What we can learn from registry data to improve lipid goal attainment

My name is Kausik Ray. I'm Professor of Public Health at Imperial College London, and consultant cardiologist.

Pleasure to talk to you today and give you some highlights from some of the registry data that was presented at the European Society of Cardiology that really informs what we need to do in terms of changing implementation and clinical medicine.

These are a list of my disclosures.

I want to remind you that lipid-lowering following myocardial infarction is essential. About 70% of people that come in with an MI are statin-naïve or lipid-lowering treatment-naïve. We know that actually, nature doesn't care how you lower LDL cholesterol. Data from the PROVE IT trial and the IMPROVE-IT trial have both shown that when you start high-intensity statin in hospital prior to discharge over the next two and a half, or in the case of IMPROVE-IT, six years, you reduce cardiovascular events. In particular, that lower LDL cholesterol that we often think about at 1.4, that's really not going to be achieved with any single monotherapy, and so IMPROVE IT really started to show us the way that we needed to think about using combination therapies in the way that blood pressure colleagues have done for many, many years.

After that, we now have the injectable therapies that came in. Largely, these were trials that didn't start injectable therapies in hospital, but they looked at people who failed to achieve cholesterol goals i.e. above 70 milligrams per deciliter at 1.8 millimoles per liter, and then adding in an injectable and with two different therapies, slightly different. One was about two and a half months after an acute coronary syndrome. This is ODYSSEY outcomes. FOURIER had one MI in the prior year. Both of these approaches showed that over and above statin therapy, adding an injectable therapy and bringing LDL cholesterol levels down well below 55 mgs per deciliter into that 35 milligrams per deciliter range reduce cardiovascular events.

When you look at the way we try and implement this, it makes absolutely no sense because what we do is we are reactive. We start with drug A, we measure cholesterol levels, ideally four to six weeks. That's impossible in routine clinical practice. Then we see the patient, and then we make another decision to add in a second drug. Then we wait to see the effect of that, and we recheck cholesterol, and then we do something else. That's ineffective, it's inefficient.

We know that combinations of different treatments will give us more effective reductions in LDL cholesterol. It's in that regard that our data from the SWEDEHEART registry that was presented at the ESC looking at attainment of non-HDL cholesterol goals. That's 2.2 millimoles per liter which is equivalent to an LDL of 1.4. Looking at the timing of that achievement and subsequent outcomes, that is so critical to the way that we practice medicine. What we basically did in that particular analysis was we know what the goals are for non-HDL, but does it matter if I achieve that early, within two months, or if I get there really slowly at one year? SWEDEHEART is a national registry. It's an unbiased selected cohort of all myocardial infarction patients within Sweden, entering the cardiac rehabilitation program linked to an outcome register. Cholesterol levels are measured approximately at the time of cardiac rehabilitation, at two months, and then again at around about one year usually when the care transitions to primary care and GPs.

A large study, 56,000 patients, median age about 64 years, median follow-up 5.4 years. If we look at non-HDL at one year in subsequent outcomes, and you look at spline plots, essentially there's a linear relationship until you get down to a non-HDL actually below 2.2. It's more like 1.9 to 2 millimoles per liter. If we're thinking about a target for all, then that is that lowest level and that is best.

If we think about how we get there, you take patients that never get to that goal, they do worse. That's the reference group. You do slightly better if you achieve that non-HDL goal within two months. If you don't maintain it at one year, you're still slightly better off than never getting there. Then there are those people who don't get to that goal within two months but get there at one year. They do similar to that previous group. The best of all is when you actually get to that goal within two months and you maintain it thereafter.

It's about early reduction, early goal attainment, and sustained goal attainment. That's what's important. How do we do that? What this slide shows you is the percentage reduction in non-HDL, with the different regimens and its relationship to outcomes. Do those people that get more than 46% reduction in non-HDL have the lowest risk of all events? How do I get there? Obviously, using higher intensity statins, but you do even better when you start to add in a second drug like ezetimibe, more people will get to that more than 46% reduction in non-HDL.

The final bit is you might say, but maybe we talk about these Kaplan-Meier curves separating over time, and essentially, we want to know if there's any benefit in that first year between two months and the end of that first year of follow-up. What we did was what's called a landmark analysis. We looked at the contribution for that early reduction in non-HDL, people getting to goal, or either the biggest reduction or the lowest on treatment LDL or non-HDL. Basically, those people that got to the lowest levels or the biggest reductions already within the first year had huge benefit. What you can see is, for example, you got a 28% relative risk reduction if you achieve an absolute reduction in non-HDL of 2.2 millimoles between your admission MI number and within two months of an MI. If you maintain that beyond one year, that benefit accumulates. It's cumulative. That benefit is now 37%.

What's important is it's not just about goals, it's changing people's risk profiles. The person that I bring from further away, down to a lower number, is going to get a much bigger absolute risk reduction, or certainly relative risk reduction, but also have a lower absolute event rate. That's very different from just somebody who's very close to goal and getting to that number.

The key take-home is achieve that non-HDL early with combination therapy and keep it there, and you get the best outcomes.

A second registry that was presented was from northwest London, my part of London, and this was looking at chronic coronary syndromes or acute coronary syndromes, patients undergoing PCI. Very simple large data set over something like 50,000 individuals and what was basically studied was what the practices were in terms of prescribing, measurement of lipids, and was it associated with outcome. There's no real surprises, but the size of this study and the duration of follow-up, and the number of deaths, for example, gives us a clear answer.

The first thing is if I measure lipids more than once, I'm more likely to do something. That's exactly what was seen. If you look at all-cause mortality or MACE, if you measured cholesterol twice, you did better than if you measured it once, you did better than if you never measured it at all. You need to measure, then you can maybe do something about it. It's important to check.

The next thing was unsurprisingly, if you prescribed statins in those people with chronic coronary syndromes or acute coronary syndromes, you had better outcomes, whether it was mortality or major cardiovascular events. If you looked at when you prescribed that, we knew this, that primary care is often very slow at implementation. If you start medications in hospital, it's more likely to be continued. It's more likely to be continued, you get better outcomes, and that's what was seen.

Care pathways should start thinking about combination therapies early and upfront so that we can actually continue that and we don't get delays in implementation of treatment.

The take-homes for all of these are that simplify your care pathways, use combination therapies, start early. If you're using a stepwise approach, at least have the decency to measure LDL cholesterol because without that you have no idea what needs to be done, and that really is how we need to think about implementation. Simple, efficient, using combination therapies because these are our highest-risk patients.

Thank you for listening.