Aliskiren on Retinal Vasculature Treatment Study
Condition: Arterial Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 3

Summary: 
      Hypertension affects approximately one fourth of the world population and therefore
      contributes substantially to the worldwide burden of cardiovascular (CV) disease and
      end-organ damage.

      Changes in small artery structure characterized by an increased wall-to-lumen ratio (WLR) are
      characteristic feature of target organ damage in hypertension. Of clinical importance,
      structural arteries of small subcutaneous arteries have been shown to be of prognostic
      significance, with adverse prognosis in subjects with higher WLR. However, the assessment of
      arteriolar structure from biopsies of subcutaneous tissue is invasive and impractical in
      clinical practice. A new approach focuses on retinal arteriolar structural parameters by
      using scanning laser Doppler flowmetry (SLDF) with automatic full-field perfusion imaging
      analyses (9). This approach allows the non-invasive assessment of both the outer diameter
      (OD) and inner diameter (ID) of retinal arterioles in vivo and, thus, analyses vascular
      remodeling of retinal arterioles by calculating WLR = (OD - ID) / ID).

      A crucial role in the efforts of prevention of end-organ damage plays the renin angiotensin
      system (RAS). The increased mechanical strain on the vasculature at a higher BP can cause
      injury to the endothelial wall. Activation of the RAS increases BP and stimulates a local
      inflammatory response to repair the injury. Long-term or repeated response to injury leads to
      endothelial dysfunction and microvascular damage, and hence end-organ damage.

      Combining RAS inhibitors may provide greater end-organ protection than use of either class
      alone. However, ONTARGET has failed to show superiority of the dual RAS blockade (ACE-I and
      ARB) in patients at high cardiovascular risk. The combination of ARBs and direct renin
      inhibitors (DRIs) emerged as the only available, valid and innovative option for blocking the
      RAS at two different sites (sequential blockade). Indeed, AVOID study and ALLAY study
      demonstrated that the DRI aliskiren has additional and to some extent blood pressure
      independent effects on albuminuria and left ventricular hypertrophy, both signs of
      subclinical organ damage in hypertension, respectively.

      However, no data are available with respect to the effects of ARBs and DRIs on vascular
      properties in the short and long term To close this gab we focus in this study on vascular
      structural and functional changes since vascular adaptation to high blood pressure occurs in
      the early phase of hypertensive disease.
    

Detailed description: 
      Hypertension affects approximately one fourth of the world population and therefore
      contributes substantially to the worldwide burden of cardiovascular (CV) disease and
      end-organ damage (1). Therefore, the goal of antihypertensive therapy is to provide effective
      long-term lowering of elevated blood pressure (BP) and prevention of hypertensive
      end-organ-damage and mortality (2).

      Changes in small artery structure characterized by an increased wall-to-lumen ratio (WLR) are
      characteristic feature of target organ damage in hypertension. (3; 4). A clinical study
      examining small arteries obtained from gluteal biopsies of patients with hypertension
      revealed that an increased WLR of subcutaneous small arteries is one of the first
      manifestations of target organ damage in hypertension that occur before proteinuria and
      cardiac hypertrophy (5). Of clinical importance, structural arteries of small subcutaneous
      arteries have been shown to be of prognostic significance, with adverse prognosis in subjects
      with higher WLR (6-8). However, the assessment of arteriolar structure from biopsies of
      subcutaneous tissue is invasive and impractical in clinical practice. A new approach focuses
      on retinal arteriolar structural parameters by using scanning laser Doppler flowmetry (SLDF)
      with automatic full-field perfusion imaging analyses (9). This approach allows the
      non-invasive assessment of both the outer diameter and inner diameter of retinal arterioles
      in vivo and, thus, analyses vascular remodeling of retinal arterioles by calculating WLR =
      (outer diameter - inner diameter) / inner diameter) (10).

      In a previous study, we could demonstrate that treated hypertensive patients with poor BP
      control have a greater WLR of retinal arterioles than those with good blood pressure control.
      Interestingly, in this cohort we did not find a significant relation between BP and WLR of
      retinal arterioles using correlation analyses. We have concluded that this lack of a relation
      might well be the result of the effects of some antihypertensive drugs to beneficially
      influence vascular structure (9). Subsequently, we analyzed WLR of retinal arterioles in a
      cohort of never-treated patients with essential hypertension and normotensive controls. In
      this cohort, both systolic BP and diastolic BP were significantly related to WLR of retinal
      arterioles independent of traditional CV risk factors and other confounders, e.g. subclinical
      inflammation, endothelial dysfunction and dietary salt intake. Moreover, in this cohort, the
      WLR of retinal arterioles was greater in hypertensive than in normotensive subjects (11).

      A crucial role in the efforts of prevention of end-organ damage plays the renin angiotensin
      system (RAS) due its dual role on salt and water homeostasis (blood pressure) and the
      vascular response to injury. The increased mechanical strain on the vasculature at a higher
      BP can cause injury to the endothelial wall. Activation of the RAS increases BP and
      stimulates a local inflammatory response to repair the injury. Long-term or repeated response
      to injury leads to endothelial dysfunction and microvascular damage (12), and hence end-organ
      damage. Therefore increasing evidence is not suppressing, that antihypertensive medications
      which inhibit the RAS may provide incremental end-organ protection.

      Recently, we have shown that hypertensive patients have an impaired vasodilatory response of
      retinal arterioles to Flickerlight test - which improves after treatment with Angiotensin
      Receptor Blockers (ARBs) - and have a reduced nitric oxide (NO) activity in the retinal
      circulation, that is normalized after treatment with ARBs (13; 14). Likewise, in a previous
      study analyzing the arterial resistance vessels also in the systemic circulation we found
      that in contrast to diuretics and placebo, valsartan improved endothelial function and
      vascular properties (estimated by pulse wave anlalysis) (15; 16).

      Combining RAS inhibitors may provide greater end-organ protection than use of either class
      alone. However, the Ongoing Telmisartan Alone and in Combination with Ramipril Global
      Endpoint Trial (ONTARGET) has failed to show superiority of the dual RAS blockade
      (Angiotensin converting enzyme inhibitor and ARB) in patients at high cardiovascular risk
      (17). The combination of ARBs and direct renin inhibitors (DRIs) emerged as the only
      available, valid and innovative option for blocking the RAS at two different sites
      (sequential blockade). Indeed, the Aliskiren in the Evaluation of Proteinuria in Diabetes
      (AVOID) study (18) and the Aliskiren in Left Ventricular Hypertrophy (ALLAY) study (19)
      demonstrated that the DRI aliskiren has additional and to some extent blood pressure
      independent effects on albuminuria and left ventricular hypertrophy, both signs of
      subclinical organ damage in hypertension, respectively (20).

      However, no data are available with respect to the effects of ARBs and DRIs on vascular
      properties in the short and long term To close this gab we focus in this study on vascular
      structural and functional changes since vascular adaptation to high blood pressure occurs in
      the early phase of hypertensive disease.
    

Intervention name(s): Aliskiren; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): orally 150 mg/d for 1 week, then orally 300 mg/d for 7 weeks; orally once per day
Other intervention name(s): Rasilez
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment