Clinical and Angiographic Outcomes With Hyperglycemic Control Post PCI
|ClinicalTrials.gov Identifier: NCT00412126|
Recruitment Status : Completed
First Posted : December 15, 2006
Last Update Posted : December 15, 2006
|First Submitted Date ICMJE||December 13, 2006|
|First Posted Date ICMJE||December 15, 2006|
|Last Update Posted Date||December 15, 2006|
|Study Start Date ICMJE||July 2002|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Volume of intimal hyperplasia in the stented segment by IVUS at 6 months following PCI|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||No Changes Posted|
|Current Secondary Outcome Measures ICMJE
||Late loss in minimal luminal diameter of stented site in coronary vessel evaluated by QCA at 6 months post-PCIb) Rate of clinical events at one year (hospital admission for unstable angina, CHF, MI, stroke, revascularization, and death)|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Clinical and Angiographic Outcomes With Hyperglycemic Control Post PCI|
|Official Title ICMJE||Does Reduction of Hyperglycemia With Insulin Impact Restenosis and Improve Clinical Outcomes Following PCI?|
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.
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
·Intensive glycemic control with insulin in diabetic (DM) patients reduces intimal hyperplasia within the stented segment after percutaneous coronary revascularization
|Study Type ICMJE||Interventional|
|Study Phase||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Insulin|
|Study Arms||Not Provided|
|Publications *||Natarajan MK, Strauss BH, Rokoss M, Buller CE, Mancini GB, Xie C, Sheth TN, Goodhart D, Cohen EA, Seidelin P, Harper W, Gerstein HC. Randomized trial of insulin versus usual care in reducing restenosis after coronary intervention in patients with diabetes. the STent Restenosis And Metabolism (STREAM) study. Cardiovasc Revasc Med. 2012 Mar-Apr;13(2):95-100. doi: 10.1016/j.carrev.2011.12.001. Epub 2012 Jan 30.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Original Enrollment ICMJE||Same as current|
|Study Completion Date||September 2005|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 90 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT00412126|
|Other Study ID Numbers ICMJE||01-223|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||Hamilton Health Sciences Corporation|
|Collaborators ICMJE||Heart and Stroke Foundation of Canada|
|PRS Account||McMaster University|
|Verification Date||December 2006|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP