New Drug Targets in Cardiac Failure
Sacubitril/valsartan, SGLT2 inhibitors, and GLP-1 receptor agonists represent the most significant new drug targets for heart failure treatment, with sacubitril/valsartan showing the strongest evidence for reducing mortality and hospitalization in heart failure with reduced ejection fraction (HFrEF).
Established Foundation of Heart Failure Therapy
- ACE inhibitors and beta-blockers remain the cornerstone first-line therapy for HFrEF, with high-quality evidence showing they reduce morbidity and increase survival 1
- Mineralocorticoid receptor antagonists (MRAs) are recommended as second-line therapy for patients who remain symptomatic despite optimal first-line treatment 2
- Diuretics are essential for managing fluid overload but do not modify disease progression 1
Newer Drug Targets with Strong Evidence
Sacubitril/Valsartan (ARNI)
- The European Society of Cardiology recommends sacubitril/valsartan as a replacement for ACE inhibitors to further reduce the risk of heart failure hospitalization and death in patients with HFrEF who remain symptomatic despite optimal treatment 2
- Sacubitril/valsartan is positioned as third-line therapy after ACE inhibitors/ARBs, beta-blockers, and MRAs in the treatment algorithm 2
- Clinical trials demonstrate that sacubitril/valsartan is superior to ACE inhibitors alone in reducing cardiovascular death and heart failure hospitalization 3
- Dosing should start at 49/51 mg twice daily for patients previously on high-dose ACE inhibitors, with titration to target dose of 97/103 mg twice daily 4
SGLT2 Inhibitors
- The European Society of Cardiology recommends SGLT2 inhibitors (dapagliflozin or empagliflozin) as additional therapy for HFrEF patients to reduce hospitalization and death risk 2
- SGLT2 inhibitors have minimal effect on blood pressure compared to other heart failure medications, making them suitable for patients with borderline hypotension 2
Emerging Drug Targets
GLP-1 Receptor Agonists
- Current guidelines do not specifically recommend GLP-1 receptor agonists for HFrEF management 5
- When considering GLP-1 RA therapy in patients with HFrEF, close monitoring for signs of worsening heart failure is recommended 5
- Lower starting doses with slower titration than standard protocols is advised when using GLP-1 RAs in HFrEF patients 5
Special Considerations for Drug Implementation
- A 36-hour washout period is mandatory when switching from ACE inhibitors to sacubitril/valsartan to avoid angioedema 4, 3
- No washout period is required when switching from an ARB to sacubitril/valsartan 4
- For patients with severe renal impairment or moderate hepatic impairment, start with the lowest dose of sacubitril/valsartan (24/26 mg twice daily) 3
- Monitor for drug interactions, particularly with statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters when using sacubitril/valsartan 3
Treatment Algorithm for HFrEF
- First-line therapy: ACE inhibitor + beta-blocker 2
- Second-line therapy: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic 2
- Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic 2
- Additional therapy: Add SGLT2 inhibitor (dapagliflozin or empagliflozin) 2
- For persistent symptoms: Consider device therapies like cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillators (ICD) for appropriate patients 6
Common Pitfalls to Avoid
- Do not co-administer sacubitril/valsartan with ACE inhibitors - ensure the 36-hour washout period is strictly observed 3
- Do not underdose sacubitril/valsartan due to concerns about renal function - while starting at a lower dose is appropriate, attempt to titrate to the maximum tolerated dose as benefits are dose-dependent 4
- Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 2
- Do not delay or substitute established guideline-directed medical therapy when considering newer agents like GLP-1 RAs 5