Effect of Cross-Linked Polyelectrolyte in HF Patients With CKD
Effect of Cross-Linked Polyelectrolyte in HF Patients With CKD
The trial presented here is a phase II, double-blind, randomized, parallel group, placebo-controlled study designed to explore the effects of CLP vs. placebo on serum K concentration and fluid overload in HF patients with renal impairment who are on the guideline-recommended combination of an ACE inhibitor or ARB, a beta-blocker, and diuretics, and have a clinical indication for the addition of spironolactone.
The principal aim of this early study was to explore the effects of CLP on multiple clinical and laboratory variables to identify the most appropriate endpoints for future pivotal clinical trials. Based on the results of pilot studies in normal volunteers and patients with end-stage renal disease (ESRD), it was speculated that a daily 15 g CLP dose might lower serum K and/or reduce fluid overload in patients with advanced HF and CKD, defined as an eGFR <60 mL/min/1.73 m.
Throughout the study, no differences were observed between CLP and placebo in serum K concentrations. In contrast, in phase I studies in healthy volunteers and ESRD patients, CLP produced significant faecal removal of K and changes in serum K (unpublished data on file). Based on these findings, the lack of effect of CLP on serum K concentrations in the present study is both surprising and difficult to explain. Neither dietary Na and K intake nor faecal K content were measured in this study and therefore it cannot be determined if co-existing HF and CKD influenced colonic handling of K in the study subjects. Experimental evidence shows that aldosterone increases colonic K secretion, whereas limiting dietary Na activates colonic K absorption. The use of an aldosterone antagonist in Na-restricted HF patients may have attenuated the ability of CLP to increase faecal K elimination. An alternative explanation is that the addition of spironolactone was associated with a rise in serum K, leading to comparable rates of hyperkalaemia in both treatment groups. It is well established that the use of an aldosterone antagonist in patients with reduced renal function can lead to increased rates of hyperkalaemia. For example, in a study of 105 HF patients with either a history of hyperkalaemia or CKD, an incidence of hyperkalaemia as high as 38.5% was seen in patients with an eGFR <60 mL/min/1.73 m. In that study the polymeric K binder RLY5016 significantly lowered serum K levels and allowed up-titration of spironolactone to a 50 mg dose in a higher proportion of subjects.
Several differences between the CLP and RLY5016 studies are noteworthy. Severity of HF was much greater in the current study than in the patients enrolled in the RLY5016 study, as indicated by a higher NYHA class and NT-proBNP levels and a lower eGFR in the CLP population. Hypokalaemia and hypomagnesaemia did not occur in the CLP study. In contrast, compared with placebo, RLY5016 was associated with a higher frequency of hypokalaemia (0% vs. 6%) and greater reduction in Mg levels (P < 0.001). This is of considerable concern in HF patients in whom hypokalaemia and hypomagnesaemia are associated with an increased risk of arrhythmias and poorer outcomes.
Another important difference between the RLY5016 and the CLP compounds is that the former binds very little sodium, whereas the latter can simultaneously bind K and Na. Due to this unique feature of CLP, the present study was designed also to evaluate the effects of this polymer on HF-related congestion and functional impairment. Favourable and consistent actions of 15 g/day CLP on parameters associated with fluid overload were observed. These effects resulted in a pattern of improvement over placebo in both physician-assessed and patient-reported outcomes. During the study period, compared with the placebo group, the patients treated with CLP lost more weight and were less likely to have severe exertional dyspnoea. Compared with placebo, 15% more CLP patients described their current dyspnoea as being moderately or markedly better than before initiation of study drug. This differential improvement in dyspnoea between study drug and placebo is similar to the 12–15% differences between either relaxin or the adenosine A1 receptor antagonist rolofylline and placebo observed in controlled clinical trials of acute HF where one would reasonably expect to see larger early changes. In addition, by the end of the study, the treatment group included more patients who improved by at least one NYHA class and fewer patients with NT-proBNP levels >1000 pg/mL, the inclusion criteria cut-off. The decongestion occurring with CLP may be related to reduction of total body Na by the polymer as well as the polymer's ability to trap free water. Fluid overload in HF patients is inevitably related to an increase and abnormal distribution of total body Na. Indeed, withdrawal of isotonic fluid by ultrafiltration improved the outcomes of hospitalized HF patients more than removal of hypotonic urine with diuretics. In the CLP group there is continuous trapping of Na and fluid both from the diet and the GI secretions. This is likely to modulate total body Na downward in a more physiological manner than might be expected from the 'peak and valley' hypotonic reductions induced by intermittent diuretic therapy. From baseline to the end of the study, the CLP group achieved a trend toward longer 6MWT distances and higher KCCQ scores. The totality of these findings, whether or not statistically significant, suggests that CLP produced a potentially clinically meaningful reduction in HF-related congestion. This is important, because hypervolaemia itself has been shown to worsen the outcomes of HF patients. The prognostic value of the 6MWT was clearly demonstrated in patients from the Studies of Left Ventricular Dysfunction (SOLVD) and from the SOLVD Registry.
The KCCQ is a self-administered, 23-item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference, and quality of life. In some studies of HF patients, the KCCQ has been shown to have greater responsiveness to clinical change than other quality of life assessment tools.
The observed overall mortality rate of 4% was as expected in a population of patients with co-existing advanced HF and CKD. All four deaths occurred in the CLP group. None of the deaths was attributed by the attending investigator to the use of blinded study drug. An independent analysis of all available patient data by a group of HF experts did not identify a unifying aetiology that could be attributed to CLP. Regardless, this imbalance in mortality mandates cautious safety monitoring in the future development of CLP including the involvement of an independent safety monitoring board.
Overall, CLP was well tolerated. The majority of GI adverse events were mild or moderate and transient. In only four instances were adverse events sufficiently severe to require study discontinuation. Interestingly, GI adverse events rates are very similar for CLP and RLY5016 (23.7% vs. 21%). Patients with adverse events leading to study drug discontinuation appear to be similar for CLP and RLY5016 (7% vs. 7%). The brief decline (within the normal range) in serum bicarbonate levels observed in the CLP group was probably a result of physiological buffering to counter a minor transient increase in ingested hydrogen ion. This finding warrants further monitoring in future trials.
Discussion
The trial presented here is a phase II, double-blind, randomized, parallel group, placebo-controlled study designed to explore the effects of CLP vs. placebo on serum K concentration and fluid overload in HF patients with renal impairment who are on the guideline-recommended combination of an ACE inhibitor or ARB, a beta-blocker, and diuretics, and have a clinical indication for the addition of spironolactone.
The principal aim of this early study was to explore the effects of CLP on multiple clinical and laboratory variables to identify the most appropriate endpoints for future pivotal clinical trials. Based on the results of pilot studies in normal volunteers and patients with end-stage renal disease (ESRD), it was speculated that a daily 15 g CLP dose might lower serum K and/or reduce fluid overload in patients with advanced HF and CKD, defined as an eGFR <60 mL/min/1.73 m.
Throughout the study, no differences were observed between CLP and placebo in serum K concentrations. In contrast, in phase I studies in healthy volunteers and ESRD patients, CLP produced significant faecal removal of K and changes in serum K (unpublished data on file). Based on these findings, the lack of effect of CLP on serum K concentrations in the present study is both surprising and difficult to explain. Neither dietary Na and K intake nor faecal K content were measured in this study and therefore it cannot be determined if co-existing HF and CKD influenced colonic handling of K in the study subjects. Experimental evidence shows that aldosterone increases colonic K secretion, whereas limiting dietary Na activates colonic K absorption. The use of an aldosterone antagonist in Na-restricted HF patients may have attenuated the ability of CLP to increase faecal K elimination. An alternative explanation is that the addition of spironolactone was associated with a rise in serum K, leading to comparable rates of hyperkalaemia in both treatment groups. It is well established that the use of an aldosterone antagonist in patients with reduced renal function can lead to increased rates of hyperkalaemia. For example, in a study of 105 HF patients with either a history of hyperkalaemia or CKD, an incidence of hyperkalaemia as high as 38.5% was seen in patients with an eGFR <60 mL/min/1.73 m. In that study the polymeric K binder RLY5016 significantly lowered serum K levels and allowed up-titration of spironolactone to a 50 mg dose in a higher proportion of subjects.
Several differences between the CLP and RLY5016 studies are noteworthy. Severity of HF was much greater in the current study than in the patients enrolled in the RLY5016 study, as indicated by a higher NYHA class and NT-proBNP levels and a lower eGFR in the CLP population. Hypokalaemia and hypomagnesaemia did not occur in the CLP study. In contrast, compared with placebo, RLY5016 was associated with a higher frequency of hypokalaemia (0% vs. 6%) and greater reduction in Mg levels (P < 0.001). This is of considerable concern in HF patients in whom hypokalaemia and hypomagnesaemia are associated with an increased risk of arrhythmias and poorer outcomes.
Another important difference between the RLY5016 and the CLP compounds is that the former binds very little sodium, whereas the latter can simultaneously bind K and Na. Due to this unique feature of CLP, the present study was designed also to evaluate the effects of this polymer on HF-related congestion and functional impairment. Favourable and consistent actions of 15 g/day CLP on parameters associated with fluid overload were observed. These effects resulted in a pattern of improvement over placebo in both physician-assessed and patient-reported outcomes. During the study period, compared with the placebo group, the patients treated with CLP lost more weight and were less likely to have severe exertional dyspnoea. Compared with placebo, 15% more CLP patients described their current dyspnoea as being moderately or markedly better than before initiation of study drug. This differential improvement in dyspnoea between study drug and placebo is similar to the 12–15% differences between either relaxin or the adenosine A1 receptor antagonist rolofylline and placebo observed in controlled clinical trials of acute HF where one would reasonably expect to see larger early changes. In addition, by the end of the study, the treatment group included more patients who improved by at least one NYHA class and fewer patients with NT-proBNP levels >1000 pg/mL, the inclusion criteria cut-off. The decongestion occurring with CLP may be related to reduction of total body Na by the polymer as well as the polymer's ability to trap free water. Fluid overload in HF patients is inevitably related to an increase and abnormal distribution of total body Na. Indeed, withdrawal of isotonic fluid by ultrafiltration improved the outcomes of hospitalized HF patients more than removal of hypotonic urine with diuretics. In the CLP group there is continuous trapping of Na and fluid both from the diet and the GI secretions. This is likely to modulate total body Na downward in a more physiological manner than might be expected from the 'peak and valley' hypotonic reductions induced by intermittent diuretic therapy. From baseline to the end of the study, the CLP group achieved a trend toward longer 6MWT distances and higher KCCQ scores. The totality of these findings, whether or not statistically significant, suggests that CLP produced a potentially clinically meaningful reduction in HF-related congestion. This is important, because hypervolaemia itself has been shown to worsen the outcomes of HF patients. The prognostic value of the 6MWT was clearly demonstrated in patients from the Studies of Left Ventricular Dysfunction (SOLVD) and from the SOLVD Registry.
The KCCQ is a self-administered, 23-item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference, and quality of life. In some studies of HF patients, the KCCQ has been shown to have greater responsiveness to clinical change than other quality of life assessment tools.
The observed overall mortality rate of 4% was as expected in a population of patients with co-existing advanced HF and CKD. All four deaths occurred in the CLP group. None of the deaths was attributed by the attending investigator to the use of blinded study drug. An independent analysis of all available patient data by a group of HF experts did not identify a unifying aetiology that could be attributed to CLP. Regardless, this imbalance in mortality mandates cautious safety monitoring in the future development of CLP including the involvement of an independent safety monitoring board.
Overall, CLP was well tolerated. The majority of GI adverse events were mild or moderate and transient. In only four instances were adverse events sufficiently severe to require study discontinuation. Interestingly, GI adverse events rates are very similar for CLP and RLY5016 (23.7% vs. 21%). Patients with adverse events leading to study drug discontinuation appear to be similar for CLP and RLY5016 (7% vs. 7%). The brief decline (within the normal range) in serum bicarbonate levels observed in the CLP group was probably a result of physiological buffering to counter a minor transient increase in ingested hydrogen ion. This finding warrants further monitoring in future trials.
