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Lancet. 2019 Sep 13. pii: S0140-6736(19)32135-X. doi: 10.1016/S0140-6736(19)32135-X.
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Agarwal R, Rossignol P, Romero A, Garza D, Mayo MR, Warren S, Ma J, White WB, Williams B
PMID: 31533906 Full Text at The Lancet
Study design: Am J Nephrol 2018;48:172–180
Supplementary Appendix: Trial Design
Introduction
Resistant hypertension is defined as uncontrolled blood pressure while taking three or more classes of antihypertensive medication or taking four or more classes of antihypertensive medication regardless of blood pressure level.
Chronic kidney disease is a major risk factor for resistant hypertension with a prevalence rate three times the rate found in the general population; in an Italian cohort, 23% of patients with CKD had resistant hypertension. Using this figure, an estimated 850 million people suffering from chronic kidney disease, resistant hypertension stands as a significant cause of morbidity.
Spironolactone is among the most effective agents at lowering blood pressure in resistant hypertension. This was demonstrated in both the ASPIRANT study, and the more recent PATHWAY-2 study, however they excluded patients with eGFR < 40 ml/min/m2. Why were patients with significant CKD excluded form these studies? Say hello to hyperkalemia. The fear of hyperkalemia has prevented the widespread use of spironolactone in CKD. Oral potassium binders may help circumvent this issue, theoretically allowing patients to harness the benefits of mineralocorticoid receptor antagonists without fear of hyperkalemia. Table 1 briefly summarises the pharmacological properties of the currently approved oral potassium binders.
Adapted from Beccari Mv, Meaney CJ. Core Evidence 2017:12, 11-24.
Patiromer is a sodium free potassium binder which has been studied in several population groups and is effective at lowering potassium, allowing the continuation of RAAS blockers as demonstrated in PEARL-HF , AMETHYST-DN, and OPAL-HK studies. (What’s with patiromer and the gems? Is it the jewel we’ve been looking for?)
Adapted from Beccari Mv, Meaney CJ. Core Evidence 2017:12, 11-24.
The AMBER study aimed to study this gem to see if it allows the persistent use of spironolactone for the treatment of resistant hypertension in patients with chronic kidney disease.
The Study
Methods
This was a phase-2, multicentre, randomised, double-blind, placebo-controlled, parallel group trial conducted at 62 outpatient centres in 10 countries across Europe, South Africa and the United States.
Inclusion criteria
Age ≥ 18 years
eGFR 25 – 45 ml/min/1.73m2 (using CKD-EPI formula)
serum potassium between 4.3 – 5.1 mmol/L
Resistant hypertension – defined as unattended systolic automated office blood pressure of 135-160 mm Hg despite 3 or more anti-hypertensive drugs – including a diuretic, and an ACEI or ARB
What was done next…
Patients who met the eligibility criteria were enrolled in a 4-week, run in period, consisting of 4 visits (S1,S2, S3 and S4). These visits were designed to ensure that patients were on stable doses of medication, had “true” resistant hypertension, and could properly and reliably use a home BP machine.
AMBER Study design. AOBP, automated office blood pressure; CKD, chronic kidney disease; eGFR estimated glomerular filtration rate; HBP, home blood pressure. * To ensure eligibility criteria, stable medication, and competent use of HBP monitor. From Am J Nephrol 2018;48:172–180.
At each visit after the initial screening visit, 2 types of office BP measurements were made –
Automated Office BP (AOBP) – using 3 measurements 1 minute apart using automated oscillometric device (the staff was supposed to leave the room to eliminate white-coat effect)
Self-measured BP (SMBP) – triplicate readings twice daily at the same times. The same device was used to record the BP during office visits (again sans-white coat)
Randomisation…
Patients meeting all eligibility criteria at the final screening were stratified according to
Potassium level: 4.3 to <4.7 vs. 4.7 to 5.1 mEq/L
History of diabetes
Patients were then randomized (1:1) via a web-based response system to receive patiromer or microcrystalline cellulose placebo in addition to open-label spironolactone. Study personnel were blinded to the results.
The protocol for dosing of spironolactone and patiromer has been well illustrated in Figure 2 and 3 respectively.
Primary endpoint
The difference in the proportion of patients remaining on spironolactone at Week 12 between treatment groups (spironolactone plus patiromer versus spironolactone plus placebo).
Secondary endpoints
the difference in systolic AOBP from baseline to Week 12 (or to the last available AOBP before addition of any new antihypertensive medications or change in any of the baseline antihypertensive medications) between treatment groups.
changes in K+ levels over time
proportion of patients with serum potassium ≥5.5 mEq/L
average daily dose and cumulative dose of spironolactone
time to discontinuation of spironolactone
changes in albuminuria (urine albumin to creatinine ratio) from baseline to Week 12.
Statistics simplified
A cohort of 280 patients was estimated to provide 90% power to detect a difference between treatment groups of ≥20% in the proportion of patients remaining on spironolactone at Week 12 at an α = 0.05. Assuming a dropout rate of 15%, the sample size could have provided approximately 80% power to detect a 4 mm Hg difference between treatment groups in change in systolic AOBP from Baseline to Week 12.
The primary endpoint were compared between treatment groups using the Cochran-Mantel-Haenszel test, stratified by baseline K+ category (4.3 to <4.7 vs. 4.7 to 5.1 mEq/L) and presence/absence of diabetes mellitus.
The secondary endpoint were analyzed using an analysis of covariance (ANCOVA) model, with baseline systolic AOBP as a covariate and baseline serum K+ and presence/absence of diabetes mellitus as categorical factors.
Funding
This study was sponsored and funded by Relypsa, Inc., a Vifor Pharma Group Company.
Results
The flow diagram below summarises the study profile of the patients screened and subsequently enrolled.
Table 1. depicts the baseline demographic characteristics of patients. Approximately 50% patients were diabetic and nearly all patients were on diuretics and RAAS inhibitors.
Primary Outcome
The primary efficacy outcome was met, with 86% patients receiving patiromer remaining on spironolactone at week 12 as opposed to 66% in the placebo arm.
Secondary Outcomes
Let’s see the secondary outcomes one by one.
So, with respect to blood pressure, significant reductions in unattended systolic automated office blood pressure from baseline to week 12 were observed in both treatment groups, with no significant difference between groups. This can be seen as intertwined lines in the graphs during all the follow up visits.
During the 12-week study, significantly more patients in the placebo group than patients in the patiromer group had serum K+ of 5·5 mmol/L or greater
Significantly greater number of patients in the placebo group discontinued spironolactone as compared to placebo and this difference was notable as early as 2 weeks.
In coherence with this outcome, the cumulative dose of spironolactone was significantly greater than in the placebo group. Compliance to spironolactone was confirmed using blood levels of the drug and its metabolites.
There was no statistical difference between treatment groups in spot urine albumin to creatinine ratio over time.
Safety
Most frequently reported adverse events were gastrointestinal disorders in 16% patients in each group, with most common adverse event being diarrhea.
Mean estimated glomerular filtration rate decreased in both treatment groups during the study. By week 12, the decrease was 2.1 mL/min per 1.73 m2 in the placebo group and 1.4 mL/min per 1.73 m2 in the patiromer group. This was reversible with discontinuation of the drug suggesting a hemodynamic effect of spironolactone. None of them had eGFR decline of 50% or greater and none required dialysis during the study period.
Discussion
Two thirds of patients receiving placebo developed hyperkalemia and patiromer reduced this risk by 50%. This enabled the continuation of spironolactone in significantly greater proportion of patients.
The study has several strengths, most importantly being the inclusion of study population with lower eGFR which had been conveniently excluded in the earlier trials. Secondly, the study population was homogenous with respect to gender. Thirdly, the co-morbidities like diabetes (50%), cardiac dysfunction (45%) were representative of the patients we routinely come across in the real world clinical practice. And finally, the spironolactone levels were periodically assessed to establish adherence to the drug.
As with any trial, it has its own limitations too. With respect to racial representation, most of the recruited patients were caucasian, so it is unclear if the benefit extends similarly to other ethnic groups.
Another point to be noted is that mean reduction in systolic blood pressure was similar between the two groups. Does it suggest that the difference in the dose “over 12 weeks” was “pharmacologically” miniscule as opposed to the “statistically significant result”, more so because drug metabolites could be detected even after 2 weeks of discontinuation.
Thirdly, the follow up period was 12 weeks; which might not have been long enough to assess differences between treatments in BP arising from the more persistent use of spironolactone.
On a final note, Patiromer has proven its worth in yet another trial – and this time in a challenging group of patients. Whether, this ability to continue RAAS blockers will provide long term morbidity and mortality benefits in population with CKD remains to be studied, but patiromer is indeed a molecule to look forward to.
Summary by NSMC Intern Lovy Gaur