Hyperkalemia

 We  will review some of the key concepts  including risk factors for hyperkalemia; the challenge of managing hyperkalemia in patients with heart failure; and the impact the novel potassium binders will have in both managing hyperkalemia and optimizing renin-angiotensin-aldosterone system, or RAAS, inhibitor therapy in heart failure patients. We'll finsh with a look at the roles of various healthcare professionals, most notably the cardiologist and nephrologist, in the care of heart failure patients, and how a team approach and effective communication can help improve patient care and outcome. Educational Impact Challenge Assess your clinical knowledge by completing this brief survey. Answering these questions again after the activity will allow you to see what you learned and to compare your answers with those of your peers. TW is a 75-year-old man with chronic kidney disease (CKD) and heart failure (HF). His serum potassium level has risen to 5.7 mmol/L while his estimated glomerular filtration rate has declined steadily over the past 18 months. When his dose of furosemide was increased from 40 mg daily to 80 mg daily, his serum creatinine grew acutely worse. He is currently asymptomatic. His current medication regimen includes furosemide, lisinopril, metoprolol XL, and spironolactone. Which of the following options is best to maintain his renin-angiotensin-aldosterone system (RAAS) inhibitor therapy while also responding to his hyperkalemia? Introduce a novel, oral potassium binder Treat with sodium polystyrene sulfonate (SPS) Eliminate spironolactone Reduce the dose of metoprolol XL The answer is : Introduce a novel, oral potassium binder. This class of drugs can reliably reduce this patient's potassium levels and allow him to enjoy the benefits of renin-angiotensin-aldosterone system (RAAS) inhibitor therapy. Sodium polystyrene sulfonate (SPS) has severe problems with tolerability and is not for long-term use. Eliminating spironolactone does not preserve RAAS inhibitor therapy in this case, and reducing the dose of metoprolol XL does not address hyperkalemia and may worsen his HF outcomes. Let's begin with a look at the typical patient with heart failure who is a candidate for RAAS inhibitor therapy.  Risk factors would you look for in a patient's risk for hyperkalemia The most well known risk factor for hyperkalemia in heart failure patients is chronic kidney disease, or CKD. The risk for hyperkalemia in these patients is due directly to renal dysfunction and abnormal potassium excretion by the kidneys.  Another important hyperkalemia risk factor is diabetes mellitus. Chronic hyperkalemia in patients with diabetes is usually the result of hyporeninemic hypoaldosteronism. Heart failure itself is also a risk factor for hyperkalemia. Heart failure can produce hyperkalemia as a result of decreased distal delivery of potassium. It's important to note that these 3 risk factors are often present in the same patient. Many patients with heart failure also have CKD and diabetes. 

The increased risk of hyperkalemia associated with the use of RAAS inhibitors It's ironic that the very treatments we use to save the lives of these patients are also major contributors to hyperkalemia.  RAAS inhibitors include the angiotensin converting enzyme inhibitors, or ACE inhibitors; the angiotensin receptor blockers, or ARBs; the mineralocorticoid receptor antagonists, or MRAs; and, the new kids on the block if you will, the angiotensin receptor neprilysin inhibitors, or ARNis. All of these drugs have the potential to produce hyperkalemia -- in fact, about 5% to 10% of patients with CKD who are being treated with a RAAS inhibitor will develop hyperkalemia. So patients with heart failure, CKD, and diabetes are at risk for hyperkalemia because of the effect these comorbidities have on potassium excretion. In addition, the use of RAAS inhibitors, the most effective treatment available for heart failure, further increases the patient's risk of hyperkalemia. This irony, has created a therapeutic gap in the care of patients with heart failure. With the recent emergence of the novel potassium binders, this gap may be about to narrow considerably. The significance of these novel potassium-binding agents in the management of heart failure patients at risk for hyperkalemia.  To help us appreciate the significance of the novel potassium binders, we should first look at how hyperkalemia has been traditionally managed in patients with heart failure.  One traditional option has been diuretics, which increases the urinary excretion of potassium and can be helpful in some patients. That said, despite an increase in the use of diuretics in hospitalized patients with heart failure, many of these patients actually develop hyperkalemia while in the hospital. So, clearly diuretics are not always effective in that setting. The other old standby therapy for severe acute hyperkalemia has been sodium polystyrene sulfate, or SPS, a cation-exchange resin that exchanges sodium for potassium in the gastrointestinal (GI) tract and removes potassium through fecal excretion. It's true that in an emergency setting, SPS has been shown to reduce serum potassium in hyperkalemic patients. However, it may also cause severe GI side effects, including gastrointestinal bleeding and necrosis. In addition, it has a slow onset of action -- approximately 4 to 6 hours -- and is associated with a variety of challenges to its use. Alternative therapies for managing hyperkalemia came largely from the inadequacy and ineffectiveness of traditional therapies There was a real gap in the management of hyperkalemia in patients with heart failure who were on RAAS inhibitor therapy. Such treatment gaps are the impetus for the development of many, if not all, new drugs. There are 2 contenders, if you will, for closing this hyperkalemia treatment gap.  One is patiromer, which was approved by the US Food and Drug Administration (FDA) in October of 2015. The other is ZS-9, which is in late-stage clinical development. Patiromer is a nonabsorbed polymer that exchanges mostly calcium for potassium primarily in the colon. It also exchanges some sodium and magnesium for potassium. ZS-9 is structurally designed as kind of a potassium ion trap, if you will. Due to its molecular structure and pore size, only potassium or some ammonium can be trapped. ZS-9 is an odorless and tasteless powder and, like patiromer, is not absorbed from the GI tract.  There were 3 clinical trials evaluating the safety and efficacy of patiromer, the PEARL-HF, OPAL-HK, and AMETHYST trials evaluated the safety and efficacy of patiromer in managing hyperkalemia in patients with heart failure and with CKD and diabetes.  

CLOSING COMMENTS We are very fortunate today to have multiple RAAS inhibitor therapies available to help our patients with heart failure feel better, stay out of the hospital, and live longer. We have been very successful with our use of the ACE inhibitors, the ARBs, the MRAs, and the ARNIs. Our success has brought on a sense of complacency in the treatment of these patients. We evaluate our patients -- we check the boxes if you will -- and say, okay, these are the drugs and the dosages that are best for this patient. The emergence of the novel potassium binders will no doubt fill a key treatment gap in the long-term management of hyperkalemia in heart failure patients on RAAS inhibitor therapy. We will use the availability of safe and effective potassium binders to renew our commitment to optimizing the titration of RAAS inhibitors to maximize the benefits that we can offer our patients. What did you learn from this activity? How do patiromer and ZS9 differ in their mechanisms of action?  Unlike patiromer, ZS-9 selectively binds K+ ZS-9 and patiromer differ in their mechanism of action. While ZS-9 selectively binds K+ in exchange for Na+ and H+, patiromer exchanges potassium for calcium. They also differ in their location of             K+ binding. ZS-9 likely binds K+ in the upper and lower gastrointestinal (GI) tract, while patiromer bind K predominantly in the colon. ZS-9 and patiromer also differ in their onset of action. ZS-9 has a faster onset of action, occurring approximately 2 hours. With patiromer, statistically significant reductions in K+were seen at 7 hours after the first dose in clinical trials. Hypomagnesemia is a concern with patiromer, while edema is a concern with ZS-9.