Guideline-directed medical therapy in Polish patients with chronic coronary syndrome and advanced chronic kidney disease: insights from the ISCHEMIA-CKD trial

ISCHEMIA trial

The current study is an analysis of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease randomized trial (ISCHEMIA-CKD, ClinicalTrials.gov number, NCT01985360). The detailed rationale and design of the trial as well as its results have been published [3, 5]. In brief, the trial randomized patients with CCS, at least moderate myocardial ischemia on stress testing, and advanced chronic kidney disease (CKD, defined as estimated glomerular filtration rate [eGFR < 30 ml/min/1.73 m²] or on dialysis) to one of the two treatment strategies: (1) initial invasive strategy of cardiac catheterization and optimal revascularization, if feasible, in addition to GDMT, and (2) an initial conservative strategy of GDMT alone, with catheterization reserved for failure of GDMT.

GDMT was advised in keeping with concurrent medical practice guidelines with updates considered when the guidelines changed during the trial [5]. Efforts were made to maintain a high level of GDMT, equally in both randomized arms of the study. The trial was approved by institutional ethics committees, and all study participants gave informed consent to participate in the study.

GDMT goals

There were 7 main GDMT goals: (1) not smoking; (2) high-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) in pre-dialysis patients and moderate- or high-intensity statin (atorvastatin 20–80 mg or rosuvastatin 10-40 mg) in dialysis patients; (3) glycated hemoglobin (HbA1c) < 8% in patients with diabetes; (4) systolic blood pressure (SBP) < 140 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg (the blood pressure target was updated to < 130/80 mm Hg during the trial in response to the changing guidelines; however, the original target was kept for the purpose of this analysis); (5) acetylsalicylic acid therapy/anticoagulant therapy; (6) angiotensin-converting-enzyme inhibitors (ACE-I)/angiotensin receptor blockers (ARB) use as tolerated; (7) b-blocker use in patients with a history of myocardial infarction (MI) or left ventricle ejection fraction (LVEF) < 40%. GDMT goal attainment was reinforced by encouraging collaboration among the site study team and participants’ personal physician. Study teams were trained to provide lifestyle counseling regarding smoking cessation, nutrition, physical activity, and medication adherence. Pedometers were offered to study participants to encourage regular exercise. Dedicated ISCHEMIA algorithms were introduced to site teams that outlined recommended lipid-lowering and blood pressure therapy. A Clinical Coordinating Center Risk Factor Management Team oversaw GDMT goal attainment progress at all sites globally, provided monthly site-specific GDMT reports to study teams, and used various communication methods to encourage medical therapy optimization, such as investigator meetings, webinars, monthly newsletters, emails, dedicated phone calls with site study teams, and in-person meetings with individual investigators to review participant level data and provide specific feedback. Participants were provided cards and key tags listing the risk factor goals (Supplementary Figure S1).

Patients were followed up at 1.5, 3, 6, and 12 months after randomization and every 6 months thereafter until the trial ended. In-clinic visits were recommended, and, if not feasible, visits by phone and by proxy were allowed.

In the current analysis, GDMT goal attainment of participants randomized in Poland were compared to all other countries at two timepoints in the trial: (1) the randomization visit; (2) the last follow-up visit. Change in GDMT goal attainment between the randomization and last follow-up visits was also performed in the subgroup of study participants randomized in Poland.

Statistical analysis

We summarized categorical and continuously measured participant baseline characteristics using frequencies and percentages or median and interquartile range (IQR), respectively. Characteristics of Polish participants and other world regions were compared using the c² test for categorical variables, and the Kruskal-Wallis for continuous variables. For two-by-two comparison involving expected cell counts less than five, we used Fisher’s exact test. To assess changes between baseline and follow-up characteristics among Polish participants, binary variables were compared using McNemar’s test for paired samples, and continuous variables using the Wilcoxon matched pairs signed rank test. P-values of less than 0.05 were considered statistically significant.

Baseline characteristics

In total, there were 105 ISCHEMIA-CKD trial participants randomized in Poland vs. 672 participants randomized in the remaining 36 countries across 5 continents worldwide. Median time from randomization to the last follow-up visit was 2.2 years (2.6 years for participants in Poland vs. 2.1 years for participants in other countries, p < 0.01). The comparison of baseline patient characteristics between the two groups is presented in Table I. Compared to other countries worldwide, ISCHEMIA-CKD participants in Poland were older (age 67 [60, 76] vs. 63 [55, 70] years, p < 0.001), more often of white race (99% vs. 59%, p < 0.001), had lower incidence of diabetes (44% vs. 59%, p = 0.004), higher incidence of prior myocardial infarction (25% vs. 16%, p = 0.04), peripheral vascular disease (12% vs. 5%, p = 0.009), and atrial fibrillation (23% vs. 7%, p < 0.001), were more often current/former smokers (64% vs. 50%, p = 0.04), and presented with longer duration of angina (2 [1, 6] vs. 1 [0, 5] years, p = 0.02).

Baseline GDMT goal attainment

Compared to other countries, participants in Poland had similar baseline rates of non-smoking and statin goal attainment (p = 0.29 and 0.16, respectively), were more often treated with antiplatelet/anticoagulants (91% vs. 83%, p = 0.04), ACE-I/ARBs (62% vs. 45%, p = 0.002), and b-blockers (95% vs. 72%, p < 0.001), and more frequently attained the blood pressure and HbA1c level goals (73% vs. 53%, p < 0.001; 96% vs. 77%, respectively, p = 0.003 for both) (Table I). Other baseline GDMT characteristics are presented in Table I.

Follow-up GDMT goal attainment

At the last FU visit, participants in Poland compared to other countries met the statin goal less frequently (24% vs. 40%, p < 0.01), showing more frequent attainment of the blood pressure, on b-blocker, and HbA1c < 8% goals (Table II). Polish participants showed sustained improvements regarding the GDMT goal attainment at the last FU visit compared to their baseline status (Table III). Table IV presents optimal revascularization therapy (ORT) characteristics of participants randomized to the invasive treatment strategy in Poland compared to other world regions.

Lipid-lowering therapy

Following two negative clinical trials of statin therapy in patients on dialysis (AURORA and 4D), KDIGO clinical practice guidelines advised against initiating statin therapy in this population of patients but recommended that statins be continued in patients already on such treatment at dialysis initiation [7–9]. In contrast to the general population of patients, KDIGO moved away from setting an LDL treatment target; instead, following the SHARP trial results, it advised statin or statin/ezetimibe treatment in the CKD population at increased cardiovascular risk [10]. The dosing of statins in patients with advanced kidney disease is also not well studied; however, due to concerns about increased risks of adverse events with high-intensity statin regimens, KDIGO recommends using low to moderate doses, avoiding high doses.

With all these considerations in mind, and given that more than 50% of the population studied comprised dialysis patients, only about 20% of ISCHEMIA CKD participants in Poland received a high-intensity statin treatment with a marginal increase over the FU to 24%, depicting the national practice patterns. In contrast to the non-CKD ISCHEMIA trial population, the overall statin adherence in patients randomized to ISCHEMIA CKD in Poland decreased during the trial duration from 89% to 81%, further highlighting difficulties in maintaining this treatment in advanced kidney disease patients [4], but also a lack of compelling evidence clearly demonstrating the balance of efficacy and safety in high-quality randomized trials.

Blood pressure goal

Reduction in blood pressure has been shown to improve prognosis in patients with advanced kidney disease. The blood pressure goal has been the subject of debate and modifications in the general population in recent years following publication of the results of the SPRINT clinical trial [11]. Although the KDIGO 2021 clinical practice guidelines recommend that adults with high blood pressure and chronic kidney disease be treated with a systolic blood pressure goal < 120 mm Hg, they note that this target is less certain in patients with advanced chronic kidney disease (G4 and G5) such as presented in this paper [12]. Regarding the ISCHEMIA-CKD trial, the initial blood pressure goal recommendation of < 140/90 mm Hg in participants without proteinuria and for participants on dialysis was changed during the trial to < 130/80 mm Hg. For the purpose of this analysis, the values consistent with the original trial’s goal are presented. The trial participants randomized in Poland showed significantly better blood pressure control, as demonstrated by the percentages of patients achieving target blood pressure and median blood pressure values, with a non-significant improvement over the trial follow-up.

Other GDMT targets

Patients randomized to ISCHEMIA-CKD in Poland presented with a very high adherence to most other GDMT goals, showing high antiplatelet/anticoagulant and b-blocker adherence which was consistent through to the last FU visit and excellent glycemic control, as indicated by a high proportion of patients achieving target HbA1c levels. Smoking habits also seem to be improving in this population, with 50% former vs. 14% current smokers. Although the proportion of patients achieving the ACE-I/ARB treatment goal exceeded that of other countries, there remains room for improvement, likely reflecting concerns about worsening renal function, hyperkalemia, and hypotension. It is therefore important to underscore that there is no lower eGFR limit that precludes use of ACE-I/ARB, and an acute creatinine level increase was shown to be associated with improved renal outcomes [13].

This post hoc analysis of ISCHEMIA-CKD GDMT goal attainment in Poland is the first systematic presentation of CCS medical treatment patterns in a sample population of high-risk patients with CCS and advanced chronic kidney disease. Compared to other countries worldwide, Polish patients showed a high level of guideline-directed medical treatment goal attainment.

This is a descriptive study, and the comparisons were not adjusted for differences in baseline patient characteristics; however, the trial enrollment criteria ensured a broadly similar study population, and all baseline differences between the compared groups have been reported, allowing readers to consider them when interpreting the data. In line with the ISCHEMIA-CKD trial policies, we did not report country-specific patient outcomes in this manuscript. Due to the sample size limitations, analyses of subgroups depending on the randomized strategy assignment, dialysis status, or other subgroup analyses, were not performed. Data on changes in diet and physical activity were not available.