Given our (or maybe just my) constant preoccupation with hyperkalemia, a key clinical question I ask myself all the time: Is normokalemia the ultimate target in dialysis care?
Fortunately, I’m not the only one asking. Today’s post summarizes findings from a brand-new, pre-proof article:
Why Do We Worry About Hyperkalemia in Hemodialysis?
Hyperkalemia is common in people on HD. Although potassium can be removed aggressively during treatment, rapid shifts may lead to arrhythmias and sudden cardiac death (SCD). More about that in my previous blog post here.
What Is Sodium Zirconium Cyclosilicate (SZC)?
SZC is a newer potassium binder that effectively lowers serum potassium in both CKD and HD populations. SZC works by exchanging sodium for potassium in the small intestine. If you want to know more about pharmalogical management of hyperkalemia – check out my previous post here.
What Did This Study Aim to Answer?
While SZC lowers potassium, whether or not it results in fewer arrhythmias, fewer strokes, or fewer cardiac deaths remains unknown. This Phase 3b trial aimed to assess whether SZC improved cardiovascular outcomes in HD patients with hyperkalemia.
Study Design Highlights
- Design: Double-blinded, placebo-controlled
- Sites: 344 across 26 countries
- Participants: Adults on thrice-weekly HD for ≥4 months with hyperkalemia (2 out of 3 pre-dialysis K ≥5.5mmol/L after the HD weekend)
- Intervention: Dose-titrated SZC or placebo (5–15g) on non-dialysis days
- Primary Endpoints:
- Sudden cardiac death
- Stroke
- Arrhythmia-related hospitalization, ED visit, or intervention
Who Was Excluded?
- History of cardiac arrhythmias or pacemakers
- Use of potassium binders within 7 days of screening
Sample Size and Study Power
The authors hypothesized a 20% event reduction in the SZC group, planning to observe 730 primary events. This required ~2,800 participants.
How Many Were Enrolled?
- ~1,350 to SZC
- ~1,350 to placebo
But, the trial was terminated early by the sponsor, after ~12 months of treatment.
Why Did the Study End Early?
- Low event rate
- High treatment discontinuation
What were the discontinuation rates?
- 30.4% in SZC
- 38.6% in placebo
Why did participants discontinue?
- Participant decision (8.7% SZC vs 14.5% placebo)
- Transplant (4.3% SZC vs 4.6% placebo)
- Adverse events (4.2% SZC vs 6.5% placebo)
What were the adverse events?
- COVID-19
- Hyperkalemia (and rescue treatment)
- Edema
- Pneumonia
- Death
- Hypokalemia
There was no major increase in adverse events with SZC compared to placebo.
Did SZC Improve Outcomes?
No. Both groups experienced 119 primary events. No significant difference in:
- Time to event
- Hospitalizations
- Stroke rates
A sub-analysis of events while on-treatment also showed no benefit.
Did SZC Improve Potassium Levels?
Yes:
- Normokalemia achieved in 74% (SZC) vs 47% (placebo)
- Fewer cases of severe hyperkalemia in the SZC group
Interestingly, both hyper- and hypokalemia were less common in the SZC group.
Why Were Event Rates So Low?
Authors proposed several reasons:
- The 5.5 mmol/L cutoff may not have captured high-risk patients
- Arrhythmic death may be overestimated in this population
- Study population had fewer patients with diabetes or structural heart disease than typical HD cohorts
- COVID-19 may have affected recruitment and event capture
Does This Mean We Can Stop Worrying About Hyperkalemia?
Not necessarily. While this trial didn’t show a reduction in hard outcomes, previous observational studies have linked potassium extremes to cardiovascular risk. These findings should refine, not eliminate, our concern.
Future care may lie in precision medicine, using tools like continuous heart rhythm monitoring to define individualized potassium targets.
Table: Summary of DIALIZE-Outcomes Trial – SZC vs Placebo
| Category | SZC Group | Placebo Group | Key Takeaways |
|---|---|---|---|
| Participants | ~1,350 | ~1,350 | Well-matched groups |
| Treatment | SZC (5–15g, titrated) | Placebo | Given on non-HD days |
| Normokalemia Achieved | 74% | 47% | Significantly better control with SZC |
| Primary Events (SCD, Stroke, Arrhythmia) | 119 | 119 | No difference in event rate |
| Severe Hyperkalemia | Fewer cases | More cases | SZC reduced severe episodes |
| Hypokalemia | Less frequent | More frequent | I am not sure why this occurred. |
| Discontinuation Rate | 30.4% | 38.6% | High dropout in both arms |
| Top Reasons for Discontinuation | Participant choice, Transplant, Adverse Events | Same as SZC | Similar across groups |
| Adverse Events | Comparable | Comparable | No major safety signal |
| Study Duration | ~12 months | ~12 months | Ended early due to low event rate |
| CV Outcomes Improvement? | ❌ No | ❌ No | No benefit despite better K control |
Clinical Takeaways
- SZC improved potassium control but did not reduce sudden death, stroke, or arrhythmia-related hospitalizations.
- Achieving normokalemia may not be sufficient to prevent cardiac events in all patients.
- The future of hyperkalemia management may shift toward individualized potassium targets based on patient-specific cardiac risk.
