Novel Interventions in Heart Failure with Preserved Ejection Fraction using Tadalafil

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It is estimated that over 300,000 Australians have heart failure (HF) at any given time and the incidence increases with increase in life expectancy. The point prevalence of chronic heart failure (CHF) has been about 1% in people aged 50–59 years, 10% in people aged over 65 years, and over 50% in people aged greater than 85 years. Despite therapeutic advances, HF remains a disease with unacceptably high mortality rates, poor quality of life and massive socioeconomic cost. Heart failure with preserved ejection fraction (HF-PEF) previously known as diastolic heart failure accounts for about 50% of patients with heart failure. HF-PEF refers to a clinical syndrome of symptoms and clinical signs of HF, normal or near normal left ventricular (LV) systolic function (EF> 50%) and evidence of diastolic dysfunction in the form of abnormal LV filling and elevated filling pressures. This can be objectively confirmed on echocardiogram. There is no difference in morbidity between patients with heart failure with reduced ejection fraction and those with preserved ejection fraction and some studies have shown similar mortality in the two conditions. The efficacy for beta blockers, angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) and aldosterone antagonists is well established in the treatment of HF with reduced EF. The efficacy for these drugs in HF-PEF is not well established. The I-PRESERVE trial studied the effects of Irbesartan (ARB) in symptomatic patients with HF-PEF. 4128 patients were enrolled and followed up for 4 years. There was no improvement in outcomes in patients on Irbesartan. The CHARM preserved trial studied Candesartan in 3000 patients with HF-PEF for a period of 3 years. There was only a small reduction in hospital admissions for heart failure in the Candesartan group.The PEP-CHF trial assessed the efficacy of Perindopril (ACE-I) in 850 patients over the age of 70 with HF-PEF. At one year there were fewer unexpected hospital admissions for heart failure in the perindopril group although the trial when completed showed no difference in its primary end point. Although therapies have proven effective in reducing morbidity and mortality from heart failure with reduced ejection fraction, mortality from HF-PEF remains unchanged. No therapies thus far have been proven to correct the abnormalities seen in HF-PEF, halt its progression, reduce its mortality or conclusively reduce its morbidity. Rationale. 1. That the addition of the phosphodiestrase-5 (PDE-5) inhibitor tadalafil will improve symptoms, exercise tolerance, pulmonary arterial pressure, right ventricular (RV) function and LV relaxation in patients with HF- PEF. Objectives. The primary objective of the study is to trial a novel agent in the treatment of HF-PEF as patients continue to be symptomatic on currently available medications. 1. We propose to use the PDE-5 inhibitor tadalafil which selectively dilates pulmonary vessels and has beneficial effects on RV function in patients with HF-PEF and assess the effect on symptoms, exercise tolerance, echocardiographic and Cardiovascular Magnetic Resonance (CMR) imaging parameters of heart failure.

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