2023: Year of Flozination and Hypertension

As November 2022 rolled in, and ASN Kidney Week and the American Heart Association were in session, several major publications appeared in high-impact medical journals that will change practice in 2023 and beyond.

In our opinion, the 10 published studies discussed below highlight the end of 2022.

(10) Anticoagulation in patients with chronic kidney disease (CKD) and kidney failure is challenging. Although no one likes warfarin, and the direct oral anticoagulants are easier to use, there are no trials in this space for patients with kidney failure on dialysis. The RENAL-AF (1) trial was published at the end of 2022 to help answer this question. This was a prospective, randomized, open-label, blinded-outcome evaluation of apixaban vs. warfarin in patients receiving hemodialysis with atrial fibrillation and a CHA₂DS₂-VASc score ≥2. Patients were randomized 1:1 to apixaban (5 mg twice daily; 2.5 mg twice daily with age ≥80 years and/or weight ≤60 kg) or dose-adjusted warfarin. The 1-year rates for major or clinically relevant, non-major bleeding were 32% and 26% in apixaban and warfarin groups, respectively, whereas 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients [26%]) and warfarin (13 patients [18%]) arms. Unfortunately, enrollment was very slow, and there was inadequate power to draw any firm efficacy conclusions. As a result, the study was terminated early. But it was very clear that clinically relevant bleeding events were approximately 10-fold more likely than stroke or systemic embolism among this population on anticoagulation. Whether we even need to give anticoagulation in patients with kidney failure on dialysis for atrial fibrillation is the bigger question for the next trial.

Anticoagulation in patients with chronic kidney disease and kidney failure is challenging.

(9) Dialysis-related studies are important for our community. An interesting study published in 2022 assessed the association between nephrologist ownership of freestanding dialysis facilities and certain clinical outcomes (2). Reassuringly, patient treatment by nephrologist owners at their owned facilities was associated with a 2.4% higher probability of home dialysis, a 2.2% lower probability of receiving an erythropoiesis-stimulating agent, and no significant difference in anemia or blood transfusions. Patient treatment by nephrologist owners at their owned facilities was not associated with differences in missed treatments, transplant waitlisting, mortality, hospitalizations, 30-day readmissions, hemodialysis adequacy, or fistula or long-term dialysis catheter use. This was a fascinating study showcasing how profit motives did not compromise patient-centered nephrologists’ care within the constraints of this cross-sectional examination.

(8) Hypertension (HTN) management is an important problem in general medicine, cardiology, and nephrology. Having more agents using novel pathways will add to the armamentarium for the battle against HTN. The next two trials published in November 2022 highlighted two novel agents for HTN management. PRECISION, a multicenter, blinded, randomized, parallel-group, phase 3 study, supports the role of endothelin (ET) receptor antagonists (ERAs) in the treatment of resistant HTN (3). Although the ET pathway has been implicated in the pathogenesis of HTN, it is currently not targeted therapeutically, and this could contribute to the failure to control HTN with currently available drugs. ET-1 is a vasoconstrictive peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, endothelial dysfunction, vascular hypertrophy and remodeling, and fibrosis. ET-1 acts through two receptors: ETA and ETB. Activation of ETA receptors in vascular smooth muscle cells results in vasoconstriction, whereas ETB receptor activation results in vasoconstriction in the vascular smooth muscle cells and vasodilation through nitric oxide release in endothelial cells. Aprocitentan is a novel, oral, dual ETA/ETB antagonist that has demonstrated a more favorable tolerability (less edema from unopposed ETB stimulation in single ETA inhibitors such as atrasentan) and improved safety profile in early clinical trials compared with other ERAs studied (4). Importantly, aprocitentan has a longer half-life and less liver toxicity than the dual ETA/ETB inhibitor bosentan used in pulmonary HTN. The unique design of the study, including a 4-week, double-blind, placebo-controlled treatment phase; a 32-week single-blind, active-treatment phase; and a 12-week, double-blind, placebo-controlled withdrawal phase provides robust data on short-term and, importantly, long-term safety and efficacy of aprocitentan with both office and ambulatory blood measurement. The safety profile, long half-life (44 h), and low potential for drug–drug interactions are conducive for a chronic treatment to be used for patients who often have several comorbidities and are treated with multiple agents. The effect shown in this study was consistent across multiple key subpopulations. Importantly, these results open the possibility of aprocitentan being used in other kidney diseases.

(7) Aldosterone synthase inhibitors target a likely cause of treatment resistance by suppressing hormone synthesis rather than by blocking the downstream mineralocorticoid receptor. The first aldosterone synthase inhibitor to enter clinical development (osilodrostat) was associated with off-target inhibition of cortisol synthesis and was ultimately repurposed to treat excess cortisol states rather than HTN (5). Preclinical and phase 1 studies have shown that baxdrostat has high selectivity (selectivity ratio, 100:1) for aldosterone synthase compared with the enzyme required for cortisol synthesis (11β-hydroxylase), which shares 93% sequence similarity with aldosterone synthase. In a recent phase 2 trial of 248 patients published in 2022 (6), the investigators examined the efficacy and safety of baxdrostat in patients with treatment-resistant HTN. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was –11.0 mm Hg, and the difference in this change between the 1-mg group and the placebo group was –8.1 mm Hg. No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level of 6.0 mmol/L or greater occurred in two patients, but these increases did not recur after withdrawal and reinitiation of the drug. This class would potentially serve to be more effective at removing circulating aldosterone (and consequent target organ damage), as well as for those who are intolerant of existing mineralocorticoid antagonists, especially the high doses often required in primary aldosteronism.

(6) Anticoagulation in patients with kidney failure on dialysis is important, as we discussed earlier. Yet another study—the AXADIA trial—was a prospective, randomized, open, blinded outcome assessment of apixaban vs. vitamin K antagonists (VKAs) for atrial fibrillation in patients on hemodialysis (7). The two arms were either apixaban (2.5 mg twice per day) or the VKA phenprocoumon (international normalized ratio [INR], 2.0–3.0). The composite primary safety outcome was defined by a first event of major bleeding; clinically relevant, non-major bleeding; or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis and/or pulmonary embolism. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.53–1.65; p (noninferiority) = 0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA. There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% vs. 24.5%; major bleedings, 10.4% vs. 12.2%; myocardial infarctions, 4.2% vs. 6.1%, respectively). In summary, comparing apixaban with VKA in patients with atrial fibrillation on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Interestingly, even on oral anticoagulation, patients with kidney failure on hemodialysis with atrial fibrillation remain at high risk of cardiovascular events. Should we move to using an agent that does not require monitoring of INR?

(5) We often get asked by our surgical and anesthesia colleagues to perform dialysis on the day before or the day of surgery in patients with kidney failure on hemodialysis. There really were not much data for that statement until a recent study, again in 2022, that may change the way we should practice perioperative hemodialysis. A retrospective cohort study of over 1 million procedures among more than 340,000 patients with kidney failure on hemodialysis looked at 1-, 2-, or 3-day intervals between the most recent hemodialysis treatment and the surgical procedure (8). The authors found that the longer intervals between the last hemodialysis session and surgery were significantly associated with higher risk of 90-day mortality in a dose-dependent manner regardless of the number of days they compared. In addition, undergoing hemodialysis on the same day as surgery was associated with a significantly lower hazard of mortality vs. without same-day hemodialysis. In the analyses that evaluated the interaction between the hemodialysis-to-procedure interval and same-day hemodialysis, undergoing hemodialysis on the day of the procedure significantly attenuated the risk associated with a longer hemodialysis-to-procedure interval. Yes, the study design is retrospective, the magnitude of the absolute risk differences is small, and the findings are susceptible to residual confounding, but we may have to face the possibly that our surgical and anesthesia colleagues do have a point.

(4) Next is the MyTEMP study (9) that focused on temperature used in maintenance hemodialysis and use of cooled dialysate or not. MyTEMP was a pragmatic, two-arm, parallel-group, registry-based, open-label, cluster-randomized superiority trial done at 97 hemodialysis centers with 15,413 patients undergoing approximately 4.3 million treatments in Ontario, Canada. Interestingly, rather than patients, centers were randomized in this cluster-randomization design. The intervention was personalized cooler dialysate (temperature, 0.5°C–0.9°C below each patient’s pre-dialysis body temperature with a lowest recommended dialysate temperature of 35.5°C or a standard temperature dialysate of 36.5°C for all patients and treatments). The study showed that the mean dialysate temperature was 35.8°C in the cooler dialysate group and 36.4°C in the standard temperature group. The primary outcome of major adverse cardiovascular outcomes occurred in 1711 of 8000 patients (21.4%) in the cooler dialysate group vs. 1658 of 7413 patients (22.4%) in the standard temperature group. The blood pressure had no major difference. The popularity of cooler dialysate as a blanket option for the whole dialysis unit is called into question by this study, although the risks and benefits of cooler dialysate in some patients on hemodialysis who are susceptible or high risk may need further study.

(3) We often wonder, as renin-angiotensin system (RAS) inhibitors are kidney protective, does stopping them at stage 4–5 CKD increase the glomerular filtration rate (GFR) and provide some breathing space in the relentless path to dialysis? To this end, the STOP ACEi (angiotensin-converting enzyme inhibitor) investigators (10) sought to assess whether discontinuing RAS inhibitors in patients with progressive stage 4–5 CKD would slow the GFR decline. Just over 400 participants were randomized in a 1:1 fashion to continue RAS inhibitors or to discontinue them. The STOP ACEi trial did not find any benefit by stopping ACEi (or angiotensin receptor blockers) in advanced CKD for the primary outcome of GFR decline. Indeed, the discontinuation arm had a 6% numerically higher risk of needing dialysis and a numerically higher risk of cardiovascular events as well. Strengths are obvious in the numbers and large randomized clinical trial study. The study cohort included primarily participants who were White, limiting the generalizability of these findings to other ethnicities. The open-label nature of this study may have contributed to bias, particularly with respect to subjective end points (e.g., quality of life), and the indication for starting dialysis. Nevertheless, perhaps in the era of good anti-hyperkalemia agents, stopping RAS inhibitors is probably not needed unless they are hypotensive.

(2) The final top 2 studies published in November 2022 really are a win for nephrology and the cardiovascular community. The sodium glucose cotransporter 2 (SGLT2) inhibitors, or flozins, have truly arrived. A meta-analysis published in Lancet (11) really highlights the importance of this. Thirteen trials involving 90,413 participants were included. In total, 82% were patients with type 2 diabetes, and the remainder did not have diabetes. Compared with placebo, adding an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk, 0.63; 95% CI, 0.58–0.69) with similar relative risks in patients with and without diabetes. In the four CKD trials, relative risks were similar irrespective of the primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury and cardiovascular death and hospitalization for congestive heart failure each by 23% regardless of whether participants had diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death but did not significantly reduce the risk of non-cardiovascular death. For all outcomes, results were broadly similar irrespective of trial mean baseline estimated GFR. Per authors, based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any hazards of ketoacidosis or amputation.

(1) The EMPA-KIDNEY trial tops the list. EMPA-KIDNEY (12) is a multinational, randomized, parallel-group, double-blind, placebo-controlled trial of the SGLT2 inhibitor empagliflozin. The primary outcome of kidney disease progression or cardiovascular death occurred in 432 of 3304 patients (13.1%) in the empagliflozin group vs. 558 of 3305 patients (16.9%) in the placebo group—a 28% risk reduction with empagliflozin. This was greater than the 18% that had been required for the power calculations. Hospitalization due to any cause was significantly lower in the empagliflozin group, occurring at a rate of 24.8/100 patient-years vs. 29.2 hospitalizations/100 patient-years in the placebo arm, indicating a 14% relative risk reduction. This is one of the largest flozin studies to date for patients with kidney diseases with and without diabetes. There were more than 800 patients with immunoglobulin A nephropathy in this study as well (13). This looks like yet another win for flozinate. There was significant benefit in terms of the primary outcome with empagliflozin, with good safety and tolerability. The benefits extend into populations without diabetes (confirming DAPA-CKD [14]) and down to a GFR of 20 mL/min/1.73 m².

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The end of 2021 saw more glomerular disease trials; the end of 2022 heading into 2023 showcased more magic of flozination and highlighted novel, anti-HTN medication pathways.