Chicago, IL—Kicking off the new Legends of Cardiovascular Medicine series during the 2012 American College of Cardiology meeting, Eugene Braunwald, MD, FRCP, Distinguished Hersey Professor of Medicine at Harvard Medical School, and Chairman of the Thrombolysis In Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital in Boston, discussed the advances made in treating acute myocardial infarction (AMI) over the past century, and presented an intriguing view of research areas anticipated to bring even greater success. Dr Braunwald is associated with many of the groundbreaking advances in cardiovascular (CV) medicine.
Illustrating the magnitude of the problem of AMI, Dr Braunwald said that every 34 seconds an American suffers an infarction. He pointed out that during his 25-minute lecture, 44 Americans will have had an AMI, and 6 of them would have died. “We cannot rest on our laurels,” he warned.
Ongoing research is focused on postinfarction treatment, building on knowledge gained from research, including the benefits of myocardial reperfusion. Three promising areas are:
- Prevention of lethal myocardial reperfusion injury
- Inhibition of thrombin generation
- Cell therapy.
Prevention of Lethal Myocardial Reperfusion Injury Post-AMI
Remote ischemic preconditioning, performed with cyclic ischemia and reperfusion in tissue remote from the coronary occlusion, reduces infarct size. More myocardium was saved at 30 days when remote ischemic preconditioning was performed in the ambulance in patients who subsequently underwent percutaneous coronary intervention (PCI) compared with those who did not have preconditioning, as proved in a recent study.
A pharmacologic approach to ischemic preconditioning also limited lethal myocardial injury. An injection of cyclosporine A immediately before PCI significantly reduced infarct size. Pilot studies of these 2 approaches are under way and are expected to move into phase 3 trials, said Dr Braunwald.
Inhibition of Thrombin Generation Post-AMI
Recurrent occlusion post-AMI remains a problem, despite treatment with coronary stents and dual antiplatelet therapy (DAPT), and can be fatal. The inhibition of excess thrombin generation, which occurs for months post-AMI, by blocking factor Xa appears to be a promising approach. Vitamin K antagonists cannot be used safely, because excessive bleeding can occur in patients receiving DAPT.
Rivaroxaban (Xarelto), one of the new factor Xa anticoagulants that blocks thrombin formation, was associated with significant reductions in CV death and all-cause mortality in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin with/without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome 2 (ATLAS ACS2)-TIMI 51 trial. Dr Braunwald, a lead investigator of this study, said that this reduction was achieved with the lowest dose of rivaroxaban studied—2.5 mg twice daily—given for 2 years in addition to guidelines-based treatment, including DAPT. Despite an increase in bleeding, no increase in fatal bleeding or intracranial hemorrhage occurred.
Cell Therapy Post-AMI
Reduced infarct size and improved left-ventricular ejection fraction (LVEF) were achieved in the REPAIR (Renal Protection Against Ischaemia Reperfusion in Transplantation) trial, one of the most promising first-generation trials of bone marrow–derived (BMD) progenitor cells. The cells were injected directly into the infarct-related artery, and patients were followed for 2 years. Event-free survival was also superior in the treated patients compared with patients in the control group.
Following on these findings, the recently announced BAMI (Effect of Intracoronary Reinfusion of Bone Marrow–Derived Mononuclear Cells on All-Cause Mortality in Acute Myocardial Infarction) trial will study the effect of intracoronary infusion of BMD mononuclear cells compared with standard care in approximately 3000 patients with a low LVEF (<45%). The cells will be injected within 3 to 6 days after successful reperfusion, and the goal is to reduce 3-year mortality by 25%. This multinational trial will begin enrollment in the second quarter of 2012.
Two proof-of-principle trials, SCIPIO (Stem Cell Infusion in Patients with Ischemic Cardiomyopathy) and CADUCEUS (Cardiosphere-Derived Auto logous Stem Cells to Reverse Ventricular Dysfunction), suggest that cardiac-derived stem cells from a patient can lead to scar resorption and tissue regeneration, and can improve myocardial function.
The discovery that stem cells reside in the heart by Piero Anversa, MD, Professor of Medicine and Anesthesia, and Director of the Center of Regenerative Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, provided the foundation for the approach studied in SCIPIO, which was led by Roberto Bolli, MD, FAHA, Professor of Medicine, Physiology and Biophysics, and Executive Vice Chair, Department of Medicine, University of Louisville, KY.
Coronary arterial infusion of autologous BMD progenitor cells reduced the size of the infarct from baseline at 4 months and 12 months and improved ejection fraction by approximately 30%, as shown by cardiac magnetic resonance. Dr Braunwald noted that these results are not yet published and are provided courtesy of Dr Bolli. The cells were obtained during bypass surgery from the right atrial appendage by Dr Bolli’s group, and the cells were isolated and expanded by Dr Anversa’s group.
The recently published results of the CADUCEUS trial demonstrated a reduction in infarct size, an increase in viable myocardium, and greater thickening of infarct segments—all reflecting better systolic performance, Dr Braunwald stated. The investigators performed subendocardial biopsies in post-AMI patients with left-ventricular dysfunction to obtain the cardiac stem cells that grew into clusters called “cardiospheres.” The cardiospheres were injected into reperfused infarct-related arteries.
“Reperfusion therapy of an infarction is a major success story,” said Dr Braunwald, “with early mortality falling by 75% over a 25-year period in clinical trials.” This therapy stands on the work of Dr Braunwald and others to understand myocardial reperfusion and led to the “open-artery hypothesis,” with the 90-minute window established to improve outcomes.
The approaches used, with newer ones replacing earlier approaches, include intracoronary thrombolysis, intravenous thrombolysis, intravenous strep tokinase, aspirin, tissue plasminogen activator, primary PCI, stenting, and thrombectomy. “I am honored that these and other therapeutic and preventive options will bring this important condition under more control early in the second century,” said Dr Braunwald.