Clinical and Angiographic Outcomes With Hyperglycemic Control Post PCI
Condition: Diabetes Mellitus; Coronary Restenosis
MeSH terms: Coronary Restenosis; Diabetes Mellitus
Study type: Interventional

Summary: 
      Coronary artery disease is a process that results in "hardening of the arteries". When the
      arteries that supply blood and oxygen to your heart muscle become clogged or narrowed, a
      heart attack may result, or you may feel chest discomfort (angina) - sometimes even while
      resting. One approach to treating this condition is a balloon procedure known as coronary
      angioplasty.

      The major limitation of coronary angioplasty is renarrowing of the artery (restenosis) in the
      first six months following the procedure requiring either repeat angioplasty or referral for
      bypass surgery. Patients with diabetes have always been identified as having higher rates of
      restenosis and poor outcomes following angioplasty, despite some important scientific
      advances. We think that the level of blood sugar control at the time of angioplasty and in
      the following months may be related to the extent of restenosis.

      We expect that a reduction in blood sugar with insulin may, in turn, reduce the restenosis
      process and improve your long-term outcome.
    

Detailed description: 
      Studies consistently show that diabetes (DM) is an independent predictor of angiographic
      restenosis as well as clinical outcomes after PCI. A common criticism of the early PCI trials
      is that stents were not routinely used. However, even when stents are used, the presence of
      DM is associated with a higher restenosis rate and lower event rate survival. In a series of
      3,554 consecutive patients (715 DM patients) undergoing stenting procedures at a single
      centre the incidence of restenosis and total vessel occlusion by angiographic assessment was
      significantly higher in diabetes. Increased restenosis rates were consistently demonstrated
      across a broad range of lesion types.

      The pathophysiology of restenosis is viewed as a complex temporal sequence of interactions
      involving several cellular and mechanical factors including elastic recoil, thrombosis,
      intimal hyperplasia, extra cellular matrix elaboration, apoptosis, oxidative stress and
      unfavorable arterial remodeling ("arterial shrinkage"). The exposure of subendothelial
      elements initiates platelet adhesion and activation. Activated platelets at the site of
      injury secrete growth factors that release smooth muscle cells from growth inhibition and
      induce their proliferation and subsequent migration from the media to the intima. Smooth
      muscle cell proliferation continues beyond the phase of platelet deposition. Extracellular
      matrix is produced and secreted by smooth muscle cells that have migrated into the injured
      intimal zone. This hypocellular matrix material forms the bulk of the intimal tissue.
      Although mechanical factors such as early vessel elastic recoil may play a major role
      following balloon angioplasty, this mechanism should not significantly affect the stented
      segments as the stent provides a rigid endovascular scaffold. Similarly, late arterial
      remodelling which has been postulated to be a significant factor for the development of
      restenosis after PCI should not have a major effect in the context of stents. Therefore, the
      major mechanism contributing to in-stent restenosis is aggressive intimal hyperplasia.

      Recent studies demonstrate that DM is characterized by diffuse intimal hyperplasia within the
      stented segment. DM is an independent predictor of the volume of intimal hyperplasia within
      the stent. The pattern of stent restenosis in patients with DM tends to be more diffuse and
      proliferative and therefore more likely to lead to total vessel occlusion. This is
      significant because diffuse restenosis is difficult to manage with repeat percutaneous
      procedures.

      Hyperglycemia has been postulated to promote the restenotic process in diabetes by the
      following mechanisms: i. endothelial cell dysfunction; ii. increased platelet aggregation and
      thrombus formation; iii. dysregulation of growth factor expression; iv. abnormal
      extracellular matrix deposition; v. advanced isolation and products.

      Approaches to preventing stent restenosis have had limited effect. Pharmacologic trials have
      universally failed to show a reduction in restenosis rates in human subjects. Recent reports
      suggested radiation therapy (brachytherapy) especially applied locally either via catheters
      or through radioactive stents has a potential to reduce the proliferative response. Although
      this approach holds great promise there are unresolved logistic issues, safety issues, and
      cost issues limiting wide-spread application.

      Preliminary studies of drug-eluting stents show initial promise in reducing restenosis rates.
      However, stent coatings can counteract the restenotic process only at points where the stent
      strut opposes the arterial wall and have little effect on neointimal tissue that can protrude
      between the struts and into the lumen. Furthermore, both brachytherapy and stent coatings
      only apply to the stented segments and the vessel whereas the arterial responses to balloon
      injury may also depend on flow characteristics (i.e. rheology) of the vessel. Therefore,
      alternative strategies that impact both local processes of the dilatation site and systematic
      processes on vessel remodelling and rheology are needed.

      Clinical trial data suggests that glycemic control may prevent restenosis. A recent study of
      patients with type 2 diabetes undergoing PCI with stent demonstrated a significant reduction
      in both neointimal area and neointimal index among participants randomized to the
      glucose-lowering agent troglitazone. Observational data from two registry studies indicate
      that diabetic patients with well-controlled hemoglobin A1c had lower rates of restenosis.

      Several lines of evidence suggest that insulin is safe and effective in controlling diabetes
      as well as reducing cardiovascular events. The recently published DIGAMI Study in which
      patients with myocardial infarction were randomized to an insulin infusion followed by at
      least three months of intensified insulin therapy showed a 31% reduction mortality in
      patients receiving intensified therapy. Subcutaneous insulin has been safely used to treat
      diabetes for almost 80 years. Patients can easily learn to both inject and titrate insulin
      response to home capillary glucose measurements. Greater than 85% of patients with type II
      diabetes who were started on insulin can achieve safe and effective metabolic control with
      one injection per day.

      Intravascular ultrasound is the most direct and sensitive technology available for
      measurement of intravascular hyperplasia volume within the stent. It is the technology that
      is most likely to uncover a benefit of insulin in reducing restenosis if one exists. This
      methodology will allow the research question to be answered with the smallest possible sample
      size. Recent studies demonstrate that detailed cross-sectional analysis of intracoronary
      stents during motorized IVUS catheter pullback is feasible with excellent reproducibility,
      safety and can be stored for off-line analysis. Establishing a mechanistic link between
      glycemic control and restenosis will support the design of larger clinical studies evaluating
      clinical outcomes.

      Primary Study Question

        -  Does intensive control of glucose levels with insulin in patients with DM reduce volume
           of intimal hyperplasia within the stented segment as evaluated by intravascular
           ultrasound (IVUS) at 6 months? Secondary Study Question

        -  Does intensive glycemic control with insulin reduce restenosis as evaluated by
           quantitative coronary angiography (QCA) at 6 months

        -  Does intensive glycemic control with insulin prevent clinical events such as hospital
           admission for unstable angina and for congestive heart failure, myocardial infarction,
           stroke, revascularization (PCI, CABG) and death at 12 months.

      Primary Hypothesis:

      ·Intensive glycemic control with insulin in diabetic (DM) patients reduces intimal
      hyperplasia within the stented segment after percutaneous coronary revascularization

      Secondary Hypothesis:

        -  The reduction in intimal hyperplasia is related to the degree of glycemic control (i.e.
           HbA1c values); and

        -  Event-free survival is improved in patients treated with insulin
    

Intervention name(s): Insulin
Intervention type(s): Drug
Intervention MeSH terms: Insulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetes Mellitus; Coronary Restenosis; Insulin; Angioplasty