The Disease Management Blog doesn’t presume that its readers rely on this corner of the blogsphere for news and information, so you’ve probably already heard that the ACCORD (the catchy acronym stands for the Action to Control Cardiovascular Risk in Diabetes) was suspended. This my blog though, so that doesn’t mean I can’t weigh in with what I’ve learned and offer up some additional speculation through the lens of disease management. Read on if you are so inclined…….
Interesting stuff. Over 10,000 persons were randomly allocated to either tight blood glucose control (target A1c less than 6%: that is VERY aggressive) versus moderate control (an A1c between 7% and 8%, which isn’t bad but doesn’t meet guidelines of the American Diabetes Association or HEDIS). As an aside, there was an additional “2x2 factorial design” that also tests the benefits of 1) aggressive blood pressure control and 2) treatment to increase the “good” or HDL cholesterol. Research subjects began to be recruited in January 2001 in 77 outpatient clinics across the United States and Canada.
What was found? Over an average of 4 years, the researchers noted an increase in the death rate among the approximately 5000 subjects assigned to the A1c less than 6% group versus the 5000 in the other group. This was quite counterintuitive: 257 died in the tight control group, versus 203 in the group assigned to an A1c between 7% and 8%. This was statistically significant and apparently not a function of the types of diabetes drugs used. The portion of the trial on tight blood sugar control has been halted; the other research on blood pressure and HDL is continuing.
To put the calculated excess death rate of 3 per 1000 into perspective, the numbers suggest that a doctor (ensconced in a population-based program of course) would need to aggressively target 333 persons with diabetes down to an A1c of 6% or less to provoke one extra death (for more on number needed to treat go here). Deaths were evenly split between cardiovascular categories and “other” (for example, cancer). Persons assigned to the low A1c group had a lower rate of heart attacks, but the irony is that they were more likely to die if that happened. Participants are being notified of the trial result and the persons in the low A1c group are being reassigned to an A1c between 7% and 8%.
Note this is an “intention to treat” analysis. In other words, the data hasn’t been sorted by the actual A1c. A technically correct interpretation is that trying to get a person with diabetes to an A1c less than 6% is associated with excess mortality. That is slightly different than the conclusion getting a person to an A1c less than 6% is associated with excess mortality. Not everyone in the aggressive control group actually got to an A1c of less than 6%.
Why is this interesting? Older readers with a background in patient care may recall the debate about the “J curve” in essential hypertension back in the 1990s. The moniker “J curve” was used because the plot of BP control on the horizontal axis versus complications on the vertical axis looked like a “J.” Some studies had suggested that lowering the blood pressure “too much” (for example, less than 70 diastolic) among persons with hypertension seemed to be associated with increased mortality. Folks speculated that a lower “head of pressure” in arteries partially blocked with atherosclerosis led to premature clotting/thrombosis and death. The HOT (another catchy acronym – Hypertension Optimal Treatment) Trial found out that was not true and that aggressive lowering of blood pressure does no harm. What’s more, for persons with diabetes, HOT showed aggressive lowering of blood pressure is beneficial.
The preliminary review of the data from ACCORD makes me wonder if the previously obsolete concept of a J curve can be resurrected for diabetes mellitus. If we forego “intention to treat” for a moment and speculate persons in the ACCORD Trial who maintained an A1c between 6% and 7% did “better” than those with an A1c greater than 7%, the question is how did the persons in the less than 6% group do compared to those with an A1c between 6% and 7%? If they did worse, J curve! If they did the same, hockey stick.
Stay tuned. It will take some time for the health services researchers to pull all that apart and present all this in a peer review, transparent forum.
So what do we know?
This is another great example of why we need to uncouple short term process (the incidence of A1c testing) or clinical measures (the A1c results themselves) from the outcome measures that people really care about. And people care about death.
Patients who are engaged in their diabetes care now have even more information to better gauge how they should be treated. They can be counseled that targeting an A1c lower than 6% isn't necessarily in their best interest. However, they should factor in the intention to treat dimensions.
The mortality was observed in an “intention to treat” context. Just because a patient has an A1c less than 6% isn’t necessarily bad, it’s having that be the target that’s apparently bad. For example, a patient with an A1c between 7% and 8% who is being aggressively treated to achieve an A1c less than 6% is also in potential trouble.
The difference in mortality rates could have happened as a result of random variation and may have nothing to do with the A1c target. While possible, it’s unlikely because the researchers probably used the "chance of variation being 5% or less" (otherwise known as p<.05) threshold. In other words, the likelihood of random variation being responsible for this is less than 5% or 1 in 20.
It took four years for the difference in mortality to become apparent. Even if we forgo the intention to treat context, a brief dip of an A1c to less than 6% in an individual patient is not cause for alarm.
Note that the participants in this study are being re-targeted to an A1c between 7% and 8%, not the ADA recommended level of less than 7%. In looking over the protocol (see page 12) the researchers argue the 7%-8% treatment range what was obtained in previous studies on the benefits of diabetes control, particularly with the drug metformin. There are some interesting data out there that says a level between 7% and 8% may be good enough. This is despite what the ADA says and what the NCQA’s HEDIS optimum measure is. Once again, enrollees in disease management program have a basis to assess the ADA/HEDIS recommendations in the context of their own preferences and values. And deciding to let the A1c creep up over 7% may not be an egregious foolhardy sin.
Keep an eye out for the J curve.