At the Society for Cardiovascular Angiography and Interventions (SCAI) annual Scientific Sessions in May 2013, Kimberly Skelding, MD, presented the three-year results of diabetic versus non-diabetic patients in the RESOLUTE US trial. Earlier RESOLUTE US results, combined with other trial data, led to the February 2012 FDA indication for the use of the zotarolimus-eluting Resolute Integrity stent (Medtronic) to treat coronary artery disease patients with diabetes mellitus. Resolute Integrity is the only drug-eluting stent to hold this indication from the FDA.
Dr. Skelding’s analysis shows that the performance of the Resolute DES persists out to three years in the diabetes subgroup, despite the higher risk nature of the diabetes patient population.
Can you talk about diabetics and coronary artery disease?
The diabetic population is at higher risk for complications after stent implantation, in percutaneous coronary intervention (PCI), as well as just coronary disease in general. Because diabetics are a higher-risk group, we treat these patients as a coronary artery disease (CAD) equivalent, even if there is no evidence they have CAD, because we know how poorly these patients do. One of the interesting things about the RESOLUTE US trial was that the diabetics didn’t statistically do worse than the non-diabetic population. There wasn’t any statistical difference in cardiac death or target vessel myocardial infarction, nor was there any statistical difference in stent thrombosis between diabetics and non-diabetics. Those are things that we worry about within the diabetic population, because of the diffuse nature of their disease. The inflammation process in diabetic vessels makes their disease more diffuse and difficult to treat.
The Resolute Integrity stent has an FDA indication for diabetic CAD patients. What does that mean to you as an interventionalist?
Having the FDA indication helps validate the outcome. We have data to show that that the Resolute stent is helpful, and so it is indicated for use in the diabetic population. Many cardiologists use all approved stents in all populations, but it is always more reassuring to have a direct indication to use a specific stent in a certain population. (It is always an issue — we still have groups of patients, including female patients, where there might not be enough data to show a difference between stents.) The FDA always has the bar raised high in order to give an indication, so having one gives some reassurance for using this particular stent in the diabetic population.
Diabetics were broken down into insulin-dependent and non-insulin dependent. Did you see any differences?
Yes. For example, if we look at target lesion revascularization, there was a difference between the three groups (insulin-dependent [8.4%], non-insulin dependent [6.0%], and non-diabetic [4.0%]), a graded difference. Of course, non-diabetics have the best target lesion revascularization rate. But an important point is that not all diabetics are the same. These results show us we might need to look more closely into the insulin-dependent group to identify what else we can be doing to help them lower their risk of events.
If we also look at cardiac death and target vessel myocardial infarction in insulin-dependent diabetics, event rates initially plateaued and then at about 18 months post procedure, start to climb.
I think that we see that there is progression of disease. When someone has a lesion treated, it is a focal treatment of the vessel, not a treatment of the entire coronary tree. It is difficult for us to standardize ancillary therapies for the diabetic population by physician and by patient compliance. We don’t know how well their hypertension was controlled, how well their hyperlipidemia was controlled, and how strong their diabetic control was. These are all things that lead to progression of disease.
What about the patients that were excluded from the trial? How does it compare to real-world practice?
There are some groups that were excluded just to clarify the data, so for example, those patients with very low ejection fractions were excluded, because they could certainly be dying of arrhythmic death, or of things that have little or nothing to do with stent implantation. Additionally, those with strokes or transient ischemic attacks (TIAs) were also excluded. I don’t think it is a “vanilla group” at all. We are always challenged when putting together a clinical trial, to not add patients who are going to add noise to the statistics because they are going to die of other issues, and that is the challenge of doing a clinical trial in general. But I don’t think this trial has excluded too many patients for invalid reasons.
Where would you like to see research go from here?
We need to continue to follow these patients in studies such as this, and in real-world data, outside of clinical trials, such as registries. As we start to use these stents extensively, the data that is collected is important; it is complementary to the data from the clinical trials. The concomitant pharmacotherapy in these trials will always be a challenge as well. In addition, there are many other medical issues that can contribute to poor outcomes, such as poor compliance in anti-lipid therapy, in diabetic management and in anti-hypertensives. Not solely poor compliance, but the presence of very reticent, difficult to treat risk factors. These issues are going to always complicate the data, so hopefully if we have large enough studies, the noise will not have as much impact.
What would you like to highlight about RESOLUTE US?
The data certainly shows that using the Resolute stent provides a benefit in the diabetic population. Diabetics are still at higher risk, but they are not as at much risk as they have been in the past with the earlier generation drug-eluting stents and certainly not as much as with bare metal stents. We are making improvements, and that’s what I think we need to do as a field, just continue to make strides in these high-risk groups.
In general, we have made great headway in treating diabetics. There used to be a huge difference between how diabetics and non-diabetics have done, and it is refreshing, as a cardiologist, to see that difference is becoming smaller. Diabetics are doing nearly as well, and certainly in some areas, just as well, as the non-diabetic population. Plus, as we search to improve the outcomes for our highest-risk populations, you can’t help but believe that we are also improving the outcomes for our lowest risk groups.
RESOLUTE US is also a reasonably sized trial with an extensive size of lesions, both in diameter and length. Although it is not a ‘real world’ study, it is close to the type of patients we see in regular practice, so the data should be generalizable.
Finally, it would be nice to see more women in these studies. In this particular study, the diabetic patient population was 62% males, and “all patients” was 68% males. While these are routine percentages for stent trials, it would be valuable to have greater numbers of women in order to compare women diabetics versus non-diabetics, and see if there is a bigger difference in the female population than the male population. As a cardiology community, we need to continually strive to get data on under-represented groups.
Disclosure: Dr. Skelding reports no conflicts of interest regarding the content herein.
Kimberly Skelding, MD, can be contacted at email@example.com.
Diabetic News: Research Shows High Blood Sugar Boosts Production of Inflammatory Cells
New research published in the May 7th issue of Cell
Metabolism reveals that high blood sugar levels boost the production of inflammatory cells, which contribute to plaque build-up in blood vessels. The researchers identify the cause of this increased production in inflammatory cells and find that blocking this new pathway could help safeguard the heart health of diabetic patients.
“We have found that the bone marrow production of immune cells is affected by high blood sugar and have identified a possible molecule mediating this effect. Both this molecule and its receptor in the bone marrow could be targeted to prevent the inflammation that occurs with type 1 diabetes,” says co-senior author Dr. Ira Goldberg of Columbia University College of Physician & Surgeons in New York City.
Dr. Goldberg and his team made their discovery by studying two mouse models of diabetes. In both diabetic models, high blood sugar levels caused a significant increase in the blood counts of certain immune cells called monocytes and neutrophils. The investigators also discovered that neutrophils secrete a molecule called S100A8/S100A9 that interacts with a receptor named RAGE (the Receptor for Advanced Glycation Endproducts) on bone marrow cells. Binding of S100A8/S100A9 to RAGE stimulated bone marrow cells to produce monocytes. This monocyte production created a vicious cycle whereby high blood sugar levels boosted neutrophil numbers, leading to excess secretion of S100A8/S100A9, which in turn stimulated bone marrow cells to produce more monocytes. These monocytes then migrated to blood vessel walls and prevented the healing of plaques.
The researchers found that treating the mice with a drug that lowers blood sugar levels not only reduced the numbers of circulating monocytes and neutrophils but also allowed plaques to normally heal after blood cholesterol was reduced. In addition, blood levels of S100A8/S100A9 in humans with type 1 diabetes correlated with immune cell counts and coronary artery disease.
“These findings illustrate a new marker for risk of vascular disease in patients with type 1 diabetes, and they suggest several new molecular targets for preventing diabetes complications,” says Dr. Goldberg.
Source: Nagareddy et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metabolism 2013 May; Online at http://dx.doi.org/10.1016/j.cmet.2013.04.001