LIVING THE LAB LIFE
A BLOG FOR ASCLS REGION V
Last Saturday, those of us who braved the cold to attend the continuing education event held at the Allina Commons in Minneapolis had the pleasure of hearing a lecture by Joshua Soldo of Roche Diagnostics entitled “The Measurement of Natriuretic Peptides in the Era of Neprilysin Inhibition.” In this lecture, information regarding a newly-approved drug for treating systolic heart failure and its impact in the clinical and laboratory setting was presented.
Heart failure (HF) is a leading cause of death in the United States, across all demographics. It occurs when the heart muscle is weakened due to damage and is no longer able to pump enough blood around the body to maintain proper oxygenation. This results in tell-tale symptoms such as shortness of breath, orthopnea, fatigue, and swelling at the lower extremities and stomach. 50% of patients diagnosed with HF will die within five years; 5.7 million adults are currently living with HF. This disease costs approximately $30.7 billion each year in the United States.
The treatment of HF has traditionally involved therapy with Angiotensin-converting-enzyme (ACE) inhibitors, Angiotensin receptor blockers (ARB), beta blockers, or Mineralocorticoid receptor antagonist (MRA). ACE inhibitors and ARBs prevent symptoms by inhibiting the Renin-Aldosterone (RAS) system, while beta blockers and MRA keep the heart rate low and the oxygen capacity high. Digoxin, diuretics, and various blood pressure medications are also indicated for many HF patients.
The B-type natriuretic peptide (BNP) hormone functions to counteract the RAS system, causing vasodilation, hypotension, and sodium/water loss. BNP (along with biologic metabolite NT-proBNP) are released into the body as a response to stretching of the cardiac wall, as seen in HF. Therefore, providers use BNP or NT-proBNP levels to assess ventricular dysfunction in HF patients. Levels of these cardiac biomarkers are also increased in situations of myocardial damage, such as in heart attacks. BNP assays do not correlate well between various platforms, NT-proBNP assays do. Therefore, the NT-proBNP assay has the advantage in long-term monitoring of HF patients, since results should correlate between laboratories. Additionally, NT-proBNP is more stable in vitro than BNP (over 72 hours compared to 4 hours), which is a valuable time difference in outpatient testing. As laboratorians, it is important that we understand the differences in these assays so that we can properly educate health care providers.
In 2015, Novartis received FDA approval for Entresto, a drug that takes a new approach to treating systolic HF. Entresto is the first drug to enter the market in a new class of drugs to treat HF: Angiotension receptor-neprilysin inhibitors (ARNi). This drug is a 1:1 molecular ratio of an ARB (Valsartan) and a neprilysin inhibitor (Sacubitril). Neprilysin functions by inactivating BNP. So, by inhibiting Neprilysin, BNP concentration in the body increases, which further amplifies the anti-RAS system activity in the body. This combination effect of Entresto therapy has produced powerful results in clinical trials. In test populations, Entresto therapy reduced cardiovascular death as well as hospitalization for HF by 20%, when compared to ACE inhibitor therapy. Overall mortality for these patients was reduced by 16%; those are the kind of results that can add years to patient’s lives. Improved physical function and reduced symptoms were also reported, increasing the quality of life for those living with HF.
Entresto is by no means perfect. It has side effects such as hyperkalemia, hypotension, renal impairment, and angioedema. Also, if a patient has been on an ACE inhibitor, they must discontinue therapy for three days before starting Entresto (which could make for a nerve-racking three days for patients and their cardiologists). The drug is also considerably more expensive that other HF treatments, limiting its accessibility to the uninsured and those with limited income.
Due to the anti-neprilysin function of Entresto, BNP and NT-proBNP levels will be elevated (at least initially) in patients on this drug. Therefore, these tests are no longer as useful in assessing if the patient’s HF is worsening (or if any other myocardial damage is occurring). It is imperative that providers, particularly in acute care or emergency medicine settings, are aware of this reality so patients can still be diagnosed and treated appropriately. In research studies involving patients on Entresto, a long-term NT-proBNP level of <1,000 pg/?? was established as a potential therapeutic target level, as patients who attained that level had reduced morbidity and mortality.
Thank you to Joshua Soldo for presenting this information. Additional thanks go out to the ASCLS members who help put this event together, and to Allina Health for hosting the event.
Clarke, W. (Ed.). (2011). Contemporary Practice in Clinical Chemistry (2nd ed.). Washington DC: AACC Press.
Department of Health and Human Services, Centers for Disease Control and Prevention. (2016). Heart Failure Fact Sheet. USA. Retrieved January 14, 2017, from http://www.cdc.gov/dhdsp/data_statistics/factsheets/docs/fs_heart_failure.pdf
Joshua Soldo. (2017). The Measurement of Natriuretic Peptides in the Era of Neprilysin Inhibition. Medical Scientific Affairs. Roche Diagnostics. Retrieved January 7, 2017
U.S. Food and Drug Administration. (2015, July 15). FDA Approves New Drug to Treat Heart Failure. Retrieved January 14, 2017, from http://www.fda.gov/NewsEvents/NewsAnnouncements?ucm453845.htm