Carat, clarity, colour, and cut: grading the DIAMOND trial

This commentary refers to ‘Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial’, by J. Butler et al., https://doi.org/10.1093/eurheartj/ehac401 and the discussion piece ‘Detailed safety analysis of DIAMOND trial: ‘primum non nocere’?’, by R. Baptista et al., https://doi.org/10.1093/eurheartj/ehad473.

Heart failure specialists, cardiologists in general, nephrologists, and other clinicians at large, need to recognize that underutilization or underdosing of guideline-directed medical therapy (GDMT) is associated with the progression of chronic diseases and worse outcomes.¹ While there are missing data with respect to large outcome trials with novel potassium binders, data from the DIAMOND trial complemented by the other trials with drugs like patiromer provide valuable information to appropriately use potassium binders to optimize therapy vs. discontinuing or underdosing GDMT due to hyperkalaemia.²

DIAMOND trial data may be assessed like other gemstones. Regarding the size (or ‘carat’) of the DIAMOND trial, unfortunately, the trial was stopped early for a variety of reasons, and hence, any interpretation of mortality or hospitalization risk is drastically underpowered. It still is the largest randomized trial confirming that potassium binders can provide long-term potassium control to enable GDMT. With respect to the risk of hypokalaemia, ‘clarity’ to all data is key to understanding the risks. The authors report hypokalaemia events from the PEARL-HF. PEARL-HF used a 25.2 g starting dose and enrolled patients ‘at risk for hyperkalaemia’.³ In contrast, DIAMOND used the on-label 8.4 g starting dose and was a mix of patients with a history of and current hyperkalaemia. We recently presented and will be reporting the results of the pre-specified subgroup analysis of patients entering the run-in of DIAMOND with current compared with a history of hyperkalaemia.⁴ This ‘cut’ of the data shows that patients with current or past hyperkalaemia can have target doses of renin–angiotensin modulators and mineralocorticoid receptor antagonist achieved in over 80% of patients while achieving and/or maintaining normokalaemia with the help of patiromer. Importantly, longer-term use of patiromer is probably only needed in patients at greatest risk for recurrent hyperkalaemia (e.g. those with lower estimated glomerular filtration rate).

When thinking about sacubitril/valsartan, looking at only the PARADIGM-HF study ‘colours’ the hyperkalaemia risks with this drug. When looking at the totality of the evidence, sacubitril/valsartan has the same risk of hyperkalaemia as traditional angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB). In a meta-analysis of 11 studies with 18 866 participants randomized to either sacubitril/valsartan or a traditional ACEi/ARB, the pooled relative risk was 1.09 [95% confidence interval (CI) 0.94, 1.26], indicating that the patients receiving sacubitril/valsartan have similar risks of hyperkalaemia when compared with patients receiving other medications (P = .42).⁵

In summary, we propose that when assessed from the totality of evidence perspective, the data with patiromer provide an opportunity to manage serum potassium levels as clinicians up-titrate hyperkalaemic patients to lifesaving GDMT including renin–angiotensin modulators and mineralocorticoid receptor antagonist. Whether there is a need to make a life-long commitment to patiromer will be based on established risk factors for patients at risk for recurrent hyperkalaemia. In patients at lower risk for hyperkalaemia, one may decline the use of a potassium binder. Hypokalaemia can be easily reviewed by lowering the dose or stopping potassium binder. However, the fear of hyperkalaemia or hypokalaemia should not hamper our commitment to establish GDMT in indicated patients in the current era.

Declarations

Disclosure of Interest

Conflict of interest: Je.B. is an employee of CSL Vifor. S.A. reported grants and personal fees from Vifor and Abbott Vascular and personal fees for consultancies, trial committee work, and/or lectures from Actimed, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BioVentrix, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Faraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Novartis, Occlutech, Pfizer, Repairon, Sensible Medical, Servier, Vectorious, and V-Wave. He is named co-inventor of two patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. Ja.B. reported consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma. B.P. reported consulting fees from AstraZeneca, Boehringer Ingelheim/Lilly, Sanofi/Lexicon, scPharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sarfez, KBP Biosciences, Cereno Scientific, PhaseBio, ProtonIntel, and Vifor Pharma; stock options from scPharmaceuticals, SQinnovations, G3 Pharmaceuticals, Sarfez, Cereno Scientific, KBP Biosciences, ProtonIntel, and Vifor Pharma; US Patent 9931412, site-specific delivery of eplerenone to the myocardium; and US Patent pending 63/045,783, histone-modulating agents for the treatment and prevention of organ damage.

References

Author notes