A Trial of Fimasartan for Early Diastolic Heart Failure
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      Approximately half of hypertensive patients have diastolic dysfunction and diastolic
      dysfunction is associated with development of congestive heart failure and increased
      mortality. Although diastolic heart failure associated with hypertension is a clinically
      significant problem, few clinical trials have been conducted and there is no proven
      pharmacological therapy to improve outcomes. To the best of the investigators knowledge,
      there has been no randomized trial to demonstrate that an antihypertensive drug improves
      diastolic function in hypertensive patients with diastolic dysfunction. The investigators
      hypothesize that fimasartan added to standard therapy will be superior to placebo in
      improving diastolic dysfunction in mildly symptomatic patients with hypertension and
      diastolic dysfunction, and try to examine this hypothesis in a double-blind, randomized
      comparison study using echocardiography.
    

Detailed description: 
      Approximately half of hypertensive patients have diastolic dysfunction and diastolic
      dysfunction is associated with development of congestive heart failure and increased
      mortality. The Framingham study reported that 51% of patients with HF have a preserved left
      ventricular (LV) ejection fraction and hypertension is the strongest risk factor for HF with
      preserved ejection fraction, also termed diastolic heart failure. The rates of death and
      morbidity in these patients are as high as in patients with HF and a low LV ejection
      fraction. Hypertensive patients are at increased risk of developing LV hypertrophy and
      myocardial fibrosis, which cause relaxation abnormality and decreased compliance of LV with a
      rise in the LV diastolic pressure. Although HF associated with hypertension is a clinically
      significant problem, few clinical trials have been conducted and there is no proven
      pharmacological therapy to improve outcomes.

      Because the activation of rennin-angiotensin-aldosterone system (RAAS) has been shown to
      induce LV hypertrophy and myocardial fibrosis, the RAAS may play a central role in the
      pathogenic process from hypertension to diastolic HF. Inhibitors of RAAS have been considered
      as a treatment option for these patients, and the angiotensin receptor blockers (ARB) have
      been of interest because they antagonize the effects of angiotensin II more completely. The
      largest clinical trial, the Irbesartan in Heart Failure with Preserved Systolic Function
      (I-PRESERVE), recently reported that treatment with irbesartan did not reduce the risk of
      death or hospitalization for cardiovascular causes among 4,128 patients who had HF with a
      preserved LV ejection fraction. The negative result observed in the I-PRESERVE trial may have
      been the consequence of the following possible factors. First, this trial may have targeted
      patients in whom the disease process was too advanced for ARBs to be effective. Second,
      irbesartan may not be an appropriate ARB for a HF trial, because ARBs are not all the same in
      terms of clinical outcome data in patients with HF. Irbesartan did not have outcome data on
      reducing HF hospitalization in high-risk hypertensive patients and telmisartan showed no
      benefits compared to placebo in these patients, although candesartan and valsartan
      significantly reduced endpoint in placebo-controlled trials. Telmisartan and irbesartan have
      PPARγ activity and this activity might neutralize the beneficial effects of ARB on HF,
      because it is well known that PPARγ agonist, rosiglitazone, increases the incidences of HF
      significantly.

      Evaluating the effect of treatments on diastolic dysfunction has been limited by difficulties
      in non-invasive measure of LV diastolic pressure, but recent advances in echocardiography
      have made it possible to assess diastolic dysfunction accurately and reproducibly. Thus,
      additional clinical studies with the other ARBs are needed in hypertensive patients with
      diastolic dysfunction and assessment of diastolic function by echocardiography will be
      helpful to determine whether addition of ARB to standard therapy is beneficial to
      hypertensive patients with diastolic dysfunction. Fimasartan is the first ARB developed in
      Korea, and was felt to be particularly appropriate for examining the hypothesis that the ARB
      can improve diastolic dysfunction associated with hypertension, because fimasartan is a
      potent and well-tolerated ARB. To the best of our knowledge, there has been no randomized
      trial to demonstrate that an antihypertensive drug improves diastolic function in
      hypertensive patients with diastolic dysfunction. We hypothesize that fimasartan added to
      standard therapy will be superior to placebo in improving diastolic dysfunction in mildly
      symptomatic patients with hypertension and diastolic dysfunction, and try to examine this
      hypothesis in a double-blind, randomized comparison study using echocardiography.
    

Intervention name(s): Fimasartan; Antihypertensive treatment
Intervention type(s): Drug; Drug
Intervention MeSH terms: Antihypertensive Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hypertension; Angiotensin Receptor Blocker; Diastolic Dysfunction