Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF

• Published in: European heart journal Vol. 38; no. 15; pp. 1132 - 1143
• Main Authors: Böhm, Michael, Young, Robin, Jhund, Pardeep S, Solomon, Scott D, Gong, Jianjian, Lefkowitz, Martin P, Rizkala, Adel R, Rouleau, Jean L, Shi, Victor C, Swedberg, Karl, Zile, Michael R, Packer, Milton, McMurray, John J V
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 14-04-2017
• Subjects: Aged; Aminobutyrates - administration & dosage; Aminobutyrates - adverse effects; Angiotensin; Angiotensin Receptor Antagonists - administration & dosage; Angiotensin Receptor Antagonists - adverse effects; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - adverse effects; AT1-receptor; Blood pressure; Blood Pressure - drug effects; Cardiac and Cardiovascular Systems; Chronic Disease; chronic hypotension systolic blood pressure heart failure blood pressure cardiovascular system safety ejection fraction cardiovascular death sacubitril / valsartan; Clinical Research; Death, Sudden, Cardiac - etiology; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Editor's Choice; Enalapril - administration & dosage; Enalapril - adverse effects; enalapril heart failure; Female; Heart failure; Heart Failure - drug therapy; Heart Failure - mortality; Hospitalization; Humans; Hypotension - chemically induced; Hypotension - mortality; Kardiologi; Male; Neprilysin; Neprilysin - antagonists & inhibitors; Stroke Volume - physiology; Tetrazoles - administration & dosage; Tetrazoles - adverse effects; Treatment Outcome; Valsartan - administration & dosage; Valsartan - adverse effects; Heart failure; AT1-receptor; Blood pressure; Neprilysin; Angiotensin
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehw570

Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP.
We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP.
All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP.
In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.