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

Literature - Böhm M, Young R, Jhund PS, et al. - Eur Heart J. 2017; published online ahead of print

Background

Heart failure combined with low systolic blood pressure (SBP) is associated with poor outcomes. Therefore, therapies that improve prognosis but lower blood pressure further are avoided in such patients [1-3]. In the PARADIGM-HF study, in which heart failure patients with reduced ejection fraction were randomised to receive either the ACE inhibitor enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily, sacubitril/valsartan reduced the primary composite endpoint of cardiovascular (CV) death or heart failure hospitalisation by 20% compared with enalapril [4,5].

Sacubitril/valsartan lowers blood pressure more than ACE inhibitors or ARBs do. The present analysis of the PARADIGM-HF study (n=8399) was conducted, in order to assess the efficacy and safety of sacubitril/valsartan compared with enalapril, according to baseline SBP, SBP 4 months after randomisation and SBP over whole follow-up. For this purpose, SBP was categorized as<110mmHg, 110 to <120mmHg, 120 to <130mmHg, 130 to <140mmHg and ≥140mmHg. Primary composite endpoint was CV death or heart failure hospitalization.

Main results

• Compared to patients with higher baseline SBP, those with lower SBP were younger, more often male and less likely to have an ischaemic background or a history of diabetes or hypertension. Patients with a lower SBP had a lower ejection fraction and slightly lower heart rate and BMI. NTproBNP and eGFR did not differ substantially across SBP category.
• At 4 months and after the complete follow-up period, SBP increased in patients with the lowest baseline SBP and decreased in those starting with a higher SBP in both treatment groups.
• The risk of the composite primary endpoint, heart failure hospitalisation, all-cause and CV death was higher in patients with lower baseline SBP; above an SBP of approximately 120 mmHg, the relationship between SBP and both types of death was flat, whereas the risk of heart failure hospitalisation was greater in patients with higher SBP (<140 mmHg approximately), creating a U-shaped relationship between SBP and heart failure hospitalisation.
• Compared with enalapril, sacubitril/valsartan reduced the risk of the primary endpoint across all SBP categories (P value for SBP-treatment interaction= 0.55). Similar findings were observed for CV death, heart failure hospitalisation and all-cause death.
• Low baseline SBP (<100 mmHg) was clearly associated with high all-cause death on enalapril, with lower rates on sacubitril/valsartan. Similar results were obtained for the primary end point.
• At each visit in each SBP group, the proportion of patients having a clinically significant worsening (five or more units) in Kansas City cardiomyopathy questionnaire (KCCQ) score was smaller in the sacubitril/valsartan group compared with the enalapril group. The benefit of sacubitril/valsartan over enalapril in preventing worsening of KCCQ was consistent across SBP groups when adjusted for baseline variables (P interaction=0.47).
• Symptomatic hypotension and hypotensive symptoms with an SBP<90 mmHg were more frequent in the group starting with an SBP <110 mmHg, irrespective of treatment allocation, and these adverse effects occurred more often in the sacubitril/valsartan group compared with the enalapril group.
• Study-drug dose reduction and discontinuation due to hypotension was more frequent in patients with a low SBP at baseline. These rates were higher for sacubitril/valsartan compared with enalapril.

Conclusion

References

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