-renal populations cannot necessarily be applied to hemodialysis patients, who possess relatively unique risk factors for SCD including “uremic cardiomyopathy”, electrolyte shifts, fluctuations in intravascular volume and derangements of mineral and bone metabolism. Pending data derived from proposed randomized controlled clinical trials, critical appraisal of existing evidence and the selective application of guidelines developed for the general population to dialysis patients are required if therapeutic nihilism, or excessive intervention, are to be avoided. We discuss the evidence supporting a role for medical therapies, dialysis prescription refinements, revascularization procedures and electrical therapies as potential interventions to prevent SCD amongst hemodialysis patients. Based on current best available evidence, we present suggested strategies for the prevention of arrhythmia-mediated death in this highly vulnerable patient population.

Objective: To assess the efficacy of statin therapy on early stage chronic kidney disease through an overview of systematic reviews. Methods: We searched for systematic reviews of randomized clinical trials (RCT) on MEDLINE, Embase, Cochrane Library, CRD, and Scopus. Independent reviewers selected the studies and extracted the relevant data. We critically appraised the included systematic reviews with the AMSTAR tool and presented the available data in the studies. Results: From 731 retrieved records, we included three systematic reviews. Statins reduced the risk of mortality for all causes and for cardiovascular causes in patients with early stage chronic kidney disease as compared to the control (highquality evidence). Statins also reduced the incidence of any myocardial infarction, non-fatal myocardial infarction, and stroke (moderate- to high-quality evidence). No differences were observed between statins and control upon the incidence of end-stage renal disease or on the outcomes assessed in patients with coronary artery disease and diabetes. Conclusion: Statins reduce the incidence of death and other relevant outcomes in patients with early stage chronic kidney disease and should be considered for such individuals who also present hyperlipidemia.

The prevalence of chronic kidney disease (CKD) in the United States has increased in the last 20 years. As CKD and cardiovascular disease (CVD) are interrelated, it is important to note that trends in the prevalence of CKD and common risk factors it shares with CVD, such as hypertension and diabetes, are likely to affect the burden of both diseases in the future. While preventing and treating CVD is of high priority in the primary care setting, a major reason why CKD continues to burden the US healthcare system is because it remains under-recognized by primary care physicians and specialists, partly due to a lack of uniform screening recommendations. This paper will review the public health implications of CKD, including its epidemiology and economic burden in the United States, its risk factor commonalities with CVD, current screening recommendations and possible prevention strategies for improvement in the future. Additionally, an emphasis will be made on encouraging primary care physicians to play a more prominent role in CKD screening and primary prevention.

The introduction of drug-eluting stents (DES) has resulted in improvement rates of restenosis and the need for repeat revascularization. However, with widespread use of DES, which reaches more than 80% of used coronary stents, concern has been raised regarding the long-term safety of this technology. The development of newer anti-restenotic agents, polymeric coatings as well as stent platforms resulted in newer DES which are associated with better safety and efficacy results. Additionally, the drawback of the first and second-generation thienopyridines, namely the rate of non-responder and interaction with other agents resulting in a lack of pharmacodynamic effect, was overcome with the development of newer generation thienopyridines. The effect of these newer agents was proven in several randomized controlled trials in different clinical settings resulting in an update of national and international guidelines. To date there is a controversies regarding antiplatelet therapy in patients being on oral anticoagulation. It is estimated that 5-7% of patients undergoing percutaneous coronary intervention have an indication for oral anticoagulation. There is a need for oral anticoagulation to prevent ischemic cerebrovascular events, and a need for dual antiplatelet therapy to prevent stent thrombosis. The combination of these, the triple therapy, results in an increase of bleeding complications, which are highly predictive of increased mortality in patients undergoing coronary intervention. With newer data from one randomized controlled trial, several ongoing randomized trials and data from several non-randomized trials the unprecisely recommendations of guidelines may change within the next update. However, there is a lack of data regarding antithrombotic strategy with respect to newer oral anticoagulants and newer generation thienopyridines. This special issue gives an overview of latest data regarding developments in drug-eluting stents and thienopyridines. Additionally it focuses on the widely debated topic of stent thrombosis and treatment strategy in oral anticoagulated patients. Thus, the readers will have an update on the complex and enlarging field of drug-eluting stents.

The interventional treatment of coronary artery disease was introduced in 1970`s by Andreas Grüntzig. The initial treatment strategy with plain old balloon angioplasty (POBA) was associated with high restenosis rates. The introduction of coronary stents, especially drug-eluting stents (DES) in 2002 has improved the results by lowering the rate of in-stent restenosis from 20-40% in the era of bare-metal stent (BMS) to 6-8%. However, in 2006 with the observation of late stent thrombosis the reputations of DES have decreased. However, improvements in stent design especially antiproliferative agents, polymeric agents as well as stent platforms improved newer generation DES. In controlled trials as well as registries the use of second-generation DES as compared to bare-metal stents (BMS) was associated with better clinical and angiographic results. A further development of these stents with use of biodegradable polymers, polymer-free stents, and biodegradable stents on the basis of poly L-lactide (PLLA) or magnesium resulted in third-generation DES and has been evaluated in preclinical and first clinical trials. However, to date, there is a lack of data comparing these thirdgeneration DES with first- and second-generatrion DES in a large scale.

Antiplatelet therapy plays an important role in the treatment of patients suffering from acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) in order to prevent atherothrombotic events and restenosis or ischemic reocclusion, respectively. Moreover, stent implantation is often performed along with PCI to ensure that the arteries remain open. However, stent thrombosis ST is a possible complication which can occur up to about one year after the procedure. Therefore, it is standard to treat patients with a dual antiplatelet regime whereby aspirin is combined with either clopidogrel, prasugrel or ticagrelor. This review summarizes the characteristics of these P2Y12 antagonists and evaluates the current and future clinical guidelines for antiplatelet therapy in the setting of PCI with or without stenting.

Stent thrombosis is a serious complication in stent era. It can be presented as death, cardiogenic shock or a large non-fatal myocardial infarction, usually with ST elevation. Risks of stent thrombosis, stent thrombosis incidence and predictors are controversial issues due to sparse and controversial data. But all attending physicians should have knowledge of the risk of stent thrombosis, predisposing and protective factors before and after the intervention. This issue is discussed in detail in this review.

In case of coronary stenting in patients taking long-term oral anticoagulants (OAC), addition of both aspirin and clopidogrel in the drug regimen (so-called triple antiplatelet therapy) is recommended. However such triple therapy increases the risk of serious bleeding events. Comparative data on the efficacy and safety of the triple therapy versus therapy with a single antiplatelet agent and oral anticoagulants in case of coronary stenting are very rare. Most studies show a decreased stroke and myocardial infarction risk, but an increased risk of bleeding events in case of triple therapy. There is general agreement that, when possible, the duration of triple therapy should be shortened followed by clopidogrel and an oral anticoagulant to minimize bleeding risk without increasing other adverse events. In patients with a high risk of bleeding, BMS should be used and triple therapy should be applied for only 1month, followed by one antiplatelet agent and oral anticoagulant. The WOEST study was the first study showing that therapy with clopidogrel and OAC is safe and reduces bleeding and mortality more effectively than triple therapy including aspirin in patients undergoing coronary stenting. Although the risk of bleeding increases with triple therapy as compared to OAC plus a single antiplatelet agent, the second treatment regimen cannot be recommended to all patients. However for those at the highest risk of bleeding it is not unreasonable to consider. Additional randomized studies are needed for the implementation of future treatment guidelines in patients with high risk for bleeding and thrombotic complications.

Adenosin diphospat (ADP) plays a crucial role in thrombus formation. Therefore its inhibition can control excess platelet generation to prevent cardiovascular events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). One of ADP’s target receptors, P2Y12 has a limited tissue distribution and is therefore an attractive pharmacological target. Thienopyridines are class of drugs that specifically and irreversibly inhibit the P2Y12 receptor. Three generations exist and in most patients, they are administered in combination with aspirin. Because of possible gastro-intestinal toxicity, a proton pump inhibitor (PPI) is often concomitantly prescribed. However, several studies suspect an interaction between thienopyridines (in particular with clopidogrel) and PPIs which decreases the inhibition of platelet formation and thus enhances the risk for cardiac events. In this review, a concise overview of pharmacokinetic and pharmacodynamic properties of all thienopyridines is given and a critical discussion of the presumed interaction with PPIs is provided.