Understanding the Safety Data in CANVAS

John Anderson, MD: The amputation risk that was shown in the CANVAS trial is not to be ignored, but it is also to be put in perspective. If I treat 1000 patients with cardiovascular disease and diabetes over a year’s period of time, the amputation risk goes from 3 patients to 6. Now, that’s not to ignore. It’s a doubling, but it’s a doubling of a very small number. In addition, since we know that a lot of those patients already had cardiovascular disease, we can do a lot of risk mitigation. Check everybody’s feet. Ask about neuropathy. If you’ve got a patient who has had an amputation and you want to put them on canagliflozin, be careful of volume status. Make sure they stay hydrated. Make sure that you’re not adversely lowering their blood pressure. You may want to pay attention to that ACE inhibitor or that other diuretic they’re on or another blood pressure medicine. It may need to be backed down. We don’t want their pulse pressure in their feet to go down. You might also go more gingerly with those patients, starting at a lower dose of canagliflozin and going up slowly over a period of time. Again, there’s a way to risk mitigate this small number of patients.

The patients most inherently at risk for amputations are exactly who you would imagine. These are patients with poorly controlled diabetes, hypertension, and smoking is huge. I can’t overemphasize how much smoking contributes to peripheral vascular disease. And so, you can look at these patients and ask questions about those who have neuropathy. For people who have insensate feet, if they don’t feel their feet very well, you’ve got to talk to them about good foot care. You’ve got to talk to them about not going barefoot, about checking their feet at night, and about maybe even having a good podiatrist and custom-molded shoes. You’ve got to actually take their shoes off when they come in the office and check the pulses in their feet, and you’ve got to ask about it at every single visit. And then, if you determine that this person is right for whatever medicine, you follow them carefully. You go a little more slowly.

One of the things that you have to do with any drug you’re going to give is weigh benefit versus risk. So, with the patients in the CANVAS trial, we’re talking about an increase of 3 to 6 per 1000 patients having an increased risk of amputation, yet you’re talking about 35% less people coming to the hospital for heart failure. You’re talking over 40% less progression in their renal disease. You’re talking about a 13% or 12% reduction in their primary major adverse events. And not only that. If you actually look at the data for the people who got the amputations, their 3-point MACE risk reduction was more like 40%, not 12%. So, these patients, the sickest of the sick, seem to be getting the best benefit. That’s how I think about these patients. I simply think they deserve the same cardiovascular benefit, and I’m not arguing empagliflozin versus canagliflozin. What I’m arguing is that the canagliflozin patients did get significant benefits. So, be careful, weigh it against the risks, and do all of those risk-mitigation strategies that I mentioned.

I would advise anybody who’s looking at these large cardiovascular outcomes trials to not do the stock knee-jerk reaction, which is, “Let’s look at who got the most in which trial,” because you cannot do that scientifically. These were different patient populations. Some did not have as much risk as the others. There are different trial designs. There are a lot of things. So, take each individual study, look at it scientifically, and come to the conclusions. Don’t just tend to take them and say, “This had this percent, and this had this percent,” because you’re really not doing justice to the clinical trial design.