Treatment Strategies in CKD Patients With Suspected Coronary Artery Disease

Abstract

Related Article, p. 463 Related Article, p. 463 The advent of symptomatic coronary artery disease is a common and concerning occurrence in the clinical life of patients with advanced chronic kidney disease (CKD).1Herzog C.A. Ma J.Z. Collins A.J. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis.N Engl J Med. 1998; 339: 799-805Crossref PubMed Scopus (803) Google Scholar Sadly, encounters with patients experiencing a recent onset or increase in the symptom burden of exercise-induced chest discomfort or dyspnea are common. Potentially difficult discussions about management options often ensue and commonly occur in stages. For example, in the absence of an acute coronary syndrome, a discussion might start with the pros and cons of initially attempting to optimize medical treatment while waiting on diagnostic tests and decisions about various management options (such as stress testing, cardiac catheterization, and possible revascularization) should symptoms fail to respond adequately to optimized medical therapy. Many factors are likely to influence these decisions, including comorbid condition burdens, the imminence of renal replacement therapy, the potential for irreversible loss of kidney function, and whether these investigations are needed anyway as part of transplantation assessment. Value systems and viewpoints regarding the tension between quality and quantity of life are often integral components of these discussions. A multiplicity of pivotal randomized controlled trials during the last 4 decades have led to well-defined management road maps for the general population. For example, in patients with stable ischemic heart disease, coronary artery bypass surgery has the same effect on survival as medical therapy, with the exception of for those with initial left ventricular ejection < 50%, for which surgery extends life.2CASS Principal Investigators and Their AssociatesMyocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial.N Engl J Med. 1984; 310: 750-758Crossref Scopus (283) Google Scholar, 3Alderman E.L. Bourassa M.G. Cohen L.S. et al.Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study.Circulation. 1990; 82: 1629-1646Crossref PubMed Scopus (400) Google Scholar Percutaneous coronary intervention (PCI) in general appears to be noninferior to coronary artery bypass.4Rodriguez A.E. Baldi J. Fernández Pereira C. et al.Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II).J Am Coll Cardiol. 2005; 46: 582-588Crossref PubMed Scopus (218) Google Scholar, 5Serruys P.W. Onuma Y. Garg S. et al.5-Year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions.J Am Coll Cardiol. 2010; 55: 1093-1101Crossref PubMed Scopus (210) Google Scholar, 6Booth J. Clayton T. Pepper J. et al.Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial (SoS).Circulation. 2008; 118: 381-388Crossref PubMed Scopus (172) Google Scholar, 7Serruys P.W. Ong A.T.L. van Herwerden L.A. et al.Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial.J Am Coll Cardiol. 2005; 46: 575-581Crossref PubMed Scopus (558) Google Scholar, 8Kapur A. Hall R.J. Malik I.S. et al.Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial.J Am Coll Cardiol. 2010; 55: 432-440Crossref PubMed Scopus (378) Google Scholar, 9Serruys P.W. Morice M.-C. Kappetein A.P. et al.Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3279) Google Scholar, 10Farkouh M.E. Domanski M. Sleeper L.A. et al.Strategies for multivessel revascularization in patients with diabetes.N Engl J Med. 2012; 367: 2375-2384Crossref PubMed Scopus (1390) Google Scholar, 11Ahn J.-M. Roh J.-H. Kim Y.-H. et al.Randomized trial of stents versus bypass surgery for left main coronary artery disease: 5-year outcomes of the PRECOMBAT Study.J Am Coll Cardiol. 2015; 65: 2198-2206Crossref PubMed Scopus (276) Google Scholar Finally, PCI has no clear advantage over optimal medical therapy in patients with stable coronary artery disease.12Pursnani S. Korley F. Gopaul R. et al.Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials.Circ Cardiovasc Interv. 2012; 5: 476-490Crossref PubMed Scopus (173) Google Scholar Clear therapeutic road maps from definitive randomized trials are not available in populations with advanced CKD. In this issue of AJKD, Charytan et al13Charytan D.M. Natwick T. Solid C.A. et al.Comparative effectiveness of medical therapy, percutaneous revascularization, and surgical coronary revascularization in cardiovascular risk subgroups of patients with CKD: a retrospective cohort study of Medicare beneficiaries.Am J Kidney Dis. 2019; 74: 463-473Scopus (11) Google Scholar report novel and thought-provoking findings from a study of 34,385 individuals in the United States with Medicare insurance and CKD that compares risks for death and end-stage renal disease (ESRD) with the options of optimized medical therapy, PCI, and surgical (coronary artery bypass grafting [CABG]) revascularization. In this study, reimbursement claims were used to define exposures and comorbid illnesses. Those admitted with claims for unstable angina or myocardial infarction were considered high risk; in the absence of these conditions, those with and without claims for cardiovascular disease in the preceding 6 months were defined as medium and low risk, respectively. Follow-up for the main study outcomes (death and ESRD) began at PCI, CABG, or when the number of classes of cardioprotective medications were first noted to increase. Ultimately, if multiple comparisons were considered, mode of therapy was only associated with outcomes in the group admitted with acute coronary syndromes (high-risk group), with adjusted death risk arrayed as CABG < PCI < medical therapy and ESRD risk arrayed as (PCI = medical therapy) < CABG. Clinical equipoise is the basis of good randomized trials. In this study, it is worth reminding ourselves that stress test, coronary angiography, and cardiac function (eg, ventricular ejection fraction) results were unavailable. Furthermore, many and possibly all of the drug classes that define medical therapy in this study are often used in the absence of overt coronary artery disease in populations with advanced CKD. In the absence of a true acute coronary syndrome, it may be worth asking whether deciding to proceed to revascularization would be a realistic therapeutic dilemma in all these individuals. In some of those without acute coronary syndromes, it seems likely that PCI or CABG were never serious considerations, possibly because findings from cardiac catheterizations were reassuring. Most physicians would strongly consider angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, statins, and possibly aspirin (especially with concomitant diabetes) for cardioprotection in this population, even in the absence of coronary disease. Thus, especially in the low- and medium-risk groups, there appears to be a substantial risk for cross-attribution of medical therapy between coronary artery disease and kidney disease. It could therefore be argued that clinical equipoise is most realistic in the high-risk group. Claims-based studies, while often having the advantages of large sample sizes, present their own intrinsic challenges. For example, it is usually necessary for participants to survive certain time periods to define exposures, which necessarily adds the potential for differential survival bias. An interesting analytical dilemma in this study involves the definition of medical therapy and when to begin follow-up for death and ESRD. In this study, after the qualifying event has occurred, medical therapy is flagged when an increase in the number of classes of agents is detected in the next 180 days, these classes consisting of lipid-lowering agents, antiplatelet agents, antianginal agents, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and β-blockers. This can lead to interesting thought experiments. Because an increase in the number of classes is impossible in those already taking all classes of agents, it appears that the study excluded those who were maximally treated, which is counterintuitive when one is attempting to replicate the optimal therapy arm of randomized trials in non-CKD populations. Conversely, going from 0 to 1 of these agents would hardly be considered optimal therapy. Finally, it is worth noting that the flagging procedure can occur up to 180 days after the qualifying event in the medical therapy; in other words, up to 180 days of immortality is necessary for cohort inclusion in this treatment arm. Although difficult to assess, one would expect that this potential immortal time bias might favor the medical therapy arm. In the non–high-risk groups, patients who underwent cardiac catheterization 8 or more days after a noninvasive stress test were excluded. PCI or CABG procedures were flagged only if they occurred within 60 days of the qualifying event; survival for at least 4 days after a qualifying event was required in the medical therapy group. Decisions such as using 180, 8, and 4 days seem arbitrary, though they are unavoidable in claims-based studies. Although the numbers themselves appear reasonable, it seems natural to question how sensitive the study findings were to varying these time points. The high-risk group showed the clearest difference in treatment-associated outcomes, with risk arrayed as CABG < PCI < medical therapy. Unlike the equal distribution that one would expect with a randomized clinical trial, the corresponding proportions in the high-risk group were 9.3%, 32.2%, and 58.5%, respectively. The study does not report how completely the demographic and comorbid illnesses accounted for treatment assignment; this being said, claims-based studies in populations with CKD typically report low values. Because this is an observational claims-based study, one is forced to ponder whether differences in treatment-associated outcomes reflect unexplained comorbidity. Although clearly in the realm of speculation, it seems reasonable to suspect that burdens of uncaptured comorbidity would track with captured comorbidity. In this regard, it is interesting that the corresponding average ages were 72.2, 75.1, and 80.3 years for CABG, PCI, and medical therapy, respectively. A similarly eye-catching pattern was present for 2 particularly relevant comorbid conditions that could be reflective of underlying disease severity: heart failure (9.4%, 16.0%, and 25.5%) and arrhythmia (8.4%, 12.5%, and 19.4%). The almost universal association between declining glomerular filtration rate and adverse outcomes in observational studies, even in extensively adjusted models, has led many to suspect that glomerular filtration rate is an excellent marker of unmeasured comorbidity. Of note, the prevalence of CKD stages 4 to 5 was highest in the medical therapy group; among 6 (of 7) noncardiac nonkidney comorbid conditions, prevalence estimates for each were highest in the medical therapy group and lowest in the CABG group. Thus, without direct estimates, one would guess that serious unmeasured comorbidity would tend to reside disproportionately in the medical therapy group. Confronted with a patient with CKD not requiring renal replacement therapy and worsening angina, one is forced to ask whether the findings from Charytan et al guide the choice of therapy. Even in the unlikely situation that analytical models captured all important comorbid conditions, to the extent that treatment allocation in this observational study was equivalent to random, the answer is not clear. “It depends” is one possible answer because the study population is elderly, so the findings are not easily generalizable to younger populations. “No” is also a possibility because the risk for prognostically important imbalance in unmeasured comorbid conditions appears substantial and the definition of optimal medical therapy lacks precision and may introduce survival bias. “Yes” may also be appropriate because comparable studies in populations with a substantial number of patients with acute coronary syndromes and CKD not treated by dialysis are absent and because this study provides previously unknown, extremely sobering prognostic information, with 1-year death rates between 16.2% and 32.0% in the group admitted with acute coronary syndromes. None. The author declares that he has no relevant financial interests. Received May 29, 2019, in response to an invitation from the journal. Accepted June 7, 2019, after editorial review by an Associate Editor and a Deputy Editor. Comparative Effectiveness of Medical Therapy, Percutaneous Revascularization, and Surgical Coronary Revascularization in Cardiovascular Risk Subgroups of Patients With CKD: A Retrospective Cohort Study of Medicare BeneficiariesAmerican Journal of Kidney DiseasesVol. 74Issue 4PreviewPrior studies suggesting that medical therapy is inferior to percutaneous (percutaneous coronary intervention [PCI]) or surgical (coronary artery bypass grafting [CABG]) coronary revascularization in chronic kidney disease (CKD) have not adequately considered medication optimization or baseline cardiovascular risk and have infrequently evaluated progression to kidney failure. We compared, separately, the risks for kidney failure and death after treatment with PCI, CABG, or optimized medical therapy for coronary disease among patients with CKD stratified by cardiovascular disease risk. Full-Text PDF