An angiotensin receptor-neprilysin inhibitor (ARNI) is a class of medication used primarily for managing heart failure. This single pill combines two distinct drug types, working on separate pathways to improve cardiac function. The first approved medication in this class is sacubitril/valsartan.
The Dual Mechanism of Action
ARNIs work through a dual mechanism, affecting heart failure pathways. One component, a neprilysin inhibitor like sacubitril, targets the enzyme neprilysin. Neprilysin breaks down beneficial proteins like natriuretic peptides. Inhibiting neprilysin leads to higher levels of these natriuretic peptides.
These peptides promote vasodilation, relaxing blood vessels, and natriuresis, helping excrete excess sodium and water. This reduces fluid overload and heart strain. The natriuretic peptide system naturally counteracts harmful hormonal systems in heart failure.
The other component of an ARNI is an angiotensin receptor blocker (ARB), such as valsartan. This component blocks angiotensin II, a hormone in the renin-angiotensin-aldosterone system (RAAS). Angiotensin II causes blood vessels to narrow, increases blood pressure, and promotes fluid retention and cardiac remodeling. By blocking angiotensin II from binding to its type 1 receptors, the ARB component dilates blood vessels, reduces aldosterone secretion, and lowers blood pressure.
Combining these two mechanisms is important because inhibiting neprilysin alone can increase angiotensin II levels. Therefore, the ARB is included to simultaneously block the negative effects of this increased angiotensin II, preventing unwanted vasoconstriction and fluid retention. This synergistic action enhances beneficial peptides while blocking harmful hormones, creating a complementary therapeutic effect.
Primary Therapeutic Uses
ARNIs are primarily prescribed for managing heart failure with reduced ejection fraction (HFrEF). HFrEF, also known as systolic heart failure, occurs when the heart’s main pumping chamber, the left ventricle, is weakened and cannot pump enough blood. This leads to symptoms like shortness of breath and fatigue as blood backs up into the lungs.
ARNIs are now considered a first-line therapy for symptomatic HFrEF, as recommended by major cardiology guidelines. They are typically used in conjunction with other standard heart failure treatments, such as beta-blockers. ARNIs have demonstrated an ability to improve the heart’s pumping function over time in HFrEF patients.
While the primary indication is HFrEF, ARNIs have also been investigated for heart failure with preserved ejection fraction (HFpEF). HFpEF occurs when the heart’s pumping function is normal, but the heart muscle is stiff and cannot relax properly to fill with enough blood. Studies suggest potential benefits in certain HFpEF subgroups.
Potential Side Effects and Safety Considerations
Patients taking an ARNI should be aware of potential side effects and require regular monitoring. One common side effect is hypotension, or low blood pressure, potentially causing dizziness. This occurs because the medication promotes vasodilation, widening blood vessels and reducing systemic vascular resistance. Adjusting the timing of other blood pressure medications or the ARNI dose may help manage this effect.
Another potential side effect is hyperkalemia, elevated potassium levels. This can happen because the ARB component affects electrolyte balance. Regular blood tests monitor potassium levels, especially during initial treatment and dose adjustments. Worsening kidney function is also a concern, requiring kidney function monitoring through blood tests.
A more serious, though rare, risk with ARNIs is angioedema, swelling of the face, lips, tongue, and throat. This reaction can be severe and requires immediate medical attention. While angioedema is rare, patients with a history of this condition should not take ARNIs. Healthcare providers assess individual risk factors before prescribing.
Comparison with Traditional Heart Failure Therapies
ARNIs are more effective than older heart failure medications, such as ACE inhibitors and ARBs. The landmark PARADIGM-HF trial showed that sacubitril/valsartan reduced the risk of cardiovascular death and hospitalization for heart failure compared to ACE inhibitors.
Major cardiology guidelines recommend ARNIs as a preferred treatment for many HFrEF patients. ARNIs provide a more comprehensive neurohormonal blockade than ACE inhibitors or ARBs alone.
When switching patients from an ACE inhibitor to an ARNI, a mandatory 36-hour “washout period” is required. This washout period is necessary to minimize the risk of angioedema, as both ACE inhibitors and neprilysin inhibition can increase levels of bradykinin, a substance contributing to this swelling. No such washout period is required when switching directly from an ARB to an ARNI.