Avoidance and Treatment of Cardiovascular Disease in Dialysis

Introduction

The prevalence and severity of cardiovascular disease in the dialysis population are well appreciated and present one of the defining therapeutic challenges in nephrology. It is also one of the most difficult issues to approach—the unique pathophysiologic processes underpinning disease in the dialysis population require specialized care, aimed at optimizing dialysis therapy and preventing cardiovascular injury associated with dialysis, and also consider the unique response to conventional medications/therapeutic approaches in this specialized patient population. These challenges present multiple pitfalls in the treatment of these patients. What may be considered a standard treatment, recognized to be effective in the general population, could potentially not only be ineffective but actually cause unintended harm. Furthermore, other specialist services may not always be aware of the specific challenges that apply to dialysis patients, making consulting with other specialties a not altogether straightforward process. It is therefore vital that nephrologists are fully informed of the hazards that can ensue in treating cardiovascular disease in their patients according to diagnostic and therapeutic evidence extracted from the non–chronic kidney disease (non-CKD) population. In recent years, mounting evidence has been published on the importance of nontraditional cardiovascular risk factors and the inefficacy of treatments designed for the general, non-CKD population; this serves to highlight the many uncertainties faced by a physician caring for a dialysis patient. An evolved understanding of these uncertainties may help prevent patients from receiving inappropriate investigations and treatments. Early evidence also provides potential ways to improve patient well-being, quality of life, and mortality outcomes.

Management of Cardiovascular Disease

The diagnosis, prevention, and treatment of cardiovascular disease in dialysis patients present several challenges. This is even more unfortunate given the high prevalence of cardiovascular disease and results from the unique combination of susceptibility and stressing factors experienced by dialysis patients.

Presentation and Diagnosis of Cardiovascular Disease

The presentation of acute coronary syndrome in dialysis patients is often atypical and may consist of shortness of breath, fatigue, or palpitations rather than classical central chest pain. A high index of suspicion is warranted in all dialysis patients presenting with otherwise unexplained symptoms; hospital admission should be considered at a low threshold to allow for the necessary investigations. However, nephrologists must always be aware that there are considerable challenges involved in applying and interpreting standard diagnostic tests.

Cardiac Enzymes

There are well-evidenced cutoffs for values of cardiac enzymes that, combined with increased assay sensitivity, are the bedrock of diagnosis for acute coronary syndromes in the general population. Increased values in high-sensitivity troponin assays are burdened by reduced specificity; the differential diagnosis of acute coronary syndrome includes heart failure, atrial fibrillation, aortic dissection, pulmonary embolism, myocarditis, cardiomyopathies, sepsis, and others. Acute kidney injury and CKD are also associated with increased troponin levels, with their levels being correlated with the degree of kidney dysfunction. This makes the diagnosis of acute coronary syndrome complicated when based on absolute values. The physiological mechanisms responsible for the degradation of troponins are still unclear and involve tissue fragmentation by serine proteases and tubular secretion. Recent evidence suggests that elevated serum troponin levels are not just the result of reduced kidney clearance but rather may be due to increased cardiac release and signal subclinical myocardial injury. Diastolic dysfunction, left ventricular hypertrophy, coronary microvascular disease, and myocardial fibrosis may underlie chronically elevated serum troponin levels—indicative of “ventricular distress.” These findings may partially explain the negative prognostic value of troponin levels in dialysis patients. Determining a “baseline” troponin value may be helpful for prognostic stratification and future comparisons; monitoring the biomarkers’ evolution over a period of hours may have some utility where the diagnosis of acute coronary syndrome is uncertain. However, clearer, evidence-based recommendations are needed.

Electrocardiography

Interpretation of electrocardiograms (ECG) in dialysis patients is not always straightforward. Studies have suggested that hemodialysis (HD) in particular induces repolarization abnormalities that may interfere with parameters, such as the calculation of the QT interval, and indeed, longstanding cardiac morphologic changes often leave highly abnormal patterns of repolarization that masquerade (especially handicapping automated ECG reporting software) as acute changes. Having a recent baseline ECG to refer to is crucial in accurate interpretation in the setting of suspected acute cardiac events.

Exercise Stress Testing

Although exercise stress remains an integral part of the workup of transplantation candidates, its utility in the dialysis population is not proven. In terms of overall risk stratification, many patients, even those under consideration for transplantation, will be unable to complete an exercise test to the required heart rate because of physical frailty, mobility limitations, autonomic neuropathy, or medication preventing them from the development of an appropriate stress response. Exercise stress testing is a poor predictor of posttransplant outcomes. Most physicians will accordingly proceed to alternative tests in order to assess the patient for reversible ischemia.

Isotope Stress Testing

In terms of risk stratification, in the general population, isotope stress testing (using pharmacological means) can be of use in patients unable to complete an exercise stress test to the required heart rate. However, there is evidence that in dialysis patients, the sensitivity of myocardial perfusion scans to detect coronary artery disease is significantly reduced. In patients who have had a negative isotope stress test and then progressed to transplantation, a negative stress test is a poor predictor of which patients have gone on to have cardiovascular events. Although isotope testing again remains a standard tool in the transplantation workup, this poor predictive value should be borne in mind when counseling a patient for transplantation, and the result of an isotope stress test should be interpreted in the context of the patient’s other symptoms and overall health.

Coronary Angiography

This remains the gold-standard investigation in the general population, but one that again is more difficult to apply in the dialysis population. The decision to go ahead with diagnostic and therapeutic coronary angiography is not always clear-cut. Although percutaneous intervention remains the treatment of choice in dialysis patients with an ongoing acute coronary syndrome, such as ST-elevation myocardial infarction (MI), many patients have cardiac events in the absence of significant stenotic lesions. Outside of an acute event, a significant proportion of symptomatic and high-risk (or higher risk as all patients regardless of age have a significantly elevated cardiovascular risk) individuals will have no treatable lesion identified (approximately 50% according to case series). Atheromatous coronary arterial disease is extremely common in dialysis patients, but the functional significance of individual lesions is much more difficult to determine. To determine the potential clinical significance of a lesion, further testing, such as the determination of fractional flow reserve, may be needed, but as yet, there is no evidence that such a directed approach improves outcomes. Aside from the diagnostic accuracy of the test, the use of iodinated contrast and subsequent impact on residual kidney function must also be considered. The decision to refer a patient for angiography should bear these realities in mind, and the potential benefits of this invasive procedure must be considered to outweigh the risks.

Prevention and Treatment Strategies

The evidence supporting pharmacologic therapies is currently limited, as dialysis patients are usually excluded from most major randomized controlled trials. Most recommendations are based on small and underpowered studies or expert opinions. Therefore, most standard treatments used in the general population lack solid evidence for efficacy and may be ineffective or harmful due to the pharmacokinetic properties of the employed drugs.

Antiplatelet Therapy

The use of antiplatelet medications in cardiovascular disease must always be balanced against the higher risk of bleeding due to uremic platelet dysfunction. In CKD as a whole, evidence derived from meta-analyses suggests that antiplatelet treatment reduces the incidence of MI but has no effect on cardiovascular or all-cause mortality and increases the risk of hemorrhagic stroke. Combination therapy with dual antiplatelets is particularly associated with higher serious hemorrhagic risk in kidney failure. Therefore, dual antiplatelet therapy after coronary percutaneous revascularization is generally advised for short periods and is not advised when concomitant oral anticoagulants are prescribed. Evidence is lacking on the newest P2Y12 inhibitors, e.g., prasugrel and ticagrelor, and therefore favors the use of clopidogrel as the principal agent. Given the higher risk of major bleeding, care must be taken in prescribing these drugs appropriately.

Revascularization Therapy

Regardless of the method of revascularization, periprocedural mortality is higher than in the general population, and long-term survival is lower. Coronary artery bypass grafting currently has the highest long-term survival of the revascularization therapies. However, it also carries the highest initial morbidity and mortality, much higher than in the general population. These risks do not appear to be significantly modified by the use of more modern approaches to avoid cardiopulmonary bypass. Percutaneous interventions are associated with a lower initial mortality but also a lower long-term survival—the benefit of coronary artery stenting is attenuated in dialysis patients. Overall, there is little difference between the two interventions. The more limited efficacy of percutaneous coronary intervention is at least partly due to the type of lesions encountered in dialysis patients, the frequency of encountering multifocal lesions, and the proximal locations of these lesions. It should be noted that the requirement for dual antiplatelet therapy also poses hazards in the form of a higher risk of major bleeding. Again, a careful calculation of the relative risks and benefits must be performed before undertaking revascularization therapy. Intractable chest angina, resistant to conservative medical therapy, remains the most consistent indication for percutaneous coronary intervention in this group.

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