In Time With TIMI: 35 Years of Cardiovascular Research
Marc Sabatine
For Marc Sabatine, MD, MPH, of the Division of Cardiovascular Medicine, going through all the clinical trials spearheaded by one of the Brigham’s premier cardiovascular research centers is like “keeping track of all of one’s children.” Since its founding by the U.S. National Heart, Lung, and Blood Institute in 1984, the Thrombolysis in Myocardial Infarction (TIMI) Study Group, which Sabatine now chairs, has conducted over 70 trials across 5,000 different sites around the world.
TIMI’s first initiative established the blood-clot-busting drug called tissue plasminogen activator as the preferred method for treating heart attacks and strokes. Over the decades, the TIMI Study Group, which is supported by federal and industry funding, has proceeded to examine a vast array of diseases, including heart attacks and strokes, as well as cardiovascular risk factors like high cholesterol and diabetes. The types of interventions under investigation have evolved too, from the thrombolytic (clot-dissolving) to the anti-inflammatory (immune response-modulating). Through its research, TIMI has become an authority on cardiovascular disease (CVD) and a leading influence shaping cardiovascular medical care worldwide.
Revolutionizing Practices: Recent TIMI Breakthroughs
Over the last decade, cardiology researchers involved in the TIMI Study Group and beyond have increasingly examined the long-term cardiovascular risks and benefits associated with therapies originally developed to treat diabetes. Prior to 2008, the U.S. Food and Drug Administration’s (FDA) primary evaluation metric for diabetes drugs was a demonstrated reduction of blood sugar level, but now, increased emphasis is placed on uncovering the potential cardiovascular health effects associated with diabetes drugs. Groups like TIMI are well-suited to fill these knowledge gaps.
In one recent study, DECLARE-TIMI 58, investigators demonstrated that dapagliflozin, a blood-sugar-lowering drug that belongs to the SGLT2 inhibitor class, reduces diabetes patients’ risk of hospitalization for heart failure by 27 percent. Further studies of dapagliflozin showed it reduced the risk of cardiovascular death or hospitalization for heart failure in patients with and without diabetes who have heart failure with a reduced ejection fraction. These findings led dapagliflozin to be the first SGLT2 inhibitor to be approved by the FDA for both those indications. The findings provide more treatment options for those with heart failure, while also offering physicians treating patients with diabetes more insight into the effects of the drugs they prescribe.
“DECLARE-TIMI 58 and similar data from other SGLT2 inhibitor trials has led to a sea-change in how guidelines for diabetes drugs are now being written,” Sabatine said. “We’ve been happy to be a part of that radical rethinking of how we treat patients with diabetes.”
Re-examining established treatments is a central tenet of TIMI’s work. Another recent study, the PEGASUS-TIMI 54 trial, focused on improving post-heart attack care by evaluating a traditional treatment practice that prescribes patients aspirin and one year of an additional blood thinner to prevent platelet-clumping. When the researchers conducted a randomized experiment in which one group continued to take the additional antiplatelet drug beyond one-year post-heart attack, they found a significant reduction in these patients’ future risk of cardiovascular events.
“One year seems like a reasonable, round number,” Sabatine said. “But we showed that by adding a second drug beyond the first year, we could significantly reduce the risk of patients dying from cardiovascular causes, or having a heart attack or stroke.”
An Arsenal of Therapies for Bad Cholesterol
Evaluating drugs that target low-density lipoprotein (LDL) cholesterol, which accumulates in blood vessels and increases heart disease and stroke risks, is another major focus of TIMI’s work. LDL cholesterol-lowering therapies have been a subject the group’s research for decades. Founding chairman Eugene Braunwald, MD, the former clinical director and first chief of the National Heart Institute, the forerunner of the NHLBI, leading investigations that demonstrated the efficacy of statins in lowering CVD risks. More recent research has zeroed in on creative ways to lower LDL cholesterol even further by targeting PCSK9, a protein which controls recycling of the LDL receptor, which is responsible for clearing LDL cholesterol from the bloodstream.
The recently completed FOURIER (TIMI 59) trial demonstrated that a powerful PCSK9 inhibitor called evolocumab, which reduces LDL cholesterol levels by up to 60 percent, also reduces the risk of heart attack and stroke in patients with a history of cardiovascular disease who are already on optimized statin therapy. FOURIER additionally showed that these therapies could produce very low levels of LDL cholesterol (down to the single digits in some patients), with continued cardiovascular benefit and no offsetting safety concerns.
Michelle O’Donoghue
Nonetheless, TIMI continues to explore an array of options for reducing cholesterol, hoping to find additional therapies. Some patients prescribed statin therapies, for example, are not always able to take the medication consistently, and some experience negative side effects. TIMI Senior Investigator Michelle O’Donoghue, MD, MPH, of the Division of Cardiovascular Medicine, is currently working on the ORION 4 / HPS4 / TIMI 65 trial in collaboration with Oxford University, examining an alternative PCSK9 inhibitor that is administered once every six months by subcutaneous injection.
This drug, called inclisiran, uses a Nobel Prize-winning technology, RNA interference, to alter the production pathways of the PCSK9 protein.
“That’s a big shift of mentality,” O’Donoghue said. “We’re trying to target production of the PCSK9 protein upstream, rather than just blocking its effects once it has been made.” The study is still underway, but its results could open doors for a new, strategic alternative for reducing LDL cholesterol.
Tailored to the Patient
Newer trials reflect an evolving understanding of how genetic factors shape cardiovascular risks. PCSK9, for example, was identified as a target protein when researchers discovered that different variants of the PCSK9 gene were strongly correlated with individuals’ LDL cholesterol levels and risks of having a coronary event.
“Genetics paved the way for us to find the target, PCSK9, in the first place,” O’Donoghue said. “Once we have initial results from our study of inclisiran in ORION, we’re going to be analyzing participants’ genetic samples on the back-end, to better fine-tune our understanding of the drug.”
Christian Ruff
David Morrow
Incorporating genetic analysis into clinical trials has become a staple of TIMI’s work. TIMI’s Genetics Core Laboratory Program, founded by Sabatine and now led by TIMI Senior Investigator Christian Ruff, MD, MPH, of the Division of Cardiovascular Medicine, was founded with the aim of using genetic data to stratify clinical risks and better assess the impact of novel drugs. Similarly, TIMI’s Biomarker Core Laboratory, founded and led by TIMI Senior Investigator David Morrow, MD, MPH, of the Division of Cardiovascular Medicine, uses blood samples collected in clinical trials to identify proteins that may be indicative of patients’ particular risks or clinical outcomes.
“We have a deep interest in personalized medicine,” Sabatine said. “The core laboratories help us look at our trials and figure out which patients are particularly high-risk and which enjoy a bigger benefit from the therapy we’re studying, enabling us to personalize the treatments for our patients.”
An Intrepid Enterprise
Clinical trials are becoming more “personal,” devoting increased attention to individuals’ genetic compositions. Simultaneously, they are growing, enrolling increasingly large numbers of participants. FOURIER, for example, enrolled over 27,500 individuals.
“We coordinate trials with up to 30,000 patients in 40 or 50 countries around the world, at over 1,000 sites,” Sabatine said. “It’s a much, much larger enterprise now than it was at its founding.”
These large, diverse sample populations allow the researchers to aggregate data on multiple elements shaping cardiovascular risks, from genetic makeup to comorbidities associated with weight and kidney function.
“TIMI was founded on the basis of improving outcomes for patients with heart disease, and over time we have kept true to that fundamental principle,” O’Donoghue said. “But we have also had the opportunity to expand in multiple directions. We need to consider a variety of different factors when selecting the right medication and the right dose for a patient. Our trials have helped generate a growing arsenal of therapies that may not only be more effective for them, but also may be better tolerated as well.”