Therapeutics
In HF, angiotensin–neprilysin inhibition reduced mortality and HF hospitalization compared with enalapril Clinical impact ratings:
多多多多多多夞
McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
多多多多多多多
Question
Conclusion
In patients with heart failure (HF) and reduced ejection fraction, does angiotensin-receptor–neprilysin inhibition with sacubitril– valsartan (LCZ696) reduce cardiovascular (CV) death or HF hospitalization compared with an angiotensin-converting enzyme inhibitor (ACE-I)?
In heart failure with reduced ejection fraction, sacubitril–valsartan reduced mortality and heart failure hospitalization compared with enalapril.
Methods Design: Randomized controlled trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGMHF] trial). ClinicalTrials.gov NCT01035255. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, data collectors, data analysts, and outcome adjudication committee). Follow-up period: Median 27 months. Trial was stopped early for benefit. Setting: 1043 centers in 47 countries. Patients: 8442 patients ≥ 18 years of age (mean age 64 y, 78% men) who had New York Heart Association class II to IV symptoms, ejection fraction ≤ 40%, and no unacceptable side effects during run-in (enalapril, 2 wk; sacubitril–valsartan, 4 to 6 wk). Exclusion criteria included symptomatic hypotension, past angioedema, systolic blood pressure < 95 mm Hg, serum potassium level > 5.4 mmol/L, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, or > 25% (amended to > 35%) decrease in eGFR between screening and randomization. Intervention: Sacubitril–valsartan, 200 mg twice daily (valsartan component equivalent to 160 mg) (n = 4187), or enalapril, 10 mg twice daily (n = 4212). Outcomes: Primary outcome was a composite of CV death or HF hospitalization. Other outcomes included all-cause mortality and decline in renal function. Patient follow-up: 99% (intention-to-treat analysis).
Main results The main results are in the Table.
Sacubitril–valsartan vs enalapril in patients with heart failure (HF) and reduced ejection fraction† Outcomes
Annual event rates Sacubitril– valsartan
CV death or HF hospitalization‡
10%
Enalapril 13%
RRR (95% CI)
*See Glossary. Source of funding: Novartis. For correspondence: Dr. J.J. McMurray, University of Glasgow, Glasgow, Scotland, UK. E-mail [email protected].
Commentary Inhibition of the renin–angiotensin–aldosterone system is a crucial aspect of managing patients with stable chronic congestive HF (CHF) and reduced systolic function. The PARADIGM-HF trial combined a neprilysin inhibitor (sacubitril) with an angiotensinreceptor blocker (ARB) (valsartan) in a single tablet and compared them with standard ACE-I therapy. Why not combine a neprilysin inhibitor with an ACE-I or use it as a single agent? When combined with an ACE-I, risk for severe angioedema increases; when used alone, it lacks efficacy in CHF. PARADIGM-HF was terminated early after an interim analysis suggested superiority of sacubitril–valsartan for the primary outcome. Stopping trials early can overestimate treatment effects (1); however, overestimation is probably small given the large sample size and number of outcome events in the trial. Should sacubitril–valsartan be preferred over ACE-Is in patients with HF? PARADIGM-HF intended to compare ACE-Is and ARBs at clinically equivalent dosages. Did it succeed? Recent evidence suggests that higher doses of ACE-Is and ARBs titrated to reduce B-type natriuretic peptide to specific target levels improve survival (2). Consequently, some may argue that a higher dose of enalapril should have been used in the comparison group. However, the dose used was evidence-based (CONSENSUS and SOLVD trials), and a higher dosage may be difficult to achieve: 12% of potential participants were excluded for intolerance to either enalapril or sacubitril–valsartan during prerandomization run-in. Most patients in the trial had mild “stable” CHF (70% had NYHA class II disease). Therefore, the 20% relative risk reduction for the primary outcome in the sacubitril–valsartan fixed-dose combination group confirms that patients with minimally symptomatic CHF can achieve mortality reductions with pharmacologic interventions. Depending on pricing, sacubitril–valsartan may well become a preferred treatment, along with -blockers and aldosterone antagonists, and in the process displace ACE-Is.
NNT (CI) at 1 y
20% (13 to 27)
38 (28 to 61) 72 (45 to 175)
Brian P. Schmitt, MD, FACP Edward Hines Jr VA Hospital Hines, Illinois, USA References
All-cause mortality
7.6%
9.0%
16% (7 to 24)
Renal function decline§
1.0%
1.2%
14% (⫺14 to 34) Not significant
†CV = cardiovascular; other abbreviations defined in Glossary. Annual event rates, RRR, annual NNT, and CI provided by author. ‡Annual event rates: CV death 6.0% vs 7.5% (P < 0.001); HF hospitalization 6.2% vs 7.7% (P < 0.001).
1. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and metaregression analysis. JAMA. 2010:303:1180-7. 2. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35: 1559-67.
§End-stage renal disease (P = 0.11), ≥ 50% decrease in estimated glomerular filtration rate (eGFR), or eGFR < 60 mL/min/1.73 m2 with > 30 mL/min/1.73 m2-decrease from randomization.
姝 2015 American College of Physicians JC2 ACP Journal Club Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/27/2015
Annals of Internal Medicine
17 February 2015
In HF, angiotensin–neprilysin inhibition reduced mortality and HF hospitalization compared with enalapril Clinical impact ratings:
多多多多多多夞
McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
多多多多多多多
Question
Conclusion
In patients with heart failure (HF) and reduced ejection fraction, does angiotensin-receptor–neprilysin inhibition with sacubitril– valsartan (LCZ696) reduce cardiovascular (CV) death or HF hospitalization compared with an angiotensin-converting enzyme inhibitor (ACE-I)?
In heart failure with reduced ejection fraction, sacubitril–valsartan reduced mortality and heart failure hospitalization compared with enalapril.
Methods Design: Randomized controlled trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGMHF] trial). ClinicalTrials.gov NCT01035255. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, data collectors, data analysts, and outcome adjudication committee). Follow-up period: Median 27 months. Trial was stopped early for benefit. Setting: 1043 centers in 47 countries. Patients: 8442 patients ≥ 18 years of age (mean age 64 y, 78% men) who had New York Heart Association class II to IV symptoms, ejection fraction ≤ 40%, and no unacceptable side effects during run-in (enalapril, 2 wk; sacubitril–valsartan, 4 to 6 wk). Exclusion criteria included symptomatic hypotension, past angioedema, systolic blood pressure < 95 mm Hg, serum potassium level > 5.4 mmol/L, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, or > 25% (amended to > 35%) decrease in eGFR between screening and randomization. Intervention: Sacubitril–valsartan, 200 mg twice daily (valsartan component equivalent to 160 mg) (n = 4187), or enalapril, 10 mg twice daily (n = 4212). Outcomes: Primary outcome was a composite of CV death or HF hospitalization. Other outcomes included all-cause mortality and decline in renal function. Patient follow-up: 99% (intention-to-treat analysis).
Main results The main results are in the Table.
Sacubitril–valsartan vs enalapril in patients with heart failure (HF) and reduced ejection fraction† Outcomes
Annual event rates Sacubitril– valsartan
CV death or HF hospitalization‡
10%
Enalapril 13%
RRR (95% CI)
*See Glossary. Source of funding: Novartis. For correspondence: Dr. J.J. McMurray, University of Glasgow, Glasgow, Scotland, UK. E-mail [email protected].
Commentary Inhibition of the renin–angiotensin–aldosterone system is a crucial aspect of managing patients with stable chronic congestive HF (CHF) and reduced systolic function. The PARADIGM-HF trial combined a neprilysin inhibitor (sacubitril) with an angiotensinreceptor blocker (ARB) (valsartan) in a single tablet and compared them with standard ACE-I therapy. Why not combine a neprilysin inhibitor with an ACE-I or use it as a single agent? When combined with an ACE-I, risk for severe angioedema increases; when used alone, it lacks efficacy in CHF. PARADIGM-HF was terminated early after an interim analysis suggested superiority of sacubitril–valsartan for the primary outcome. Stopping trials early can overestimate treatment effects (1); however, overestimation is probably small given the large sample size and number of outcome events in the trial. Should sacubitril–valsartan be preferred over ACE-Is in patients with HF? PARADIGM-HF intended to compare ACE-Is and ARBs at clinically equivalent dosages. Did it succeed? Recent evidence suggests that higher doses of ACE-Is and ARBs titrated to reduce B-type natriuretic peptide to specific target levels improve survival (2). Consequently, some may argue that a higher dose of enalapril should have been used in the comparison group. However, the dose used was evidence-based (CONSENSUS and SOLVD trials), and a higher dosage may be difficult to achieve: 12% of potential participants were excluded for intolerance to either enalapril or sacubitril–valsartan during prerandomization run-in. Most patients in the trial had mild “stable” CHF (70% had NYHA class II disease). Therefore, the 20% relative risk reduction for the primary outcome in the sacubitril–valsartan fixed-dose combination group confirms that patients with minimally symptomatic CHF can achieve mortality reductions with pharmacologic interventions. Depending on pricing, sacubitril–valsartan may well become a preferred treatment, along with -blockers and aldosterone antagonists, and in the process displace ACE-Is.
NNT (CI) at 1 y
20% (13 to 27)
38 (28 to 61) 72 (45 to 175)
Brian P. Schmitt, MD, FACP Edward Hines Jr VA Hospital Hines, Illinois, USA References
All-cause mortality
7.6%
9.0%
16% (7 to 24)
Renal function decline§
1.0%
1.2%
14% (⫺14 to 34) Not significant
†CV = cardiovascular; other abbreviations defined in Glossary. Annual event rates, RRR, annual NNT, and CI provided by author. ‡Annual event rates: CV death 6.0% vs 7.5% (P < 0.001); HF hospitalization 6.2% vs 7.7% (P < 0.001).
1. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and metaregression analysis. JAMA. 2010:303:1180-7. 2. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35: 1559-67.
§End-stage renal disease (P = 0.11), ≥ 50% decrease in estimated glomerular filtration rate (eGFR), or eGFR < 60 mL/min/1.73 m2 with > 30 mL/min/1.73 m2-decrease from randomization.
姝 2015 American College of Physicians JC2 ACP Journal Club Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/27/2015
Annals of Internal Medicine
17 February 2015
