August 10, 2016Open Access
View Full PaperKicking the Tyres of a Heart Failure Trial: Physician Response to the Approval of Sacubitril/valsartan in the USA
Key Result
Sacubitril/valsartan is superior to target doses of an ACE inhibitor in reducing cardiovascular death and disease progression in patients with chronic heart failure and reduced ejection fraction.
Key Points
- This review evaluates physician response to sacubitril/valsartan approval and addresses misconceptions about its efficacy.
- Analyzed the design and patient enrollment of the PARADIGM-HF trial.
- Considered the replicability and applicability of trial results in clinical practice.
- Examined concerns regarding the safety of neprilysin inhibition.
- PARADIGM-HF trial had appropriate comparators and typical patient enrollment reflecting real-world conditions.
- Results were highly persuasive and applicable to patients on low doses of ACE inhibitors and ARBs.
- Guidelines now recommend sacubitril/valsartan for chronic heart failure alongside ACE inhibitors and ARBs.
Structured PICO
Does sacubitril/valsartan reduce cardiovascular death and clinical disease progression compared to ACE inhibitors in patients with chronic heart failure and reduced EF?
P
Population
Patients with chronic heart failure and a reduced EF (HFrEF) with mild to moderate symptoms
I
Intervention
Sacubitril/valsartan (angiotensin receptor-neprilysin inhibition)
C
Comparator
ACE inhibitor (target doses)
O
Outcome
Cardiovascular death and clinical disease progressionhard clinical
This review addresses misconceptions about the PARADIGM-HF trial and supports the guideline recommendation of sacubitril/valsartan as the preferred renin-angiotensin system inhibitor for HFrEF.
Limitations
- Hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug
Abstract
Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB.