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CORONARY HEART DISEASE IN ESRD PATIENTS INTRODUCTION • Cardiovascular disease is the single best predictor of mortality in patients with ESRD. Fig 5. Causes of death among period prevalent patients 1997–1999, treated with hemodialysis, peritoneal dialysis, or kidney transplantation. NKF K/DOQI guidelines RISK FACTORS • A large percentage of dialysis patients have traditional risk factors for cardiovascular disease. • Many dialysis patients have more than one of these risk factors, resulting in an even higher risk of adverse outcomes. • Some risk factors result directly from the loss of renal function and/or the utilization of measures aimed at replacing such function. RISK FACTORS • CKD alone: Should be considered to be in the high risk category, equivalent to that of patients with known CHD. Risk increases with increasing renal dysfunction and/or severity of proteinuria. • Increased calcium intake and disorders of mineral metabolism: may directly enhance coronary arterial calcification. Vascular calcification among dialysis patients is also associated with abnormalities of calcium and phosphorus, dialysis vintage, hypertension, and other factors. RISK FACTORS • Anemia. • Uremia and Renal replacement therapy: Result in an increase of oxidant stress producing complement fragments and cytokines, increased adhesion molecules in endothelial cells, and other proinflammatory factors that may provide the proper milieu for the development of accelerated atherosclerosis. RISK FACTORS • Increased plasma homocysteine levels: due to decrease renal removal, low serum levels of vitamin cofactors required for homocysteine metabolism. • Abnormal nitric oxide metabolism: inhibition of NO synthesis may cause vasoconstriction and hypertension, thereby resulting in adverse cardiovascular outcomes. • Increase fibrinogen levels. CLINICAL MANIFESTATIONS • Angina during dialysis: most common presentation in patients with coronary disease. • Exercise-induced Angina, dyspnea, arrhythmias. • Silent Myocardial ischemia. SCREENING AND DIAGNOSIS Who should be screened? SCREENING AND DIAGNOSIS (K/DOQI guidelines) • All patients upon initiation of renal replacement therapy, independent of symptoms. • Kidney transplant wait list patients should be reevaluated at intervals ranging from every year to every three years. • Change in symptoms and signs, including recurrent hypotension, heart failure that is unresponsive to changes in dry weight, and hypotension that prevents attaining dry weight. SCREENING AND DIAGNOSIS (Modalities) • Base line ECG and ECHO for all patients. • Exercise or pharmacologic stress Echo: the K/DOQI guidelines state that dobutamine Echo was more sensitive in diagnosing obstructive coronary artery disease in the dialysis population. • Angiography: should be considered in dialysis patients who are candidates for coronary interventions and have positive stress tests or have signs and/or symptoms of coronary artery disease. SCREENING AND DIAGNOSIS (Angiography) • Among those with residual renal function, N-acetylcysteine and iso-osmolar radiocontrast media should also be administered to help decrease the risk of radiocontrast nephropathy. • Administration of sodium bicarbonate hydration is not recommended, given the increased intravascular volume. SCREENING AND DIAGNOSIS (Acute MI) • Diagnosis is based upon the clinical presentation, the electrocardiogram, and relevant laboratory tests. • Serum cardiac enzymes: CK-MB and cTnT alone are often associated with false positive results. The most specific marker for myocardial damage among patients with ESRD appears to be serial measurements of cTnI. SERUM CARDIAC ENZYMES Use in prognosis • There is an increasing evidence that elevations in serum troponin levels in stable asymptomatic patients with ESRD are predictive of worse long term and short term outcomes. • Further study is required to determine whether a more aggressive approach to treatment should be employed among asymptomatic patients with ESRD and elevated cTnT and (possibly) Creactive protein levels. PREVENTION • Hypertension: The targeting goal should ideally be set individually based upon the patient's cardiac and neurologic status, comorbid conditions, age, and other clinical factors. • Goal: – pre-dialysis value <140/90 mmHg on no medications, if possible. – BP <135/85 mmHg during the day and <120/80 mmHg by night, if clinical characteristics permit. PREVENTION • Hypertriglyceridemia: treatment with lifestyle changes and a triglyceridelowering agent should be considered for those with fasting triglycerides ≥500 mg/dL that cannot be corrected by removing an underlying cause. PREVENTION • Hypercholesterolemia: There are no randomized, controlled trials testing the hypothesis that dyslipidemias cause ACVD in patients with CKD. A number of retrospective, cross-sectional studies found no relationship, or even paradoxical correlations between dyslipidemias and ACVD in hemodialysis patients. However, none of these studies was a long-term, prospective, cohort study, and it is likely that illness, inflammation, and poor nutrition confounded the relationships between dyslipidemias and ACVD. PREVENTION • Hypercholesterolemia – 4D Trial ( Deutsche Diabetes Dialyse Studie): randomized, placebo-controlled study in 1,255 type 2 diabetic patients on chronic HD. Out of those patients, 619 were treated with 20 mg atorvastatin compared to 636 matched controls treated with placebo for a median of 4 years. Wanner, C, Krane, V, Marz, W, et al. Atorvastatin in patients with \Type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238. Copyright © 2005 Massachusetts Medical Society. Wanner, C, Krane, V, Marz, W, et al. Atorvastatin in patients with \Type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238. Copyright © 2005 Massachusetts Medical Society. PREVENTION • Hypercholesterolemia: – 4D Trial: the study did not exclude the possibility that statin therapy provides some long-term cardiovascular benefits in dialysis patients with increased cholesterol levels. Statin therapy was well tolerated and not associated with an increased incidence of adverse effects. – SHARP and AURORA: Ongoing trials that will test the efficacy of statins in patients with CKD, including those with ESRD. PREVENTION • Hypercholesterolemia: – Recommendation: statins should be administered to dialysis patients with elevated serum LDL cholesterol. (Weak evidence) – Goal: • serum LDL-cholesterol < 100 mg/dL. • Non-HDL cholesterol concentration < 130 mg/dL among patients who have a goal LDL cholesterol at baseline and fasting triglycerides ≥200 mg/dL. PREVENTION • Hyperhomocysteinemia: HOST study compared the effect of folic acid, pyridoxine, and vitamin B12 versus placebo on vascular outcomes in 2056 patients with CKD, including ESRD. At a median followup of 3.2 years, there was no difference between the groups in terms of total mortality, myocardial infarction, stroke, and amputations. PREVENTION • Increased calcium phosphorus product: the K/DOQI guidelines recommend that the calcium phosphate product be maintained below 55 mg2/dL2 in dialysis patients. However, it is unclear whether maintaining lower calcium/phosphorous levels is associated with a decreased risk of heart disease. PREVENTION • Increase oxidative stress: some recommend vitamin E. (Level C) • Fish oil: Only one randomized study of the effects of omega-3 fatty acids for secondary prevention has been performed in dialysis patients. The ability of this approach to prevent coronary events in patients with ESRD requires further study, particularly in larger trials. TREATMENT RECOMMENDATIONS • Anemia: Goal Hemoglobin level 11 to 12g/dl. Higher Hemoglobin levels are NOT RECOMMENDED. (Level B) • Hypertension: Should be controlled by removal of fluid and, if necessary, antihypertensive medications. PHARMACOLOGIC THERAPY OF STABLE ANGINA • The optimal choice of antianginal agent varies with the presence or absence of comorbid conditions, principal route of elimination and effect upon blood pressure, particularly in patients prone to hypotension during dialysis. • Nitrates and, if necessary, beta-blockers or calcium channel blocker. (Level C) PHARMACOLOGIC THERAPY OF STABLE ANGINA • Aspirin: Although there is a paucity of data related to the effectiveness and safety of ASA in patients with ESRD the K/DOQI guidelines recommend the administration of aspirin. (Level C) PHARMACOLOGICAL THERAPY OF ACUTE CORONARY SYNDROMES • All dialysis patients presenting with ACS should be treated as in the nondialysis population, with the exception of specific attention to drugs that have altered clearances in kidney failure. (Level C) • The mortality after acute MI in dialysis patients has been reported to be approximately 75% in 2 years, in part due to inadequate post-MI treatment. PHARMACOLOGICAL THERAPY OF ACUTE CORONARY SYNDROMES • Aspirin, beta-blockers and Nitroglycerin should be given, if indicated and appropriately dosed, in dialysis patients. (Level C) • Thrombolytic agents: should be administered, when appropriate, to patients with renal failure. However, PCI is the preferred modality in most patients, as recommended by K/DOQI guidelines. (Level C) PHARMACOLOGICAL THERAPY OF ACUTE CORONARY SYNDROMES • Thrombolytic agents: caution with Hypertension. • Glycoprotein IIb/IIIa inhibitors: should be administered when indicated. Abcximab may be preferred since it does not require any renal dose adjustment. Tirofiban requires dose adjustment. Eptifibatide is contraindicated. (Weak evidence) PHARMACOLOGICAL THERAPY OF ACUTE CORONARY SYNDROMES • Heparin: the mainstay of therapy in unstable angina and is typically used in acute myocardial infarction for patients with or without renal insufficiency. Administration requires careful attention to dosing, particularly with low molecular weight. INVASIVE MANAGEMENT • The short-term and long-term mortality after coronary revascularization procedures in dialysis patients is considerably higher than those in the general population. • Based upon retrospective and observational studies, the K/DOQI guidelines recommend that CABG and PCI are appropriate revascularization techniques. (Level C) • The indication for these procedures are similar to the ones for patients without renal failure. INVASIVE MANAGEMENT • CABG is the preferred therapy in those with three vessel and/or left main disease.(Level C) • CABG may also be preferred in those who are candidates for internal mammary graft utilization, given a possible survival advantage over PCI. INVASIVE MANAGEMENT • There is no data on the impact of using sirolimus-eluting, paclitaxel-eluting stents or brachytherapy on re-stenosis after PCI in dialysis patients, but these techniques may improve the long-term outcome of dialysis patients after PCI. • Follow up after PCI: The clinical detection of restenosis after initially successful coronary artery intervention may be more difficult in the dialysis patient because symptoms can mimic those resulting from recurrent ischemic disease. Provocative stress imaging should be considered to detect clinically silent re-stenosis 12-16 wks after PCI.