Screening and treatment for cardiovascular disease in patients with chronic renal disease

Screening and Treatment for Cardiovascular Disease in Patients With Chronic Renal Disease Sean W. Murphy, MD, Robert N. Foley, MB, and Patrick S. Parfrey, MD INDEX WORDS: Kidney failure; myocardial ishemia; heart hypertrophy; aspirin; screening.

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ARDIOVASCULAR DISEASE (CVD) is very prevalent in patients with chronic renal disease (CRD) and accounts for much of the morbidity and mortality in this population. Many aspects of the management of this patient group differ from that of patients with cardiac disease in the absence of renal disease. This article makes specific recommendations regarding the use of antiplatelet therapy and coronary revascularization procedures for the treatment of coronary artery disease (CAD) in patients with CRD. The treatment of left ventricular hypertrophy (LVH) with antihypertensive agents and by correction of anemia is also addressed. Finally, recommendations are made regarding screening for CAD and LVH in patients with CRD. In each instance the evidence supporting these recommendations is presented. ANTIPLATELET THERAPY IN THE TREATMENT OF CORONARY ARTERY DISEASE

Clinical Recommendations ● Decreased platelet aggregation and increased bleeding time occur in patients with CRD, especially chronic renal insufficiency (CRI) and hemodialysis (HD) patients. Elevated levels of fibrinogen and other procoagulant factors are also observed in CRD. ● It is not known whether the abnormalities in platelet function and pro-coagulant activity are related to CVD in CRD. ● Aspirin therapy probably worsens the platelet defect in CRD and increases the risk of bleeding, especially in CRI and HD patients. ● Aspirin (75 to 325 mg/d) reduces the risk of

From the Divisions of Nephrology and Clinical Epidemiology, Memorial University of Newfoundland, St John’s, Newfoundland, Canada. Address reprint requests to Patrick S. Parfrey, MD, The Health Sciences Center, 300 Prince Philip Dr, St John’s, NF, Canada A1B 3V6. E-mail: [email protected]

娀 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3205-0312$3.00/0 S184

CVD events in patients with CAD in the general population. ● In CRD patients with CAD, it is reasonable to prescribe aspirin to reduce the risk of subsequent CVD outcomes. ● In other patients, individual treatment decisions must be based on consideration of patients’ individual risks, benefits, and preferences. It may be reasonable to prescribe low-dose aspirin (75 to 162 mg/d) in patients at highest risk for developing CAD, particularly if their risk of side effects is low. Introduction The American Heart Association1 has concluded that aspirin therapy is of proven value in the treatment of acute myocardial infarction (MI), following acute MI, as well as long-term use in patients with a wide range of prior manifestations of CVD. In the general population, the percent reduction of cardiac disease in patients with prior MI, stroke, transient ischemic attacks, unstable angina, coronary artery bypass graft surgery, coronary angioplasty, atrial fibrillation, valvular heart disease, and peripheral vascular disease is about 25%. On the other hand, the US Preventative Services Task Force2 has concluded that there is currently insufficient evidence to recommend routine aspirin prophylaxis for the primary prevention of MI in asymptomatic persons. However, in men with risk factors for CAD who lack contraindications to aspirin use, the benefits may outweigh the harm. In these cases, the use of aspirin for the primary prevention of CVD should be an individual clinical judgment. Recently, the indications for aspirin prophylaxis in high-risk patients have expanded. The American Diabetes Association3 now recommends aspirin (81 to 325 mg/d) in patients with diabetes and other risk factors to reduce the risk of CVD. The Hypertension Optimal Treatment (HOT) Trial4 demonstrated improved CVD outcomes in hypertensive patients randomized to treatment with aspirin 75 mg/d, which reduced major cardiovascular events by 15% and all

American Journal of Kidney Diseases, Vol 32, No 5, Suppl 3 (November), 1998: pp S184-S199

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myocardial infarctions by 36% with no effect on the incidence of stroke. Contraindications to aspirin use in the general population include allergy to aspirin, history of uncontrolled hypertension, liver or kidney disease, peptic ulcer or other gastrointestinal disease, bleeding problems, or other risk factors for bleeding or cerebral hemorrhage. However, other than allergy, the risk of low-dose aspirin is generally thought to be lower than with higher doses. Chronic Renal Disease Patients with CRD have a complex coagulation disorder manifest by both thrombotic and bleeding tendencies. Bleeding symptoms in uremic patients are often mild, such as ecchymosis, purpura, or epistaxis, but excessive bleeding following trauma or surgery can occur.5 The bleeding symptoms in uremic patients correlate best with prolonged bleeding times.5-7 The bleeding time is prolonged in at least half of patients with CRI when creatinine clearance is less than 20 mL/min and becomes more prevalent with increasing severity of renal impairment.6,8,9 Factors that are thought to play a role in the hemostatic defect in patients with CRD include anemia,9-11 intrinsic platelet defects,6,8,12-14 abnormal function of von Willebrand factor,15,16 uremic toxins,5,16 and endothelial factors, such as increased production of nitric oxide.18,19 Treatment by HD or peritoneal dialysis (PD) partly reverses the defect in platelet function and the prolonged bleeding time.13,20,21 Partial correction of anemia with either blood transfusions10,11 or erythropoietin22,23 improves the prolonged bleeding time but does not correct it entirely.11 Patients with CRD are also at higher risk of thrombotic events than the general population, and this has been attributed to higher levels of procoagulant activity in this group.5 Numerous investigators have reported increased levels of thrombin concurrent with high levels of fibrinogen in patients with CRD.8,24-26 In addition to high fibrinogen, elevated levels of factors VII and VIII have been found in uremic patients.27-29 In a recent study of 48 patients with a creatinine clearance less then 20 mL/min who were not treated with dialysis, the mean levels of thrombinantithrombin complexes, fibrinogen, and factor VIIc were higher than in healthy controls, consistent with a prothrombotic state. At the same time,

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plasmin-antiplasmin complexes and fibrinogen and fibrin degradation products were elevated, suggesting an activation of fibrinolysis. These abnormalities were correlated with the platelet defect, leading the investigators to postulate that the increased generation of thrombin and/or plasmin was a key mediator in not only the development of a prothrombotic state, but also the bleeding diathesis of uremia.8 Both HD and PD patients have higher levels of fibrinogen and procoagulant activity.27,30-32 In HD patients, activation of coagulation has been related to the dialysis membrane.30,31 Renal transplant recipients (RTRs) also have an increased thrombotic tendency.5 In those patients treated with cyclosporine A, enhancement of platelet aggregation by cyclosporine may be at least partly responsible.34,35 Elevated plasma fibrinogen and factor VII concentrations have been found to be independent risk factors for CVD in the general population.35-37 There is no evidence concerning the relationship of either the abnormal coagulation activity or the defect in platelet function to CVD in CRD, nor the efficacy of antiplatelet or anticoagulant therapy in preventing CVD outcomes in CRD. Aspirin diminishes platelet aggregation and may increase bleeding time further in dialysis patients than normal controls.38-40 For a number of reasons, the complications from aspirin would probably be greater in patients with CRD then in the general population, especially patients with CRI and HD patients. First, CRI, HD, and PD patients already have a defect in platelet function. Second, most HD patients undergo intermittent anticoagulation with heparin during the hemodialysis procedure, and a substantial minority are prescribed warfarin to prevent thrombosis in vascular accesses. Third, patients with CRD have a higher prevalence of conditions that are relative contraindications to aspirin therapy, especially poorly controlled hypertension and gastrointestinal conditions associated with bleeding.41 Fourth, iron deficiency due to chronic blood loss is an especially important problem in HD patients. Fifth, in one study, aspirin was associated with an increased risk of hemodialysis arteriovenous graft thrombosis, although another antiplatelet agent, dipyridamole, was not.42 Although there is no evidence for the efficacy of aspirin in CRD, the improvement in CVD

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outcomes in patients with preexisting CVD in the general population is sufficiently high that the benefits are likely to outweigh the harm. Consequently, in the setting of acute presentations of CAD, patients should be treated in the same manner as patients without CRD, including 325 mg/d aspirin. It is also reasonable to recommend the usual low-dose enteric-coated aspirin for CRD patients with stable CAD. Patients who have undergone angioplasty may require a higher dose of aspirin (eg, 325 mg/d). However, in view of the probable increased risk of adverse effects of aspirin in CRD, it is not currently possible to recommend universal use of aspirin for the primary prevention of CAD in CRD. Individual patient risks and benefits must be considered and discussed prior to beginning therapy. In patients considered to be at highest risk of developing CAD, such as those with diabetes, primary prevention with aspirin (75 to 162 mg/d) may be reasonable, particularly if the risk of side effects appears to be relatively low (eg, PD patients and RTRs). The risks may outweigh the benefits in low-risk patients, especially patients with CRI and HD patients without CVD risk factors. CORONARY REVASCULARIZATION FOR THE TREATMENT OF CORONARY ARTERY DISEASE

Clinical Recommendations ● The medical management of CAD in patients with CRD is similar to the general population. ● In addition, control of extracellular fluid (ECF) volume and partial correction of anemia are important therapeutic adjuncts. Optimal target hematocrit for improving CVD outcomes is not well established. It is reasonable to adopt the NKF-DOQI recommendation of a target hematocrit of 33% to 36%. Further modification based on individual decision making is suggested. ● The risks of coronary arteriography, percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG) are higher in patients with CRD. ● Initial technical success of coronary revascularization and relief of symptoms in patients with CRD are similar to the general population. Coronary revascularization may improve survival in high-risk patients with CRD.

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● Early restenosis appears to be more common after PTCA in patients with CRD than in the general population. Early experience with intravascular stents is favorable. ● As in the general population, patients should be considered for coronary revascularization if they are at high risk of acute MI or if they remain symptomatic despite medical therapy. ● CABG appears to be the revascularization procedure of choice in CRD, but PTCA with stenting may be a reasonable alternative in selected cases. Introduction The American Heart Association and American College of Cardiology have issued guidelines for the management of patients with unstable angina and acute MI, including long-term management after MI.43 Coronary arteriography, possibly with coronary revascularization, is recommended for patients with recurrence of myocardial ischemia spontaneously or after minimal exertion, left ventricular dysfunction, or signs of severe ischemia at low level of exercise during a stress test. Aspirin and β-adrenergic blockade are recommended indefinitely, as is an angiotensinconverting enzyme (ACE) inhibitor for patients with left ventricular dysfunction.43 Risk factor reduction is emphasized, especially smoking cessation and reduction of elevated blood pressure and LDL cholesterol. In addition, participation in a formal rehabilitation program is encouraged, including 20 minutes of moderate exercise at least three times a week.43 Patients with stable angina pectoris who have not had an MI are treated with anti-anginal agents for relief of symptoms. Indications for coronary arteriography and other aspects of medical management are similar to patients who have had an MI. Patients with congestive heart failure (CHF), arrhythmias, or hemodynamic instability as manifestations of myocardial ischemia generally receive more aggressive therapy.44,45 A number of clinical trials have now been completed, and a consensus is emerging regarding the indications for coronary revascularization based on stratification of risk.45-47 Coronary revascularization is indicated for improvement of survival in high-risk patients or for relief of symptoms as an alternative to medical therapy in low-risk patients.45-47 High-risk patients include

SCREENING AND TREATMENT FOR CARDIOVASCULAR DISEASE

those with left main CAD; three-vessel disease, moderate symptoms, and reduced LV function; and two-vessel disease and involvement of proximal left anterior descending coronary artery.47 In high-risk patients, CABG surgery reduces the rate of subsequent MI and improves survival, compared to medical therapy.46 CABG is generally preferred to PTCA in high-risk patients.46 Low-risk patients include those with single vessel disease and normal LV function.47 In these patients, a strategy of initial medical therapy is reasonable for relief of symptoms. PTCA provides greater alleviation of symptoms but does not improve rates of mortality or acute MI.46 Moderate-risk patients include those with multivessel CAD and normal LV function.47 Coronary revascularization is often necessary for relief of symptoms. In these patients, PTCA and CABG produce roughly equivalent rates of mortality and acute MI, but PTCA-treated patients require more revascularization procedures.46 Chronic Renal Disease Symptoms of myocardial ischemia in CRD appear similar to those in the general population, although there may be a higher prevalence of silent ischemia due to the higher prevalence of diabetes. Between 25% and 40% of asymptomatic renal transplant candidates have been found to have significant CAD when screened with coronary arteriography.48-50 Myocardial ischemia may be aggravated by anemia, increased LV end-diastolic pressure associated with ECF volume overload, and by fluid shifts during rapid ultrafiltration during hemodialysis. The medical treatment of the acute presentations of CAD (unstable angina and acute MI) are generally the same as in the general population.51 Similarly, the medical therapy for the nonacute presentations of CAD (stable angina and CHF) is also the same as in the general population. In addition, control of ECF volume and partial correction of anemia are important therapeutic adjuncts in CRD. The Amgen Normal Hematocrit Cardiac Trial compared the benefit of maintaining a normal hematocrit level, as compared to the usual target level of 30% in hemodialysis patients with preexisting cardiac disease. The normal hematocrit group had increased mortality and increased vascular access (both fistula and graft) loss.139 Consequently, normalization of hematocrit with

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erythropoietin is not recommended. Until further information becomes available, it is reasonable to adopt the NKF-DOQI recommendation of a target hematocrit of 33% to 36%.52,140 Further modification based on individual decision making is suggested. Contrast nephropathy. The risks of coronary arteriography for patients with CRD are somewhat different from the general population. Preexisting impairment in renal function is a major risk factor for contrast-induced acute renal insufficiency, and therefore, patients with CRI and RTRs are at higher risk for this complication.53 The risk of clinical nephrotoxicity is related to the severity of prior renal impairment, and in patients with marked impairment in renal function, infusion of radiocontrast during cardiac catheterization may precipitate ESRD.53 In maintenance HD and PD patients, intravenous contrast may cause a reduction in residual renal function. The risk of contrast-induced acute renal insufficiency in high-risk patients may be lessened by using nonionic contrast media54 and by saline infusion.55 Coronary artery bypass grafting. The potential risks and benefits of coronary revascularization procedures in patients with CRD are also different from the general population, although this has not been well studied to date. The existing studies are mostly small, retrospective, and generally do not make adjustment for comorbid factors. Given this, the reported perioperative mortality of CABG surgery in patients on PD or HD has ranged from 0% to 20%, substantially higher than in the general population (Table 1). It should be noted that in many of these case series, a substantial proportion of the patients had severe CAD (left main or three vessel disease) and/or required urgent surgery. When the results of existing studies are combined, the perioperative mortality is approximately 8% to 9%, about three times the expected rate for non-ESRD patients. When compared to the results of the Coronary Artery Surgery Study (CASS),68 however, this mortality rate is not different than that reported in non-ESRD patients with similar LV function, suggesting that perioperative mortality depends largely on LV function.69 In addition to the higher mortality rates, the perioperative morbidity of CABG surgery is significantly greater in dialysis patients than in matched controls.59,63

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Table 1. Perioperative (30-day) Mortality Rates and 1- to 5-Year Unadjusted Actuarial Survival Rates in HD or PD Patients Undergoing CABG Survival (%) Investigators

Year

No. of Patients

Perioperative Mortality (%)

1 yr

2 yr

3 yr

5 yr

Marshall et al56 Rostand et al57 Opsahl et al58 Deutch et al59 Blakeman et al60 Batiuk et al61 Ko et al62 Owen et al63 Rinehart et al64 Koyanagi et al65 Samuels et al66 Jahangiri et al67 Total/Mean

1986 1988 1988 1989 1990 1991 1993 1994 1995 1996 1996 1997

12 (25*) 20 39 16 26 25 16 21 60 23 13 19 290

1 (8) 4 (20) 1 (2.6) 1 (6) 0 5 (20) 3 (19) 2 (9) 2 (3) 0 4 (31) 1 (5) 24 (8.4)

83* — 92 — — 95 — 84 76 — — 87 86.2

— — 92 — — 77 — 45 66 — — 78 71.6

69* — — — — 70 — — 52 — — 59 62.5

48* — — — — — — — 40 83 — — 57

*Analysis includes patients from previously reported series.

In terms of long-term survival after revascularization, 2-year survival rates for HD and PD patients undergoing CABG have been reported to range from 45% to 92%, but again, adjustment for comorbid factors has generally not been performed (Table 1). Few studies have taken place for a long enough period of time to determine the 5-year cumulative survival of dialysis patients after CABG, but those that have suggest that it is approximately 50%.56,64,65 These unadjusted survival rates are similar to those seen in the ESRD population as a whole,70 but are much lower then the overall 5-year survival rate of 85% following CABG reported in the Coronary Artery Surgery Study.68 There have been no randomized trials of CABG versus medical management in patients with CRD and symptomatic CAD. In one retrospective study, 39 dialysis patients with intractable angina underwent CABG; these patients were matched with a control group of 39 dialysis patients with less severe CAD. There was no significant difference in 3-year survival probability when the risk of cardiac death was assessed, suggesting that patients with severe CAD do benefit from the procedure.58 In the only randomized trial of revascularization versus medical therapy in ESRD patients to date, 26 diabetic patients who were asymptomatic but were found to have one or more coronary artery stenosis on screening coronary angiography prior to renal transplantation were randomly assigned to either revasculariza-

tion (PTCA or CABG) or medical therapy.71 Only patients with an LV ejection fraction of 35% or more were randomized. Ten of 13 medically managed and two of 13 revascularized patients had a cardiovascular end point (unstable angina, MI, or cardiac death) within a median follow-up time of 8.4 months, and the trial was stopped early by an external review committee. Although this provides good evidence that revascularization improves the prognosis of asymptomatic CAD in this select population, it should be noted that medical therapy in this instance consisted only of a calcium channel blocking drug and aspirin. Furthermore, only 11 of 13 patients were taking the prescribed calcium channel blocker and only 8 were taking aspirin at the time of end point occurrence or at last follow-up.71 Irrespective of any survival benefit, CABG usually offers excellent symptomatic relief from angina pain.56,57,61,63 There is even less data concerning the risks and benefits of revascularization procedures in the other target groups, those with CRI and RTRs. There is some evidence, not surprisingly, that patients with CRI and CAD who are not dialysis dependent have higher perioperative morbidity after CABG.72,73 In a recent study, 38 patients undergoing CABG with a serum creatinine level greater than 150 µmol/L but not on dialysis were compared to a cohort of 152 patients matched on six prognostic variables. The patients with renal insufficiency had more comor-

SCREENING AND TREATMENT FOR CARDIOVASCULAR DISEASE

bidity and postoperatively were more likely to require blood transfusions. The renal insufficiency group had longer ventilation times, ICU stays and postoperative hospital stays, and required dialysis after CABG more frequently.73 Thus, CRI appears to be a significant adverse prognostic factor after CABG, at least in the short term. With respect to RTRs, there is no doubt that CVD is an extremely important factor in determining the short- and long-term survival of patients undergoing renal transplantation. CAD is the most frequent cause of late transplant recipient mortality and is more prevalent in diabetic patients.74,75 There is very little information as to the outcome of revascularization procedures in RTR, and the existing literature consists only of case reports and small series of patients. Given the results thus far, however, it is likely that RTRs with near normal renal function have a perioperative mortality rate and long-term survival rates associated with CABG that are comparable to the non-ESRD population.57,76-80 Coronary angioplasty. The role of PTCA in the management of CAD in patients with CRD has been questioned in recent years. This is mainly due to the fact that while PTCA is often initially successful in dilating stenotic vessels in patients with ESRD, it is associated with frequent recurrence of symptoms, usually resulting from restenosis (Table 2). In patients without ESRD, for comparison, the immediate success rate of PTCA is approximately 90%, and approximately one third will develop recurrent angina over the next 12 months due to restenosis.87 The

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results of the various studies of PTCA in ESRD patients are difficult to compare. In some cases, investigators have performed repeat cardiac catheterization in all patients in a series, but more often, only those patients with a recurrence of ischemic symptoms are subjected to repeat arteriography. This likely results in a bias overestimating of the rate of restenosis of coronary lesions. Early results from studies using PTCA with stenting of dilated vessels in the CRD population suggest a lower restenosis rate with this procedure,85,86 but these results are very preliminary and more studies are required. There are no studies comparing PTCA to medically managed patients with CRD and CAD. A comparison of 5,473 chronic dialysis patients who underwent PTCA and 6,798 dialysis patients who had CABG was undertaken using the USRDS database. No account was taken of selection bias in the choice of revascularization procedure. This bias makes comparison of rates between CABG and PTCA undesirable. The study demonstrated an initial all-cause, in-hospital mortality rate of 14.2% in the CABG group and 5.1% in the PTCA groups. Despite this initial difference in mortality, the PTCA group had higher long-term morbidity, as the MI risk for the PTCA group was 14% per year compared to 6% per year in the CABG group (P ⬍ 0.05).88 This is consistent with the results of a retrospective study in which 24 ESRD patients with symptomatic CAD were treated with PTCA and 60 patients were treated with CABG. The 2-year survival rate was 66% in the CABG group and 51%

Table 2. Initial Success Rates and Rates of Restenosis (6 months to 1 year) for PTCA in Patients With ESRD No. of PTCAs

Restenosis on Repeat Angiogram

Investigators

Year

Patients

Lesions

Success

Symptom Recurrence

Patients

Lesions

Kahn et al81 Reusser et al82 Ahmed et al83 Rinehart et al64 Koyanagi et al65 Schoebel et al84 Toriyama et al85 Toriyama et al85 ‡ Kishore et al86 ‡

1990 1994 1994 1995 1996 1997 1997 1997 1997

17 13 21 24 20 20 — — 12

49 13 23 25 38 — 83 29 16

47/49 12/13 12/21 23/25 29/38 20/20 — — 16/16

12/15* 6/12 9/11* 13/22* — 13/20 — — 4/11*

11/12† 2/3† 7/7† 9/13† 7/10† 12/20 — — 3/4,† 1/7

26/32† 2/3† — — — — 46/83 8/29 —

*Excludes patients not discharged with a patent angioplasty vessel or death as initial manifestation of recurrent disease. †Repeat coronary arteriography in patients with recurrent ischemic symptoms. ‡Studies using PTCA with coronary artery stenting.

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in the PTCA group. The incidence of recurrent angina or the combined end points of angina, MI, or cardiovascular death within the 66 months of follow-up was 88% after PTCA and 47% after CABG.64 A more recent study reported on 23 dialysis patients who underwent CABG and 20 who had PTCA. A 5-year cardiac event-free survival of 70% was found in the CABG-treated patients and 18% in the PTCA group.65 Most of the existing data, therefore, suggest that while the overall survival of CRD patients treated with PTCA and CABG may not be different, there is a substantially higher long-term cardiac morbidity rate associated with PTCA. There are no data concerning the efficacy of PTCA in the other target groups, those patients with CRI and RTR. Overall, the indications for coronary revascularization in CRD are generally similar to those in the general population. In high-risk patients and in patients with persistent symptoms of myocardial ischemia despite maximal medical therapy, whose life expectancy is greater then six months, revascularization appears to be beneficial. CABG is currently the revascularization procedure of choice, although angioplasty with stenting may prove to be a reasonable alternative in single vessel disease or multiple vessel disease with culprit lesions. In the latter antiplatelet therapy used with stenting could theoretically exacerbate the bleeding diathesis of uremia. As in the general population, coronary arteriography should be reserved for patients in whom revascularization would be undertaken if critical CAD were identified. TREATMENT OF LEFT VENTRICULAR HYPERTROPHY WITH ANTIHYPERTENSIVE AGENTS AND CORRECTION OF ANEMIA

Clinical Recommendations ● Hypertension and anemia are associated with LVH in CRD. ● Treatment of hypertension and anemia cause regression of LVH in CRD, but the effect on clinical CVD outcomes is not known. ● It is not known if target blood pressure in patients with LVH should be lower than recommended elsewhere for the treatment of hypertension. All classes of antihypertensive agents suitable for initial therapy are effective in causing

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regression of LVH in the general population, and there is not sufficient evidence to recommend the superiority of any class of agent for regression of LVH. ● Optimal target hematocrit for the correction of anemia for regression of LVH is not known. Based on current guidelines for the treatment of anemia to improve exercise tolerance and quality of life, it is reasonable to recommend a target hematocrit of 33% to 36%. Introduction Treatment of hypertension leads to regression of LVH in the general population and is associated with improved CVD outcomes.89,90 Almost all classes of antihypertensive agents have been shown to induce regression of LVH in the general population, although some studies show superiority of ACE inhibitors over other antihypertensive agents.91,92 A recent observational study of 430 patients with essential hypertension has shown that a reduction in LV mass during treatment is a favorable prognostic marker that predicts a decreased risk of future CVD events, independent of baseline LV mass, baseline blood pressure, and degree of blood pressure reduction.93 However, no controlled studies show that regression of LVH offers additional benefits beyond that offered by reduction of blood pressure. Consequently, the JNC recommendations94 for blood pressure control in the general population do not differ for patients with or without LVH: optimal blood pressure control is defined as ⱕ 120/80 mm Hg, the target blood pressure for antihypertensive therapy is ⬍ 140/90 mm Hg. Chronic Renal Disease LVH is very common in patients with CRD. Eighty-four percent of patients have LVH, LV dilatation, or low fractional shortening at the initiation of ESRD therapy.95-97 LVH has been found in 38% of patients with CRI prior to the requirement for dialysis.98 The pathogenesis of LVH in this group is considered to be multifactorial,99 but in the ESRD population hypertension is associated with progression of LVH,96,100-102 and the presence of LVH and/or LV dilation is clearly a poor prognostic factor.95,96 As in the general population, there is evidence that treatment of hypertension leads to regression of LVH in patients with CRD.103-105 It is likely that a

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number of classes of antihypertensive agents lead to regression of LVH. In one study of a small number of hypertensive dialysis patients, it was found that combined antihypertensive therapy using ACE inhibitors, calcium antagonists, and β-blockers over a period of 2 years was associated with a decrease in LV mass.103 There is increasing evidence, however, that ACE inhibitors are more effective than other antihypertensive agents in causing LVH regression. In the only randomized trial thus far in ESRD patients, 14 patients were randomized to the ACE inhibitor, perindopril, and 10 received the calcium channel blocker, nitrendipine. After 1 year, only the perindopril-treated patients had a significant reduction in LV mass, and this was independent of the changes in blood pressure.105 A more recent study randomized 72 hypertensive patients with LVH and CRI who did not require dialysis to monotherapy with either captopril or enalapril. At 1 year, there was a significant reduction in LV mass index of approximately 20% in both groups.104 It has been proposed that ACE inhibitors induce regression of LVH by mechanisms independent of their antihypertensive effect.106 This is supported by a nonrandomized observational study of a small number of normotensive dialysis patients with LVH who were treated with lisinopril that was administered as 2.5 to 20 mg every other day for 2 years. The investigators found a significant reduction of LV mass in the treated patients versus untreated controls.107 However, as in the general population, it is not known whether the regression of LVH in patients with CRD leads to greater improvement in CVD outcomes than control of blood pressure alone. There is not sufficient evidence to support the superiority of one class of antihypertensive agents for regression of LVH in CRD. Therefore, it is reasonable to use the recommendations already developed for target blood pressure and antihypertensive agents of choice in CRD target populations (see Table 2, p. S123). Anemia is also associated with the progression of LVH in the ESRD population.98,102,108,109 Partial correction of anemia using recombinant erythropoietin has consistently been shown to induce some regression of LVH.110-114 In Canada, a randomized, controlled trial of normalization of hemoglobin with erythropoietin versus partial

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correction of anemia in HD patients without symptomatic cardiac disease but who have LV disorders is reaching completion. The optimal target hematocrit for the treatment of anemia for regression of LVH is not known. Based on current NKF-DOQI guidelines52 for treatment of anemia to improve exercise tolerance and quality of life in HD and PD, it is reasonable to recommend a target hematocrit of 33% to 36%. SCREENING FOR CORONARY ARTERY DISEASE

Clinical Recommendations ● The prevalence of asymptomatic CAD is 20% to 40% in CRD. ● Routine screening for inducible ischemia is not recommended in CRD patients without clinical manifestations of CVD. ● It is reasonable to use general population guidelines for screening prior to noncardiac surgery in patients with CRD. Screening is recommended when the combination of risk factors and the nature of the surgery places the patient at moderate risk of an acute presentation of CAD. ● Screening of potential RTRs is a special case of preoperative screening. The rationale for screening this target population is the planned elective noncardiac surgery (as discussed above) and the desire to avoid subsequent renal allograft injury associated with cardiac catheterization. The American Society of Transplant Physicians (ASTP) recommends screening all patients except those at lowest risk. Introduction Asymptomatic individuals may be screened for CAD by stress testing to detect inducible ischemia. Exercise, dipyridamole, and dobutamine are the tools most commonly used to induce myocardial ischemia. Methods available for detecting ischemia include thallium or sestamibi scintigraphy and echocardiography. The criterion standard for evaluating these diagnostic tests is coronary arteriography. The sensitivity and specificity of these tests in detecting CAD in the general population is approximately 80% to 90% (Table 3). A major but uncommon side effect of all tests is precipitation of unstable angina or acute MI. The prevalence of CAD in asymptomatic individuals in the general population is not known

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Table 3. Sensitivity and Specificity of Stress Testing for Inducible Ischemia (%, as Compared to Coronary Arteriography) in the General Population and in Patients With CRD Chronic Renal Disease†

General Population* Method

Sensitivity Specificity Sensitivity Specificity

Exercise ECG Dipyridamoleradionuclide Dobutamineechocardiography

65

85

⬍50‡

⬍50‡

80§

80

40-85

75-80

80

90

70-95

95

ischemia.2 The American Heart Association, American College of Cardiology, and American College of Physicians have issued clinical practice guidelines for screening prior to noncardiac surgery.117,118 These groups recommend screening prior to noncardiac surgery when the combination of clinical risk factors and the nature of the surgery places the patient at moderate cardiovascular risk (Table 4). Chronic Renal Disease

*Data from Braun & Marwick.115 †Data from Murphy & Parfrey.116 ‡Limited by frequent inability to exercise to target heart rate. §Lower in patients with diabetes.

precisely. Studies of routine screening in asymptomatic individuals do not show a benefit. The US Preventative Health Services Task Force does not recommend routine screening for inducible

The prevalence of CAD in nondiabetic CRD is approximately 20%.96 The prevalence is between 30% and 50% in diabetic CRD and rises considerably with age.121-123 The prevalence of silent ischemia is high in this population. This has been best demonstrated in diabetic ESRD patients, because they are often subjected to screening coronary angiography before renal transplantation. In one series of 100 diabetics with ESRD, for example, 75% of the patients with angiographically demonstrated CAD had no typical angina symptoms.122 The prevalence of asymp-

Table 4. Comparison of Indications for Stress Testing Before Elective Surgery in the General Population and Befre Renal Transplantation General Population*

RTR Candidates†

Low-Risk

Intermediate-Risk

⬍3 MRCI§ Class I

3-15 MRCI Class I

Risk factors

⬍2

ⱖ2

NA

Type of surgery

—

Nonvascular Vascular

—

—

—

—

Decision for stress testing

No

Yes,㛳 or proceed to coronary arteriography if indicated

No

Yes

No, proceed to coronary arteriography㛳

Risk (%)‡ History

No

Yes

High-Risk

⬎15 MRCI Class II-III

Low-Risk

High-Risk

— — No history of History of CAD CAD or CHF or CHF Nondiabetic and age ⬍50 yrs

— Persistent myocardial ischemia

Diabetic and Diabetic and aged ⬍50 aged ⬎50 year, or nonyears diabetic and aged ⬎50 years

*ACP Clinical Guideline. Ann Intern Med 127:309-312, 1997. †ASTP Clinical Practice Guideline. J Am Soc Nephrol 6:1-34, 1995. de Lemos JA, Hillis LD: J Am Soc Nephrol 7:2044-2054, 1996. ‡Risk for perioperative MI or death from CAD. §Modified Cardiac Risk Index (includes history of MI, angina, CHF, aortic stenosis, arrhythmias, age, comorbid conditions, functional status, emergency v elective surgery; see ACP Clinical Guidelines.118 㛳If a candidate for coronary revascularization.

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tomatic CAD in nondiabetic ESRD patients is less well defined. Overall, these values are probably higher than in the general population. As in the general population, exercise and pharmacological agents can be used to induce myocardial ischemia, and radionucleotide scintigraphy and echocardiography can be used to detect ischemia. Exercise electrocardiography has been the traditional method of noninvasive testing for CAD. The sensitivity of exercise electrocardiography is only 50% to 60% for single vessel disease but exceeds 85% for triple vessel disease in the non-ESRD population.124 This assumes, however, that the patients achieve an adequate exercise level (ie, 85% of the ageadjusted predicted maximal heart rate). The majority of patients with CRD cannot exercise to work loads that produce myocardial ischemia because of poor exercise tolerance or cardiodepressant medications. In one study of 85 diabetic uremic patients, only six achieved an adequate exercise level125; similar results were found in another study, with only 12 of 60 diabetic ESRD patients achieving adequate heart rates.121 For this reason, there is increased reliance on pharmacological agents for noninvasive testing for CAD in these patients. One of the most widely available methods currently in use is dipyridamolethallium testing. The sensitivity of this method ranges from 37% to 86% and the specificity is about 75% in ESRD patients.126-128 A positive dipyridamole-thallium scan has been found to be a significant predictor for future adverse cardiovascular events in this population.129-132 Somewhat better results have been reported using dobutamine echocardiography. The reported sensitivity in patients with CRD is very high at 69% to 95%, and the specificity is approximately 95%,133-135 making this method the test of choice if it is available. Overall, the risk of precipitation of unstable angina or MI by stress testing appears to be low. In 60 asymptomatic hemodialysis patients combined dipyridamole-exercise thallium imaging had a sensitivity of 92%, a specificity of 89%, and an overall accuracy of 90% for detection of coronary stenosis. This test was also a strong risk factor for future coronary events.141 The risk and benefit of screening asymptomatic patients with CRD has not been studied

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carefully, with the exception of patients being evaluated for renal transplantation. As discussed above, the incidence of silent ischemia in ESRD patients is high, particularly in diabetics. In the general population, there is some suggestion that silent ischemia might lead to an increased mortality rate.136,137 There is no evidence, however, that revascularization of such patients would prolong their survival. Even though the prevalence of CAD in asymptomatic persons may be higher in patients with CRD than in the general population, the additional risks of coronary arteriography and the absence of proven benefit make it difficult to recommend routine screening of these patients. It is reasonable to follow the general population recommendations for screening prior to noncardiac surgery in CRD. An additional side effect of screening in patients with CRI or RTRs would be the potential for acute renal insufficiency following coronary arteriography or loss of residual renal function in HD and PD patients. Patients undergoing renal transplantation evaluation may be a special case. The rationale for screening transplant candidates is the planned elective surgery and the wish to avoid subsequent renal allograft injury due to cardiac catheterization and contrast administration. As discussed earlier, one randomized trial of a small number of diabetic transplant candidates showed that a strategy of screening coronary arteriography and CABG surgery or PTCA prior to transplantation reduced acute MI and CAD mortality compared to medical therapy.71 However, whether screening would improve survival in lower risk patients is not known. The American Society of Transplant Physicians (ASTP) recommends screening in all patients except those at lowest risk (Table 4). Patients at highest risk (ie, with symptoms of angina and a history of CAD or asymptomatic individuals with diabetes and those over age 50) may simply undergo coronary arteriography without noninvasive testing.119 SCREENING FOR LVH

Clinical Recommendations ● The prevalence of asymptomatic LVH in CRD is 50% to 75% and varies inversely with the level of renal function. ● Currently, recommendations for treatment of hypertension and anemia in CRD patients

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without clinical manifestations of CVD do not differ in patients with or without LVH. ● At the present time, there is not sufficient evidence to recommend for or against routine screening for increased LV mass in CRD patients without clinical manifestations of CVD. Introduction The criterion standard for detection of LVH is evaluation of LV mass by echocardiography. Echocardiography is widely available and free of major adverse side effects. LV mass in asymptomatic individuals within the general population varies with age, gender, weight, and blood pressure. In the general population, increased LV mass is a risk factor for CVD, notably MI, CHF, and death.89,90 Presently, recommendations for the treatment of hypertension do not differ for patients with or without LVH.94 Consequently, screening for increased LV mass is not recommended for individuals without clinical manifestations of CVD. Chronic Renal Disease The prevalence of asymptomatic LVH in CRD is higher than in the general population and varies directly with the level of blood pressure and inversely with the level of renal function and hematocrit.95-97 In addition to detecting increased LV mass, echocardiography can detect a number of other abnormal patterns of LV structure and function, which are highly prevalent in CRD and associated with subsequent CVD, including LV dilation and systolic dysfunction.93 There is a high rate of interobserver agreement in interpreting two-dimensional echocardiograms from hemodialysis patients.138 Such patients can, however, have significant alterations of their LV end-diastolic volumes because their plasma volume increases between dialyses, and therefore standardization of the timing of echocardiograms relative to their dialysis sessions is advisable.138 There are no studies comparing management of asymptomatic patients with CRD who underwent routine screening for LVH versus those who did not. Presently, there are not sufficient data to recommend for or against routine screening of asymptomatic persons with CRD.

MURPHY, FOLEY, AND PARFREY

RESEARCH RECOMMENDATIONS

Observational Studies ● Determine the levels of fibrinogen and its association with CVD risk factors, CVD outcomes, and CRD outcomes ● Determine whether defects in platelet function are associated with CVD and CRD outcomes. ● In HD patients, determine whether thrombogenic factors or defects in platelet function are associated with HD vascular access thrombosis. ● Determine if the distribution of CAD lesions is different than in the general population. ● Determine risk factors for myocardial ischemia in the absence of CAD. ● Determine sensitivity and specificity of ECG and cardiac enzyme criteria for acute MI. ● Determine the clinical presentations associated with echocardiographic abnormalities. ● Compare prognostic significance of clinical diagnosis of congestive heart failure versus echocardiographic determination of LV dysfunction. ● Determine the relationship of anemia to CVD mortality and morbidity. ● Establish registries for CRD patients undergoing cardiac catheterization and revascularization procedures. Clinical Trials ● Determine the safety of aspirin and other antiplatelet therapy. ● Determine the effect of aspirin and other antiplatelet therapy on CVD and CRD outcomes. ● In HD patients, determine the effect of aspirin and other antiplatelet agents on vascular access thrombosis. ● In HD and PD patients, determine the effects of β-blockers on arrhythmias and CVD mortality. ● In HD and PD patients, determine the effect of ACE inhibitors on LV mass and CVD mortality. ● In HD and PD patients, compare the results of CABG versus PTCA with stents on CVD outcomes. ● Determine effect of various target hematocrit levels for treatment of anemia on LV mass and clinical CVD outcomes.

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