Worse survival when using lower than recommended doses of ACEi/ARBs or beta-blockers in heart failure
Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European studyOuwerkerk W, Voors AA, Anker SD, et al. - European Heart Journal 2017; published online ahead of print
Based on relevant randomized studies, ESC guidelines for the treatment of heart failure (HF) recommend up-titration to maximum tolerated doses of beta-blockers and ACE-inhibitors (ACEi) or ARBs, if ACEis are not tolerated [1,2]. However, in daily clinical practice, many patients do not achieve the recommended doses, due to various reasons including low blood pressure and/or heart rate (HR), renal dysfunction, and electrolyte disturbances, or due to inadequate prescription adherence [3,4].
The BIOSTAT-CHF  is a European project designed to determine profiles of HF patients who do or do not respond to recommended therapies. In current analysis, the predictors, reasons and clinical outcomes of patients who did not reach recommended treatment doses of ACEi/ARBs and beta-blockers, were evaluated.
For this purpose, data of more than 2.500 patients with new-onset or worsening HF were studied. The diagnosis was confirmed either by LVEF ≤40% or by BNP values >400 pg/ml and/or NT-proBNP plasma levels >2000 pg/ml. Further eligibility criteria were furosemide ≥40 mg/day or equivalent at the time of inclusion as well as either no previous treatment with ACEi/ARBs and beta-blockers or low-dose (≤50% of target) of these drugs at time of inclusion. ACEi/ARBs and beta-blockers were up-titrated within 3 months and only patients who reached the end of the 3 months up-titration period were included in this analysis.
- Only 22% of patients reached the recommended dose of ACEi/ARBs and 12% of patients reached the recommended beta-blocker dose.
- Independent predictors for achieving lower percentages of recommended ACEi/ARB doses were female gender, country of inclusion, lower BMI and eGFR and higher alkaline phosphatase values. Predictors for lower beta-blocker doses were higher age, country of inclusion, lower HR and DBP, and more signs of congestion.
- There were marked differences in dose-up-titration across Europe. Achieved ACEi/ARB and beta-blocker doses were lower in South and Central European countries and higher in Scandinavian countries.
- After adjustment for indication bias, patients reaching 0% and 1–49% of recommended ACEi/ARB doses had a higher risk of mortality (HR 1.76, 95% CI 1.54–1.98 and HR 1.50, 95% CI 1.33–1.67, respectively) and a higher risk of the combined endpoint of death and/or HF hospitalization (HR 1.77, 95% CI 1.61–1.94 and 1.23, 95% CI 1.09–1.36, respectively).
- Patients who reached ACEi/ARB doses between 50% and 99% of the recommended doses had a similar risk of death and the combined endpoint, compared to those reaching ≥100% of the recommended treatment dose (HR 0.82, 95% CI 0.62–1.02 and HR 0.86, 95% CI 0.71–1.00, respectively).
- Patients reaching 0% and 1–49% of recommended doses of beta-blockers had a higher risk of mortality (HR 2.41, 95% CI 2.13–2.68 and HR 1.91, 95% CI 1.74–2.08, respectively) and a lower risk of the combined endpoint (HR 1.51, 95% CI 1.29–1.72 and HR 1.27, 95% CI 1.15–1.39, respectively).
- Patients who reached beta-blocker doses between 50–99% of the recommended dose had a similar risk of the combined endpoint (HR 1.04, 95% CI 0.89–1.20), but an increased risk of death (HR 1.29, 95% CI 1.07–1.51) compared to those reaching ≥100% of the recommended treatment dose.
- Patients not reaching the recommended dose of ACEi/ARBs because of intolerance due to symptoms, side effects or non-cardiac organ dysfunction had the highest mortality rate (HR 1.72, 95% CI 1.43–2.01), whereas the HR for ‘other reasons’ was 1.46 (95% CI 1.19–1.73, P=0.1457).
- Not reaching the recommended dose of beta-blockers because of intolerance due to symptoms, side effects or non-cardiac organ dysfunction was associated with an increased mortality risk (HR 1.70, 95% CI 1.36–2.05), while the mortality risk was not increased in patients who did not reach the recommended dose for ’other reasons’ (HR 1.18, 95% CI 0.86–1.50, P=0.0001).
In the BIOSTAT-CHF study, reaching less than 50% of the recommended dose of ACEi/ARBs and beta-blockers was associated with worse survival. Patients who did not reach the recommended ACEi/ARBs or beta-blocker doses because of intolerance had worse survival compared to patients who did not reach their therapeutic targets because of other reasons. These findings support the adherence with the ESC guidelines on HF therapy, according to which maximum tolerated doses of ACEi/ARBs and beta-blockers are recommended.