Cardiac Disease in Chronic Uremia: Management

Cardiac Disease in Chronic Uremia: Management Jayanti Venkatesan and William L. Henrich Heart disease is a common cause of morbidity and mortality in end-stage renal disease (ESRD) patients. The management of heart disease in these patients requires a multidimensional approach to the management of heart failure, coronary disease, and arrhythmias, and to risk factors such as hypertension, anemia, secondary hyperparathyroidism, and electrolyte/acid-base disturbances. Coronary artery disease management includes use of antianginal drugs and revascularization of coronary arteries with angioplasty ± stent placement or coronary artery bypass grafting. The long-term outcomes of these procedures need to be assessed and improved. Hypertension occupies a major role in the pathogenesis of heart disease in ESRD, and early and adequate control of hypertension is likely to have a major impact on the progression of cardiac disease. This entails the achievement of optimal volume status, combined with the appropriate use of antihypertensive agents such as calcium channel blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, vasodilators, alphablockers, and central sympatholytic drugs. In ESRD patients, specific dialysis-related complications such as intradialytic hypotension and pericardial effusion may have additional effects on cardiac function and require attention. The choice of dialysate composition and membrane may influence clinical outcomes with specific effects on cardiac performance. © 1997 by the National Kidney Foundation, Inc. Index Words: Drug therapy; management; heart failure; coronary artery disease; arrhythmias; hypertension.

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his review focuses on the management of four clinical problems in chronic uremia: (1) heart failure, (2) coronary artery disease, (3) hypertension, and (4) arrhythmias. In addition, aspects of dialysis therapy important in patients with cardiac disease are discussed ..

Management of Congestive Heart Failure in End-Stage Renal Disease The prevalence of heart failure in dialysis patients is 42%,1 and that of persistent or recurrent heart failure is about 10%.2 The rate of heart failure is rising3 because of the increasing age of the general population, as well as the end-stage renal disease (ESRD) population,4 and an overall improvement in the therapy of congestive heart failure (CHF), which has resulted in a reduction in the early fatality rate in the disease, and may have allowed patients to survive to be treated with· dialysis, although this remains to be proved. It is clear that CHF is associated with a poor prognosis in the general population, with a 5-year survival of less than 50%.5 The same is true for ESRD patients, with a median survival of 3 years in patients with heart failure at the start of dialysis therapyP CHF may present with either systolic or diastolic dysfunction, a diagnostic differentiation requiring echocardiography. Several different factors contribute to

myocardial dysfunction seen in chronic uremia. These need consideration in the management of CHF in these patients. Effect of Hemodialysis In ESRD patients, euvolemia is maintained with dialysis and dietary restriction of sodium and fluids. Hemodialysis has been shown to have a beneficial effect on left ventricular (LV) function by achieving fluid balance that results in improved blood pressure (BP) control, as well as by removing uremic toxins, which may have deleterious effec'ts on myocardial function. Dialysis has also been shown to improve LV contractility, especially in patients without LV hypertrophy.9 This short-term improvement in contractility after dialysis may be attributable to an increase in ionized calcium during dialysis,lO an effect that may be further potentiated by a concomitant decline in the serum potassium concentration. ll,12 The effect of dialysis on improved LV function, therefore, may not entirely be due to its effect on volume.

From the Medical College of Ohio, Toledo. Address Correspondence to William 1. Henrich, MD, 3000 Arlington Ave, Toledo, OH 43614. © 1997 by the National Kidney Foundation, Inc. 1073-4449/9710403-0009$3.00/0

Advances in Renal Replacement Therapy, Vol 4, No 3 (July), 1997: pp 249-266

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Drug Therapy for CHF Ace inhibitors. The Cooperative North Scandinavian Enalapril Survival study (CONSENSUS) in 1987 showed a clear survival benefit in patients with New York Heart Association functional class IV heart failure treated with enalapril,13 It should be noted that patients with advanced renal failure were not included in this trial. However, many of the pathophysiological mechanisms leading to heart failure are similar in patients with and without renal failure. Therefore, it may be reasonable to extrapolate these findings to ESRD patients, and recommend use of angiotensin-converting enzyme (ACE) inhibitors in these patients, if there are no contraindications. It is to be noted, however, that there has not been any large scale study to evaluate the effect of ACE inhibitors on heart failure in the ESRD population. Furthermore the effect of angiotensin II receptor blockade has not been investigated in this population. Vasodilators. The Veterans Administration Cooperative Study in 1986 showed a slight mortality benefit in patients treated with hydralazine and nitrates in patients with CHF.14 A subsequent review of vasodilator drugs in CHF, however, failed to show a difference in mortality. I S It is reasonable to use these drugs in patients in whom ACE inhibitors cannot be used because of intolerance or contraindications. These drugs may be contraindicated in patients with diastolic dysfunction as the cause of CHF, because they may exacerbate diastolic dysfunction by inducing increased inotropy in the heart. Digoxin. Digoxin therapy is beneficial in patients with dilated cardiomyopathy and CHF. In a recent meta-analysis, seven doubleblind, randomized trials of the efficacy of digoxin in the treatment of CHF, it appeared that digoxin was useful in patients who have dilated left ventricles and systolic dysfunction.l 6 Use of digoxin in ESRD patients must be weighed against the potential for toxicity in these patients. One must also bear in mind that digoxin is not dialyzable. Digoxin is not indicated in patients with hypertrophic heart disease or diastolic dysfunction. Beta-blockers. Beta-blockers have been shown to have a mortality benefit after an acute myocardial infarction (MI).17 The role of

beta-blockers in CHF is not proven. In small trials, metoprolol appeared to improve symptoms of CHF in patients with idiopathic dilated cardiomyopathy.1 8,19 Xamoterol, which is a beta-l selective agonist, but acts as a beta-l antagonist when the sympathetic tone is high, was shown to have a beneficial effect on symptoms in patients with CHF, but no mortality benefit was evident. 20,21 Beta-blockers should be used with caution because of their negative inotropic effect. Further studies to evaluate the role of beta-blockers in CHF are currently underway (beta blocker evaluation survival test [BEST] trial). Management of Secondary Hyperparathyroidism There is substantial experimental and clinical evidence that parathyroid hormone has detrimental effects on the myocardium. In animal studies it has been shown that chronic exposure to high levels of parathyroid hormone (PTH) results in increased calcium content of the myocardium and impaired myocardial function. 22 Several clinical studies have shown a similar effect in humans as well,23-25 AIth~)Ugh the myocardial effects of PTH are widely studied and accepted, the effects of parathyroidectomy on myocardial function are less clear because of conflicting data. Improvement in myocardial function was shown after parathyroidectomy24 and after PTH suppression with vitamin 0. 25 Zuchelli et aF6 reported that parathyroidectomy did not cause any alteration in LV function in 10 ESRD patients. 26 Other studies have found no definite correlation between serum PTH level and LV function. 27 This variability in findings may be because PTH is only one of the several uremic toxins that have an effect on the myocardium. Nevertheless, in ESRD patients with chronic heart failure and elevated PTH level to greater than twice the upper limit of normal, it is reasonable to consider suppressing PTH levels with intravenous 28 or oral calcitriol,29 Effect of the Dialysis Fistula The blood flow through an arteriovenous fistula may vary between 500 mL and several liters per minute. There appears to be a good linear correlation between arteriovenous fistula flow and LV end-diastolic diameter. The

Management of Cardiac Disease

fistula usually results in an increase in venous return and cardiac output. However, although cardiomegaly is common after a traumatic central atrioventricular (A-V) fistula, it is relatively uncommon after placement of a peripheral A-V fistula. There are several case reports of cardiac insufficiency related to fistulae with high floWS. 30,31 In some of these cases, cardiac function improved after the flow in the fistula was decreased by surgical banding. 3 1,32 However, the exact role of the A-V fistula on heart function in ESRD patients is unknown due to the lack of prospective studies. Management of Anemia Anemia is an almost universal problem in the ESRD population. There is clear evidence that chronic anemia due to any cause leads to changes in myocardial structure and function. Coronary blood flow must increase to maintain adequate oxygen delivery to hypertrophied muscle, thereby exaggerating the impact of coronary occlusive lesions. In a recent prospective study, it has been shown that anemia is an independent risk factor for heart failure at the start of dialysis, and for recurrence of heart failure. 33 The introduction of recombinant erythropoietin has had a major impact in the management of anemia in ESRD patients. The response to erythropoietin is dose dependent, and most patients require between 50 and 100 units/kg three times a week for initial effect, after which the dose may be modified to maintain the hematocrit between 32% and 36%.34 Patients treated with erythropoietin show an improvement in iron utilization and require fewer blood transfusions. 34 Several studies have shown that the cardiac adaptive changes that occur during anemia are ameliorated to some extent with correction of anemia with erythropoietin: there is a fall in cardiac output and an increase in peripheral vascular resistance and venous tone. 35-37 There is also a decrease in left ventricular mass and hypertrophy because of a decrease in cardiac output, and a consequent reduction in the diminished workload leading to a decrease in length of the myofilaments. 38 However, definite mortality benefit resulting from such left ventricular regression has not been proven. Echocardiographic studies have shown are-

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duction in LV end-diastolic diameter, LV endsystolic diameter, stroke volume, and cardiac output, with improvement in ejection fraction, fractional shortening, and velocity of circumferential fiber shortening. 39 In a long-term study of the effect of erythropoietin therapy, there was also an increase in exercise capacity, as well as a reduction in exercise-induced cardiac ischemia. 4o A major side effect of erythropoietin therapy is a rise in mean arterial blood pressure, which is seen in about 25% to 30% of patients, probably because of an increase in peripheral vascular resistance and changes in blood rheology. This warrants close monitoring of blood pressure, especially if hypertension is not well controlled before beginning erythropoietin therapy. This effect can be minimized by achieving a slow increase in hematocrit rather than by rapid correction. No other organ dysfunction or antibody formation to erythropoietin have been observed. 34 To obtain an optimal and adequate response to erythropoietin therapy, several other facts must be borne in mind. Patients should have adequate nutrition, iron, folate, and B12 vitamins. Ongoing blood loss from the gastrointestinal (GI) tract, surgery, hemolysis, and clotting in the extracorporal circuit during dialysis need to be corrected. Chronic infection, inflammation, liver disease, and malignancy will also impair the response to erythropoietin. Hyperparathyroidism and aluminum toxicity are other conditions common in ESRD patients that can lead to erythropoietin resistance. 34

Management of Coronary Artery Disease in End-Stage Renal Disease There is a high prevalence of coronary artery disease in ESRD patients, and ischemic heart disease is an important cause of mortality in this group. The reasons for this increased prevalence is probably due to the more frequent occurrence of coronary risk factors in this population, including hypertension, diabetes, left ventricular hypertrophy, and lipid abnormalities. 41 -45 In addition, the mean age of the dialysis population is rising, and there is an increase in the prevalence of diabetes in the general population.4 Over half the patients who begin mainte-

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nance hemodialysis have evidence of coronary artery disease before the initiation of dialysis, and approximately half of the 40% of patients, who develop evidence of coronary ischemia subsequently, do so in the first year of dialysis.43 Ischemic heart disease may present with the typical anginal symptoms, particularly during dialysis, or CHF without chest pain. Conversely, hypotension could result in a decline in myocardial function due to ischemia as well. In the latter case, it may be diagnosed by electrocardiographic or echocardiographic changes. Myocardial ischemia during dialysis may often lead to hypotension and arrhythmias, with or without chest pain. Hemodynamic changes that occur during dialysis, including tachycardia, and increased ventricular contractility due to increased ionized calcium concentration,lO can increase myocardial oxygen requirement. Tachycardia and hypotension during dialysis reduce coronary filling. Many of these patients have left ventricular hypertrophy and anemia that further aggravate myocardial ischemia. These patients can therefore develop ischemic symptoms even in the absence of significant atherosclerotic occlusions on coronary angiography.46,47 Coronary Risk Factors Although a direct relationship between conventional coronary risk factors and coronary artery disease (CAD) has not yet been proved in the ESRD population, it is still prudent to address these factors especially in the younger patients with the highest cardiac risk. These include cessation of smoking,45,48 control of hypertension,49-52 and prevention of coronary calcification by controlling secondary hyperparathyroidism. 53 Antihypertensive therapy should be directed at the regression of left ventricular hypertrophy (LVH), which often is a risk factor for myocardial ischemia, although it has not been proved that regression of LVH is beneficial. In addition, volume status and anemia should be optimized to decrease myocardial workload and also to prevent developmentofLVH. Management of Lipid Abnormalities It is well accepted that renal failure is associated with abnormalities in lipid metabolism.

Dyslipidemia is associated with increased atherogenicity. However, in the ESRD population, the long-term benefit of treating hyperlipidemia in lowering cardiac risk is not proved. 54 The major lipid abnormality in ESRD population is hypertriglyceridemia, of which the role as a coronary risk factor is unclear. 55 Hypercholesterolemia is not as common as hypertriglyceridemia in the dialysis population. However, many of the patients with a relatively normal serum cholesterol may have low high-density lipoprotein (HDL), low apolipoprotein AI, and high apolipoprotein B levels, as well as high lipoprotein (a) and very-low-density lipoprotein (VLDL) levels. 56 These abnormalities may contribute to the atherogenesis seen in uremic patients. Treatment of lipid abnormalities in ESRD patients may pose practical problems. Dietary modification, weight reduction, and exercise are usual recommendations for nonuremic patients, which may be difficult to achieve in ESRD patients, because they already have multiple dietary restrictions, and their exercise capacity may be quite limited. Drug therapy of hyperlipidemia in ESRD has been shown to be effective in correcting lipid abnormalities, but none of them have been shown to have an impact on the incidence, prevalence, or outcome of cardiovascular morbidity and mortality. Of the lipidlowering agents, the 3-hydroxy 3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors are the most widely used, although studies regarding their use in the ESRD population are limited. Clofibrate and gemfibrozil use has been associated with a higher incidence of myopathy and rhabdomyolysis, even in patients with mild renal insufficiency. Niacin has been shown to have increased potential for toxicity in patients with renal failure as well. These drugs, therefore, are of limited use in the drug therapy of lipid disorders in dialysis patients. Finally, fish oil has been shown to have beneficial effects on lipids, but its efficacy has not been documented in patients with renal failure. 57-59 In addition, compliance may be a problem with this form of therapy. A reasonable approach to management of hyperlipidemia would be dietary counseling, a modest exercise program, and cautious use of HMG CoA reductase inhibitors.

Management of Cardiac Disease

Management of Angina: General Measures One of the most important factors in the management of angina in dialysis patients is correction of anemia and maintenance of an adequate hematocrit level. The usual target is a hemoglobin of at least 10 g/ dL and a hematocrit of 30%. In most patients, anemia can be successfully treated with erythropoietin. 6o Care should also be taken to prevent hypotensive episodes during dialysis by repeated evaluation of "estimated dry weight" and use of a bicarbonate rather than an acetate bath. 61 It has been shown that biocompatible dialyzer membranes are associated with a lesser degree of complement activation, which results in less hypoxia during dialysis. 62 Whether use of biocompatible dialyzers correlates with less severe angina for this reason is not clear. Drug Therapy of Angina Nitrates are the mainstay of treatment for acute anginal episodes. The response to longacting nitrates is comparable to that seen in nonuremic patients, and nitrate tolerance is usually not a major problem. When angina occurs during dialysis, however, administration of sublingual nitrate may predispose to hypotension. Therefore, whenever possible, this should be avoided. Other measures such as nasal oxygen administration, decreasing dialysis blood flow, and fluid replacement may alleviate the symptoms of angina. Betablockers and calcium channel blockers are useful adjuncts to the medical therapy of angina. Short-acting calcium channel blockers should be used with caution, because they may cause unpredictable changes in blood pressure.

Coronary Revascularization Angioplasty Coronary angioplasty and intravascular stent placement procedures are becoming increasingly common in the management of acute coronary syndromes, as well as in chronic ischemic heart disease. This is mostly because of the relative noninvasive nature and the shorter hospital course required after these

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procedures. Published data regarding the outcome of coronary angioplasty in the ESRD population has generally been less favorable when compared with nonuremic patients. In one study, of the dialysis patients with singlevessel disease who received percutaneous coronary angioplasty (PTCA), 75% obtained an angiographic success as compared with 92% in nonuremic patients. Recurrence rate was about 32%, requiring repeat angioplasty.63 A second study, which compared PTCA and coronary artery bypass graft (CABG) in dialysis patients, found no difference in 2-year survival between the two groups, but the postprocedure risk of angina, MI, and cardiovascular death was greater after PTCA than CABG.64 Another retrospective study reported higher procedural morbidity in dialysis patients (38% v 0% in nondialysis control patients) as well as a higher cardiac event rate of 50% in dialysis patients (v 15% in control) during a follow-up of 2 years. 65 The major impediment to the more widespread use of PTCA in ESRD patients is the high restenosis rate of coronary vessels within 6 months of the procedure. Until a salutary experience with the addition of stenting is proved effective, most centers elect CABG as the preferred therapy for multiple-vessel disease. It is acknowledged, however, that this preference is center-specific, that is, the local expertise of the resident interventionists and surgeons must be factored into the therapeutic decision. There are no long-term data regarding the outcome of coronary angiopIa sty and stent placement in ESRD patients. However, it may be appropriate to consider PTCA in patients who are poor surgical risks, particularly those with severe angina and single-vessel disease who have failed medical therapy. Coronary Artery Bypass Grafting CABG appears to be an effective means of treating the symptoms of ischemic heart disease in ESRD patients. Perioperative mortality ranges from a low of 0%66 to 20%.67 When various studies are combined, the overall perioperative mortality is about 8%, which when compared to the Coronary Artery Surgery Study (CASS)68 in non-ESRD patients, was not significantly different in groups with similar

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degrees of left ventricular function. The perioperative mortality therefore seems to depend largely on left ventricular function. The longterm effect of CABG on cardiac mortality in ESRD patients is less clear. In two of the largest series of 39 and 20 patients, mortality at the end of a mean follow-up of 35 months was 30.9% and 38.3%, respectively. The survival is considerably less than the findings in CASS, which showed a 5-year survival of 62% for patients with poor LV function. Generally patients with stable angina and good LV function (EF > 50%) do equally well with medical or surgical management. 69 These patients probably do not need coronary angiography, unless the diagnosis of coronary heart disease is in question. Conversely, patients with unstable angina, patients who cannot be controlled on medical therapy and whose symptoms interfere with dialysis treatments, should undergo angiography. Long-term survival is improved with CABG in patients with left main coronary artery disease and three-vessel disease, particularly if there is mild to moderate LV dysfunction (EF 34% to 50%), as compared with medical therapy.7o Patients with poor LV function (EF <35%), and whose symptoms are not controlled medically, also seem to do better with operative intervention, as compared with medical management, in the nondialysis population, although perioperative mortality is higher than in patients with good LV function. 68,7o It is not clear whether these data apply to ESRD patients as well. Insulindependent diabetic patients who are evaluated for transplantation should probably undergo coronary angiography, even if they are asymptomatic. About 20% of them have significant silent coronary disease. Coronary revascularization either by angioplasty or CABG improves the combined incidence of unstable angina, MI, and cardiac death as compared with medical management. 71 Finally, if the patient is at high risk for any procedure and has poor LV function, consideration should be given to transferring the patient to CAPD, which may be less hemodynamically stressful and has been associated with a salutary outcome.72

Management of Hypertension in Dialysis Patients Arterial hypertension occurs in 80% to 90% of ESRD patients beginning dialysis (blood pressure greater than 140/90), in contrast to 15% to 20% in the general population.73 There are several causes of hypertension in the ESRD population. Some of these include sodium and volume excess, activation of the renin~angiotensin axis, abnormalities of the sympathetic nervous system, increase in endothelium-derived vasoconstrictors, decrease in endothelium-derived vasodilators, calcification, and reduced compliance of blood vessels, hyperparathyroidism, and the use of erythropoietin. In many cases, ESRD may be superimposed on preexisting essential hypertension. With such a variety of causes for hypertension in these patients, management usually requires a multifocal approach. Effect of Dialysis on Hypertension It is clear that control of salt and water status

plays a major role in the management of hypertension in ESRD patients. Hypertension is either eliminated or markedly improved in about 80% of patients who have started dialysis and achieved "dry weight." The phenomenon is seen with both hemodialysis 74,75 and peritoneal dialysis.76 Achievement of dry weight should be done gradually during hemodialysis in the first few months to avoid hypotensive episodes and muscle cramps. Use of an acetate bath may contribute to hypotension because of its vasodilatory and cardiosuppressant effect?7 The blood pressure decrease does not always parallel the decrease in weight by ultrafiltration and may lag behind by several hours.78 The activation of the renin-angiotensin axis may be a factor in maintaining the BP in some of these patients.79 Therefore, vigorous ultrafiltration and aggressive use of antihypertensive drugs may result in hypotension during the interdialytic period. These patients may require ambulatory BP monitoring between dialyses to optimize antihypertensive treatment. In contrast, some patients may have a tendency to a rise in

Management of Cardiac Disease

BP during hemodialysis, which may be secondary to activation of the renin-angiotensin system from vigorous ultrafiltration.79,8o Other possible mechanisms include dialytic removal of antihypertensive drugs and an increase in plasma ionized calcium concentration, which may increase vasoreactivity.81 Finally, adequacy of dialysis may also be important, because Charra et al82 have shown an association between longer dialysis time and better BP control. In their study, patients with a Kt/V of >1.6 had remarkable control of hypertension. 82 Although it is difficult to separate the effect of longer dialysis time from better fluid control on BP, in this study the hypertension control seemed to be independent of the increase in volume status in the predialysis state, suggesting that better removal of "uremic toxins" may have contributed to the BP control. Control of blood pressure is usually smoother in most patients on peritoneal dialysis, probably because of better cardiovascular tolerance. 83 Frequent use of hypertonic dialysate, however, may lead to a decline in ultrafiltration capacity of the peritoneal membrane, and may present as a lack of BP control. 84 Sodium and Water Restriction In general, most patients with ESRD and hypertension are advised to follow sodium and fluid restriction, to prevent excessive interdialytic weight gain, and thereby to achieve better BP control. A restricted sodium intake will prevent an increase in total body exchangeable sodium. 85 Fluid restriction should be calculated according to daily urine output and insensible losses, if no other fluid losses such as diarrhea, vomiting, and fever are present. Loop diuretics occasionally may be added in patients with residual urine output to minimize weight gain between dialyses. Diet and fluid restriction may be liberalized in patients on continuous ambulatory peritoneal dialysis (CAPO), but repeated use of hypertonic dialysate to maintain volume balance must be avoided. Drug Therapy of Hypertension in End-Stage Renal Disease Calcium channel blockers. These are probably the most widely used group of agents (Table 1)

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in the treatment of hypertension in renal failure. These drugs act by decreasing peripheral vascular resistance, and some of them, such as verapamil and diltiazem, lower cardiac output. The major advantage of these drugs is the absence of deleterious effects on lipids, glucose, and uric acid metabolism. 86,87 There is some experimental evidence that calcium antagonists slow the progression of renal disease in animal88 and human89 studies. The half-life of these agents is not altered by renal failure, and dosage adjustments are usually not necessary. Postdialysis supplements are not required. 90-93 Calcium antagonists have been shown to lead to regression of left ventricular hypertrophy.94 They increase compliance of mediumsized arteries and are useful in the treatment of hypertenSion with stiff arteries, as in systolic hypertension in older patients. 95 There is also some evidence for anti atherosclerotic properties of these agents,96,97 but they have not been shown to cause regression of existing plaques. Beta-blockers. These are also effective drugs in the management of hypertension, especially in the settings of coronary artery disease, post-MI, and patients with hypertrophiC, hyperdynamic cardiomyopathy. They have been shown to cause regression of LVH.94 They may, however, adversely affect the lipid profile. 98 The beta-blockers must be used with caution in diabetics, patients with reactive airways, and in peripheral vascular disease. Betablockers also may cause hyperkalemia by blockade of the sympathetic nervous system and the renin-angiotensin axis, and decreasing the intracellular shift of potassium. The lipid-soluble beta-blockers, such as pindolol, are metabolized and not excreted by the kidney. The dosage for these drugs does not need to be modified in renal failure. In contrast, the water-soluble beta-blockers, such as propranolol, metoprolol, atenolol, and nado101, are almost entirely excreted by the kidneys. In addition, water-soluble agents may be removed by hemodialysis and therefore require postdialysis supplementation. 99 ACE inhibitors. Use of ACE inhibitors in renal failure has both advantages and limitations. The role of ACE inhibitors in slowing the progression of renal disease, especially in dia-

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Table 1. The Common Side Effects of Various Classes of Antihypertensive Drugs, as Well as Comorbid Conditions Influencing Choice of Antihypertensive Agents

Drugs

Comorbid Conditions of Preferred Use

Side Effects

Diuretics

Systolic hypertension in elderly, CHF, COPD

Electrolyte disturbances. May precipitate gout Worsen hyperlipidemia and glucose tolerance Sexual dysfunction

Beta-blockers

CAD, supraventricular arrhythmias, gout

May worsen COPD, asthma Avoid in IDDM, poor LVF, peripheral vascular disease, heart block

Alpha-blockers

PVD Hyperlipidemia, gout, sexual dysfunction, depression

Orthostatic hypotension, syncope, headache, palpitations

ACE inhibitors

CHF, COPD, CRF, Diabetes, PVD, hyperlipidemia, depressio~ sexual dysfunction

Hyperkalemia, cough, rash, angioedema ARF in bilateral RAS Rarely proteinuria Contraindicated in pregnancy

Calcium channel blockers

CAD, COPD, DM, PVD Hyperlipidemia, sexual dysfunction Supraventricular arrhythmia (verapamil and diltiazem)

Headache, dizziness Tachycardia, constipation Verapamil/ diltiazem contraindicated in heart block

Central alpha-agonists

Adjunctive therapy for severe hypertension

Sedation, dry mouth Rebound hypertension Alpha-methyldopa can lead to hemolysis, liver damage

Direct vasodilators

CRF CHF (hydralazine)

Headache, tachycardia hypotension +ANA, lupus (hydralazine). Minoxidil can cause hypertrichosis and serous effusions.

Abbreviations: CHF, congestive heart failure; COPO, chronic obstructive pulmonary disease; 100M, insulin-dependent diabetes mellitus; LVF, left ventricular function; PVO, peripheral vascular disease; CRF, chronic renal failure; RAS, renal artery stenosis.

betic nephropathy, is well recognized.1 00,101 These drugs also may reduce proteinuria in nondiabetic renal disease. 102 ACE inhibitors are widely used and effective in patients with associated heart failure, in whom they have been shown to reduce mortality103 and also cause regression of LVH.94 They are particularly effective in scleroderma renal crisis, where angiotensin II plays an important role in the pathogenesis of the hypertension and renal failure. 104 The three commonly used ACE inhibitors, captopril, enalapril, and lisinopril, are all cleared by the kidney, and therefore require dose reductions in renal failure. 90

The major side effect of ACE inhibitors in renal failure is hyperkalemia, which often becomes a limiting factor in their use. These drugs have no adverse effects on glucose or lipid metabolism. Angiotensin II receptor antagonists may be useful in patients who develop ACE inhibitor-induced cough. Vasodilators. These drugs act by a direct effect on the arterial wall, leading to a decrease in peripheral vascular resistance. Hydralazine dose may need modification in renal failure, although it is mainly metabolized in the liver. lOS Minoxidil is a potent vasodilator and may be used in resistant cases of hypertension. This

Management of Cardiac Disease

drug is sometimes associated with pericardial effusion. In general, however, vasodilators do not lead to regression of LVH.94 These drugs also may lead to reflex tachycardia and an increase in plasma renin activity (PRA). Alpha blockers. Drugs such as prazosin, doxazosin, and terazosin are effective in renal failure, and dosage adjustment is usually not necessary. These drugs also cause regression of LVHIS and have a beneficial effect on lipid metabolism. 106 These drugs are not removed during dialysis, and postdialysis supplementation is not required. Central sympatholytic drugs. Clonidine 107 and alpha-methyldopa are effective in the treatment of hypertension in renal failure. These drugs are partly eliminated by the kidneys and may require dose adjustment. The major side effects are sedation and xerostomia. These drugs also cause regression of LVH94 and have no adverse effects on lipid profile.

Management of Arrhythmias in End-Stage Renal Disease The assessment and interpretation of arrhythmias in ESRD patients is quite difficult because of the wide variations in fluid, electrolyte and acid-base balance, changing load of uremic toxins, and the repeated stress of hemodialysis. There is considerable variation in the frequency and severity of arrhythmias during dialysis, as well as in the interdialytic period. lOS Because of these factors, there is no consensus on the frequency of arrhythmias in ESRD patients. Reports range from not significantly different from control populations109,lIo to severe life-threatening arrhythmias.1 lI Ischemic heart disease and left ventricular hypertrophy are the most common predisposing factors in the causation of arrhythmias in the nonuremic population. Coronary artery disease has been associated with a higher frequency of arrhythmias in some studies 109,lIO,1l2 but not in all.1 13,1I4 In nonuremic patients with hypertensive left ventricular hypertrophy, ventricular arrhythmias have been shown to be more frequent l15 and seem to correlate with severity of hypertrophy.116 This association, however, has not been well documented in ESRD patients. Whether LVH is a

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cause of fatal arrhythmias (sudden death) in dialysis patients has not been clarified. Effects of Dialysis on Arrhythmias The hemodynamic and metabolic alterations that occur during dialysis would logically seem to be favorable to the development of arrhythmias. There are, however, studies that show an increased incidence of ventricular arrhythmias (PVCs) during and immediately after dialysis,113,117 and some that do not show differences. 109 The dialysis method, membrane, and the buffers do not seem to have a direct effect on the incidence of arrhythmias. lIS Dialysis-associated hypotension did seem to be an important factor in precipitating highgrade ventricular arrhythmias, irrespective of the type of dialysis. l1S,119 The observation that arrhythmias are less frequent during CAPD may be due to maintenance of relatively stable blood pressure, and the absence of sudden hypotensive events. 120 Use of digoxin in hemodialysis patients has often raised concern regarding precipitation of arrhythmias, especially in the immediate postdialysis period, when both hypokalemia and relative hypercalcemia may occur. l10,1l2,121 Keller et al 122 studied 55 patients in a crossover study, both on and off digoxin, and found no increase in incidence of arrhythmias when patients were on digoxin. 122 Therapy of Arrhythmias in End-Stage Renal Disease Patients Drug therapy of arrhythmias in dialysis patients is more complicated as compared with nonuremic patients. This is because of altered pharmacokinetics and protein binding,123 as well as the clearance of the drug with dialysis. Drug interactions should also be kept in mind, because ESRD patients are often on multiple medications. Many of the drugs used to treat arrhythmias may themselves become arrhythmogenic under certain conditions. The decision to treat arrhythmias with a specific drug should therefore be taken after carefully considering the risk-benefit ratio. The treatment of arrhythmias in ESRD patients should take into consideration the following factors:

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1. Presence of underlying heart disease, including coronary artery disease, left ventricular hypertrophy, and left ventricular dysfunction: The significance of ventricular arrhythmias in the presence of cardiac ischemia, LVH, and poor ejection fraction is much higher than in those without these abnormalities. 124,125 Whenever feasible, the underlying heart disease must be appropriately addressed and treated. 2. Atrial versus ventricular arrhythmias: Atrial arrhythmias are common in ESRD patients. One study reported a higher incidence of atrial arrhythmias in ESRD patients after 1\11 as compared with nonuremics. 111 In general, atrial arrhythmias tend to be asymptomatic. The more clinically significant atrial arrhythmias are bradyarrhythmias and tachyarrhythmias, of which atrial fibrillation is most frequently encountered. Systemic anticoagulation is often indicated in patients with chronic atrial fibrillation to decrease the risk of thromboembolic events. Asymptomatic, isolated premature ventricular contractions (PVCs) in the absence of underlying heart disease does not require specific therapy. The goals of treating ventricular arrhythmias are to abolish sustained and unsustained ventricular tachycardia and reduce the frequency of paired ventricular premature complexes, with an overall reduction in total PVCs by 50% during Holter monitoring and exercise testingP6 The predictive value of Holter monitoring in the primary treatment of arrhythmias is not proven, and the criteria for prediction of efficacy of a specific antiarrhythmic drug are not clear. Although the test has severallimitations, the major advantage of Holter monitoring is ease of technique and noninvasiveness. Electrophysiological testing, howeve:4 has been shown to be more accurate in predicting response and prognosis with specific antiarrhythmic agents127 but has the disadvantage of being invasive, and carries the risk of provoking dangerous arrhythmias. More recently, signal-averaged electrocardiogram (ECG) is being used to identify patients with the substrate for ventricular arrhythmias, and a higher risk of sudden cardiac death. 128 The use of this technique in ESRD patients has not yet been fully studied.

3. Correction of metabolic factors: Several metabolic abnormalities may contribute to the risk of development of arrhythmias and should be corrected. These include hypokalemia and hyperkalemia, hypocalcemia and hypercalcemia, hypomagnesemia, anemia, an acid-base disturbances. Careful evaluation of "dry weight" should also be done in these patients. Excessive fluid removal can lead to hypotension and thereby precipitate arrhythmias. Conversely, fluid overload may worsen left ventricular function and lead to myocardial ischemia, which in turn can precipitate arrhythmias. 4. Antiarrhythmic drugs: The use of specific antiarrhythmic drugs should be cautiously undertaken in ESRD patients, because of their proarrhythmic potential. Whenever possible, careful documentation of the need for such agents should be weighed against the risk of significant side effects. Attempts should be made to identify the most effective and safest drug by electrophysiological testing, if feasible. Beta-blockers have been the only drugs to show a benefit in post-MI and long QT syndrome. 129 Class I antiarrhythmic drugs have not been shown to improve prognosis in arrhythmias complicating heart failure.1 30 The ACE inhibitors have been shown to reduce the incidence of PVCs in heart failure,131 but the mortality benefit of these drugs is by improving pump function, rather than by reducing sudden cardiac death.13 Patients who fail drug therapy may be considered for surgical ablation or implantation of defibrillator devices. Table 2 shows the commonly used antiarrhythmic drugs and the dosage adjustment necessary in renal failure. Table 3 depicts the active metabolites and half-life of the drugs in ESRD patients.

Dialysis Therapy in Patients With Cardiac Disease Hypotension During Dialysis Hypotension during hemodialysis is a common problem, with the reported incidence between 20% and 50%.132 Patients with underlying heart disease have a higher risk of developing significant and symptomatic hypotension during dialysis,133 probably because of

259

Management of Cardiac Disease

Table 2. Use of Antiarrhythmic Drugs in Renal Failure

Dosage Adjustment in Renal Failure CFR (mLimin) Drug Classla Quinidine Procainamide Disopyramide Class Ib Lidocaine Phenytoin Mexiletine Tocainide ClassIc Encainide Flecainide Propafenone Class II Propranolol Atenolol Acebutolol Metoprolol Nadolol Pindolol Sotalol TImolol Class III Bretylium Amiodarone ClassN Verapamil Diltiazem Nifedipine Nimodipine Isradipine Nitrendipine Miscellaneous Digoxin Digitoxin Dobutamine

10-50

<10

Unchanged q6-12h q12-24h

75% q8-24h q24-36h

Unchanged Unchanged Unchanged Unchanged

Unchanged Unchanged 75% 50%

Unchanged 75% Unchanged

50% 50% Unchanged

Unchanged 50% 50% Unchanged 50% Unchanged 30% Unchanged

Unchanged 25% 25% Unchanged 25% Unchanged 20% Unchanged

25%-50% Unchanged

Avoid Unchanged

Unchanged Unchanged Unchanged Unchnaged Unchanged Unchanged

Unchanged Unchanged Unchanged Unchanged Unchanged Unchanged

50% Unchanged Unchanged

10%-25% 50%-75% Unchanged?

Dialysis Method

Supplementation

D I I

Yes (H) Yes (H) No (H)

D D

No (H) No (H) No (H) Yes (H)

D D

D D D D D

No (H) No (H) No (H,P) No (H) Yes (H) No (H) Yes (H) Yes (H) No Yes (H) No (H) No (H) No (H) No (H, P) No(H,P) No(H,P) No (H,P) No (H) No (H,P)

D D

No (H,P) No(H,P)

Abbreviations: D, dosage reduction; H,hemodialysis; I, interval extension; P, peritoneal dialysis.

Table 3. Route of Excretion, Major Metabolites, and Half-Life of Antiarrhythmic Drugs in ESRD

Drug

Major Route of Excretion

Active Metabolites

Half-Life in ESRD

Procainamide Disopyramide Quinidine Propafenone Lidocaine Amiodarone Tocainide Flecainide Mexilitine Bretylium

Renal (60%) Renal (50%) Hepatic (80%) Hepatic (100%) Hepatic (95%) Hepatic (90%) Hepatic (60%) Hepatic (75%) Hepatic (90%) Renal (90%)

NAPA* MonodesaIkyI disopyramide 3 OH quinidine 50H propaphenone and others Glycinoxilide Desethylamiodarone None Several None

Prolonged X2 Prolonged X2-3 Unchanged Unknown Unchanged Unchanged Prolonged X1.5 Prolonged X2 Prolonged Xl.5 Prolonged x 2-3

*N acetylprocainamide has half-life 6 to 8x that of normal in ESRD.

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Venkatesan and Henrich

decreased ability of the cardiovascular system to respond to sympathetic stimulation.1 34 Hypotension in these patients may worsen cardiac ischemia and lead to angina or myocardial infarction and may precipitate arrhythmias. Therefore, it is especially important to avoid episodes of hypotension in these patients. Because hypotension is often related to the amount of fluid removed during dialysis, it may be necessary to limit the total fluid removed during each session to about 2% of total weight/hour.1 35 This usually reduces blood volume by <20%, which may be the critical level below which hypotension is more likely to occur. These patients, therefore, require repeated counseling regarding sodium and fluid restriction, to minimize the interdialytic weight gains. Use of bicarbonate dialysate has clearly been shown to reduce the incidence of hypo tension during dialysisP6 Another measure to reduce episodes of hypotension is to avoid meals during or immediately before dialysisP7 Reducing the dialysate temperature to about 35°C may improve the sympathetic response to a decline in blood pressureP8 Raising the dialysate sodium is also helpful in reducing hypotensionP9 Use of isolated ultrafiltration for fluid removal is usually better tolerated than volume removal combined with dialysis, because fluid removal through convective solute removal leads to less vasodilation than diffusive solute removal. Plasma osmolality remains constant during isolated ultrafiltration, and this reduces fluid recruitment from the plasma volume. Use of a biocompatible dialyzer membrane such as poly acrylonitrile or polysulfone has also been reported to reduce the incidence of hypotension,138 but this is not a universal observation. Improvement of anemia often helps to alleviate hypotensive episodes during dialysis. This may be done acutely with blood transfusion, or by the use of erythropoietin in chronic situations. This may partly be because of improved myocardial function and partly because of improvement in peripheral vascular tone. 140 Recurrent hypotension also may occur in patients with autonomic dysfunction. In some of these patients, it is believed that there is a

paradoxical withdrawal of sympathetic tone in response to hypotension. 139,14U42 This abnormal response may be mediated through volume depletion, LV cavity collapse, and a central nervous system serotonin surge.1 43,144 Serotonin uptake inhibitors may be useful in blunting this response,145,146 but the exact role of serotonin in mediating dialysis-associated hypotension has not been elucidated. In patients who do develop hypotension, reducing the ultrafiltration rate and administration of normal saline is the initial treatment of choice. Use of intravenous albumin may temporarily alleviate the symptoms, although the routine use of albumin is limited by its expense. Hypertonic saline and mannitol also may be used in the treatment of acute hypotension during dialysis. Effects of Dialysate Composition Dialysate potassium concentration is of particular importance in patients with cardiac disease. A rapid decrease in serum potassium level may precipitate arrhythmias in patients with heart disease, particularly if they are on digoxin therapy. In general, patients on digoxin should be on a 3 mEq/L potassium dialysate, unless they manifest persistent hyperkalemia. In the latter situation, lower dialysate potassium may be used, provided serum potassium is monitored to avoid hypokalemia. Dialysate calcium also may need consideration in patients with heart disease. First, it has been shown that an increase in ionized calcium during dialysis improves myocardial contractility.1° However, with the routine use of calcium salts as phosphate binders, and the more widespread use of oral and intravenous calcitriol, the calcium concentration in the dialysate often has to be reduced to prevent hypercalcemia. Use of calcitriol has been shown to be effective in suppressing parathyroid hormone, which may be a significant cardiotoxin in these patients. Use of citrate anticoagulation may lead to serious cardiac arrhythmias, and ionized calcium should be closely monitored.1 47 Raising the dialysate sodium concentration has been shown to reduce the incidence of hypotension during dialysis, by improving the mobilization of fluid from the extravascular compartment. 148 However, constant high dialy-

261

Management of Cardiac Disease

sate sodium has a tendency to increase thirst in the postdialysis period, thus leading to increased weight gain. The use of sodium modeling, or variation of the sodium from a higher concentration at the onset of dialysis (150 mEq/L) to a lower concentration toward the end of dialysis (130 mEq/L), may help reduce this problem, although this has not been conclusively proved. A flow sheet for the evaluation of hypotension during dialysis is shown in Figure 1.

Effect of Dialyzer Membrane It has been suggested that biocompatible membranes may be associated with better hemodynamic stability during dialysis,138 although this effect is not very significant. Cuprophane membranes are associated with increased complement activation, increase in cytokines such as interleukin I (IL-I), -II, and -VI and tumor necrosis factor, as well as a decrease if.!. blood neutrophil count.1 49 The elaboration of cytokines could, in tum, lead to the produc-

Hypotension during Hemodialysis

! Discontinue or decrease antihypertensive drugs

,

~

Hypotension

Resolved

!

1 Reevaluate EDW

1

Observe

,

Hypotension Persists

Resolved

!

! Observe Check for: (1) Fluctuations in UFR (2) High UFR (1 IDWG) (3) Dialysate Na (too low) (4) Food ingestion during HD (5) Dialysate temperature (too wann) ! Hypotension persists

1 Evaluate for cardiac disease

Resolved

1 Observe

! (1) (2) (3) (4)

Left ventricular dysfunction

Diastolic dysfunction Pericardial disease Autonomic dysfunction

lEB Modify dialysis by:

Treat appropriately

(1) (2)

Sodium variation Cool temperature dialysate

Hypotension resolved

(3) (4)

1 Na dialysate Isolated ultrafiltration and dialysis

Observe

!

!

Figure 1. Algorithm for management of dialysis-associated hypotension.

262

Venkatesan and Henrich

tion of vasodilators such as nitric oxide and thereby lead to hypotension. ISO This theory has been difficult to substantiate in dialysis patients. There is also increased release of lipoxygenase from platelets, resulting in endothelial injury.149 There is however, no proven link between the type of dialyzer membrane and the incidence of cardiac disease in dialysis patients. Pericardial Effusion in End-Stage Renal Disease Patients One of the complications of uremia is inflammation and effusion in the pericardial space. Although acute pericarditis is most often associated with the "uremic state," this complication also may occur in patients who are undergoing regular maintenance dialysis. The overall frequency of this condition is reported to be between 8% and lO%lSI in patients who are on dialysis. These patients may present with recurrent or persistent hypotension during hemodialysis. If there is no sign of impending tamponade, these patients are usually managed with intensive dialysis, without anticoagulation to prevent hemopericardium. If there is a large effusion causing cardiac constriction or evidence of tamponade, surgical intervention is usually indicated, with either creation of a pericardial window or pericardiectomy. Continuous Ambulatory Peritoneal Dialysis and Heart Disease There is no evidence that the mode of dialysis therapy enhances the clinical outcomes of patients with any form of heart disease. It is known, however, that there is less hemodynamic fluctuation with CAPD than with hemodialysis. Hypotension is less common, although not entirely absent in patients receiving CAPD. Cardiac risk factors, coronary artery disease, and arrhythmias are managed in the same manner as one would in hemodialysis patients. Patients who are symptomatic during dialysis because of recurrent angina, hypotension, or arrhythmias, and whose symptoms cannot be controlled by any other measures, may be considered for a switch to CAPD. One recent study1s2 reported an improved survival of patients with LVH and CHF who were switched from hemodialysis to CAPD.

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