1. Novant Health Hospital Elmira Darvish
This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.
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BACKGROUND
Background Previous studies have shown that patients with chronic kidney disease (CKD) benefit from the use of
Renin-Angiotensin-Aldosterone-Systeminhibitors (RAAS-I), as this class of medication will slow the
progression of CKD. In doing so, they also reduce renal excretion of potassium(K+) causing hyperkalemia.
Potassiumis an essential dietary mineral that acts as an intracellular cation and has an important role in
membrane activation, ion and solute transport,and the regulation of cell volume. Alteration in K+ level can
lead to life threatening arrhythmias and is associated with increased mortality risk. This limits the use of
RAAS-I and the potential benefit they will offer to this patient population. Treatment of hyperkalemia is
currently limited to the use of resins such as sodium or calcium polystyrene sulfonate.These agents are
associated with serious gastrointestinal(GI) adverse effects thus limiting their use. Patiromer is non-
absorbed anionic polymer that binds to K+ in exchange for calcium in distal colon where K+ concentration
is the highest.This increases fecal excretion of K+. It was approved on 21st Oct 2015. It will available as a
powder form that must be mixed with water to produce an oral suspension.
Other trials
Trial Results
ZS-9 Significant reduction of potassiumlevels at 48 hours and maintenance of
normokalemia during 12 days of the maintenance therapy.
Chernin, G., et. al. Low-dose SPS was safe and effective as a secondary preventive measure for
hyperkalemia induced by RAAS-I in CKD patients with heart disease.
GENERAL STUDY OVERVIEW
Title/Citation Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors. N Engl J Med.
January 2015;10.1056/NEJMoa1410853
Funding Relypsa: the biopharmaceutical company for Veltassa (Patiromer)
Null Hypothesis In patients with kidney disease and hyperkalemia receiving RAAS-I, the use of patiromer will not
significantly impact serum K+ levels
Trial design
(Two phases)
 Part-A: 4-week single group, single-blind initial treatment
 Part-B: 8-week placebo-controlled, single-blind, randomized withdrawal phase.
Objectives Evaluate safety and efficacy of Patiromer in patients with CKD who were receiving at least one RAAS-I
and who had hyperkalemia.
METHODS
Inclusion criteria * 18 to 80 years old with stage 3 or 4 CKD
* Estimated glomerular filtration rate (GFR) of 15 to <60 per 1.73 m2 of body-surface-area
* Serum potassiumlevel of 5.1 to <6.5 mmol/L at two screening
* Stable dose of one or more RAAS-I for at least 28 days
* Stable dose of other antihypertensive medications for at least 28 days
Exclusion criteria * Potassiumrelated electrocardiogram changes
* Severe gastrointestinaldisorders
* Uncontrolled and unstable arrhythmias
* Clinically significant ventricular arrhythmias
* Cardiac surgery,kidney or heart transplant,Acute coronary syndrome, transient ischemic attack, or
stroke within the past 2 months
* SBP: < 110 or ≥ 180 and DBP: <60 or ≥110 mmHg
* Type I diabetes,emergency treatment of Type II diabetes
* Exacerbation of acute heart failure within the previous 3 months
* New York Heart Association (NYHA) Class IV heart failure
Interventions Part-A: Initial phase (4 weeks)
 Mild hyperkalemia (serum K+ 5.1 to <5.5 mmol/L): patiromer 4.2 g twice daily
 Moderate-severe hyperkalemia (serum K+ 5.5 to < 6.5 mmol/L): patiromer 8.4 g twice daily
Part-B: Withdrawal Phase (8 weeks)
 Initial K+ levels (5.5 to < 6.5 mmol/L) decreased to 3.8 to <5.1 mmol/L were then randomized to either
continue receiving patiromer or placebo.
Follow-
up/Monitoring
Study duration: 14 weeks (Feb.-Aug. 2013) screening (day 1), part A treatment (4 weeks), part B (8
weeks). Early withdrawals at any time and/orineligibility for part B: 3, 7 and 14 days after stopping the
drug. Patients K+ levels were evaluated on day 3 of each phase and weekly after.
Monitoring for adverse effects: hypokalemia, hyperkalemia, EKG changes,GI side effects, allergic
reactions, worsening of renal functions and electrolyte imbalances.

2. Novant Health Hospital Elmira Darvish
This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.
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Primary Endpoints Part A: Mean change in serum K+ from baseline to week 4
Part B: Change from baseline serum K+ to either:
◦ 3.8 to < 5.5 mmol/L up to Week 4; or
◦ First local serum K+ <3.8 mmol/L or ≥ 5.5 mmol/L
Secondary
Endpoints
Part A: Proportion of patients with serum K+ of 3.8 to < 5.1 mmol/L within 4 weeks
Part B: Within 8 weeks, serum K+ value ≥ 5.5 mmol/L or serum K+ value ≥ 5.1 mmol/L
Statistical analyses * Sample size of n = 40 was needed to provide over 90% power
* Based on two-sided, one-sample paired t-test, alpha was determined to be 0.001
* Mean change K+ levels and 95% Confidence Interval (CI) was calculated using longitudinal repeated-
measures model to include covariates’ presence or absence (hypertension,diabetes,baseline K+ values)
* Changes in serum K+ level was ranked from lowest to highest due to constrains on the timing of
interventions that differed for each patient.This ranking was used to compare median change using
Hodges-Lehmann estimator
* Analysis-of-variance model on ranks was used for study group comparison
* Part A: intent-to-treat and Part-B: per-protocol
* The Kaplan–Meier method was used to characterize the time to the first event for exploratory efficacy
end points.
RESULTS
Enrollment 395 patients were screened. 243 were enrolled in the initial treatment phase.85/92 and 134/151 completed
part A. 15/85 and 92/134 were eligible for part B randomization (n=107). Reasons for withdrawal:
experienced adverse events,withdrew consent or met the protocol specified withdrawal criteria.
Baseline
characteristics
Majority were white men, average age of 64.2±10.5 years and mean K+ level of 5.6±0.5 mmol/L
*97% hypertension *46% stage 3 CKD *45% stage 4 CKD
*57% type-II diabetes *42% heart failure *25% myocardial infarction
All patients were receiving at least one RAAS-I at baseline. Use of non-RAAS-I was reported in 54% of
the patients.
Primary Outcomes Part A: Mean change in serum K+ levels -1.01± 0.03 (95% CI -1.07 to -0.95, P < 0.001)
Part B: Median change from baseline serum K+ (<3.8 or 5.5 <)
 Placebo: baseline level = 4.45 mmol/L, median change 0.72 (95% CI 0.46-0.99, P < 0.001)
 Patiromer: baseline K+ level of 4.49 mmol/L, median change 0
Secondary
Outcomes
Part A: Proportion of patients with serum K+ (3.8 to < 5.1 mmol/L): 76% (95% CI 70 to 81)
Part B: Reoccurrence of hyperkalemia
Serum K+
levels ≥ 5.5 mmol/L Serum K+
levels ≥ 5.1 mmol/L Between groups comparison
Placebo 60% (95% CI: 47-74) 91% (95% CI: 83-99) P < 0.001
Patiromer 15% (95% CI: 6-24) 43% (95% CI: 30-56) P < 0.001
Other Outcomes * More patients in the placebo group required interventions for hyperkalemia (62% vs. 16%)
* At the end of part-B, more patients in the patiromer group were still on RAAS-I therapy (94% vs. 44%)
* Most common adverse side effects were constipation (11% Part A and 4% in Part B) followed by
diarrhea and nausea and hypomagnesemia. Magnesiumsupplements were provided in 4% of patients on
patiromer.
AUTHORS’ CONCLUSIONS
Among patients with CKD who were taking RAAS-I and had hyperkalemia, treatment with patiromer was associated with
reduction in serum K+ levels and maintenance of normal K+ levels.
GENERALIZABILITY/CRITIQUE/DISCUSSION

3. Novant Health Hospital Elmira Darvish
This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.
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Patient Population * Study population represented patient population who generally benefit from RAAS-I therapy i.e. history
of CKD with diabetes and hypertension.
* Serum K+ levels (5.1 to < 6.5 mmol/L) were representative of the broad range of hyperkalemia that is
observed in patients with CKD and receiving RAAS-I.
*Exclusion criteria include conditions that are usually seen concurrently in patients with CKD such as high
Body Mass Index (BMI), alcohol and drug abuse,swallowing disorder and GI disorders, active cancer,
extreme blood pressure variations, unresolved acute coronary syndromes.
* Patients requiring emergency treatment of hyperkalemia were excluded due to ethical reasons and the
acute nature of their condition. Although these criteria may be appropriate, it limits applicability of the
drug for acute hyperkalemia.
* Patients who were on other antihypertensive medications including loop and thiazide diuretics were
included as long as the dose was stable for the past 28 days and patient was still hyperkalemic. This was
a great compromise for a confounding factor
* 8/55 patients in the patiromer group and 4/52 patients in placebo were stage 2 CKD that were
accidentally included in the study due to the difference in staging by the laboratories. This can
potentially impact the outcome (potential for type I error).
Intervention * Single-blinded design was necessary because the investigators had to be able to adjust the dose of
patiromer or reduce the dose of RAAS-I based on K+ levels. Restricting the number of un-blinded
personneland restricting access to the information minimized bias.
* Appropriate to have patients blinded throughout part A and B as the packaging of placebo and drug
weighed differently (2g vs. 4.2g).
* Patients were not restricted on diet but were counseled at each visit to restrict K+ intake (goal ≤ 3g/day).
Dietary K+ intake can have great impact on the serum levels and simple counseling is very subjective and
the emphasis on this matter may vary from one centerto another. The common practice goal for K+
restriction is ≤ 2g/day.
* There was no mention of how compliance to either placebo or patiromer was assessed during the study
* The duration of the study (12 weeks) may have been appropriate to observe reduction in K+ levels but it
may not have been long enough to determine positive or negative effects associated with chronic use of
patiromer.
Endpoints * This study is more focused on the efficacy of patiromer rather than safety.
* The end point of this trial is clinically significant to management of hyperkalemia in a non-acute setting.
Statistics * Power was met. Number of patients needed in each arm was 40. In the withdrawal phase each arm had at
least 50 patients.
* Use of t-test was appropriate for the independent samples (part-B)
* This study is prone to Type I error i.e. rejection of a true-null hypothesis (false-positive)
* Data is nominal, ordinal and continuous and appropriate statisticaltests were performed
* Wide CI raises the question for potential influence of confounding factors
* Use of mean for the measure of central tendency is appropriate in part-A as data is continuous
* Use of median for the measure of central tendency is appropriate in part-B as data is ordinal
PRESENTER’S CONCLUSIONS
Patiromer certainly will have a great impact on the management of hyperkalemia in the studied patient population because the
alternative therapies currently available are associated with more severe side effects in comparison to patiromer, however a
comparative study may be necessary between patiromer and alternative therapies (such as Kayexalate). However, the use of
patiromer is limited based on the exclusion criteria of patients with the aforementioned serious comorbidities. Use of patiromer
may be more appropriate in an outpatient setting that does not require rapid correction of K+ levels. Based on the data provided
in this study,the use of patiromer is associated with reduction in serum K+ levels and maintenance of normal K+ levels.
STRENGTHS WEAKNESSES
*Strong study design with appropriate statistical adjustment for
comparison
* Great ethical consideration for trial design
* Appropriate patient population with some of the most
commonly seen comorbidities.
* Sample was representative of patient population in an
outpatient setting
* Appropriate length of therapy to see an effect
*Serious adverse events were not attributed to the drug based
on investigators’ judgment
* Relypsa funded the study and presence of conflict of interest
with some investigators and possible bias
* Diet was not considered and can be a great confounder
* Inappropriate length of therapy to observe complications
associated with chronic use of patiromer
* Exclusion criteria limits the use of patiromer in an inpatient
setting (based on patient population)
APPLICATION TO CLINICAL PRACTICE

4. Novant Health Hospital Elmira Darvish
This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.
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The use of this medication is limited for patients with hyperkalemia in an acute setting and various comorbidities that were not
studied. Applicability of this medication for CCU patients is limited initially, but once patients are stable, they may be able to
start using patiromer for maintenance of potassium levels after hospital discharge.