PracticeUpdate: Cardiology | Vol1 - No.2 - 2016

CONFERENCE COVERAGE

ESC 2016

6

Two trials of stem cells fail to meet primary endpoints but improve health status Two trials of regenerative therapy for heart failure failed to meet their primary endpoints but brought clinically relevant benefits.

N-acetylcysteine reduces post-MI infarct size by a third

Trial 1: A phase 2, randomised, single-blind, placebo-controlled, crossover, multicentre study Javed Butler MD, of The State Univer- sity of New York at Stony Brook, reported on the first trial. He and a colleague de- livered a single dose of mesenchymal stem cells intravenously to patients with chronic nonischaemic cardiomyopathy. Significant cardiac structural or functional improvement did not occur but several clinically relevant benefits were observed. Dr Butler said the trial “demonstrated that a more convenient and less invasive infusion strategy is safe, well-tolerated and shows improvements in multiple measurements of patient health status.” Previous work in this field has focused almost exclusively on the more invasive approach of injecting stem cells directly into the heart. Dr Butler and his colleague used “is- chaemia tolerant” mesenchymal stem grown under chronic hypoxic conditions, with the aim of enhancing their potential benefits. He explained, “The premise was that stem cells may exert immune modulatory properties, which are enhanced when grown under hypoxic conditions.” This potential immune modulation and anti- inflammatory effect also opens the door to new methods of delivery. “Virtually all studies of stem cell therapy for heart failure have centred on the con- cept that the cells must be injected di- rectly into the heart to trigger new growth, but if stem cells yield anti-inflammatory benefits, direct cardiac delivery may not be necessary to repair and stimulate the dysfunctional viable myocardium.” Patients with nonischaemic cardiomyo- pathy and left ventricular ejection fraction ≤ 40% were randomised to intravenous ischaemia-tolerant mesenchymal stem cell therapy (n=10) or placebo (n=12) for 90 days and then crossed over to the other treatment. Stem cells were donated

(clinical summary score +5.22, P = 0.02, and functional status scores +5.65, P = 0.06) at 90-days post infusion. Additionally, ischaemia-tolerant mes- enchymal stem cell infusion resulted in significant alterations in several inflamma- tory cells, “supporting the immunomodu- latory and anti-inflammatory mechanisms of ischaemia-tolerant mesenchymal stem cells,” noted Dr Butler. Dr Butler concluded, “To our knowl- edge, this trial represents the first expe- rience with intravenously administered ischaemia-tolerant mesenchymal stem cells in patients with any type of chronic cardiomyopathy. Further studies should explore the efficacy of serial dosing to produce more sustained immunomodula- tory effects and thereby perhaps facilitate improvement in left ventricular structure and function, and in clinical outcomes.” Trial 2: CHART-1, the largest cardiac regenerative therapy trial to date Jozef Bartunek, MD, PhD, of OLV Hos- pital, Aalst, Belgium, presented results of the Congestive Heart failure cardiopoi- etic Regenerative Therapy (CHART-1). This trial used bone-marrow stem cells to promote heart repair. The cells did not significantly improve the primary outcome over a sham procedure among patients with congestive heart failure, but results revealed critical new insights. Dr Bartunek explained that thought results were neutral in the overall patient population, an exploratory analysis iden- tified a subgroup of patients who may benefit from cardiopoietic cell therapy. “Within a well-defined patient population, based on baseline heart failure severity, this therapy showed benefit,” he said. “Lessons learned from CHART-1 will now provide the foundation for the design of the ensu- ing CHART-2 trial, which will target these patients.” Cardiopoietic cell therapy involves the isolation of mesenchymal stem cells from

a patient’s own bone marrow. Exposing these cells to a “cardiogenic cocktail” turns them into cardiopoietic cells, which are then injected into damaged heart tissue. The CHART-1 study randomised pa- tients with symptomatic ischaemic heart failure from 39 hospital centres in Europe and Israel. Patients received either a sham procedure (n=151) or cardiopoietic cells (n=120). At 39 weeks, no significant difference between groups was observed for the primary efficacy endpoint, a composite of all-cause mortality, worsening heart failure events, Minnesota Living withHeart Failure Questionnaire total score, 6-minute walk distance, and left ventricular end-systolic volume and ejection fraction. A subgroup analysis of patients with se- vere heart enlargement at baseline (left ven- tricular end-diastolic volumes between 200 and 370 mL), however, suggested a positive effect of the cell treatment over sham. Dr Bartunek concluded, “Outcomes for all components of the composite endpoint, including mortality and worsening heart failure, were ‘directionally consistent.’” He, added that “the effect was also related to clinically meaningful improved quality of life, greater 6-minute walk distance, and reduced left ventricular end-systolic volume for cell treatment vs sham.” “We observed a modifying effect of treatment intensity, with suggestion of a greater benefit with a lower number of injections. Overall safety was demon- strated across the study cohort, with no difference in adverse clinical outcomes observed between groups.” Ongoing analyses will evaluate 12-month clinical outcomes. Dr Bartunek said, “Insights from the CHART-1 trial carry implications for targeting the patient population that should be considered for cardiopoietic cell therapy in future clini- cal trials or for broader clinical consid- erations. More generally, indexes of heart failure severity and optimised therapeutic intensity should be considered.”

The addition of intravenous N-acetyl- cysteine to intravenous glyceryl trinitrate reduced infarct size by approximately one third in patients undergoing percutaneous coronary intervention after ST-segment el- evation acute myocardial infarction. This outcome of N-AcetylCysteine In Acute Myocardial infarction (NACIAM), a placebo- controlled, double-blind trial, was reported at the 2016 ESC Congress. S ivabaskari Pasupathy, BS, of the University of Ad- elaide, Australia, explained, “Timely and effective myocardial reperfusion by percutaneous coronary intervention is the treatment of choice for limiting my- ocardial infarct size and improving clinical outcomes in patients presenting with ST-segment elevation acute myocardial infarction, additional pharmacological in- terventions may help reduce infarct size further. Any intervention that reduces myocardial infarct size by approximately a third might reasonably be expected to substantially improve long-term outcomes.” NACIAM included 112 patients with ST-segment elevation acute myocardial infarction (mean age 64 years) from three Australian hospitals. All underwent emergency percutaneous coronary intervention and received low dose intravenous glyceryl trinitrate. They were randomised before the percutaneous coronary intervention to receive either high-dose (15 g/24 h) N-acetylcysteine or placebo, both deliv- ered intravenously over 48 h, “the hypothesis being that N-acetylcysteine might reduce infarct size, ei- ther by potentiating the effects of glyceryl trinitrate or via ‘scavenging’ of reactive oxygen species,” said Ms Pasupathy. Cardiac magnetic resonance imaging performed within 1 week (early) and again 3 months post myo- cardial infarction (late) showed that patients who received N-acetylcysteine experienced reductions in infarct size of 33% and 50%, respectively, compared to placebo (P = 0.02 for both). A similar but not signifi- cant trend toward reduction in creatine kinase release was observed. Additionally, myocardial salvage, measured at 1 week, approximately doubled in patients who re-

by a health volunteer and grown under hypoxic conditions from the moment of extraction. At 90-days post infusion, no major differences in primary safety endpoints of all-cause mortality, all-cause hospitalisa- tion, and adverse events were observed. Secondary endpoints of car- diac remodelling (left ventricular ejection fraction and ventricular volumes), assessed by cardiac magnetic resonance imaging, did not differ between groups at 90-days. Ischaemia-tolerant mesenchymal stem cell adminis- tration did result in the second- ary endpoints of better health status and functional capacity, however. Specifically, compared with placebo, ischaemia-tolerant mesenchymal stem cell therapy resulted in statistically signifi- cant improvements in 6-min- ute walk test (an estimated 36 m more than placebo, P = 0.02) and Kansas City Cardio- myopathy Questionnaire scores

ceived N-acetylcysteine (60% vs 27%, P < 0.001). Evidence of ac- celerated tissue reperfusion and hypochlorous acid “scavenging” was also observed. Over 2 years of follow-up, the combination of car- diac readmissions and deaths was less frequent in N-acetylcysteine- treated (three vs 16 patients, P < 0.01). Safety endpoints including hy- potension, bleeding, and contrast- induced nephropathy were similar in both groups. Ms Pasupathy concluded, “In- travenous N-acetylcysteine ad- ministration was associated with more rapid chest pain resolution, improved myocardial salvage, a fa- vourable in-hospital safety profile, sustained infarct size reduction at 3 months post ST-segment eleva- tion acute myocardial infarction, and promising clinical outcomes at 2 years. While the results were encouraging, NACIAM should be regarded as the precursor to a follow-up study sufficiently sized to meet clinical endpoints.”

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