Potassium as a Treatable Biomarker in Cardiovascular Disease: New Keys to Hyperkalemia Nicholas Wettersten, MD Associate Professor Heart Failure, Mechanical Circulatory Support and Transplant March 1 st, 2019
Potassium Too Little or Too Much
Causes of High Potassium Bananas, oranges, cantaloupe, honeydew, apricots, grapefruit (some dried fruits, such as prunes, raisins, and dates, are also high in potassium) Cooked spinach Cooked broccoli Potatoes Sweet potatoes Mushrooms Peas Cucumbers Zucchini Eggplant Pumpkins Leafy
Medications Beta blockers Digoxin intoxication Mannitol Suxamethonium Verapamil ACE inhibitors ARBs Direct renin inhibitors NSAIDs Calcineurin inhibitors Aldosterone antagonists Potassium-sparing diuretics Trimethoprim Pentamidine Salt substitutes and salt alternatives Penicillin G Stored blood products Drug Saf. 2014 Sep;37(9):677-92. doi: 10.1007/s40264-014-0196-1
These Medications Save Lives 1.00 0.95 0.90 0.85 Probability of Survival 0.80 0.75 0.70 0.65 0.60 0.55 0.50 Spironolactone Placebo 0.45 Pitt, NEJM, 1999 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 Months
But At a Cost of Hyperkalemia Rate of Admission for Hyperkalemia (per 1000 patients) 14 12 10 8 6 4 2 0 1994 1995 1996 1997 1998 1999 2000 2001 Study Year Online release of RALES N Engl J Med 2004; 351:543-551; DOI: 10.1056/NEJMoa040135
Which Can Be Deadly 2.5 Rate of In-Hospital Death from Hyperkalemia (per 1000 patients) 2.0 1.5 1.0 0.5 Online release of RALES 0.0 1994 1995 1996 1997 1998 1999 2000 2001 Study Year N Engl J Med 2004; 351:543-551; DOI: 10.1056/NEJMoa040135
Dyskalemia Common and Deadly Over 5000 HF patients One year follow up Hyperkalemia - 24.4% Hypokalemia - 20.3% Increased Mortality Savarese, JACC HF, 2018
Important Comorbidities Chronic Kidney Disease Heart Failure Diabetes Mellitus Hypertension
How Do We Treat? Emergency Calcium Insulin Beta-agonists Bicarbonate Dialysis Loop Diuretics
Sustained Potassium Reduction Maintenance Therapy Sodium Polystyrene Sulfonate (Kayexlate) Approved in 1958 - prior to laws requiring drugs prove effectiveness and safety Best evidence 30 patients published in NEJM in 1961 showing Kayexlate lowered or did not increase potassium Binds potassium in colon (also binds sodium, calcium, magnesium) 15-60 grams four times a day (1500 mg sodium per 15 g) Diarrhea Reported cases of colonic necrosis and severe hypercalcemia May worsen heart failure exchanging sodium for potassium Hosp Pharm 2015;50(11):959 960
Sustained Potassium Reduction Maintenance Therapy Patiromer Sorbitex Calcium Calcium loaded polymer, exchanges calcium for potassium in colon Can bind sodium and magnesium 8.4 grams administered either once or twice a day (twice a day in trials), can advance up to 25.2 grams Onset in 7-48 hours, duration 12-24 hours Powder mix with water (90 ml), store in refrigerator
Chemical structure of active ingredient Calcium-sorbitol counterion OH OH [Ca 2+ ( HO OH) 0.5 ] 0.5 OH OH - O O H 2 O Patiromer anion F m n p n p m = number of 2-fluoro-2-proprenoate groups m = 0.91 Sarwar, JACC, 2016
Able to Advance Heart Failure Therapies European Heart Journal, Volume 32, Issue 7, 1 April 2011, Pages 820 828
Able to Use RAAS Inhibition Serum Potassium, meq/l 5.8 5.6 5.4 5.2 5.0 4.8 4.6 Hyperkalemia Mild Moderate 4.4 4.2 Baseline 1 4 8 12 16 20 24 28 32 36 40 44 48 52 4 23 d Day 3 a Study Visit, wk 1 c Day 3 b of patients Treatment Follow-up Bakris, JAMA, 2015
Caveats Give 3 hours separated from other medications (before and after) Possible drug-drug interactions decreasing absorption Possible worsening CKD Mild GI distress not infrequent (constipation/diarrhea) Hypomagnesemia, hypokalemia, hypocalcemia
Sustained Potassium Reduction Maintenance Therapy Sodium Zirconium Cyclosilicate (ZS-9) Crystal lattice that exchanges sodium to bind potassium throughout GI tract Given as 5-15 grams once daily for maintenance Onset 1 6 hours, duration 4 12 hours Powder mix with water (240 ml)
Sarwar, JACC, 2016
Rapid and Sustained Potassium Reduction Placebo (N=61) ZS-9, 10 g (N=63) P<0.05 5.4 On Drug On Drug vs. Placebo Off Drug Serum Potassium (mmol/liter) 5.2 5.0 4.8 4.6 4.4 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Initial Day Packham, NEJM, 2015
Anker, Euro J HF, 2015 Efficacious in Heart Failure Patients
Caveats Administered with a loading dose of three times a day for 1-2 days 1000 mg per 10 gram dose Could exacerbate HF, edema not infrequent in trials Give 2 hours separated from other medications (before and after) Mild GI distress not infrequent (constipation/diarrhea) Hypomagnesemia, hypokalemia, hypocalcemia
Summary Hyperkalemia is common Hyperkalemia significantly increases mortality Kayexlate not clinically proven effective and has risks Two new agents available (Patiromer and ZS-9) to bind potassium Both proven efficacious Both safe Both shown to allow continuation of neurohormonal blockade
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