Publications of the Week, September 25


NT-proBNP-guided therapy in heart failure with reduced EF

Felker GM, Anstrom KJ, Adams KF, et al. Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2017 Aug 22;318(8):713-720. doi: 10.1001/jama.2017.10565. PubMed PMID: 28829876.
Fonarow GC. Biomarker-Guided vs Guideline-Directed Titration of Medical Therapy for Heart Failure. JAMA. 2017 Aug 22;318(8):707-708. doi: 10.1001/jama.2017.10540. PubMed PMID: 28829853.

In this study involving patients with heart failure with reduced ejection fraction (HFrEF) the use of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not effective in reducing mortality and hospitalizations for heart failure (HF).

Over 890 patients with HFrEF (median ejection fraction, 25%) were randomized to have usual treatment or treatment guided by serial measurement of NT-proBNP. All clinicians received current practice guidelines for HF management and were provided with target doses of proven drug therapies. They were encouraged to prioritize the use of neurohormonal antagonists (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists) over diuretics unless there was a perceived need to treat congestion or volume overload.

During up to 24 months of observation (median, 15 months) there were no major differences in the main outcomes (cardiovascular mortality of 12% vs 13% in the control group, cardiovascular mortality or HF hospitalization of 37% in both groups).

These results contrast with some of the previous reports indicating the benefit of using NT-proBNP. The authors point out that the use of neurohormonal antagonists in this study was similar in both groups, and that levels of NT-proBNP declined similarly in both groups. This suggests that the lack of difference was related to the control group being treated similarly to the experimental group, possibly due to attempts to adhere to current practice guidelines. The authors also point out that doses of neurohormonal drugs achieved in both groups were lower than those considered as target doses (in the case of beta-blockers, doses were slightly lower than 50%), possibly due to intolerance of higher doses among patients with severe HF.

The accompanying editorial reinforces the concept of implementing known therapies at the tolerated doses rather than using biomarkers to guide therapy.

Heart failure and preserved EF: effectiveness of pharmacotherapy

Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart. 2017 Aug 5. pii: heartjnl-2017-311652. doi: 10.1136/heartjnl-2017-311652. [Epub ahead of print] PubMed PMID: 28780577.

Among patients with heart failure and preserved left ventricular function, only beta-blockers decrease total and cardiovascular mortality.

The efficacy of different treatments in patients with clinical syndrome of heart failure and preserved ejection fraction is not clear (in this meta-analysis preserved ejection fraction was defined as ≥40%, as most studies were performed in such a population). Current recommendations include the use of diuretics for symptom control and management of comorbidities, including hypertension. Recently, some organizations defined left ventricular ejection fraction (LVEF) from 40% to 49% as intermediate or borderline, but specific therapeutic data in this population are lacking.

Among patients with LVEF ≥40%, beta-blockers reduced all-cause mortality by about 20% (risk ratio [RR], 0.78; 95% confidence interval [CI], 0.65-0.94; among >1,000 patients). Angiotensin-converting enzyme inhibitors (RR, 1.10), angiotensin receptor blockers (RR, 1.02), and mineralocorticoid receptor antagonists (RR, 0.92) have not shown such effects. Cardiovascular mortality was decreased by beta-blockers (RR, 0.75; 95% CI, 0.60-0.94). Heart failure hospitalizations were decreased in a pooled analysis of all renin-angiotensin-aldosterone system antagonists by 10% (RR, 0.90; 95% CI, 0.82-0.98; among >11,700 patients). Treatments appeared more effective in studies examining patients with a lower ejection fraction.

Rivaroxaban +/- aspirin in stable cardiovascular disease

Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118. [Epub ahead of print] PubMed PMID: 28844192.

A low dose of rivaroxaban (2.5 mg twice daily) in addition to aspirin (100 mg daily) was associated with better cardiovascular outcomes but more bleeding in comparison to aspirin alone.

This study involved over 27,300 patients with stable cardiovascular disease – with over 90% with coronary artery disease – who were randomized to treatment with aspirin 100 mg daily, rivaroxaban 5 mg twice daily, or a combination of aspirin 100 mg daily and rivaroxaban 2.5 mg twice daily.

After a mean follow-up of 23 months, death occurred in 3.4% of patients in the combination treatment group and 4.1% of patients on aspirin alone (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.71-0.96). Cardiovascular mortality was also lower (1.7% vs 2.2%; HR, 0.78; 95% CI, 0.64-0.96). Other outcomes that occurred at lower frequency among patients treated with the combination of drugs versus aspirin alone included a combination of cardiovascular death, stroke, or myocardial infarction (primary outcome of the study; 4.1% vs 5.4%); stroke (0.9% vs 1.6%); or hospitalization for cardiovascular causes (14.2% vs 15.3%). There was no difference in hemorrhagic stroke (0.2% vs 0.1%).

Bleeding occurred with higher frequency among the combination treatment group: major bleeding, 3.1% versus 1.9%; minor bleeding, 9.2% versus 5.5%, gastrointestinal bleeding, 1.5% versus 0.7%. There was no difference in intracranial bleeding (28 vs 24 bleeding episodes in over 9,100 patients in each arm) or fatal bleeding (15 vs 10 episodes). One of the critical outcomes, which were understood as cardiovascular death, nonfatal stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ, occurred in 4.7% of combination-treatment patients and 5.9% of aspirin-alone patients (HR, 0.80; 95% CI, 0.70-0.91).

The use of a higher dose of rivaroxaban alone was associated with a higher rate of bleeding and no cardiovascular advantages in comparison to aspirin alone.

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