ACE inhibitors & ARBs in HFpEF

CHARM-Preserved: Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-81.

I-PRESERVE: Massie BM, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67.

PEP-CHF: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338-45.

Bottom-line: In patients with HFpEF & well-controlled hypertension, ACE inhibitors and ARBs do not reduce the risk of hospitalization or death.

However, since uncontrolled hypertension is one of the predominant causes of HFpEF and an important risk factor for HF progression, most patients with HFpEF will end up receiving an ACEI/ARB anyway to control BP.

Patients & Generalizability

These trials generally enrolled older individuals with clinical HF and a LVEF >40-45%. Notably, these trials excluded multiple conditions that may be classified as "HFpEF", namely valvular heart diseases such as aortic stenosis, pericardial disea… — These trials generally enrolled older individuals with clinical HF and a LVEF >40-45%. Notably, these trials excluded multiple conditions that may be classified as "HFpEF", namely valvular heart diseases such as aortic stenosis, pericardial disease and certain cardiomyopathies.

Due to the exclusion criteria noted above, most of the cases of HFpEF in these trials were caused by hypertension (I-PRESERVE, PEP-CHF) or ischemia (CHARM-Preserved). it is thus worth mentioning that BP was well-controlled on average at baseline in … — Due to the exclusion criteria noted above, most of the cases of HFpEF in these trials were caused by hypertension (I-PRESERVE, PEP-CHF) or ischemia (CHARM-Preserved). it is thus worth mentioning that BP was well-controlled on average at baseline in all of these trials.

Interventions

I: ACE inhibitor or ARB
- CHARM-Preserved: Initially, candesartan 4-8 mg PO once daily, doubled q2 weeks to target 32 mg PO daily by week 6
  - At 6 months: 67% on target dose
- I-PRESERVE: Initially, irbesartan 75 mg PO once daily, doubled q1-2 weeks to target 300 mg PO daily
  - 88% achieved target dose
- PEP-CHF: Initially, perindopril 2 mg PO once daily, increased to 4 mg PO daily after 2 weeks
  - ~90% on 4 mg daily at 1 year
C: Matching placebo

Results

Internal validity

All 3 trials are randomized, allocation-concealed, double-blind trials with loss-to-follow-up <2% and intention to treat analysis
Other considerations:
- I-PRESERVE employed 1 to 2-week single-blind placebo run-in phase. Patients that remained clinically stable in this phase were randomized
- PEP-CHF: Trial recruitment stopped early due to expected futility

Other studies

Meta-analysis of 13 RCTs of RAAS inhibition (including ACE inhibitors, ARBs and mineralocorticoid antagonists) in HFpEF (Herz 2016;41:76-86): When all pooled together,
- No statistically significant difference in
  - Hospitalizations: HR 0.99 (0.96-1.03)
  - CV death: HR 0.98 (0.89-1.09)
  - Death: HR 0.99 (0.92-1.07)
  - 6-minute walk test distance
- Statistically significant reduction in HF hospitalization (HR 0.89, 0.82-0.97), though this was driven by TOPCAT trial of mineralocorticoid antagonists. The lack of a reduction on death or all-cause hospitalization suggests that the reduction in HF-related hospitalization is offset by an increase in other events (e.g. syncope or falls from hypotension, hyperkalemia).