Time to revisit the paradigm for coronary vascular disease in patients with ESKD

Issue: February 2020

ByNupur Gupta, MD

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Cardiovascular disease is the leading cause of morbidity and mortality among patients with chronic kidney disease.¹ There is a progressive increase in mortality risk with declining eGFR below 60 mL/min/1.73 m² to 75 mL/min/1.73 m², after risk adjustment for traditional CVD risk factors.²

Patients with chronic kidney disease are five to 10 times more likely to die of CVD before developing ESKD.³ Both CKD and ESKD modify the clinical presentation and cardinal symptoms of coronary artery disease (CAD) making recognition of ischemia difficult.⁴ Traditionally, it is recommended patients should undergo routine assessment for CVD because regular screening may help identify patients with CKD who would benefit from interventions to reduce CVD risk.⁵

Patients with CKD 4 and 5 and ESKD are a challenging group to treat due to high mortality and non-specific angina symptoms and have difficulty in achieving optimal medical therapy.⁶ Currently, the American College of Cardiology/American Heart Association does not have guidelines specific for patients with CKD.

Conservative vs invasive approaches

The ISCHEMIA-CKD trial was conducted to evaluate the outcomes of an initial invasive approach vs. conservative therapy in patients with CKD (eGFR <30 mL/min/1.73m²) or ESKD with stable ischemic heart disease (SIHD). It was designed to run parallel with the ISCHEMIA trial (NCT01471522). It is the largest randomized control trial on SIHD exploring clinical outcomes in patients with advanced CKD, including patients on dialysis.

A total of 777 patients were enrolled in the study, and were randomized 1:1 to an initial invasive approach (cardiac catheterization and revascularization) along with optimal medical therapy (OMT) or to conservative OMT alone, then followed for 2 to 4 years.⁷ The study results were presented at an American Heart Association scientific session in Philadelphia in 2019.

Results showed no difference in cardiovascular events or mortality between groups. Coronary angiography was performed in 85% of patients in the invasive arm and in 22% of those in the conservative arm, with revascularization performed in 50% and 12%, respectively. The symptoms of chest pain or frequent angina did not improve despite the revascularization at the end of the follow-up period.⁸

Adverse events like initiation of maintenance dialysis and a composite of initiation of maintenance dialysis or death were reported higher in the invasive arm (HR adjusted = 1.48, CI: 1.04 – 2.11, P = .02).⁹ Optimizing techniques using a hydration protocol for percutaneous coronary intervention (PCI) based on the Prevention of Contrast Renal Injury with Different Hydration Strategies (POSEIDON) trial and contrast volume threshold (for hard stop) was provided to the site based on participants’ eGFR and body weight. Protocols for ultra-low volume and zero contrast PCI techniques were also used.^10,11 Despite this approach, there was an increased risk for procedural complications, including AKI, major bleeding, vessel dissection, myocardial infarction and death with no long-term benefit with the invasive procedure.⁶

Impact of the study

This study is monumental for the development of future guidelines and trials regarding cardiac intervention in patients with advanced CKD who are underrepresented in most trials. The patients referred for the parent trial with lower eGFR were evaluated for ISCHEMIA-CKD, expanding the recruitment. Future studies could show similar strategies to recruit patients with CKD rather than excluding them, optimizing the resources. At this juncture, it has opened the pandora’s box questioning many clinical practice guidelines and trial designs in nephrology. This trial elucidates how we evaluate the value of various treatment alternatives. In medicine, we often assess the impact of interventions — without fully appreciating the value of that treatment compared to conservative therapy.

CKD and ESKD ameliorate the clinical presentation of key symptoms of CAD. Only 44% of patients with CKD 3 or higher who present with acute myocardial infarction (AMI) report chest, arm, shoulder or neck pain compared with 72% of patients with preserved kidney function. Dyspnea seems more common among patients with CKD.¹² A separate quality-of-life analysis based on the Seattle Angina Questionnaire failed to show a positive impact of the invasive approach.⁸ However, the main ISCHEMIA trial did demonstrate a symptomatic benefit. Thus, detection of ischemia in CKD requires a heightened suspicion for anginal equivalents, such as shortness of breath or fatigue. Traditional symptoms have low prevalence. Intradialytic hypotension and myocardial stunning are hemodialysis-specific syndromes associated with mortality and should be used for assessment of CAD.⁹

CKD with statins

Medical management with statins in patients with CKD remains controversial. The main reasons are the contribution of atherosclerotic disease and that CV mortality is low, and the representation of patients with advanced CKD in previous trials is minimal.¹³ Even after adjustment for known CAD risk factors, including diabetes and hypertension, mortality risk progressively increases with worsening CKD. The Kidney Disease Improving Global Outcomes guidelines propose the use of statins in patients with CKD older than 50 years of age but not in patients on dialysis based on the previous studies.¹⁴

This study suggests risk factor reduction with both medical and lifestyle is noninferior to revascularization, although the question of patient engagement and how to achieve these targets prevails. The adoption of an interdisciplinary approach could enhance patient engagement, coordination of care and probably reduce complications, which has been Achilles’ heel for patients with advanced CKD.

Renal transplant guidelines recommend noninvasive screening tests for coronary disease both at the time of evaluation and periodically while on the waiting list among patients with identifiable CAD risk factors.¹⁵ The goal is to identify the need for medical therapy or revascularization. It is unclear if screening for CAD improves patient survival or transplant outcomes. In this study, patients who would be eligible for transplant by eGFR criteria did not receive any improvement in survival with intervention.¹⁶ It questions the guidelines for delisting patients due to high risk of intervention or high burden of CAD, thus aligning with goals of Advancing American Kidney Health.

Conclusion

At this point, it is hard to assess the immediate impact of this trial on clinical practice. There are questions being raised regarding appropriate guideline, and will likely lead to increased scrutiny from payers, providers and regulators. We should try optimal medical therapy in stable patients and proceed to intervention if it fails. The decision to pursue revascularization should be a shared decision-making process among the multidisciplinary team, the patient and the patient’s caregivers.

• References:
• 1. US Renal Data System 2019 Annual Data Report: Epidemiology of Kidney Disease in the United States. 2019;doi:10.1053/j.ajkd.2019.09.002.
• 2. Manjunath G, et al. Kidney Int. 2003;doi:10.1046/j.1523-1755.2003.00838.
• 3. Go AS, et al. NEJM. 2004;doi:10.1056/NEJMoa041031.
• 4. Schmidt A, et al. Am Jrnl of Kid Diseases.2001;doi:10.1053/ajkd.2001.20584.
• 5. Sarnak MJ, et al. Am. Jrnl of Kid Diseases.2014;doi:10.1053/j.ajkd.2014.10.005.
• 6. Boden WE, et al. NEJM. 2007;doi:10.1056/NEJMoa070829.
• 7. Bangalore S, et al. Am Heart Journal. 2018;doi:10.1016/j.ahj.2018.07.
• 8. S B. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches—Chronic Kidney Disease Trial. American Heart Association Scientific Session. Philadelphia, 2019.
• 9. Stefansson BV, et al. Clin. Jrnl of Nephrology. 2014;doi:10.2215/CJN.02680314.
• 10. Brar SS, et al. Lancet.2014;doi:10.1016/S0140-6736(14)60689-9.
• 11. Ali ZA, et al. Eur Heart Journal. 2016;doi:10.1093/eurheartj/ehw078.
• 12. Sosnov J, et al. Am Jrnl Kid Diseases.2016;doi:10.1053/j.ajkd.2005.11.017.
• 13. Sarnak MJ, et al. Jrnl Am College of Cardiology.2019;doi:10.1016/j.jacc.2019.08.1017.
• 14. Wanner C, et al. Kid. Intl.2014;doi:10.1038/ki.2014.31.
• 15. Lentine KL, et al. Am Jrnl of Nephrology.2012;doi:10.1159/000345476.
• 16. Wang LW, et al. Cochrane Library.2011;doi:10.1002/14651858.CD008691.pub2.

 

For more information:
• Nupur Gupta, MD, is an assistant professor of Clinical Medicine at IU Health, Indianapolis.

Disclosure: Gupta reports no relevant disclosures.