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The neurohormonal paradigm for HF: Are we there yet?
New therapies, research are changing HF management.
Many advances and discoveries have been made during the past few decades in the medical management of HF. Guidelines for the management of chronic HF were previously released based on findings from trials that demonstrated benefit in reducing mortality and/or morbidity due to HF with reduced ejection fraction.
The Veterans Administration Cooperative Study (V-HeFT I) was the first randomized, double blind, placebo-controlled trial to show a reduction of mortality in patients with HF with reduced ejection fraction (HFrEF) using vasodilation treatment. This was soon followed by benefits shown with ACE inhibitors, beta-blockers and angiotensin receptor blockers, then mineralocorticoid receptor antagonists. Currently, 2013 guidelines from the American College of Cardiology and American Heart Association recommend an ACE inhibitor and a beta-blocker as the backbone of medication management for HFrEF, and a mineralocorticoid receptor antagonist is recommended in selected patients. Generally, an angiotensin receptor blocker is reserved as an alternative for patients who cannot tolerate ACE inhibitors due to cough or angioedema. Table 1 summarizes selected landmark trials that support use of these agents.
Quest for therapeutic agents
Despite important advances in the treatment of HFrEF accomplished with drug and device therapy, HF remains the primary reason for hospital admission in the elderly population. Additionally, the outcome of patients hospitalized for acute HF remains poor, with unforgivingly high postdischarge mortality and readmission rates. Consequently, the quest for novel therapeutic agents that can demonstrate incremental benefits to existing standard therapy remains a priority among clinicians in this challenging field.
Since the early 2000s, there have been studies assessing an ACE inhibitor or angiotensin receptor blocker in combination with a neprilysin inhibitor, with a mechanism of action that targets the natriuretic peptide system. Neprilysin is a neutral endopeptidase involved in the metabolism of a number of vasoactive peptides. The neprilysin inhibitor works by decreasing the breakdown of natriuretic and vasoactive peptides, including substance P, bradykinin and angiotensin. An increase in these peptides results in vasodilation and sodium and water excretion, and may also have effects on cardiac remodeling. On the contrary, neprilysin inhibition also increases the amount of angiotensin II, which has vasoconstrictive properties, opposing the effects seen with natriuretic peptides. This provides good reasoning to support the use of a neprilysin inhibitor with an agent that blocks the renin-angiotensin-aldosterone system, such as an ACE inhibitor or angiotensin receptor blocker.
OVERTURE-HF study
The first large study to evaluate the benefits of a neprilysin inhibitor in patients with HFrEF was published in 2002. OVERTURE-HF compared oral omapatrilat 40 mg once daily, a dual-mechanism drug composed of the ACE inhibitor enalapril and a neprilysin inhibitor, with oral enalapril 10 mg twice daily.
In the study, 5,770 patients with HFrEF were randomly assigned to omapatrilat or enalapril alone. The primary endpoint was death or hospitalization due to HF. Previous smaller studies showed benefits of combination ACE and neprilysin inhibition when compared with enalapril alone; however, results of the OVERTURE-HF study showed otherwise. Omapatrilat was noninferior to enalapril: 914 patients in the omapatrilat group and 973 in the enalapril group experienced death or HF hospitalization (HR = 0.94; 95% CI, 0.86-1.03). An analysis of adverse events showed differences between the two groups. The researchers reported 561 cases of dizziness and 564 cases of hypotension in the omapatrilat group. This was relatively higher compared with 401 cases of dizziness and 332 cases of hypotension in the enalapril group. Patients in the omapatrilat group also experienced more angioedema (24 cases vs. 14 cases). The researchers did not report any P values or statistical measures for these safety endpoints.
Tables provided by: Phan Y and Ly C.
Although results of the OVERTURE-HF trial showed that omapatrilat reduced morbidity and mortality in patients with HF, it did not show statistical superiority over enalapril alone. Omapatrilat, manufactured by Bristol-Myers Squibb, did not receive FDA approval, potentially because of the lack of advantage over enalapril and a higher incidence of potentially life-threatening angioedema due to an increase in bradykinin and substance P secondary to the inhibition of ACE, neprilysin and amionopeptidases P (APP). This led to speculation about whether the issues regarding safety were due to the effects of the ACE inhibitor component of omapatrilat.
A new combination
Since angiotensin receptor blockers do not directly inhibit ACE and APP and, thus, are associated with a lower incidence of angioedema, the development of sacubitril/valsartan (formerly known as LCZ696, Novartis) resulted as a combination of valsartan and the neprilysin inhibitor sacubitril (pro-drug AHU377), in a 1:1 molar ratio of both agents combined. In July, the FDA approved the use of sacubitril/valsartan for the reduction of CV death and HF-related hospitalization among patients with HF and reduced ejection fraction.
In a dose-escalation study, after oral administration, sacubitril/valsartan dissociated to its individual components and was quickly absorbed, with a maximum plasma concentration of 1.7 to 2.2 hours for valsartan and 0.5 to 1.1 hours for sacubitril. AHU377 was rapidly converted to LBQ657 via ester hydrolysis and its maximum plasma concentration obtained 1.9 to 3.5 hours after oral administration. Additional pharmacokinetic parameters are shown in Table 2. Some small studies in healthy participants assessed the potential for pharmacokinetic drug-drug interaction of sacubitril/valsartan with other drugs such as omeprazole, metformin, levonorgestrel-ethinyl estradiol, hydrochrorothiazide, amlodipine, carvedilol and digoxin. Each coadministration with sacubitril/valsartan was found to have no clinically relevant drug interactions.
PARADIGM-HF study
For the phase 3 PARADIGM-HF trial, researchers randomly assigned 8,436 patients with NYHA class II, III or IV HF to Entresto 200 mg twice daily or enalapril 10 mg twice daily. PARADIGM-HF is one of the largest trials to propose a new drug for substitution rather than an add-on strategy for HFrEF. The primary endpoint was death or hospitalization due to HF. Secondary endpoints included death from any cause, improvement in HF symptoms, new-onset atrial fibrillation and development or progression of renal dysfunction. The trial was completed in three phases: a screening phase; a single blind run-in phase in which all patients received enalapril for 2 weeks, followed by a single blind run-in phase if no unacceptable side effects occurred with the previous run-in phase, in which all patients received sacubitril/valsartan for an additional 4 to 6 weeks (enalapril was discontinued a day before the initiation of sacubitril/valsartan); and a double blind phase with randomization in a 1:1 ratio. Patients were assessed every 2 to 8 weeks during the first 4 months then every 4 months thereafter. The results were first presented at the 2014 European Society of Cardiology Congress.
Abbreviations: C, concentration; hrs, hours; max, maximum; T, time.
PARADIGM-HF was terminated early due to an overwhelming benefit of sacubitril/valsartan in comparison with enalapril. At the time of early termination — approximately 27 months into follow-up — there were 914 cases of death or hospitalization due to HF in patients assigned sacubitril/valsartan and 1,117 cases in patients assigned enalapril (HR = 0.8; 95% CI, 0.73-0.87). Looking at each outcome individually, the sacubitril/valsartan group had lower rates of death (711 vs. 835 cases; HR = 0.84; 95% CI, 0.76-0.93) and lower rates of hospitalization due to HF (21% reduction; P < .001). The safety profile showed a smaller percentage of patients taking sacubitril/valsartan experienced a decline in renal function with an elevated serum creatinine level greater than 2.5 mg/dL (3.3% vs. 4.5%; P = .007), elevated serum potassium greater than 5.5 mmol/L (16.1% vs. 17.3%; P = .15) and greater than 6 mmol/L (4.3% vs. 5.6%; P = .007), and cough (11.3% vs. 14.3%; P < .001). However, patients in the Entresto group had a higher rate of symptomatic hypotension (14% vs. 9.2%; P < .001) and higher incidence of angioedema (19 patients vs. 10 patients; P = .13), Notably, these adverse effects may be drastically underestimated since the run-in phase of the study excluded nearly 20% of patients who did not tolerate either treatment option and were dropped before randomization.
The results of PARADIGM-HF trial could hold the answers to many questions regarding the benefits of neprilysin inhibition in patients with HFrEF. However, the generalizability and external validity of the trial is questionable. Less than 1% of study participants had class IV HF at the time of study entry, which illustrates that the safety and efficacy of initiating sacubitril/valsartan in patients with severe symptoms remains unknown, as well as its role during and after hospitalization due to HFrEF. In the study, patients had to be on a stable dose of a beta-blocker and an ACE inhibitor or angiotensin receptor blocker for at least 4 weeks before the screening period (maximal target dose had to be tolerated for at least 2 weeks). Therefore, protocols may be required to assist with initiating sacubitril/valsartan, as this agent should not be initiated in patients who do not tolerate or who are not anticipated to tolerate an angiotensin receptor blocker. These protocols will need to incorporate inclusion and exclusion criteria to establish safety parameters before using sacubitril/valsartan. Exclusion criteria should include patients who are symptomatic on stable doses of beta-blockers and ACE inhibitors or angiotensin receptor blockers at maximal target doses; patients with systolic BP lower than 95 mm Hg; estimated glomerular filtration rate below 30 mL/min/1.73 m2; and a potassium level greater than 5.4 mmol/L due to the side-effect profile of ACE inhibitors or angiotensin receptor blockers.
Regardless of its limitations, the PARADIGM-HF trial clearly represents a landmark in the history of HF trials, with a new class of agent that not only met its primary efficacy endpoint compared with standard therapy, but also showed tolerable safety profile.
Future directions
In July, the FDA approved the use of sacubitril/valsartan for the reduction of CV death and HF-related hospitalization among patients with HFrEF. It is anticipated that there will be a few changes to the current set of HF guidelines regarding sacubitril/valsartan, as well as the recently approved medication ivabradine (Corlanor, Amgen), which received FDA approval in April, as seen with the European Society of Cardiology guidelines, which included ivabradine for patients with chronic symptomatic HF even after being stable on a beta-blocker, ACE inhibitor/angiotensin receptor blocker, and mineralocorticoid receptor antagonist with a heart rate greater than 70 bpm.
Notably, additional indications for sacubitril/valsartan are being entertained as Novartis is currently recruiting for participants for the PARAGON-HF study, which will compare sacubitril/valsartan with valsartan alone in patients with HFpEF for morbidity and mortality (ClinicalTrials.gov NCT01920711). Sacubitril/valsartan also is being studied for other CV benefits such as arterial stiffness in patients with hypertension. Hopefully, more unanswered questions will be addressed from these trials to guide the integration of sacubitril/valsartan into practice.
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- For more information:
- Yvonne L. Phan, PharmD, BCPS, is assistant professor of clinical pharmacy at the Philadelphia College of Pharmacy, University of the Sciences, Philadelphia. Christine Ly, PharmD, is from CVS Pharmacy.
Disclosure: The authors report no relevant financial disclosures.