CITI nov13 - Alert: A Few More Important Details on Hypertension in the ZS-9
vs. Veltassa Debate That You May Not Know (But Should)
The ZS-9 HARMONIZE trial appears to have defined a sig. higher bar for
hypertension than either the Veltassa studies or the FDA and AHA's
hypertension thresholds — In the Ph. 3 ZS-9 HARMONIZE trial (ZS004) high
blood pressure was defined as ≥180/105 mmHg (Figure 1). The source is Page 97
of Supplement 1 of the JAMA study report for ZS004. The higher ≥180/105 mmHg
threshold apparently used in ZS004 is substantially higher than the FDA and AHA
threshold for Stage 1 hypertension (>140/90 mmHg). In fact, AHA defines Stage 2
hypertension as >160/100 mmHg and only hypertensive crisis as >180/110 mmHg.
By contrast, AMETHYST-DN trial defined hypertension as >130/80 mmHg and
enrolled pts with average systolic BP>130 and ≤180 and diastolic BP>80 and ≤110.
We do not know if the ZS005 long-term study used a similar hypertension
definition as in HARMONIZE (ASN poster did not disclose) — However, the 7%
rate of hypertension reported at ASN in ZS005 may underestimate the rate of
hypertension if the ZS004 cutoffs (≥180/105 mmHg) were also used to analyze the
data vs. the more typical FDA/AHA hypertension cutoff (>140/90 mmHg).
Regardless, the normalized rate of worsening hypertension in AMETHYST-DN
appears to be ~50% of the normalized hypertension rate in ZS005 — Assuming
the 7% rate of hypertension in ZS005 correlates with patient exposure to ZS-9, we
would expect the hypertension rate in ZS005 to climb to ~15% once all ~700
patients achieve 12 months of exposure (i.e. 104 hypertension cases, 56 more than
reported at ASN) as weighted average exposure at ASN is only ~6 months. By
contrast, the 7.9% rate of worsening hypertension in AMETHYST-DN is not subject
to change because the data already reflects all patients completing 12 months (see
Figure 2 for hypertension rate calculations).
And finally, the ZS-9 HARMONIZE trial appears to allow concomitant
medication changes but no hypertension benefits were seen — According to
the ZS004 study report the clinic staff was instructed to "note any changes in
concomitant medications" (Page 48 of Supplement 1 of the JAMA paper). Thus it
appears concomitant medications (likely including BP drugs) could be modified in
HARMONIZE (though unclear if adjustments were permitted in ZS005). Despite
this, no mean change in BP was observed in ZS004, in contrast to AMETHYST-DN
where oral meds could be adjusted too and where a decrease in BP was seen.
Because lowering K+ and thus enabling optimal RAASi should facilitate BP
lowering, we speculate that ZS-9's failure to lower BP may be related to an
offsetting impact of sodium absorption.