Hello, my name is Christian Ruff, and I’m the Director of General Cardiology at Brigham and Women’s Hospital and a clinical trialist at the TIMI Study Group. Today, on Clot Chronicles, we’re going to discuss the biggest practice-changing trials presented at the 2019 European Society of Cardiology. 

It was really an incredible congress, and there were four, I think, key studies that changed the way we think about treating patients with cardiovascular disease; two were with respect to heart failure. One was the PARADIGM-HF study, which was a follow-up of the sacubtril/valsartan, or ARNI therapy, for patients with heart failure. 

Previously, there’d been a blockbuster trial that showed in patients with heart failure and reduced ejection fraction—those with an ejection fraction (EF) of 40% or lower—that the addition of sacubitril/valsartan significantly improved outcomes in patients with heart failure reducing cardiovascular death and heart failure hospitalization. 

The PARAGON trial was, essentially, a similar design, except looking at the other end of the spectrum: patients with heart failure with preserved ejection fraction (in this trial defined as an EF of 45% or greater). Overall, there was a nonsignificant 13% reduction in total heart failure hospitalizations and cardiovascular death—so technically, a neutral study. 

There were some very interesting subgroup findings that suggested there may have been more benefit in women compared to men and also in patients who had mild reductions in systolic dysfunction—between 45% and the median of the trial, which was 57%. I think this trial underscores two important principles. One, that HFpEF is just a very different patient population than HFrEF; and two, that within heart failure with preserved ejection fraction, it’s a very heterogenous patient population, and we need to do better to figure out the differences between these patients as they respond differently to our guideline-recommended therapy. 

The second major blockbuster finding—probably the largest finding—was the DAPA heart failure study. That trial studied the SGLT2 inhibitor, dapagliflozin, in patients with heart failure with reduced ejection fraction. Now, we know that these class of drugs are glucose-lowering drugs that were initially studied in diabetics. And they were shown, in patients with diabetes, to prevent heart failure hospitalization and cardiovascular death in patients with a history—or no history—of heart failure. 

This was a dedicated study in patients with heart failure with reduced ejection fraction and showed an overwhelming benefit for reducing heart failure hospitalization and cardiovascular death regardless of whether the patients even had diabetes at baseline. So, this is really a game-changing study, and I think that this therapy, which was initially developed as a diabetes medication, will be used for the treatment of patients with heart failure with reduced ejection fraction. 

The next blockbuster finding was actually a genetics study, a mendelian randomization, that helps inform us about what lifetime treatment of blood pressure and cholesterol might do for individuals in a population. This was a study that looked at genetic variants that predisposed individuals from the UK Biobank to lower LDL cholesterol, lower systolic blood pressure, or both. And it found that variants in a genetic score associated with lower blood pressure and lower cholesterol resulted in a substantially lower lifetime risk of developing cardiovascular disease. 

This is an incredibly important study because it informs us that even modest reductions in blood pressure and cholesterol can have substantial reductions in lifetime cardiovascular morbidity and mortality. What we really need to do to transform this into practice is to confirm that pharmacologic treatment of blood pressure and cholesterol will lead—over a long period of time, decades—to these same robust findings and essentially prevent the progression of coronary disease. So, really practice-changing implications.

And along the lines of cholesterol, there was actually very exciting breaking science regarding a novel way of lowering LDL. We know that statins lower bad cholesterol, as well as the PCSK9 antibodies. There was a presentation of the ORION-11 trial data, which was a novel PCSK9 inhibitor, actually a small, interfering RNA that is only given twice a year. And the results suggested that giving the small interfering RNA can actually lower LDL persistently by about 50%. So, really an incredible technological advance, one that’s very exciting for patients when we think about compliance (only giving a drug twice a year). And there is a large outcomes study that, obviously, will need to be confirmed, that lowering LDL by this mechanism leads to the expected reduction in cardiovascular events. 

So, it was an incredibly exciting ESC, and I think several studies came out that change how we treat and protect patients from cardiovascular disease.

Thank you. For Clot Chronicles, this is Dr. Christian Ruff.