The Cardio-Kidney Patient: Epidemiology, Clinical Characteristics and Therapy

Abstract

Patients with chronic kidney disease (CKD) are at high risk to develop cardiovascular disease with its manifestations coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. In addition, the presence of CKD has a major impact on the prognosis of patients with cardiovascular disease, leading to an increased morbidity and mortality if both comorbidities are present. Therapeutic options including medical therapy and interventional treatment are often limited in patients with advanced CKD, and in most cardiovascular outcome trials, patients with advanced CKD have been excluded. Thus, in many patients, treatment strategies for cardiovascular disease need to be extrapolated from trials conducted in patients without CKD. The current article summarizes the epidemiology, clinical presentation, and treatment options for the most prevalent manifestations of cardiovascular disease in CKD and discusses the currently available treatment options to reduce morbidity and mortality in this high-risk population.

Patients with chronic kidney disease (CKD) exhibit an elevated risk to develop cardiovascular disease (CVD) with its different manifestations of coronary artery disease (CAD), heart failure (HF), or arrhythmias and sudden cardiac death (SCD). The complex interaction with pathophysiological characteristics of CKD like activation of the renin-angiotensin system, fluid retention, or oxidative stress lead to changes in the heart such as ventricular hypertrophy or fibrosis (reviewed in the study by Jankowski et al¹). In contrast, HF contributes to congestion, hypoperfusion, and declining kidney function, thus promoting kidney failure. Figure 1 depicts in a simplified manner the interaction between CVD and CKD.

Figure 1.

Simplified scheme depicting the interaction of cardiovascular disease and chronic kidney disease. RAAS indicates renin-angiotensin-aldosterone; and SNS, sympathetic nerve system.

Epidemiology

CKD is one of the strongest risk factors for CVD as manifested by CAD, HF, arrhythmias, and SCD. Patients with CKD exhibit a pronounced risk for cardiovascular events with 50% of all patients with CKD stage 4/5 experiencing CVD. In addition, cardiovascular mortality accounts for 40% to 50% of all deaths in patients with advanced CKD stages 4 and 5. Cardiovascular mortality increases as soon as the eGFR (estimated glomerular filtration rate) drops below a level of 60 to 75 mL/min per 1.73 m² with a hazard ratio (HR) between 2.5 and 3 in those with CKD stage 3b as shown by data from the CKD prognosis consortium that included 629 746 patients.² In addition, similarly, cardiovascular mortality increases as the urine albumin-creatinine ratio (UACR) exceeds 5 mg/g with a tremendous increase in patients with a UACR above 300 mg/g.³

Since estimation of clinical outcomes in patients with CKD helps to guide patient counseling and therapy, the International CKD Prognosis Consortium developed a calibrated risk assessment tool that can predict the timing and occurrence of clinical outcomes in patients with severely decreased eGFR based on commonly measured clinical characteristics.⁴

Cardiovascular Risk Reduction in CKD

Blood Pressure Lowering

Hypertension is a major risk factor for CVD and CKD while cardiovascular events can effectively be reduced by blood pressure lowering in patients with and without CKD. A meta-analysis of 18 randomized controlled trials including 15 924 participants with CKD found more intensive blood pressure lowering (from 148 to 132 mm Hg) to result in a significant 14% reduction in all-cause mortality (odds ratio [OR], 0.86 [95% CI, 0.76–0.97]; P=0.01) in comparison to a less intensive blood pressure lowering (from 148 to 140 mm Hg) with similar efficacy in patients with more or less severe renal dysfunction.⁵ Blood pressure targets do consequently not differ in patients with CKD aiming for a reduction <140/90 mm Hg in all patients, which should be extended to <130/80 mm Hg if tolerated.⁶ Ongoing controversy exists whether systolic blood pressure should further be lowered to targets <120 mm Hg. This debate was steered by the SPRINT trial (Systolic Blood Pressure Intervention Trial), which randomized patients without diabetes (n=9361) with a systolic blood pressure >130 mm Hg to a target of <120 mm Hg in comparison to <140 mm Hg. Importantly, intensified blood pressure lowering led to reduced cardiovascular events (HR, 0.75 [95% CI, 0.64–0.89]; P<0.001) and all-cause mortality (HR, 0.73 [95% CI, 0.60–0.90]; P=0.003), which was similarly found in patients with and without CKD, suggesting broad applicability.^7,8 Interpretation of trial results remains, however, complicated due to a specific methodology with unattended blood pressure measurements performed in the SPRINT trial, which does not match the general assessment of office blood pressure in clinical practice.⁹ This uncertainty has created deviating blood pressure recommendations by different societies. The Kidney Disease: Improving Global Outcomes 2021 guideline adopted the results of the SPRINT trial and recommends systolic blood pressure to be lowered <120 mm Hg in patients with CKD but without diabetes.¹⁰ In contrast, the European Society of Cardiology and American College of Cardiology/American Heart Association guidelines recommend office blood pressure targets <130/80 mm Hg in patients with CKD with the European Society of Cardiology guideline advocating to avoid systolic blood pressure values <120 mm Hg.^6,11

Prognostic improvement has best been documented for ACE (angiotensin-converting enzyme) inhibitors, which in a network meta-analysis of 44 randomized trials including 42 319 patients with CKD lowered kidney events by 46% (OR, 0.54 [95% CI, 0.41–0.73]), cardiovascular events by 27% (OR, 0.73 [95% CI, 0.64–0.84]), cardiovascular death by 27% (OR, 0.73 [95% CI, 0.63–0.86]), and all-cause death by 23% (OR, 0.77 [95% CI, 0.66–0.91]) when compared with placebo.¹² Still, blood pressure lowering especially with renin-angiotensin-system (RAS) inhibitors often increases serum creatinine. This is thought to reflect reversible hemodynamic effects in the kidney and not renal injury. The recently published STOP ACEi trial (multi-centre randomised controlled trial of angiotensin converting enzyme inhibitor [ACEi]/angiotensin receptor blocker [ARB] withdrawal in advanced renal disease) randomized 411 patients with advanced CKD (eGFR, <30 mL/min per 1.73 m² of the body surface area) to either discontinuation or continuation of RAS inhibition. During a mean follow-up of 3 years, no difference was observed in renal function between both treatment groups while end-stage kidney disease occurred numerically more often in the discontinuation group (62% versus 56%; HR, 1.28 [95% CI, 0.99–1.65]). No statistical difference in adverse events was found between both groups, which by number occurred, however, more often in the discontinuation group (cardiovascular events, 108 versus 88; deaths, 20 versus 22). These results support the continuation of RAS inhibition in advanced kidney disease.¹³

Lipid Lowering

Lipid abnormalities characteristically found in patients with CKD include high triglycerides, low HDL (high-density lipoprotein) cholesterol (HDL-C), and small dense LDL (low-density lipoprotein) particles.¹⁴ These lipid abnormalities mimic and overlap with metabolic disease and diabetes as the most prevalent cause for CKD. Atherosclerosis is driven by lipid particles entering the subendothelial vascular space to promote foam cell formation and immune cell recruitment.¹⁵ Among all lipid particles, LDL cholesterol (LDL-C) has the highest atherogenic potential, which similarly holds true for patients with or without CKD. Epidemiological and genetic studies suggest triglyceride-rich lipoproteins and their remnant particles to also provide atherogenic potential.¹⁵ Prevention and treatment of CVD is, however, most efficiently reached by LDL-C reduction, making LDL-C the primary target for lipid-lowering therapy. Every atherogenic lipid particle incorporates 1 ApoB (apolipoprotein B) lipoprotein. Circulating ApoB concentrations can consequently be used to quantify the number of atherogenic lipid particles and can substitute LDL-C as a therapeutic target. Non–HDL-C (total cholesterol−HDL-C) quantifies the atherogenic cholesterol and is considered a secondary therapeutic goal after reaching LDL-C targets.¹⁵

Effectiveness of LDL-C–lowering therapy is most efficiently reached in patients with high baseline cholesterol and high cardiovascular risk. Impaired kidney function is sufficient to justify aggressive LDL-C reduction. A meta-analysis of 31 trials including 48 429 patients with CKD demonstrated statin-dependent LDL-C lowering to significantly reduce cardiovascular risk by 23% and all-cause mortality by 9% in the CKD population.¹⁶ In the SHARP Trial (Study of Heart and Renal Protection), 9270 patients with CKD (mean eGFR, 26.6 mL/min; including 20% with a eGFR <15 mL/min) were randomized to simvastatin 20 mg/ezetimibe 10 mg versus placebo, resulting in 32 mg/dL lower LDL-C and a 17% reduction of cardiovascular events.¹⁷ Using PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition, similar cardiovascular risk reduction was reached in patients with and without CKD in the FOURIER trial (Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease Trial),¹⁸ although PCSK9 inhibition less efficiently lowered cardiovascular risk in patients with CKD in the ODYSSEY OUTCOMES trial (Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome Trial).¹⁹

Importantly, cardiovascular efficacy of LDL-C reduction declines with progressive impairment of renal function and is lost in patients with end-stage renal disease. This was demonstrated in the German Diabetes and Dialysis Study in which cardiovascular risk was not reduced by atorvastatin 20 mg in 1255 patients with diabetes and end-stage renal disease despite 41% LDL-C lowering.²⁰ Also, in AURORA (Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis), rosuvastatin 10 mg did not modify cardiovascular risk (relative risk [RR], 0.96 [95% CI, 0.84–1.11]; P=0.59) in 2776 patients requiring hemodialysis despite 43% LDL-C reduction.²¹ Consistently, a meta-analysis of 28 statin trials including 183 419 patients reported declining cardiovascular efficacy of LDL-C reduction with progressive renal impairment. While patients with eGFR ≥60 mL/min per 1.73 m² experienced relative cardiovascular risk reduction of 22% (RR, 0.78 [CI, 0.75–0.82]) for every mmol of LDL-C lowering (38 mg/dL), this remained present for patients with eGFR 45 to 60 mL/min per 1.73 m² (RR, 0.76 [95% CI, 0.70–0.81]), while effectiveness was reduced for eGFR 30 to 45 mL/min per 1.73 m² (RR, 0.85 [95% CI, 0.75–0.96]) and lost in patients requiring dialysis (RR, 0.94 [95% CI, 0.79–1.11]).²² The mechanisms responsible for this decline of efficacy of LDL-C–lowering therapy with progressive CKD remain incompletely understood but may be attributable to competing risk from nonvascular causes of disease. As a consequence, other prevailing risk factors including inflammation and oxidative stress are currently explored as possible therapeutic targets in the CKD population.

In clinical praxis, Kidney Disease: Improving Global Outcomes recommends all patients with CKD >50 years with eGFR <60 mL/min per 1.73 m² but not receiving chronic dialysis (eGFR categories G3a–G5) to be treated with statin or statin/ezetimibe combination independent of baseline LDL-C.²³ The European Society of Cardiology guidelines recommend LDL-C targets <70 mg/dL (ApoB, <80 mg/dL; non–HDL-C, <100 mg/dL) for CKD stage 3 and LDL-C <55 mg/dL (ApoB, <65 mg/dL; non–HDL-C, <85 mg/dL) for CKD stage 4/5 in combination with at least 50% reduction of baseline LDL-C.¹⁵ Kidney transplant recipients are also recommended to receive statin therapy, although backed by limited trial evidence.²³ Initiation of statin therapy is not recommended in patients requiring dialysis but should be continued if prescribed earlier.¹⁵

Myalgia remains the most prevalent adverse event in statin-treated patients. No dose adjustment of statin therapy is required for CKD stage 3, whereas only moderate statin doses should be prescribed in CKD stage 4/5. Ezetimibe is recommended for patients with insufficient statin-dependent LDL-C reduction reaching additional 15% to 20% LDL-C reduction with no need for dose adjustment in CKD. Additional LDL-C lowering can be reached by PCSK9 inhibition providing 50% to 60% LDL-C reduction. PCSK9 inhibition can be performed with antibodies (evolocumab or alirocumab) requiring drug application every second week or in monthly intervals,^24,25 while it can also be reached by a siRNA (inclisiran) targeting hepatic protein synthesis with 6 monthly application intervals.²⁶ No dose adjustment of either strategy is required in CKD. Cardiovascular outcome data still need to be established for inclisiran. As an additional drug, LDL-C reduction can be reached with bempedonic acid inhibiting hepatic ACL (ATP citrate lyase) as part of the cholesterol synthesis pathway. Bempedonic acid lowers LDL-C by 15% to 20% with no need for dose adjustments in mild or moderate renal impairment.²⁷ Bempedonic acid mildly increases creatinine concentrations in a reversible manner. Cardiovascular outcome data still need to be presented.

After reaching LDL-C targets, non–HDL-C provides a secondary therapeutic goal especially relevant for patients with high triglycerides. Lowering of triglycerides should primarily by reached by lifestyle and dietary interventions. Pharmacological triglyceride lowering can be reached by fibrates, nicotinic acid, and omega-3 fatty acids. Application of fibrates or nicotinic acid failed to reduce cardiovascular risk in various trials in statin-treated patients.²⁸ As a limitation, these studies did not select patients with high baseline triglycerides. Still, in the recently published PROMINENT trial (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes Trial), pemafibrate failed to lower cardiovascular risk in statin-treated patients with diabetes and elevated triglycerides.²⁹ As a consequence, high triglycerides and low HDL-C do not provide a target of pharmacological therapy and should only be considered as an indicator of cardiovascular risk.

Triglyceride lowering can further be reached by high-dose omega-3 fatty acids (>2 g/day), but data on cardiovascular outcome remain controversial.

Glucose Lowering

Diabetes is a strong risk factor for both CVD and CKD. Tight glycemic control have been shown to reduce worsening of diabetic nephropathy as assessed by albuminuria, independent of the glucose-lowering agent used. Current guidelines recommend personalized HbA1c (hemoglobin A1c) targets with a general suggestion of an HbA1c <7% with the avoidance of hypoglycemia.³⁰ With respect to the effect of certain glucose-lowering agents, the ongoing FLOW trial (A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease Trial) is investigating the effect of once weekly semaglutide subcutaneous versus placebo in patients with CKD on kidney disease progression and the risk of death related to the kidneys or the cardiovascular system (https://www.clinicaltrials.gov; unique identifier: NCT03819153).

SGLT2 Inhibitors

Three large cardiovascular outcome trials assessed the effect of SGLT2 (sodium-glucose cotransporter 2) inhibitors in patients with CKD with and without diabetes. CREDENCE (Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy)³¹ included patients with CKD and type 2 diabetes while DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease)³² and EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease)³³ also enrolled patients without diabetes. A recent meta-analysis showed that SGLT2 inhibitor treatment in patients with CKD (mean eGFR, between 40 and 45 mL/min per 1.73 m²) reduces both the risk of kidney disease progression and the risk of cardiovascular death or hospitalization for HF with comparable effects on kidney disease progressions in patients with or without diabetes.³⁴ In addition, the SCORED (Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease) trial included 10 584 patients with type 2 diabetes and CKD with an estimated glomerular filtration rate of 25 to 60 mL/min per 1.73 m² of body surface area and risks for CVD to receive sotagliflozin, an SGLT1/2 inhibitor, or placebo. Sotagliflozin reduced the primary end point—a composite of the total number of deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF—by 26%.³⁵ Patients with CKD are at increased risk of hyperkalemia. A recent meta-analysis investigated in 6 trials (EMPAREG-Outcome [Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes], CANVAS-Program [Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes], DECLARE-TIMI 58 [Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes], VERTIS-CV [Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes], CREDENCE, and DAPA-CKD) including a total of 49 875 participants with diabetes and CKD stage 4 different SGLT2 inhibitors. The use of SGLT2 inhibitors reduced the risk of serious hyperkaliemia, defined as a potassium ≥6.0 mmol/L, by 16%.³⁶

Finerenone

Two dedicated trials (FIGARO-DKD [Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes]³⁷ and FIDELIO-DKD³⁸) assessed the effect of the novel nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in patients with diabetes and CKD. Both trials demonstrated that finerenone compared with placebo reduced the risk of kidney failure and cardiovascular events. A prespecified pooled efficacy and safety analysis of these trials, named FIDELITY (Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis), showed in 13 171 patients that finerenone on top of optimized RAS blockade significantly reduced the risk of the composite cardiovascular outcome of time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or HF hospitalization by 14%, with a number needed to treat over 3 years of 46.³⁹ The effect was mainly driven by a reduction in HF hospitalization despite the fact that patients with a history of HF with reduced ejection fraction (HFrEF) were excluded in these studies. The effect of finerenone on HF-related outcomes was not modified by baseline eGFR or UACR or the presence or absence of HF at baseline.⁴⁰ Still, the analysis also demonstrated a nonsignificant trend for a reduction of cardiovascular death or nonfatal myocardial infarction. In addition, finerenone significantly reduced the risk of the composite kidney outcome (kidney failure, sustained eGFR decrease ≥57%, or renal death) by 27% with a number needed to treat of 60 over 3 years. Interestingly, a small proportion of patients in these trials were also treated with an SGLT2 inhibitor, and predefined subgroup analyses suggest that the effect of finerenone is independent of a concurrent treatment with an SGLT2 inhibitor.

Figure 2 summarizes current strategies to reduce cardiorenal risk in patients with CKD.

Figure 2.

Reduction of cardiorenal risk in patients with chronic kidney disease (CKD). ACE indicates angiotensin-converting enzyme; ARB, angiotensin-II receptor blocker; CV, cardiovascular; Hba1c, glycated hemoglobin; HHF, hospitalization for heart failure; HR, hazard ratio; LDL, low-density lipoprotein; OR, odds ratio; SGLT2, sodium-glucose cotransporter 2; and T2D, type 2 diabetes mellitus. ¹Fatal or nonfatal myocardial infarction, stroke, and heart failure; cardiovascular death. ²Doubling of serum creatinine level, 50% decline in eGFR, or end-stage kidney disease (ESKD). ³All SGLT2 inhibitor CVOTs (cardiovascular outcome trials). ⁴Only SGLT2 inhibitor trials in patients with CKD. ⁵Sustained decrease in eGFR (estimated glomerular filtration rate) (≥50%) from randomization, a sustained low eGFR, end-stage kidney disease, or death from kidney failure. ⁶Kidney failure (ESKD or an eGFR <15 mL/min per 1.73 m²), sustained ≥57% decrease in eGFR from baseline, or renal death. ⁷ESKD or an eGFR <15 mL/min per 1.73 m².

CAD and CKD

Cardiovascular risk of patients with CKD is multifactorial and attributable to classical risk factors and comorbidities including hypertension, dyslipidemia, and diabetes often present in this population in conjunction with less-well-defined kidney-specific risk modifiers related to disturbed renal hemostasis, calcium-phosphate metabolism, and accumulation of uremic toxins.⁴¹ This leads to a more complex atherosclerotic vascular pathology present in CKD combining diffuse macrovascular disease with prominent calcification, greater atherosclerotic necrotic core, and higher prevalence of plaque rupture in addition to microvascular dysfunction.⁴¹ A recent study found atherosclerotic disease progression especially in patients with declining renal function featuring noncalcified lesions while stable CKD patients rather progressed with calcified plaques.⁴²

Classical cardiovascular risk calculators do not incorporate renal function and systematically underestimate cardiovascular risk of the CKD population. This has made eGFR <60 mL/min to be considered as a cardiovascular risk equivalent while eGFR <30 mL/min is considered very high cardiovascular risk asking for a multifactorial approach.⁴³ This combines coronary revascularization in selected individuals with optimal treatment of hypertension, dyslipidemia, diabetes, and possibly inflammation in all patients with CKD.

CAD and Revascularization

Acute Coronary Syndrome

Acute coronary syndrome requires immediate and early revascularization in ST-segment–elevation myocardial infarction and non–ST-segment–elevation myocardial infarction independent of renal function.^44,45 The diagnosis of acute coronary syndrome proves, however, more challenging in patients with CKD attributable to atypical symptoms and reduced specificity of cardiac biomarkers. In 1 study, only 40% of patients presenting with acute myocardial infarction and advanced CKD had chest pain in comparison to 61% in non-CKD patients.⁴⁶ Further, chronic elevation of troponin levels in patients with CKD requires dynamic changes to enable the detection of acute cardiac injury.⁴⁷ Consequently, in a CKD cohort of 2312 patients without known CVD, 43% had troponin levels above the conventional upper reference level, which increased to 68% in those with eGFR <30 mL/min per 1.73 m². Each 15 mL/min per 1.73 m² decrement in eGFR was associated with a ≈40% higher threshold of the 99th percentile of hsTnT (high-sensitivity troponin T) (1.45 [95% CI, 1.31–1.60]) with 126 (95% CI, 100–144) ng/L being the 99th percentile of the whole CKD cohort.⁴⁷ This diagnostic limitation is attributable to the detection of small circulating fragments of cardiac troponin T present in CKD by established assays. New assays only detecting the long or mildly truncated form of troponin T seem to improve diagnostic sensitivity in patients with CKD and acute coronary syndrome.⁴⁸

Chronic Coronary Syndrome

The detection of ischemic CAD is hindered by reduced diagnostic sensitivity and specificity of diagnostic tests in individuals with CKD. This can be attributable to more prevailing microvascular disease and presence of interstitial myocardial fibrosis, hampering the interpretation of myocardial perfusion imaging.⁴⁹ Consequently, no obstructive CAD was found in every fourth CKD patient with moderate-to-severe ischemia detected by noninvasive methods in the ISCHEMIA-CKD (Management of Coronary Disease in Patients with Advanced Kidney Disease) trial.⁵⁰ Prognostic relevance of myocardial perfusion imaging was further questioned in the same study as it did not predict death or myocardial infarction. Extensive and often medial vascular calcification occurring disproportional to the severity of obstructive CAD also reduces the diagnostic accuracy of computed tomography angiography in patients with CKD. Clinical judgment consequently remains of special importance in this population.⁵¹

The prognostic benefit of coronary revascularization in patients with CKD and stable CAD was recently evaluated in the ISCHEMIA-CKD trial.⁵⁰ Seven hundred seventy-seven patients with eGFR <30 mL/min per 1.73 m² and moderate-to-severe myocardial ischemia were randomized to early angiography and revascularization (either by percutaneous coronary intervention or coronary artery bypass grafting) or sole optimal medical therapy. The mean age of the population was 63 years with 69% men and 54% end-stage renal disease and a mean eGFR of 23 mL/min per 1.73 m² in the remaining population. The invasive group received coronary angiography in 85.2% of patients and revascularization procedure in 50.2% (85% by percutaneous coronary intervention [PCI] and 15% by coronary artery bypass graft [CABG]), whereas in the conservative group, coronary angiography was performed in 31.6% and revascularization in 19.6%. During a mean follow-up of 2.2 years, there was no difference in the primary outcome of death from any cause or myocardial infarction between both study arms (HR, 1.01 [95% CI, 0.79–1.29]; P=0.95). Similarly, no difference in total mortality or cardiovascular death was found while spontaneous myocardial infarction was reduced numerically in the invasive group (37 versus 52 events; HR, 0.72 [95% CI, 0.47–1.09]), which was partially balanced by more procedure-associated myocardial infarctions (7 versus 4 events). More strokes (22 versus 6; HR, 3.76 [95% CI, 1.52–9.32]; P=0.004), although mostly not procedure related, occurred in the invasive arm. Terminal renal failure requiring dialysis was increased by number in the invasive group (36 versus 29; P=0.14), which became significant in the combined analysis with mortality (HR, 1.48 [95% CI, 1.04–2.11]; P=0.03). No difference in procedure-associated acute kidney injury was found (7.8% versus 5.4%; P=0.26); still the median time to dialysis initiation was shorter in the invasive group (6 versus 18.2 months; P=0.004).⁵⁰ Long-term follow-up will be required to unmask possible delayed effects.⁵²

These findings are consistent with similar trials performed in patients without CKD including the recently published ISCHEMIA trial⁵⁴ or COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation)⁵³ and BARI2D (the Bypass Angioplasty Revascularization Investigation 2 Diabetes).⁵⁴ Still, a meta-analysis of trials comparing early coronary revascularization with optimal medical therapy versus medical therapy specifically in patients with CKD (n=3422) reported early revascularization to result in lower incidence of myocardial infarction compared with medical therapy alone (RR, 0.71 [95% CI, 0.54–0.94]; P=0.02).⁵⁵ This result was mainly driven in patients with stable CAD, suggesting a potential benefit.

Current guidelines suggest coronary revascularization to be reserved for patients with persistent complains despite optimal medical therapy and relevant ischemia. Findings are relevant for renal transplant candidates in which myocardial ischemia testing and preemptive revascularization is mostly performed before kidney transplant listing. Renal transplantation listing was performed in 25% of the ISCHEMIA-CKD population. Listed patients were younger (60 versus 65 years) and more likely to be on dialysis (83% versus 44%). There was no difference in the primary outcome in the invasive versus conservative group between patients listed (HR, 0.91 [95% CI, 0.54–1.54]) or not listed (HR, 1.03 [95% CI, 0.78–1.37]) for renal transplantation.⁵⁶ These findings do not support routine coronary angiography or revascularization in patients with advanced CKD and chronic coronary syndromes before transplant listing. A recent statement from the American Heart Association suggested renal transplant candidates to not require cardiac stress testing if aged <60 years, left ventricular function EF >40% without regional wall abnormalities, no diabetes, cerebrovascular disease, or peripheral artery disease, duration of dialysis or prior kidney transplant <5 years, and no evidence of silent myocardial infarction on ECG.⁵⁷ The currently running CARSK trial (Screening for Asymptomatic Coronary Artery Disease in Kidney Transplant Candidates Trial) is testing the relevance of screening for occult CAD in renal transplantation candidates and will include 3306 patients with up to 5-year follow-up during wait-listing and for 1 year after transplantation.⁵⁸

HF and CKD

CKD is a risk factor for the development of HF and vice versa, or both can coexist on the basis of shared risk factors. Nearly half of all patients with HF experience CKD with higher prevalence in studies in acute (53%) versus chronic HF (42%). In addition, the prevalence of CKD in HF is associated with a stepwise increasing mortality (1.59-fold elevation in mild to 2.17-fold increase in severe renal impairment).⁵⁹ Furthermore, elevated urine albumin has been shown to be prognostic for HF outcomes, albeit to a lesser extent than impaired eGFR.⁶⁰ Traditionally, HF has been divided into distinct phenotypes based on the measured left ventricular ejection fraction. Currently 3 entities are distinguished: HFrEF with an ejection fraction ≤40%, HF with mildly reduced ejection fraction (HFmrEF) with an ejection fraction between 41% and 49%, and HF with preserved ejection fraction (HFpEF) with an ejection fraction ≥50% and objective evidence of cardiac structural and functional abnormalities consistent with the presence of LV diastolic dysfunction/raised filling pressures, including raised natriuretic peptides.⁶¹

In the Swedish Heart Failure Registry of 40 230 patients, 8875 (22%) had HFpEF, 8374 (21%) had HFmrEF, and 22 981 (57%) had HFrEF, with a CKD prevalence of 56%, 48%, and 45%, respectively. One-year mortality with versus without CKD was 23% versus 13% in HFpEF, 22% versus 8% in HFmrEF, and 23% versus 8% in HFrEF, respectively (P<0.001 for all). After adjustment, CKD was more strongly associated with death in HFrEF and HFmrEF than in HFpEF.⁶²

The diagnosis of HF in the population with nondialysis CKD parallels that of the population without CKD. If cardiac insufficiency is suspected, the determination of at least 1 natriuretic peptide is recommended. A plasma concentration of BNP (B-type natriuretic peptide) <35 pg/mL or NT-proBNP (N-terminal pro-B-type natriuretic peptide) <125 mg/mL makes the diagnosis of HF unlikely (higher cutoff values apply for patients with atrial fibrillation: BNP, <105 pg/mL; NT-proBNP, <365 pg/mL), with falsely low values occurring in obesity.⁶³ In contrast, BNP and NT-pro-BNP can be elevated in CKD as reduced renal function decreases the fractional plasma clearance of both BNP and NT-proBNP.⁶⁴ If the values are elevated, echocardiography is recommended to confirm the diagnosis of HF.⁶¹ In patients on dialysis, typical HF symptoms such as dyspnea, paroxysmal nocturnal dyspnea, orthopnea, or edema can be intermittently dependent upon whether evaluation occurs before or after fluid removal by renal replacement therapy. Therefore, the 11th Acute Dialysis Quality Initiative proposed a classification scheme based on patient-reported dyspnea assessed both pre- and post-ultrafiltration, in conjunction with echocardiography.⁶⁵ However, the diagnostic approach is the same as in patients not on dialysis. Whenever possible, imaging should be performed when patients on dialysis are close to dry weight. Monitoring of HF in CKD includes usual standard of care by measuring sodium, potassium, creatinine (eGFR), UACR, and natriuretic peptides. Changes in volume status can be detected by changes in weight, physical examination, chest radiography, or lung ultrasound. Patients with CKD are less likely to receive guideline-directed medical therapy, probably due to concerns about kidney function, hyperkalemia, and hypotension.

Treatment of HFrEF

In general, the basis of therapy for HFrEF (left ventricular ejection fraction ≤40%) to reduce mortality in all patients is a 4-fold drug therapy consisting of ACE inhibitors/angiotensin receptor-neprilysin inhibitors, β-blockers, MRA, and SGLT2 inhibitors. However, patients with CKD and an eGFR <30 mL/min per 1.73 m² have largely been excluded from clinical trials. Therefore, recommendations for this group are largely based on data from the general population.⁶⁶

ACE Inhibitors/Angiotensin Receptor-Neprilysin Inhibitors

ACE inhibitors were the first class of drugs to show a reduction in mortality and morbidity in patients with HFrEF, and solid data exist for the use of ACE inhibitors in patients with CKD stages 1 to 3 plus HFrEF, but no data exist for those with CKD stage 4/5.

The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan showed a significant reduction in the primary end point of cardiovascular death and HF-related hospitalization compared with the ACE inhibitor enalapril, and this benefit has also been found in patients with an eGFR of 30 to 60 mL/min per 1.73 m².⁶⁷ Therefore, angiotensin receptor-neprilysin inhibitors are effective in patients with HF and CKD stages 1 to 3; in patients with CKD stage 4/5, no data are available. One small study including 301 patients with HFpEF investigated the renal effects of sacubitril/valsartan. Therapy with sacubitril/valsartan for 36 weeks was associated with preservation of eGFR compared with valsartan therapy but an increase in UACR.⁶⁸

β-Blockers

β-Blockers lead to a reduction in mortality and morbidity in patients with HFrEF and existing therapy with ACE inhibitors and diuretics. A meta-analysis of 6 studies analyzing the effect of β-blocker therapy in congestive HF and CKD stages 3 to 5 shows that patients with advanced CKD benefited from β-blocker therapy.⁶⁹ In patients on dialysis, considerations should be given to the potential for dialyzability of certain β-blockers as in a propensity-matched population-based retrospective cohort study, the use of metoprolol was associated with an increased mortality risk compared with low-dialyzability β-blocker such as bisoprolol.⁷⁰

Mineralocorticoid Receptor Antagonists

MRAs (spironolactone and eplerenone) reduce mortality and hospitalizations due to HF in patients with HFrEF, but in these trials, only patients with CKD stages 1 to 3 were enrolled.^71,72 In the RALES trial (Randomized Aldactone Evaluation Study), spironolactone exhibited similar risk reduction in all-cause mortality and the combined outcome of all-cause mortality and hospital stay for HF, compared with patients with higher baseline eGFR. However, these benefits went along with an increased risk of hyperkalemia and worsening renal function, but the substantial net benefit of spironolactone therapy remained.⁷³ Similarly, in a post hoc analysis in patients with an eGFR of 30 to 60 mL/min per 1.73 m² of the EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone was equally effective to reduce cardiovascular death or HHF (hospitalization for heart failure), which was consistent across the different eGFR strata.⁷⁴ Patients treated with eplerenone had an increased risk of potassium >5.5 mmol/L but not of potassium >6.0 mmol/L.⁷⁴ Given these data, a close monitoring of renal function and potassium is warranted in patients with HF and CKD, especially if eGFR declines.

No data from large clinical trials exist in patients with CKD stages 4 and 5, and these agents are formally contraindicated in advanced CKD. The DOHAS (Dialysis Outcomes Heart Failure Aldactone Study) trial, a prospective, multicenter, randomized controlled, open-label trial in 5 Japanese centers, investigated the use of spironolactone in oligoanuric hemodialysis patients versus a control group. In this population, spironolactone reduced the primary outcome—a composite of death from cardiovascular and cerebrovascular events or hospitalization for cardiovascular and cerebrovascular events.⁷⁵ Ongoing large-scale studies such as the ACHIEVE trial (Aldosterone Blockade for Health Improvement Evaluation in End-Stage Renal Disease; https://www.clinicaltrials.gov; unique identifier: NCT03020303) and ALCHEMIST (Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial; https://www.clinicaltrials.gov; unique identifier: NCT01848639) will shed more light on this topic.

Diuretics

Treatment with diuretics is indicated in patients with venous congestion and New York Heart Association (NYHA) class II as well as in patients with congestive HF stage NYHA classes III and IV. Patients can be treated with loop diuretics or thiazides, but patients with CKD stages 4 and 5 should receive either loop diuretics alone or thiazides in combination with loop diuretics. In particular, the latter should be monitored for hypokalemia. After cardiac decompensation, at least a low-dose diuretic therapy should be continued.

SGLT2 Inhibitors

Two large cardiovascular outcome trials conducted in patients with HFrEF with or without diabetes have shown that dapagliflozin or empagliflozin significantly reduces the combined end point of cardiovascular death and chronic heart failure (CHF) hospitalization compared with placebo. The DAPA-HF trial included 4744 patients with symptomatic HF and an ejection fraction <40% to receive either placebo or dapagliflozin in addition to recommended therapy. Over a median of 18.2 months, dapagliflozin relatively reduced the primary end point—a composite of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular death by 26%. In addition, dapagliflozin resulted in an 18% relative risk reduction of cardiovascular death and a 17% relative risk reduction of all-cause mortality.⁷⁶ The EMPEROR-Reduced trial included 3730 patients with symptomatic HF and an ejection fraction below 40%. During a median of 16 months, empagliflozin significantly reduced the primary end point—a composite of cardiovascular death or hospitalization for worsening HF by 25%. This was driven by the total hospitalizations of HF, which were reduced by 30%.⁷⁷ In addition, these agents reduce kidney end points and worsening of nephropathy. Given that these studies included patients with an eGFR down to 30 mL/min per 1.73 m² (DAPA-HF [Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction])⁷⁶ or 20 mL/min per 1.73 m² (EMPEROR-Reduced [Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure]),⁷⁷ these agents seem to be effective in patients with CKD stages 3 and 4. SGLT2 inhibitors can be initiated with an eGFR as low as 20 mL/min per 1.73 m². In addition, treatment can be continued until dialysis initiation.

Treatment of HFmrEF/HFpEF

Various cardiovascular outcome trials have assessed the effect of drugs with proven benefit in HFrEF in patients with HFmrEF/HFpEF (left ventricular ejection fraction, ≥40%). Until recently, none of these trials could show a significant reduction of the cardiovascular primary end point. However, recently, 2 large cardiovascular outcome trials with the SGLT2 inhibitors empagliflozin or dapagloflozin, EMPEROR-Preserved (Empagliflozin in Heart Failure with a Preserved Ejection Fraction)⁷⁸ and DELIVER (Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction),⁷⁹ convincingly showed in patients with an ejection fraction above 40% that SGLT2 inhibitor treatment reduces the combined end point of HF hospitalization or cardiovascular death compared with placebo. Prespecified subgroup analyses did not show a significant difference between patients with eGFR <60 mL/min per m² and an eGFR ≥60 mL/min per m², suggesting that patients with HFmrEF/HFpEF and CKD benefit from the treatment with one of these SGLT2 inhibitors. The role of MRAs in the treatment of HFmrEF/HFpEF is still under discussion. The TOPCAT trial (Spironolactone for Heart Failure with Preserved Ejection Fraction Trial) was the first to compare the effect of spironolactone to placebo with nonsignificant difference in the primary end point. However, a recent post hoc analysis that stratified only the patients of the TOPCAT Americas according to kidney function showed consistent efficacy of spironolactone across the range of eGFR, while the risk of adverse events was amplified in the lower eGFR categories.⁸⁰ The significance for nonsteroidal MRAs in the treatment of HFmrEF and HFpEF is currently investigated in the ongoing FINARTS-HF (Study to Evaluate the Efficacy and Safety of Finerenone on Morbidity & Mortality in Participants With Heart Failure and Left Ventricular Ejection Fraction Greater or Equal to 40%) study (https://www.clinicaltrials.gov; unique identifier: NCT04435626), which evaluates the effect of finerenone compared with placebo in the reduction of cardiovascular death and total HF events, including HF hospitalization and urgent visits for HF in patients experiencing HF with an ejection fraction ≥40%.

Arrhythmias and CKD

Atrial Fibrillation in Patients With CKD

In patients with advanced CKD atrial fibrillation is the most common arrhythmia and its incidence is increased in hemodialysis patients.⁸¹ Recent data using implantable loop recorders suggest that the prevalence of atrial fibrillation in patients with hemodialysis ranges from 27% to 40%.⁸² The presence of atrial fibrillation in patients with advanced CKD is associated with an increased cardiovascular morbidity and mortality as shown in a recent analysis in subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2018 for an outpatient visit. Among the 12 394 patients, 699 patients had AF, 2752 patients had CKD, and 325 patients had both AF and CKD. Patients with both CKD and AF had a 3.0-fold (95% CI, 2.0–4.4) increased risk for bleeding, a 4.2-fold (95% CI, 3.0–6.0) increased ischemic stroke risk, and a 2.2-fold (95% CI, 1.9–2.6) increased mortality risk after adjustment as compared with subjects without atrial fibrillation and CKD.⁸³

No dedicated trials have been conducted in patients with atrial fibrillation with respect to rate control or rhythm control, and data need to be extrapolated from trials that excluded patients with CKD. A recent meta-analysis assessed the effect of CKD or hemodialysis on the recurrence of atrial fibrillation after catheter ablation. In this analysis, patients with CKD demonstrated a higher risk of atrial fibrillation recurrence compared with patients without CKD with 2.34-fold higher risk.⁸⁴

Interesting novel data were generated from the FIDELIO-DKD (Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes Trial) trial. This trial which randomized finerenone versus placebo in 5674 patients with type 2 diabetes and CKD new-onset atrial fibrillation occurred in 3.5% on finerenone and 5.4% on placebo, resulting in a significant 29% relative risk reduction (HR, 0.71 [95% CI, 0.53–0.94]; P=0.016). Thus, in patients with diabetes type 2 and CKD, finerenone could be an option to reduce not only HF hospitalization but also the new onset of atrial fibrillation.⁸⁵

In addition, a recent meta-analysis on SGLT2 inhibitors in diabetes, HF, and CKD trials suggests that the incidence of atrial fibrillation, reported as a serious adverse event, was 0.9% in individuals who received an SGLT2 inhibitor compared with 1.1% in those receiving placebo raising the hypothesis that SGLT2 inhibitors may also prevent the occurrence of atrial fibrillation in patients with CKD.⁸⁶ These data are in line with a recent meta-analysis suggesting that SGLT2 inhibitors significantly reduced the risk of atrial fibrillation independent of the presence of CKD or diabetes.⁸⁷

Anticoagulation in AF and CKD

No dedicated trials have examined the clinical risks and benefits of anticoagulation in patients with advanced CKD. Observation studies suggest that warfarin is associated with a 76% reduction in relative risk for ischemic stroke or systemic embolism among patients with atrial fibrillation and CKD stage 3.⁸⁸ In contrast, in dialysis patients, the effect of warfarin for stroke prevention is controversial with some data suggesting harm due to the increased bleeding risk. In addition, a recent meta-analysis could show that the relative frequency of hemorrhagic stroke seems to increase as kidney function declines.⁸⁹

A consensus statement from Kidney Disease: Improving Global Outcomes did not recommend routine warfarin in patients with atrial fibrillation on hemodialysis.⁹⁰ Vitamin K antagonists are in particular challenging given the increased risk for calciphylaxia.⁹¹ In a recent small trial, the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a vitamin K antagonist (VKA) with a target international normalized ratio (INR) of 2 to 3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. After a median follow-up of 1.8 years, the primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group (HR for the primary end point: 0.41 [95% CI, 0.25–0.68], P=0.0006 in the rivaroxaban group and 0.34 [95% CI, 0.19–0.61], P=0.0003 in the rivaroxaban and vitamin K2 group, compared with the VKA group).⁹² Data from a retrospective observational study suggest that in patients with kidney failure and nonvalvular atrial fibrillation, treatment with apixaban was not associated with a lower incidence of new stroke, transient ischemic attack, or systemic thromboembolism but was associated with a higher incidence of fatal or intracranial bleeding.⁹³

A recent meta-analysis of 6 randomized controlled trials and 19 observational studies compared the efficacy and safety of NOACs (non-vitamin K antagonist oral anticoagulant) and warfarin in patients with CKD requiring anticoagulation therapy. Compared with warfarin, NOACs significantly reduced the risk of stroke, systemic embolism, or venous thrombosis/embolism by 19% (HR, 0.81 [95% CI, 0.68–0.97]) in patients with CKD stage 3 and significantly lowered the risk of major bleeding by 31% (HR, 0.69 [95% CI, 0.56–0.85]) in patients with CKD stages 4 and 5, suggesting that NOACs are associated with better efficacy in early CKD, as well as similar efficacy and safety outcomes to warfarin in patients with CKD stages 4 and 5, or dialysis patients. Of note, the results of patients with CKD stages 4 and 5 and dialysis patients were from observational studies underscoring the need for randomized controlled trials in patients with advanced CKD.⁹⁴

Sudden Cardiac Death in CKD

SCD accounts for >60% of mortality in advanced CKD stages.⁹⁵ The rate of SCD in hemodialysis patients is higher than in the general population (59 versus 1 death in 1000 patient-years, respectively).⁹⁶ The pathophysiology of SCD in patients with CKD differs from the general population. In patients on hemodialysis, CAD and typical changes in the myocardium of patients such as hypertrophy and fibrosis seem to contribute to arrhythmia and SCD. Moreover, dialysis itself is a risk factor for SCD with a high estimated risk within the first 12 hours after dialysis and after a long dialysis-free interval. A recent randomized trial demonstrated that prophylactic implantable cardioverter-defibrillator (ICD) therapy did not reduce the rate of SCD or all-cause mortality in dialysis patients.⁹⁷ No dedicated trials exist on the best strategy to reduce the risk of SCD in advanced CKD, and current guidelines do not distinguish patients with or without dialysis with respect to the indication of primary prophylactic ICD implantation in patients with a left ventricular ejection fraction of ≤35.

Article Information

Sources of Funding

K. Schuett is supported by Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; project ID 322900939 [C07]). N. Marx is supported by Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; project ID 322900939 [M03 and M05]). M. Lehrke is supported by Deutsche Forschungsgemeinschaft (German Research Foundation; TRR 219; project ID 322900939 [M03]; LE1350/9-1) and Deutsche Herzstiftung.

Disclosures

K. Schuett has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Merck Sharp and Dohme, Novo Nordisk, Novartis, and OmniaMed and served as a consultant for Amgen, AstraZeneca, Bayer, and Boehringer Ingelheim. N. Marx has received support for clinical trial leadership from Boehringer Ingelheim and Novo Nordisk; served as a consultant to Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, and Bristol Myers Squibb; received grant support from Boehringer Ingelheim, Merck, and Novo Nordisk; and served as a speaker for Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. M. Lehrke received grants and personal fees from Boehringer Ingelheim, MSD, and Novo Nordisk and personal fees from Amgen, Sanofi, AstraZeneca, Bayer, Lilly, Daiichi Sankyo, Novarits, Amylin, MSD, Novo Nordisk, and Abiomed.