Table 1.
Main clinical trials of pharmacological therapy in heart failure with preserved ejection fraction.
| Trial Name (Years) | Drug (Posology) | Sample Size | ClinicalTrials.gov Identifier | Follow up Duration | Results |
|---|---|---|---|---|---|
| RAAS and Neprylisin Pathway | |||||
| I-PRESERVE (2002–2008) | Irbesartan (Oral, from 75 to 300 mg daily vs. placebo) | 4128 | NCT00095238 | 49.5 months | Irbesartan did not improve outcomes (death from any cause or hospitalization for CV cause) |
| CHARM-PRESERVED (1999–2003) | Candesartan(32 mg once daily vs. placebo) | 3023 | NCT00634712 | 36.6 months | Candesartan did not improve outcomes (cardiovascular mortality or hospitalization due to congestive HF) |
| TOPCAT(2006–2013) | Spironolactone(Oral, 15 mg to 45 mg daily vs. placebo) | 3445 | NCT00094302 | 39 months | Spironolactone did not significantly reduce the incidence of the primary composite outcome of death from CV causes, aborted cardiac arrest, or hospitalization for the HF management |
| ALDO-DHF (2007–2012) | Spironolactone(Oral, 25 mg daily vs. placebo) | 422 | ISRCTN94726526 | 12 months | Long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, symptoms or quality of life |
| PARAGON-HF (2019–2019) | Sacubitril/Valsartan(Oral. Two periods:(1) a single-blind treatment from 3 to 8 weeks with valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid(2) a double-blind randomized treatment with sacubitril/valsartan 200 mg bid or valsartan 160 mg bid | 4822 | NCT01920711 | 35 months | Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for HF and death from CV causes |
| Oxidative stress and Nitric oxide pathway | |||||
| KNO3CK OUT-HFpEF (2016–2022) | Potassium Nitrate (KNO3)(Oral, 6 millimoles of inorganic nitrate per capsule, three times daily for 6 weeks vs. placebo) | 76 | NCT02840799 | N/A | Outcome: VO2 (ongoing study) |
| INDIE-HFpEF (2016–2018) | Inorganic nitrite or nitrate preparations(Nebulized sodium nitrite at 46 mg then 80 mg three times per day vs. placebo) | 105 | NCT02742129 | 17 months | Administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity and VO2 |
| SOCRATES-PRESERVED (2013–2015) | Vericiguat(Oral, 2.5 mg once daily for 2 weeks, up-titration to 5 mg orally once daily for 2 weeks, up-titration to 10 mg orally once daily for 8 weeks vs. placebo) | 477 | NCT01951638 | 16 weeks | Vericiguat, did not change NT-proBNP levels at 12 weeks compared with placebo but it was associated with improvements in quality of life |
| NEAT-HFpEF (2014–2016) | Isosorbide mononitrate(6-week dose-escalation regimen of isosorbide mononitrate, from 30 mg to 60 mg to 120 mg once daily vs. placebo) | 110 | NCT02053493 | 6 weeks | Patients who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than patients who received placebo |
| Inflammation pathway and calcium handling | |||||
| D-HART (2014–2017) | Anakinra(Subcutaneous, Interleukin-1 blockade, 100 mg subcutaneously once daily for 12 weeks vs. placebo) | 60 | NCT02173548 | 12 weeks | Anakinra significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with HFpEF and elevated plasma CRP levels. |
| HELP (2018–2020) | Levosimendan(Injectable Solution 0.075–0.1 µg/kg/min for 24 h weekly vs. placebo) | 38 | NCT03541603 | 6 weeks | Levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6 min-walking-test |
| Fibrosis pathway | |||||
| PIROUETTE (2017–2020) | Pirfenidone(Oral, 801 mg three times daily vs. placebo | 129 | NCT02932566 | 12 months | Change in myocardial ECV from baseline to 52 weeks |
| SGLT-2 inhibition | |||||
| EMPEROR-Preserved (2017–2021) | Empagliflozin(Oral, 10 mg daily vs. placebo) | 5988 | NCT03057951 | 20 months | Time to first event of adjudicated CV death or HHF (ongoing) |
| DELIVER (2018–2022) | Dapagliflozin (Oral, 10 mg daily vs. placebo) | 6263 | NCT03619213 | 27 months | Composite of CV death, HHF and urgent HF visit (ongoing) |
RAAS: renin angiotensin aldosterone system; CV: cardiovascular; HF: heart failure; VO2: maximal oxygen consumption; NT-proBNP: N-terminal-pro hormone brain natriuretic peptide; PCWP: pulmonary capillary wedge pressure; HHF: heart failure hospitalization; CRP: C-reactive protein; ECV: extracellular volume fraction.