In the current era of so-called “evidence-based medicine,” the treatment of patients with CKD and concomitant CAD should be based on solid data gathered from randomized clinical trials that included a large number of patients. Despite the indisputable fact that CAD is of great importance as a major determinant of cardiovascular morbidity and mortality in patients with CKD, our knowledge of how best to treat CAD in this special group of patients is less clear by far than what we already know regarding the management of CAD in patients without CKD. The main reason is that patients with CKD are consistently more often excluded from cardiovascular trials than patients with other comorbidities, such as diabetes, hypertension or smoking. In a paper by Charytan and Kuntz, who reviewed 86 cardiovascular trials that randomized more than 400,000 patients, 80% of the trials excluded subjects with end-stage renal disease (ESRD), whereas baseline renal function was reported in only 7% of the trials .
The simple transposition of a proven therapeutic strategy in reducing cardiovascular morbidity and mortality in patients with CAD and preserving renal function in those with CAD and CKD may not be so simple after all. Two recent clinical trials have proven that point exactly. Since the first publication of the Scandinavian Simvastatin Survival Study in the mid-1990s, statin therapy has become one of the cornerstones of the management of patients with proven CAD (and patients at high risk for CAD) and no CKD . On the other hand, in both the 4D and AURORA studies, the use of atorvastatin or rosuvastatin, respectively, in patients at high cardiovascular risk undergoing hemodialysis failed to decrease the composite primary end point of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, even in those subgroups of patients with diabetes, a history of CVD or high levels of low-density lipoprotein (LDL) cholesterol or high-sensitivity C-reactive protein [34, 35].
We must point out, however, that in both studies less than 40% of enrolled patients had any form of atherosclerotic CVD, including CAD, so those studies were not performed exclusively in patients with CAD and CKD. It is our understanding that if a patient presents with documented CAD, regardless of renal function status, statin therapy should be initiated and maintained, targeted to a level of LDL cholesterol below 70 mg/dl. In fact, two post hoc studies of the 4D and AURORA data indicate that statins may reduce cardiac events in selected groups of patients treated by dialysis [36, 37]. In patients with a wide range of renal insufficiency, not necessarily on dialysis, the recent SHARP trial also showed a beneficial effect of simvastatin plus ezetimibe on the incidence of major atherosclerotic events . There is a clear tendency toward recommending statin therapy according to the criteria for the general population in patients with CKD. On the other hand, it is still unclear if statins should also be recommended for CKD patients with no risk factors for coronary events as defined for the general population.
In light of the lack of studies specifically conducted in patients with CKD and CAD, we recommend following the current guidelines for the overall medical management of patients with chronic CAD proposed by the American Society of Cardiology and American Heart Association or the European Society of Cardiology, which have been advocated by the National Kidney Foundation Task Force on Cardiovascular Disease since the late 1990s ‐. This multifaceted approach to overall cardiovascular risk reduction includes, in addition to lifestyle modifications (diet, physical activity and smoking cessation), statins and aspirin for all patients. β-blockers should be used in patients with symptomatic angina and/or after myocardial infarction as well as in patients with CAD and left ventricular dysfunction. Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin type II receptor blockers (ARBs)) should be used in hypertensive patients with CAD with or without diabetes, as well as in patients with left ventricular dysfunction. Attention should be paid not only to initiating those drugs in patients with CAD and CKD on dialysis but also to keeping them on those drugs in cases of patients who undergo kidney transplantation, thereby minimizing the risk of a periprocedural cardiovascular event that could jeopardize the overall benefit conferred by an otherwise successful transplant. The possibility that renin-angiotensin blockers may cause serum creatinine levels to fall more slowly in recipients of live donor renal transplants still needs confirmation . The dire consequences of coronary events during and in the early posttransplantation period should be always considered, however, even if some adverse side effects are anticipated.
This cardioprotective selection of drugs is increasingly being used in patients with CAD, however, for reasons that are still unclear, the prescription of these cardioprotective medications is less frequent among patients with CKD compared to the general population. In a previous study, we showed that in 119 patients with ESRD and CAD followed in a single center, the baseline use of aspirin and statins, in the range of 52% and 17%, respectively, was unexpectedly low . In the same study, the use of ACE inhibitors (or ARBs) in 103 patients with diabetes and CKD was only 34%.
Thus, regarding the medical management of patients with CAD and stage V CKD, clinicians face two major challenges: (1) the lack of clinical trials specifically designed to assess the extension of the benefit of modern medical treatment and (2) the therapeutic nihilism that keeps physicians and healthcare providers from prescribing cardioprotective drugs with proven benefit in reducing cardiovascular mortality in the overall population.
Myyocardial revascularization: percutaneous coronary intervention or coronary artery bypass graft
The American Heart Association and American College of Cardiology recently jointly issued a document regarding criteria for the appropriateness of myocardial revascularization in patients with stable angina . Briefly, myocardial revascularization procedures are indicated on the basis of three distinct elements: clinical presentation (that is, angina functional class), the results of noninvasive testing (stress-induced myocardial ischemia) and the extension of obstructive lesions. Patients who are more symptomatic and receiving optimal medical therapy with high-risk results evidenced by noninvasive tests and more extensive CAD should be referred for myocardial revascularization procedures. Again, in light of the lack of trials specifically designed to study patients with CAD and CKD, we are compelled to apply the same criteria established for patients with preserved renal function to patients with CKD.
There are two major caveats to that approach. The first one is that patients with ESRD are usually self-limited regarding physical activity, which may mask exercise-induced ischemia as a diagnostic clue to the severity of CAD. Moreover, even when patients do present with acute coronary syndrome, fewer with renal failure will have chest pain compared to those with normal renal function, making the clinical suspicion of CAD even more challenging . The second issue relates to noninvasive testing for the diagnosis of CAD in patients with CKD. It is well-accepted now that the overall sensitivity and specificity for the diagnosis of CAD in patients with CKD are lower than those found in patients with normal renal function . Therefore, clinicians may miss two of the three important elements that could lead to a clear indication for myocardial revascularization.
If one finally manages to overcome the previously alluded difficulties in the decision-making process and decides to refer a patient for a myocardial revascularization procedure, another question immediately follows: What kind of revascularization technique should be used, percutaneous or surgical?
As a general rule, the results of coronary interventions in patients with ESRD undergoing dialysis are worse than those performed in the general patient population. In various retrospective studies, perioperative death during coronary bypass graft (CABG) surgery in patients with ESRD undergoing dialysis varies from 5% to 20%, roughly three to four times higher than the rate in the general patient population. The 5-year mortality in CABG patients with ESRD who are undergoing dialysis is about 48%, compared with 15% in the general patient population .
Given the higher mortality rates in patients with CKD who undergo CABG surgery, referring a patient for such a risky procedure can be made only if the procedure not only provides symptom relief but also yields a clear reduction in mortality compared to those patients kept on medical treatment. In this regard, an early retrospective investigation showed that dialysis patients who underwent CABG surgery had a better prognosis than those treated medically . A subsequent small, prospective study in hemodialysis patients with diabetes also showed that coronary intervention (surgery or angioplasty) was associated with reduced cardiac mortality and events . It should be mentioned, however, that in both studies medical therapy was suboptimal by current standards. More recently, we looked at the impact of modern medical treatment of CAD compared to myocardial revascularization on the long-term occurrence of events in a registry of 230 patients with CKD and documented significant CAD (≥70% stenosis). In that study, 184 patients were kept on medical treatment and 46 were referred for myocardial revascularization, although 16 of them refused the procedure . The event-free survival rates at 12 and 48 months were 86% and 61%, respectively, for patients kept on medical treatment alone and 97% and 79%, respectively, for those who had any revascularization procedure. Among those who refused the procedure, however, the event-free survival rate at 48 months was only 26%. We concluded that medical therapy in selected patients promotes acceptable long-term event-free survival rates and that failure to intervene may lead to an adverse outcome when myocardial revascularization was clearly indicated on the basis of the current guidelines.
In another study, Herzog and colleagues collected data from the US Renal Data System to compare the long-term survival of 15,784 dialysis patients after percutaneous angioplasty, coronary stenting or CABG surgery . The 2-year all-cause survival rate was 56.4 ± 1.4% (CABG surgery), 48.2 ± 1.5% (angioplasty) and 48.4 ± 2.0% (coronary stenting). There was a statistically significant difference between the groups that indicated superior results of surgery over the other types of treatment.
Current data support previous observations regarding the overall superior benefit of CABG surgery over percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) in patients with CKD on hemodialysis. In a small, nonrandomized study, Sunagawa et al. compared the event-free survival rates in patients with CKD on hemodialysis who underwent either CABG surgery (n = 29) or PCI (n = 75) . They were able to show that at 2-year follow-up, the cardiac death rate was 0% for the patients who had CABG procedures and 16% for PCI-treated patients. During the later follow-up period, there were six deaths in the CABG group and twenty-seven (including six sudden deaths) in the PCI group. These authors concluded that the use of DESs in this patient population carries a higher risk for sudden death which might be due to stent thrombosis.
As we have discussed, the currently available data gathered is based on either (1) registries of patients with CKD and significant CAD that look retrospectively at outcomes according to different therapeutic strategies or (2) post hoc analysis of subgroups of patients with CKD prospectively enrolled in cardiovascular trials. What we are in great need of is a randomized clinical trial that enrolls only patients with CKD and significant CAD in whom both strategies (medical and invasive treatments) are equally justifiable based on current guidelines. Such a study has been proposed  and would provide the best evidence for choosing the right therapeutic strategy for treating CAD in this high-risk group of patients.