Infarct size, LV function, clinical endpoints
In patients with initial TIMI 0/1 flow, there was no difference between caldaret treatment and placebo Day 7/discharge and Day 30 infarct size by SPECT (Table 4). SPECT assessment occurred between Days 5 and 9 in the majority (87.8%) of patients, 11 patients having SPECT on Day 10 or later and 17 patients on Day 4 or earlier. There were also no differences in second- ary endpoints of MI size by serum marker AUCs of CK, CK-MB, TnT, and LDH (Table 5); LVEF, LVESV, or LVEDV at either Day 7/discharge or Day 30 (Table 6); 30-day mortality, major adverse cardiovascular events, or new/worsening CHF (Table 7); heart rate, systolic and diastolic pres- sure at Day 7/discharge.
Subgroup analyses
Prospectively planned stepwise regression analyses of the efficacy endpoints identified that infarct location had a highly significant (P <0.0001) effect on the primary efficacy parameter compared with other covariates. Figures 2 and 3, respectively, describe the treatment effects in the subgroup of anterior and non-anterior MI patients with initial TIMI 0/1 flow. The com- posite clinical endpoint (MACE, CHF, and re-admission for CHF) was 22 (42.3%), 14 (27.5%), and 13 (27.1%) patients in the anterior MI-LD, HD, PL groups, respectively, up to Day 30. Higher cardiac marker values in the TIMI 0/1 placebo group were not due to the higher proportion of placebo TIMI 0 patients as analyses for patients with TIMI 0 showed both CK and CK-MB geometric mean values were still lower with drug than with placebo (CK: HD 11.5%; LD 16.2%, and CKMB: HD 10.6%; LD 9.9%).
table 7. Clinically adjudicated endpoints up to Day 30 in patients with pre-PCI TIMI flow grade 0/1
Events LD n = 88 (%) HD n = 70 (%) Placebo n = 89 (%) Endpoint Cardiac mortality 1 (1.1) 1 (1.4) 1 (1.1) Non-cardiac mortality 0 0 0
Resuscitated sudden death 1 (1.1) 1 (1.4) 1 (1.1)
CHF 19 (22) 14 (20.0) 14 (16)
Re-admission for CHF 3 (3.4) 1 (1.4) 2 (2.2)
Re-infarction 4 (4.5) 1 (1.4) 1 (1.1)
Stroke 1 (1.1) 0 0
Composite clinical endpointa 28 (32) 15 (21) 20 (23)
er 9 18 comes in an terior infar ct pa tien ts with pr e-PCI TIMI flo w gr ade 0/1.
19 3. e 3. Study out comes in non-an terior infar ct pa tien ts with pr e-PCI TIMI flo w gr ade 0/1.
er 9
disCussion
The CASTEMI study is the first human experience with caldaret in patients with large STEMI under- going primary PCI. The most important finding of this pilot study was the safety of caldaret in patients selected for large MI by ECG criteria. Unlike reports of calcium channel blockers in this set- ting, this unique intracellular calcium modulator appears to be well tolerated even at HD. In theory, active prevention of intracellular calcium overload using this new molecular entity might promote more favourable cellular response to reperfusion associated with epicardial recanalization.
The limitations of this pilot study with regard to efficacy evaluations are associated with smaller treatment effects that might still be clinically meaningful (which could be missed in this relatively small cohort), the careful interpretation required of surrogate marker data, and a low overall endpoint and mortality rate even with selection of large infarctions into the study. The data showing higher rates of better pre-PCI TIMI flow in the treatment groups may also point to properties of caldaret for which there is no currently understood mechanism.
Within this negative study, the observations from the analyses controlling for infarct loca- tion showed some directional trends, possibly chance findings, in biomarkers measured. Understanding these observations requires study in an independent clinical trial.
Although the benefits of reperfusion may be limited by ‘reperfusion injury’,3,4,8 the mecha-
nism and clinical relevance of such injury remains poorly understood and multiple negative human studies have been reported,9,17,18 including those with agents that modulate calcium
homeostasis.19 However, when administered before the onset of ischaemia, peri-operative
infarct size has been reduced with Na+/H+ exchange inhibitors in CABG.11
Reperfusion injury in clinical practice has long been reported in anecdotes of epicardial reperfusion followed by rapid clinical deterioration. In animal studies, pre-treatment with a number of compounds prior to reperfusion can limit infarct size. In human patients, however, similar drugs have not shown clear benefit,17 including in this pilot report with caldaret treat-
ment prior to PCI. Thus, the ultimate contribution of such medical strategies for ‘facilitated PCI’ in STEMI to reduce infarct size remains controversial.4,17
ConClusion
With direct effect on intracellular calcium modulation, but different from calcium channel blockers, this first human pilot study demonstrates the safety of caldaret in patients with large STEMI treated with bolus and infusion of drug beginning prior to PCI. Efficacy measures were confounded by dependence on surrogates and the modest size of the cohort enrolled, with the study failing to show benefit in primary and secondary endpoints. The numerical trends in
referenCes
1. Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24:28-66.
2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20. 3. Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial
infarction: distant dream or near reality? Heart 2000;83:381-387.
4. Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol 1993;21:537-545.
5. Matsumura K, Jeremy RW, Schaper J, Becker LC. Progression of myocardial necrosis during reperfu- sion of ischaemic myocardium. Circulation 1998;97:795-804.
6. Shigekawa M, Iwamoto T. Cardiac Na(+)-Ca(2+) exchange: molecular and pharmacological aspects. Circ Res 2001;88:864-876.
7. Jennings RB, Steenbergen C Jr, Reimer KA. Myocardial ischemia and reperfusion. Monogr Pathol 1995;37:47-80.
8. Black SC. In vivo models of myocardial ischemia and reperfusion injury: application to drug discov- ery and evaluation. J Pharmacol Toxicol Methods 2000;43:153-167.
9. Mahaffey KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the AMISTAD trial. J Am Coll Cardiol 1999;34:1711-1720.
10. Rupprecht HJ, vom DJ, Terres W, et al. Cardioprotective effects of the Na(+)/H(+) exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA. Circula- tion 2000;101:2902-2908.
11. Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium–hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischaemic situations. Main results of the GUARDIAN trial. Circulation 2000;102:3032-3038.
12. Satoh N, Kitada Y. Cardioprotective effect of MCC-135 is associated with inhibition of Ca2+ overload
in ischaemic/reperfused hearts. Eur J Pharmacol 2004;499:179-187.
13. Satoh N, Sato T, Shimada M, et al. Lusitropic effect of MCC-135 is associated with improvement of sarcoplasmic reticulum function in ventricular muscles of rats with diabetic cardiomyopathy. J Pharmacol Exp Ther 2001;298:1161-1166.
14. Satoh N, Kitada Y. Effects of MCC-135 on Ca2+ uptake by sarcoplasmic reticulum and myofilament
sensitivity to Ca2+ in isolated ventricular muscles of rats with diabetic cardiomyopathy. Mol Cell
Biochem 2003;249:45-51.
15. Kawasumi H, Satoh N, Abe Y, et al. MCC-135, a new agent for the treatment of heart diseases. Jpn J Pharmacol 1998;76(Suppl. I):277P.
16. Yarbrough WM, Mukherjee R, Escobar GP, et al. Modulation of calcium transport improves myo- cardial contractility and enzyme profiles after prolonged ischemia-reperfusion. Ann Thorac Surg 2003;76:2054-2061.
17. Bolli R, Becker L, Gross G, et al. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 2004;95:125-134.
18. Kopecky SL, Aviles RJ, Bell MR, et al. A randomized, double-blinded, placebo-controlled, dose- ranging study measuring the effect of an adenosine agonist on infarct size reduction in patients undergoing primary percutaneous transluminal coronary angioplasty: the ADMIRE study. Am Heart J 2003;146:146-152.
19. Zeymer U, Suryapranata H, Monassier JP, et al. The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the ESCAMI trial. J Am Coll Cardiol 2001;38:1644-1650.