AHA meeting highlights stem cell infusions, individualized therapy, and CAD pharmacotherapies

AHA meeting highlights stem cell infusions, individualized therapy, and CAD pharmacotherapies

ABSTRACTS OFFERED at this year’s American Heart Association 2007 Scientific Sessions included several prominent themes: The search for means to more accurately individualize therapy; the challenge of providing optimal pharmacotherapies for coronary artery disease prevention and treatment; and most far-reaching, the promise of effective stem cell therapy to reverse the myocardial damage caused by infarction. We review below a selection touching on these recurring themes. The meeting welcomed a total of more than 26 thousand attendees, among them nearly 19 thousand medical professionals (9 thousand of these international).

3D guidance of autologous stem cells

Delivery with three-dimensional guidance of autologous stem cells into scarred myocardium through a catheter is feasible, safe and demonstrates improved viability, quality of life, NYHA class and heart function, according to Dr Nabil Dib, University of California, San Diego. Dib presented final 1-year results of the CAuSMIC Trial (Catheter-Based Delivery of Autologous Skeletal Myoblasts [ASM] for Ischemic Cardiomyopathy), the first US randomized, controlled trial of this therapy. He noted that prior Phase I trials have shown epicardial injection of myoblasts to provide significant improvement to heart function with long-term safety. Percutaneous delivery, however, potentially would offer the advantage over surgical delivery of being less invasive, of being available to high-risk patients and of being capable of being repeated, if necessary. In CAuSMIC, investigators harvested muscle cells, isolated and expanded them, and then injected them into the scarred myocardium using the 3-D NOGA guidance and injection system with a delivery needle capable of being adjusted between 2-10 mm for penetration of scar tissue. Patients were randomized to optimal medical therapy or one of 4 doses of cells (30 x 106, 100 x 106, 300 x 106, or 600 x 106 in 3-24 injections of 0.25 ml over 20 seconds). The primary objective was to evaluate safety and feasibility of this procedure. Efficacy was a secondary measure. The study population consisted of 23 patients with ischaemic cardiomyopathy and ejection fractions (EF) of 40% or lower. In addition, all had prior documented myocardial infarction (MI) with congestive heart failure (CHF) NYHA class 2-4 and were receiving optimal medical therapy. Investigators excluded individuals with left ventricular wall thickness < 5 mm. All procedures were performed successfully and safely. Two ventricular tachycardia events requiring cardioversion occurred during mapping before the ASM injections. There were no deaths, MIs or cerebrovascular events. One CHF hospitalization was reported in each of the groups. Quality of life (Minnesota Living With Heart Failure Score) improved significantly in the ASM group (6 months, p=0.02, 12 months, p=0.002), as did NYHA classification (6 months, p<0.0001; 12 months, p<0.0001). In the ASM group, NYHA classification was 2.7 at baseline, 1.5 at 6 months and 1.7 at 12 months. In the control group, NYHA was 2.4 at baseline, 2.7 at 6 months and 2.8 at 12 months. Dib concluded that three-dimensional guided catheterbased delivery of ASM is feasible and safe. Viability, quality of life, NYHA class, and heart function are improved. A larger 165 patient Phase II trial has been cleared by the FDA.

Late-breaking clinical trial

AHA discussant Dr Gordon Tomaselli, Baltimore, MD, who reviewed a series of three stem cell Late-Breaking Clinical Trial presentations, urged caution regarding interpretation of results. “Improvements in these studies may be occurring spontaneously, through effects of medical therapy or through effects of revascularisation. Without consideration of these phenomena, we have to be very careful about attribution of efficacy to the therapies.” Against aspirin and clopidogrel, the standard of care for patients undergoing percutaneous coronary interventions (PCIs), the TRITON TIMI 38 trial pitted aspirin and prasugrel, a novel thienopyridine. The hypothesis of this Late-Breaking Clinical Trial was that prasugrel’s quick production of higher levels of inhibition of platelet aggregation (IPA) would reduce clinical ischaemic events in acute coronary syndrome (ACS) patients. The TRITON population, said Dr Elliott Antman, Brigham and Women’s Hospital, Boston, MA, consisted of 13,608 individuals, among whom 26% were undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI). The remainder, all of whom had already undergone angiography, had moderate-high-risk unstable angina or non-STEMI or STEMI within the last 14 days (with ischaemia or undergoing medical therapy). Patients were randomized double-blind to aspirin and loading/ maintenance doses of clopidogrel 300mg/75mg or prasugrel 60 mg/10 mg. The primary endpoint was combined cardiovascular (CV) death, MI, stroke, with TIMI major bleeds and life-threatening bleeds as safety endpoints. Median therapy duration was 12 months. Antman stated that the primary endpoint occurred significantly more often in the clopidogrel group (12.1% versus 9.3% for prasugrel, hazard ratio [HR] 0.81, P=0.004). The benefit was significant in both the loading dose and maintenance dose periods. Stent thrombosis was significantly higher in the clopidogrel group (2.4% versus 1.1%, HR 0.48, P<0.0001). Bleeding (TIMI major plus non- CABG bleeds), however, was more common with prasugrel (1.8% versus 2.4%, HR 1.32, P=0.03). Life threatening bleeds were also higher (0.9% versus 1.4%, HR 1.52, P=0.01). Bleeding risk was highest among those with prior stroke/TIA, age >75 years and weight <60 kg. AHA discussant Dr Eric Topol, Scripps Health, La Jolla, CA, praised the TRITON prasugrel findings, stating that they signify an expansion of the antiplatelet armamentarium. He also expressed concern over the 4.73 hazard ratio for bleeding among patients undergoing bypass graft surgery. With clopidogrel, he said, “…there is already tremendous concern.” Topol also called the trial structure, with its atypical inclusion of patients with angiograms already conducted, “artificial.” Potential for bleeding with prasugrel was also on the minds of the moderators of a subsequent session on acute MI and PCI, when asked if they would favor prasugrel approval based on current data. Dr William B Hillegass, University of Alabama, Birmingham, AL, said that while he favored approval, he felt also that until further study shows lower prasugrel doses to be safer, “…a very good effort has to be made to educate clinicians to avoid prasugrel in prior stroke or low-weight patients.” Dr Christoph Bode, University of Freiburg, Germany, said, “I wouldn’t approve it for all patients, only those who are problematic, for example those who have had prior stent thrombosis.” The session included results of an early phase trial of a novel thrombin receptor antagonist (TRA), SCH30348, among patients undergoing non-urgent PCIs. Most striking among the findings, presented by Dr Lisa K Jennings, University of Tennessee Health Science Center, Memphis, TN, was a reduction in ischaemic events without increased bleeding. The potential advantage may be explained, Jennings said, by the TRA-PCI sub-study of four inducers of IPA (thrombin receptor agonist peptide [TRAP], adenosine diphosphate [ADP], collagen and arachidonic acid), showing that TRA affected only TRAP-induced platelet aggregation. Moderator Hillegass commented, “It’s an early-stage, underpowered trial, but it’s very encouraging to think that it [SCH530348] might reduce ischaemic events without this inexorable trade-off between bleeding events and ischaemic events.” A further “Late-Breaker” examining the pharmacology of the PCI environment was EVA-AMI. It compared the GP2b/3a inhibitors abciximab and eptifibatide, both of which, stated investigator Dr Uwe Zeymer, Herzzentrum Ludwigshafen, Germany, have been shown to reduce events in elective PCI patients. Both acquisition and hospitalization costs have been shown to be significantly lower with eptifibatide than with abciximab (Coons JC, Annals of Pharmacotherapy, 2005, Vol 39, No. 10, pp. 1621-1626), but the agents have not been directly compared.

EVA-AMI

The EVA-AMI objective was to show non-inferiority for eptifibatide in patients scheduled for primary PCI receiving abciximab bolus + 12- hour infusion or eptifibatide double-bolus + 24 hour infusion. The primary endpoint was complete ST resolution at 1-hour post-PCI, a marker of myocardial reperfusion that is closely linked to mortality after STEMI. Complete reperfusion was similar between groups (59.6% abciximab, 63.1% eptifibatide, NS), as were in-hospital events (death, reinfarction, heart failure, TVR and CABG) among EVA-AMI’s 429 patients (mean age 61 years). Zeymer concluded, “Eptifibatide given as a double-bolus is equally effective as abciximab as adjunct to primary PCI with respect to myocardial reperfusion.” Also, Zeymer said preliminary analysis showed no differences in clinical events. A further study including eptifibatide, CLEAR-PLATELETS 2, suggested that individual platelet reactivity testing may guide future pharmacotherapy choices. Lead author Dr Paul Gurbel, Sinai Hospital, Baltimore, MD, noted that high periprocedural platelet reactivity and high platelet-fibrin cloth strength may increase risk for periprocedural myocardial infarction (MI). In CLEAR-PLATELETS 2 investigators enrolled 200 individuals undergoing elective coronary stenting, randomizing them to a clopidogrel (loading dose of 600 mg for clopidogrelnaïve patients and 75 mg/d maintenance for those chronically dosed) with bivalirudin (standard dose) plus or minus the GP IIb/IIIa inhibitor eptifibatide (Integrilin, standard dose). All patients received aspirin (325 mg/d). Investigators evaluated the relationship between platelet aggregation and markers of myocardial necrosis (CKMB, troponin) by inducing aggregation with ADP, collagen and TRAP. Gurbel reported that in the absence of eptifibatide it took the clopidogrel loading dose about 6 hours to achieve the level of reduced platelet aggregation found in patients on the clopidogrel maintenance dose, and secondly that inhibition of platelet aggregation with eptifibatide was immediate and significantly greater than in the bivalirudin alone groups, without response variability. Furthermore, cardiac marker release was significantly higher in the groups not receiving eptifibatide. Major bleeding was higher in the eptifibatide groups in the first 30 days (3% for clopidogrel + bivalirudin + eptifibatide versus 0% for clopidogrel + bivalirudin), but not from 31-180 days (1% versus 0%, respectively), however. Although the trial was not powered for clinical events, Gurbel found lower rates of periprocedural MI in the eptifibatide groups (10% for clopidogrel + bivalirudin versus 2% with eptifibatide added), supporting that post-stent infarction is linked to platelet reactivity. In an interview, Gurbel said that if a patient receiving clopidogrel has platelets that are highly aggregable with ADP stimulation, addition of a gp2b/3a inhibitor may be appropriate. “That suggests that selection of patients for adjunctive GPIIb/IIIa blockade may be facilitated in future studies by individualized platelet function measurements.” The number of patients with multiple lipid disorders, obesity, diabetes and metabolic syndrome is rapidly increasing. At the same time, however, stated Dr Christie Ballantyne, Baylor College of Medicine, Houston, TX, “…experience is showing that aggressive treatment with high-dose statins doesn’t adequately lower cardiovascular risk.” Niacin, Ballantyne stated, reduces apolipoprotein-B-containing particles (non-HLD-C) and is the most potent agent available for improving HDL-C. Ballantyne presented results from SEASCOAST (Safety and Efficacy of A Combination of NiAcin ER and Simvastatin in PaTients With Dyslipidemia) I and II, clinical trialS conducted among patients who had failed to attain lipid target levels following statin monotherapy.

SEACOAST

SEACOAST compared low- and high-dose combinations of niacin (Niaspan extended-release, Abbott)/simvastatin (1000/20 mg or 2000/20 mg in SEACOAST I; 1000/40 mg or 2000/40 mg in SEACOAST II) against simvastatin monotherapy (20 mg in I; 80 mg in II). Patients in SEACOAST I all had reached NCEP III CHD risk-adjusted targets and those in SEACOAST II were higher-risk and could be at any LDL-C level. Target levels, Ballantyne noted, were HDL-C ≥40 mg/dL, triglycerides <150 mg/dL and NCEP cardiovascular risk factor adjusted goals for non-HDL-C and LDL-C. The primary endpoint of the double-blind, randomized trials was non-HDL-C. Presenting results of the SEACOAST analyses, co-investigator Dr Richard Karas, Tufts New England Medical Center, Boston, MA, said that after 24 weeks in SEACOAST I the simvastatin/niacin combination among 314 patients significantly improved non-HDL-C by ~25%, LDL-C by about 15% and triglycerides by ~ 35%, with HDL increasing by ~25%. Most flushing episodes were mild or moderate in intensity and overall discontinuations due to flushing were modest at 7.5% for the two combination arms. Also, he said, in SEACOAST II (N= 343 patients), among those receiving the higher dose combination, more attained lipid target levels (48.8% reaching LDL, non-HDL and triglyceride goals as compared with 18.7% for simvastatin 80 mg, P<0.001). Sixty-one percent achieved the non-HDL-C goal (versus 57.5% for simvastatin 80 mg, NS). In that higher-dose group, 5.0% discontinued due to flushing. “Flushing is not a side-effect of niacin. It is an effect,” Karas commented. He and Ballantyne both emphasized, however, the value of educating patients to take aspirin a half-hour before their dose (preferably at bedtime). Ballantyne summarized, stating that more than half of patients who had failed to attain lipid target levels following statin monotherapy achieved these target levels with a niacin/simvastatin combination. In addition, the combination improved multiple clinically relevant lipid parameters among the high cardiovascular risk SEACOAST population. “With good education and motivated patients, you can use this drug well and get better management of lipid disorders. Without spending the time on instruction, you may not see these numbers in practice. In our clinic, we take the extra time,” he said.

PG-guided therapy