The Hk Challenge

Reliable K+ Control

Proven RAASi Enablement

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Proven RAASi Enablement

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PROVEN RAASI ENABLEMENT1–3

OPAL-HK1

AMBER2

PEARL-HF3

VELTASSA®

Veltassa® is proven to allow guideline-recommended RAASi therapy1–3

RAASi therapy remains the foundation of pharmacotherapy for patients with CKD and HF.4,5

KDIGO Guidelines:

RAASi therapy should be administered using the highest approved dose that is tolerated4

ESC Guidelines:

The four pillars of an ACEi/ARNi, BB, MRA and SGLT2i are recommended to reduce mortality for all HFrEF patients5
  • RAASi therapy significantly reduces the risk of kidney failure and CV events in patients with CKD6,7
  • RAASi therapy is associated with a 63% reduction in all-cause mortality in patients with HFrEF.8 Current drug treatment for HFrEF patients is based on four classes of drugs: the addition of SGLT2i to therapy with ACEi/ARNi/BB/MRA reduced the risk of CV death and worsening HF in patients with HFrEF5

Hyperkalemia is one of the main reasons for RAASi down-titration and discontinuation.9,10

  • Suboptimal RAASi usage is associated with a significantly higher risk of mortality9

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Veltassa® trials were specifically designed to include patients on RAASi therapy in a variety of patient populations.

Overall, in Veltassa® phase 2 and 3 clinical studies:

RAASi

99.5%

of patients were receiving RAASi therapy at baseline11

87.0%

had CKD with eGFR <60 mL/min/1.73 m2 (majority had CKD 3/4)11

65.6%

had diabetes mellitus11

47.5%

had heart failure11

Veltassa® is the only K+ binder proven to enable RAASi therapy in multiple placebo-controlled trials.1-3

Continue RAASi therapy

94%

of patients with Veltassa®

OPAL-HK1

86%

of patients with Veltassa®

AMBER2
Increase dose of MRA

91%

of patients with Veltassa®

PEARL-HF3

Opal-HK1

Phase 3, two-part, single blind randomised withdrawal study1

Study objectives:

Determine the safety and efficacy of Veltassa® to control hyperkalemia in patients with CKD

Part A: 4–week Veltassa® treatment phasePart B: 8–week randomised withdrawal phaseNormokalemiapatientsCKD patients onRAASi therapy (n=243)ModerateHKMildHKWeek 8Week 4BaselineWeek 4BaselinePlacebo + RAASi therapyVeltassa® + RAASi therapyPart A: Study EndpointsPart B: Study EndpointsPrimaryendpointPrimaryendpointSecondaryendpointSecondaryendpointR

NormokalemiapatientsVeltassa® + RAASi therapyPlacebo + RAASi therapyRPart A:4–week Veltassa® treatment phasePart A: Study EndpointsPart B:8–week randomised withdrawal phasePart B:Study EndpointsModerateHKMildHKCKD patients on RAASi therapy (n=243)PrimaryendpointPrimaryendpointSecondaryendpointSecondaryendpointBaselineBaselineWeek 4Week 4Week 8

Baseline comorbidities/treatments:100% with CKD /97% with HTN/57% with T2DM/42% with HF/100% receiving RAASi

The dosing regimen used in OPAL-HK was 8.4 g of patiromer twice-daily.1 The recommended starting dose is 8.4 g once-daily.11 The daily dose may be increased or decreased on a weekly basis by 8.4 g once-daily as necessary to reach the desired target range, up to a maximum dose of 25.2 g daily.11 Veltassa is licensed for the treatment of hyperkalemia in adults.11

4-week treatment phase

Veltassa® significantly reduced elevated serum K+ values, with overall mean change of −1.01 ± 0.03 mEq/L at Week 4.1

  • 76% of patients achieved normokalemia at Week 41
  • Most common AE: mild-to-moderate constipation (11%)1
Adapted from Weir et al, 2015PlaceboVeltassa®Percentage of patients (%)CKD 3/4 subpopulationCKD 4/5 subpopulationHFsubpopulationDiabetes subpopulation302010405060709080100093%39%86%35%55%91%45%RAASi therapy use at end of treatment period for subpopulations12,13

8-week randomised withdrawal phase

At week 4 of the randomised withdrawal phase: serum K+ increased in the placebo arm and remained within the normal range in the Veltassa® arm with a between-group difference of 0.72 mEq/L.1

From the start of withdrawal phase to week 4:1

Veltassa® group (N=55)

Patients in the Veltassa® group

remained normokalemic:

Baseline (mean): 4.49 mEq/L

Week 4 (estimated median change): 0 mEq/L

Placebo group (N=52)

Patients in the placebo group became

mildly hyperkalemic:*

Baseline (mean): 4.45 mEq/L

Week 4 (estimated median change): +0.72 mEq/L
  • At Week 8: more patients on Veltassa® remained on RAASi therapy (94%) compared with placebo (44%)1
  • During the randomised withdrawal phase and through its follow-up period, the proportion of patients with one or more AEs was similar in the placebo group and the Veltassa® group1
  • Most common AEs: mild-to-moderate constipation, diarrhoea, nausea (all 4%)1

DOWNLOAD THE OPAL-HK INFOGRAPHIC
Adapted from Weir et al, 2015Patients who remained on RAASi therapy at end of withdrawal phasePercentage of patients (%)Veltassa®Placebo302010405060709080100044%94%p=0.019Percentage of patients who remained on RAASi therapy at Week 8
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AMBER2

Phase 2, 12-week, randomised, double-blind, placebo-controlled trial2

Study objectives:

To evaluate the use of Veltassa® to allow more persistent use of spironolactone in patients with CKD and rHTN

Primary endpointSecondary endpoint2 week safety follow-up121110987654321Week: BaselineSpironolactone + blinded Veltassa®Spironolactone + blinded placeboRPatients with CKD and rHTN (N=295)

RSpironolactone + blinded Veltassa®Spironolactone + blinded placeboPatients with CKD and rHTN (N=295)Primary endpointSecondary endpointBaselineWeek2 week safety follow-up121110987654321

Baseline comorbidities/treatments:100% with CKD/49% with T2DM/45% with HF/100% receiving RAAS

  • During the study, among patients treated with placebo, 2 out of 3 developed hyperkalemia with spironolactone. Veltassa® reduced the risk of hyperkalemia by half in patients on spironolactone (p<0.0001)2
  • At Week 12, significantly more patients receiving Veltassa® (86%) remained on spironolactone compared with those receiving placebo (66%; p<0.0001)2
  • The safety profile of Veltassa® in this study was consistent with previous reports; the most frequently reported AEs were GI-related2

DOWNLOAD THE AMBER STUDY INFOGRAPHIC
Adapted from Agarwal et al, 2019Patients who remained on spironolactone at Week 12Percentage of patients (%)Veltassa®Placebo302010405060709080100066%86%p<0.0001More patients were able to start and continue spironolactone over 12 weeks
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PEARL-HF3

Phase 2, 4-week, double-blind, randomised, placebo-controlled, parallel-group study3

Study objectives:

Evaluate efficacy and safety of Veltassa® in patients with chronic HF

Primary endpointSecondary endpointDay 15Day 28Day 14BaselinesK+ >3.5– ≤5.5 mEq/L: Patients discontinued from studysK+ >5.1– ≤5.4 mEq/L: Spironolactone up-titrated to 25mg/daysK+ >3.5– ≤5.1 mEq/L: Spironolactone up-titrated to 50mg/dayVeltassa® + spironolactonePlacebo + spironolactoneRHF Patients (N=104)

RHF Patients (N=104)Primary endpointVeltassa® + spironolactonePlacebo + spironolactoneBaselineDay 28Day 14Day 15Secondary endpointsK+ >3.5– ≤5.5 mEq/L: Patients discontinued from studysK+ >5.1– ≤5.4 mEq/L: Spironolactone up-titrated to 25mg/daysK+ >3.5– ≤5.1 mEq/L: Spironolactone up-titrated to 50mg/day

Baseline comorbidities/treatments:100% with HF/~55% with CKD/~52% with T2DM/98% receiving RAASi

Veltassa® resulted in significantly lower serum K+ levels vs placebo at every measured time point between Day 3 and Week 4, despite an increase in spironolactone dose at Day 15.3

9/10

Patients treated with Veltassa® were able to initiate and use higher doses of spironolactone1*
  • Significantly fewer patients treated with Veltassa® developed hyperkalemia (serum K+ value >5.5 mEq/L) vs placebo (p=0.015)3
  • Significantly more patients treated with Veltassa® (91%) than placebo (74%; p=0.019) were able to have their spironolactone dose increased to 50 mg3

The most common AEs were GI disorders (e.g. flatulence, diarrhoea, constipation and vomiting), which were reported with higher frequency with Veltassa® (21%) than with placebo (6%).3

DOWNLOAD THE PEARL-HF INFOGRAPHIC
Adapted from Pitt B et al, 2011.Percentage of patients (%)Veltassa®Veltassa®PlaceboPlacebo302010405060709080100074%25%91%7%p=0.019p=0.015Proportion of HF patients on 50 mg/day of spironolaction and frequency of hyperkalemia (Serum K+ >5.5 mEq/L)

The most common AEs were GI disorders (e.g. flatulence, diarrhoea, constipation and vomiting), which were reported with higher frequency with Veltassa® (21%) than with placebo (6%).3
DOWNLOAD

CKD patients on RAASi therapy (n=243)

CKD 3/4 (eGFR 15–<60 mL/min/1.73m2) with hyperkalemia (sK+ 5.1- <6.5 mEq/L) using RAASi therapy

Mild HK

Baseline sK+ 5.1–5.5 mEq/L; Veltassa® 8.4g/day starting dose (n=92)

Moderate HK

Baseline sK+ 5.5–6.5 mEq/L; Veltassa® 16.8 g/day starting dose (n=151)

Normokalemia Patients

Eligible criteria: Baseline moderate HK patients who fell within the target sK+ range (3.8-5.1 mEq/L) at 4 weeks while receiving RAASi therapy

R

Normokalemia patients receiving RAASi therapy were randomised to receive placebo or Veltassa® for a duration of 8 weeks

Part A: Study endpoints

Primary endpoint

Mean change in sK+ from baseline to Week 4

Secondary endpoint

Proportion of normokalemia patients within sK+ 3.8–5.1 mEq/L at Week 4

Part B: Study endpoints

Primary endpoint

Treatment group differences in median change in sK+ over the first 4 weeks

Secondary endpoint

Proportion of patients with a recurrence of mild (>5.1 mEq/L) or moderate (>5.5 mEq/L) hyperkalemia

Patients with CKD and rHTN (N=295)

Patients eligible for inclusion were aged ≥18 years and older, with an eGFR of 25 to ≤45 mL/min per 1.73m2, serum K+ between 4.3 and 5.1 mmol/L and rHTN

Primary endpoint

Difference between treatment groups in the proportion of patients remaining on spironolactone treatment at Week 12

Secondary endpoint

Difference between treatment groups in the change in systolic AOPB from baseline to Week 12

Week 1

Veltassa® dose titration permitted after 1 week

Week 3

Spironolactone dose titration permitted after 3 weeks

HF Patients (N=104)

CHF patients indicated to receive spironolactone with sK+ 4.3-5.1 mEq/L and:

  • CKD (eGFR <60 mL/min/1.73 m2) and on ≥1 ACEi/ARB or BB

Placebo + spironolactone

Spironolactone 25mg/day (n=49)

Veltassa® + spironolactone

Veltassa® 30 g/day + spironolactone 25mg/day (n=55)

Primary endpoint

  • Mean change in serum K+ levels from baseline to end of the study (Day 28)

Secondary endpoint

  • Proportion of patients with serum K+ 5.5 mEq/L at anytime during the trial
  • Proportion of patients whose spironolactone dose could be increased to 50 mg/day

Mean serum K+ change from baseline to Week 4 for all subjects was -1.01 mEq/L

Significant reduction within 7 h (-0.2 mEq/L; p≤0.004)

Mean serum K+ <5.5 mEq/L within 20 h

Significant K+ reduction (0.75 mEq/L) at 48 h (14 h after last dose)

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Adverse events should be reported to the Vifor Pharma group.

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