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The Veterans Administration Diabetes Trial (VADT) and Lessons for Patient Safety

2008-07-14 14:47:06
By: Richard Hellman, MD, FACP, FACE

Three important trials were presented last month at the American Diabetes Association’s 68th Scientific Sessions. Two of the trials, the ACCORD and ADVANCE, were published in the June 12, 2008 edition of the New England Journal of Medicine, but at the time of the presentation, the authors of the Veterans Administration Diabetes Trial (VADT) had just closed their database and had not yet completed all of their analysis of the data. But even with the preliminary data, some important conclusions can be drawn.

The first conclusion of the VADT was an important negative result. The researchers could not show that, in the setting of improved control of cardiovascular risk factors such as blood pressure, lipid control, and lifestyle training, intensive glycemic control reduced the incidence of major cardiovascular events.

There were, however, some intriguing findings. For example, a significant reduction in risk of cardiovascular events was found in the patients with a shorter duration of diabetes. After 15 years’ duration of diabetes, the risk associated with intensive therapy, as measured by a hazard ratio, was >1 and tended to increase with increasing duration of diabetes.

Another unexpected finding was regarding hypoglycemia. Overall the hazard ratio for having a major cardiovascular event in patients who had a major hypoglycemic episode in the previous three months was 2.062, but in those on standard therapy the hazard ratio was 5.855 vs. only 1.277 in those on intensive therapy.

In contrast, it was hardly surprising that coronary artery calcification (CAC) proved to be very strongly associated with a major coronary event, an association even stronger than a prior history of cardiovascular event. For those with a CAC score >400, the relative risk of a cardiovascular event was 7.5 times that of the entire study population. Only 6% of all patients studied had a CAC score >400. Certain complications were associated with a disproportionally high likelihood of having a CAC score >400. For instance, 80% of patients with proliferative diabetic retinopathy had a CAC score >400.

The authors evaluated the relative cardiovascular risk associated with rosiglitazone use. This was not an easy task, because although the majority of patients received this agent, there were many differences in timing, duration, and dose of rosiglitazone therapy. Consequently, the biostatisticians chose a case-control study method of analysis. They reported that their analysis showed no increased cardiovascular risk for rosiglitazone, but admitted that this analysis might be less compelling because the VADT was not originally designed to study rosiglitazone, and as a result, the statistical technique best suited for the analysis, the case control study, did not yeld as high a level of evidence as a randomized controlled trial would produce.

But do the VADT results provide guidance in our efforts to improve patient safety in diabetes therapy? The answer, I think, is a qualified “yes”. The implication of the first analysis of the VADT is to make clearer that the strategy used in therapy must be tailored to fit the needs of the individual patient.

As an example: before beginning intensive therapy on 65-year-old diabetic patient of 25 years duration of diabetes with proliferative diabetic retinopathy and prior recent history of severe hypoglycemia, a thorough assessment of the patient’s true risk and status regarding cardiac risks is in order. Does this patient have high grade coronary artery disease? Does this patient have the ability to clearly see what they are taking? Can they sense hypoglycemia, or do they have hypoglycemic unresponsiveness? Does the patient have associated mild dementia or depression? What about the support from family and companions, is that sufficient regardless of the strategy offered to the patient?

The data on hypoglycemia has surprising implications. Often, physicians may assume that if intensive therapy is followed by an episode of hypoglycemia, then standard therapy might be a safer choice. The VADT data, however, showed that the risk for a major cardiovascular event after a major hypoglycemic event was much higher in the standard therapy group. The reason why is unclear. Could there be, for instance, a subset of those on standard therapy for which standard therapy may be more dangerous? It may be that some patients with previous episodes of severe hypoglycemia may benefit from either a more intensive approach or a different monitoring strategy. More analysis of these preliminary findings is urgently needed.

The VADT will, along with the ACCORD and ADVANCE trials, be recognized as landmark studies, but from the point of view of patient safety issues, these studies may well mark the entrance of major research efforts into just how best to implement our more fundamental research insights.

Clearly, strategies for glycemic control need to be individualized. The challenge for the clinical investigators will be to delineate enough of the important barriers to and risks of successful implementation of core strategies so that when we design long-term outcome research studies, we will be able also to analyze the relative importance of factors crucial to successful implementation of the therapeutic plans. To the patient, both attention to the barriers to and risks of implementation of a core strategy, such as intensive glycemic control, may make all the difference between success and failure. Our patients must be able to comprehend and consistently apply what they have been taught in order to get the positive clinical outcomes they need. And we need to provide what they need in education, training, and guidance in order to help them succeed.

Leave a Comment

There are 7 comments

Prasanna Rao-Balakrishna – UK

July 14, 2009 - 17:23

Subject: Preventing Hypoglycaemia is as important as the tight glycaemic control

Preventing hypoglycaemia is as important as the tight glycaemic control. It is important to note that glycaemic control depends on the insulin regimen, patient's own counter regulatory hormone response & insulin resistance status, the calorie intake, frequency of testing for blood glucose, interpretation and acting on the results. During acute illness it is not possible to control the counter-regulatory hormone response and the insulin resistance status, but with adequate training, frequent testing and appropriate structured response should be possible, thereby preventing a hypoglycaemia. A trial which focuses as much on hypoglycaemia avoidance as well as tight glycaemic control is needed.

Reply to Prasanna Rao-Balakrishna

Richard Hellman MD

July 16, 2009 - 11:25

Subject: RE: Preventing Hypoglycaemia is as important as the tight glycaemic control

Dr Rao-Balakrishna makes a very interesting suggestion, that preventing hypoglycemia is as important as the tight glycemic control, and suggests a trial that focuses on two end-points, the avoidance of hypoglycemia as a co-equal goal in importance to tight glycemic control.

In fact, there is a great deal we do not know about hypoglycemia in critically ill states, and it is far from clear what the short and long term consequences are of mild, moderate, or even brief periods of severe ypoglycemia for critically ill patients. We do know that severe hypoglycemia can be a marker for increased mortality, as it was clearly shown in the VADT trial, but interestingly, those deaths did not usually occur during the hypoglycemic episodes, and the relationship between severe hypoglycemia and subsequent mortality was strongest in the conventional therapy group, suggesting that the hypoglycemic events may have been a consequence of an underlying vulnerability rather than the cause of mortality.

One of the limitations of an approach focused just on the outcomes of glycemia is that from the patients' standpoint, the most important issues are their clinical outcomes: mortality, morbidity, and disability. In contrast, those outcomes may not match the relative frequency of hypoglycemia at all. For example, there is a disconnect between the very high frequency of hypoglycemia in the Van Den Berghe RCT's in critical care published in 2001, 2006, and 2009. Both the surgical ICU study of 2001 and the 2009 pediatric studies showed very excellent outcomes with respect to mortaliy and morbidity in the presence of relatively frequent hypoglycemia.

I again would like to thank Dr Rao-Blakrishna for pointing us again to this very unsettled issue of the importance of hypoglycemia prevention, for the debate as to what we can and should do rages on. There are many creative ideas that have been proposed, but we need more data to guide us as to how to obtain the best clinical outcomes with the tools we have without either unacceptably high levels of hypoglycemia or hyperglycemia.

Richard Hellman MD
Editor-In-Chief
Patient Safety Exchange Website

MRR – Texas

March 31, 2009 - 16:29

Subject: NICE_SUGAR

Several interesting points came to mind when I reviewed the NICE-SUGAR study; the degree of severe hypoglycemia, the degree of cardiovascular mortality, the conventional group’s blood glucose levels are significantly lower than the vast majority of other outcome studies, and the number of severe septic patients in the intensive control branch of the study. According to the 2008 sepsis guidelines, the glycemic control target level for the septic patient is already in question and perhaps sepsis should be an exclusion criteria?

I was tasked with the development and oversight of a Tight Glycemic Control Program pilot study from May 2006 through April 2008 for a South Texas community hospital/level 2 trauma center. This included a 14 bed CCU, 12 bed M/S ICU and 12 bed trauma ICU as well as 4 M/S wards. Clinical inertia was our most difficult element to overcome and for the most part this was never accomplished. Clinical inertia was not only evident on physician's part, but also administration, nursing, nutritional services, pharmacy, and the patients themselves. Accountability to noncompliance to protocols was lacking as well. The philosophy that inpatient glycemic control was not necessarily treating diabetes, yet acute hyperglycemia was never fully accepted. When results like ACCORD, ADVANCE, and VADT were released, I would usually take the phone off the hook and leave the hospital because those wbeepdo not support inpatient glycemic control would come out en mass wishing to compare apples to oranges. That is not necessarily the case with NICE-SUGAR. In our Trauma ICU, where support was highest, for the entire year of 2007, we had only 7% BG > 200mg/dL, less than 2% hypoglycemia under 50 mg/dL, and nearly 75% BG between 80 - 150 mg/dL.

Overall, I applaud the NICE-SUGAR research team for a job very well done and thank them for their contribution to this ongoing discussion. I do support further research to differentiate specific glycemic control target ranges for specific diagnosis, but I too fear this could cause a pendulum swing in the opposite direction resulting in less facilities participating in inpatient glycemic control resulting in less data for differentiation.

NISSIM GABAY – VENEZUELA

March 26, 2009 - 15:25

Subject: NICE -SUGAR

I think that the central goal of the ADA/AACE impatient glucose targets is safe with the protocols .
Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia.
Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of
insulin is preferred in critically ill patients.
Be careful with this trial [NICE -SUGAR] to overcome clinical inertia.

Dr. Orlin Sergev – Charleston, SC

March 16, 2009 - 16:28

Subject:

Dear Dr Hellman:
I enjoyed all the editorials on patients' safety that you have recently published. I think that they raise questions which we as physicians are not always open about. Safety itself is frequently a topic that we love to discuss but it's never our fault. In this connection, the article about overconfidence and medical errors is timely - especially, at this time of expected health care changes. Briefly, I do not think we as physicians are different from any other specialists in different areas. Lack of adequate knowledge in a special area is always a good reason to be noisy and seemingly overconfident. Most of us agree that the more you know the more you realize how much more you do not know. Overconfident behavior in front of outsiders seem to be the cover of ignorance. I think we have to improve medical education in order to make medical decisions safer. Just remember the pilot of the plane that landed in Hudson river - quiet professional on top of his performance. We in medical profession must lead in patients' safety. In order to do that we have to lead the health care reform. We have to regain our authority, responsibility and accountability. (accountability without authority and responsibility is meaningless - see Dr Hellman's article on Medicare). We have to lead the health education of the society - most of the tragic mistakes in life happen from ignorance. First and foremost, of course, we have to maintain the superiority in medical knowledge. We must improve the quality of medical education. Instead of multiple choice questions we have to put back in place the stern professor wbeepmade clinical judgements based on knowledge, experience, and gut feeling and set up a good personal example for the next generation of physicians. Pilot "Sully" did not read the manual and the guidelines how to handle the critical situation - all his life before, however, prepared him for the right on the spot decision. Decisions based on profound knowledge and experience are the safest! Let's start the health care reform with ourselves.
Do not stop learning and teaching your team about sound and safe medical practices. When we have achieved that, we can confidently go out and regain our authority over various bureaucracies (government agencies-Medicare, insurances, medical malpractice law, etc).

james t poulos – west lafayette in

March 03, 2009 - 15:09

Subject: NICE-SUGAR

There was an article in acta scandinavia in january that showed very little hypoglycemia when intensive therapy is done right! I came across the article on medlinx in mid January, but it was actually published in October 2008. authors: Kaukonen KM et al in acta anaethesiol scandinavia and titled severe hypoglycemia in intensive insulin therapy.

Reply to james t poulos

Dr Hellman

March 04, 2009 - 16:12

Subject: Further thoughts related to the NICE-SUGAR study

Dear Dr. Poulos,

Thank you for calling attention to the study by Kaukonen KM et al. Your excellent point adds to the discussion generated by the NICE-SUGAR study. Their preliminary data analysis showed that error by provider was the most common cause of hypoglycemia. Their data implied, as I stated in my recent editorial, that improving the training and performance of those managing the insulin infusions greatly decreases the threat of hypoglycemia.

In this study by Kaukonen, done at the Helsinki University Central Hospital in Helsinki, Finland, the authors evaluated the incidence of hypoglycemia in all patients treated in two intensive care units between February 2005 and June 2006. They showed that severe hypoglycemia during intensive insulin therapy was rare in clinical practice. Analyzing data for 1124 patients and 61,203 glucose measurements, they found 36 measurements of severe (≤ 2.2mmol/L) hypoglycemia in 25 patients, with an incidence of 0.06% of severe hypoglycemia.

They commented that the frequency of blood glucose monitoring correlated inversely with the frequency and magnitude of severe hypoglycemia. In surgical patients, it is of note that five of the six instances of hypoglycemia occurred when a nurse failed to comply with the protocol.

The Helsinki group’s observations are entirely in keeping with the preliminary data from the NICE-SUGAR study and make a good deal of common sense. When the rate of decrease of glucose is rapid, for example greater than 1mg/dl/minute, simple arithmetic can tell us when the next glucose determination needs to occur to be able to safely avoid severe hypoglycemia. But if the frequency of checking of glycemic levels is arbitrary, and set too low, then hypoglycemia is to be expected much more often. The Kaukonen group avoided this by making sure the blood glucose sampling was relatively frequent.

In our clinical practice setting as well, the principles of safe handling of insulin infusions have been:

1.frequent monitoring, always at least hourly in ICU settings, more often when dealing with lower glycemic levels;
2.intensive training of nurses to make them expert in understanding how best to use algorithms;
3.specific points at which prolonged hyperglycemia or hypoglycemia necessitates immediate consultation with the responsible physician;
4.review of data to indicate variations in performance and appropriate correction and retraining when appropriate.

We too have extensive experience over many years with the safe use of insulin infusions in inpatient settings with relatively rare severe hypoglycemic episodes and little morbidity.

The NICE-SUGAR study should provide important information. We should not get too far ahead of their forthcoming data, but there is already abundant data, such as the important study from Helsinki, which show us that with a safer system of care, more ambitious glycemic control is both achievable and safe.

Kaukonen KM et al. Severe hypoglycemia during intensive insulin therapy, Acta Anaesthesiol Scand. 2009 Jan;53(1):61-65. Epub 2008 Oct 20.