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European Heart Journal Advance Access originally published online on October 9, 2006
European Heart Journal 2006 27(21):2516-2523; doi:10.1093/eurheartj/ehl304
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Results of the first clinical study of adjunctive CAldaret (MCC-135) in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction: the randomized multicentre CASTEMI study

Frits W. Bär1,*, Dan Tzivoni2, Maurits T. Dirksen3, Antonio Fernández-Ortiz4, Guy R. Heyndrickx5, Johannes Brachmann6, Johan H.C. Reiber7, Neelima Avasthy8, Jun Tatsuno9, Martin Davies8, Mark G. Hibberd10, Mitchell W. Krucoff11 on behalf of the CASTEMI Study Group

1 Department of Cardiology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands
2 Shaare Zedek Medical Centre, Jerusalem, Israel
3 Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
4 Hospital Clinico San Carlos, Madrid, Spain
5 Onze Lieve Vrouwziekenhuis, Aalst, Belgium
6 Medizinischen Klinik, Coburg, Germany
7 Heart Core, Leiden, The Netherlands
8 Mitsubishi Pharma Europe Ltd, London, UK
9 Mitsubishi Pharma Corporation, Tokyo, Japan
10 CardioCorp, Lexington, MA, USA
11 Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA

Received 23 December 2005; revised 31 August 2006; accepted 21 September 2006; online publish-ahead-of-print 9 October 2006.

* Corresponding author. Tel: +31 43 3875098; fax: +31 43 3875104. E-mail address: f.baer{at}cardio.azm.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Aims To examine the safety and efficacy of intravenous caldaret in patients with large acute ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).

Methods and results STEMI patients (n=387) with ≥10 mm summed ST-deviation on electrocardiogram were randomized to receive a 48 h infusion of caldaret 57.5 mg [lower dose (LD)], caldaret 172.5 mg [higher dose (HD)], or placebo, starting before PCI. Both HD and LD were well tolerated. In 247 patients with pre-PCI TIMI 0/1, there was no effect of HD or LD on single photon emission computed tomography infarct size or ejection fraction assessed at Day 7 and Day 30. Subgroup analyses suggest that future work in patients with anterior MI might be warranted.

Conclusion This first human experience with caldaret prior to direct PCI for large STEMI shows a good safety profile. No evidence of efficacy was discerned. Subgroup analyses in anterior MI patients showed some effects in endpoints studied, however, these findings require confirmation in a further study if a drug effect is to be established.

Key Words: Reperfusion damage • Acute myocardial infarction • Primary PCI


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Percutaneous coronary intervention (PCI) for patients with acute ST-elevation myocardial infarction (STEMI) achieves high epicardial recanalization rates and low mortality.1,2

Even when epicardial reperfusion is successful, microvascular ‘reperfusion injury’ may account for up to 50% of the final infarct size and mechanisms of reperfusion injury may include intracellular calcium overload.3–5 Acidotic conditions associated with ischaemia and reperfusion activate the Na+/H+ exchanger, and Na+ extrusion is prevented by inhibition of Na+/K+ ATP-ase, leading to elevated intracellular sodium levels, which in turn increase intracellular calcium levels via Na+/Ca2+ exchange.3,6 Calcium overload contributes to cell death, myocardial hypercontracture, and arrhythmias.7 Damage by reperfusion injury may also be mediated by other cell-mediated processes.3,4,8

Therapies targeting reperfusion injury might reduce infarct size and improve outcomes.4,9–11 In animal models, caldaret (5-methyl-2-[piperazine-1-yl] benzenesulfonic acid monohydrate; MCC-135) inhibits intracellular calcium overload induced by ischaemia and reperfusion,12 enhances calcium uptake into and inhibits calcium leakage from the sarcoplasmic reticulum,13,14 and is selective for ischaemic myocardium.13 In reperfusion models, caldaret reduces myocardial infarct size,15 decreases cardiac markers,16 and improves left ventricular (LV) function.16 To test the theoretical benefit of caldaret, as an indirect calcium scavenger and an adjunct to direct PCI for STEMI, a pilot study of the safety and effectiveness of two doses of caldaret compared with placebo was conducted in human subjects.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Dose
In this study, 57.5 mg caldaret [lower dose (LD) group], 172.5 mg caldaret [higher dose (HD) group], or placebo as a 45 min loading infusion (40 mL/hour) started prior to PCI, followed by maintenance infusion (4.2 mL/hour) for 24–48 h (minimum requirement of 24 h), was utilized in this study. These doses covered the anticipated therapeutic dose range, based on cardiovascular pharmacology studies in dogs, and a previous Phase I trial in healthy volunteers, which demonstrated that intravenous caldaret at doses up to the HD used were safe and well tolerated.

Trial design
CASTEMI, a multicentre, randomized, double-blind, placebo-controlled trial, examined the safety and efficacy of intravenous infusions of caldaret in patients undergoing primary PCI for STEMI. Caldaret was administered in addition to accepted standard therapy.

Within 6 h of the onset of symptoms of STEMI, eligible patients were randomized unstratified in blocks of six (1:1:1) using an interactive voice recognition system to receive LD, HD, or placebo. Coronary angiography determined thrombolysis in myocardial infarction (TIMI) flow grade prior to PCI. Angiograms were assessed by a blinded angiographic core laboratory (Heart Core, Leiden, The Netherlands). Efficacy endpoints and clinical evaluations were performed on Days 1–5, Day 7 [or discharge, if sooner (Day 7/discharge)], and Day 30. The PCI technique used followed local protocol.

Patient population
Patients were enrolled between April 2002 and February 2003 in 29 centres in Belgium, Germany, Israel, The Netherlands, and Spain. The study complied with the Declaration of Helsinki, was approved by local Ethics Committees, and written informed consent obtained from all patients.

Inclusion criteria
Inclusion criteria: male or female patients ≥18 years of age (≥35 years in Germany) with ongoing chest pain of ≥20 min, presenting within 6 h of onset of symptoms; confirmatory electrocardiogram (ECG) showing a large STEMI defined as ST-segment elevation of ≥0.2 mV (2 mm) in two contiguous anterior or extremity leads, and ≥1.0 mV (10 mm) summed from all leads; with a vascular access suitable for angiography.

Exclusion criteria
Major exclusion criteria: fibrinolytic therapy for the index infarct; previous MI overlapping the location of the index MI; cardiogenic shock unresponsive to intravenous fluid; severe congestive heart failure (CHF; NYHA grade IV); known renal dysfunction (serum creatinine >1.5 x upper limit of normal); cerebrovascular event within the past 6 months; current therapy with catecholamines, phosphodiesterase inhibitors, or calcium sensitizers.

Study endpoints
Safety assessments
The safety population comprised 381 (98.4%) of 387 patients receiving study infusions. Safety endpoints were frequency and nature of treatment-related treatment-emergent adverse events (TEAEs); 30-day mortality; vital signs and laboratory safety; heart rhythm, conduction abnormalities, and ST-segment recovery by continuous 12-lead digital ECG monitoring over 24 h from the onset of drug infusion (eECG Core Laboratory, Duke University Medical Center, Duke Clinical Research Institute, NC, USA). An independent Data and Safety Monitoring Committee reviewed safety data during the study. Safety analyses were performed in all patients treated regardless of initial TIMI flow.

Efficacy measures
Efficacy analyses, prospectively defined, included 247 patients with initial TIMI 0/1 flow. The primary efficacy endpoint was infarct size, determined by single photon emission computed tomography (SPECT) on Day 7/discharge in patients with pre-PCI TIMI flow grade 0/1. Resting SPECT imaging was obtained using 22–25 mCi 99 mTc-sestamibi and analysed in a blinded core laboratory (Heart Core, Leiden, The Netherlands) using Quantitative Gated SPECT and Quantitative Perfusion SPECT analytical packages (Software version 1.0, Cedars-Sinai Medical Center, Los Angeles, CA, USA) on a UNIX system. All participating centres were tested by the core laboratory to verify the quality of SPECT images.

Secondary endpoints were

  • Area under the concentration–time curve (AUC) for total creatine kinase (CK) and its MB isoenzyme (CK-MB) to 72 h; for troponin T (TnT) and lactate dehydrogenase (LDH) to Day 5 (Quest Diagnostics, Heston, UK or St George's Hospital, London, UK).
  • Infarct size on Day 30; LV end-systolic volume (LVESV) and LV end-diastolic volume (LVEDV) on Day 7/discharge and Day 30; global LV ejection fraction (LVEF) on Day 7/discharge and Day 30, determined by SPECT.
  • Clinical endpoints, adjudicated by an independent blinded committee (Dr Marc A. Pfeffer, Brigham and Women's Hospital Cardiovascular Division, Boston, MA, USA), consisted: all-cause mortality, cardiac mortality, and resuscitated sudden death up to Day 30; CHF and re-admission for CHF up to Day 30; stroke and re-infarction up to Day 30; composite clinical endpoint up to Day 30, consisting of time to event for major adverse cardiovascular events (death, re-infarction, revascularization procedures, CHF, and re-admission for CHF).
  • Blood samples at intervals up to 72 h measured caldaret concentrations (Covance Laboratories Ltd, Harrogate, UK).

Sample size and statistical analyses
The safety set analyses includes all randomized patients who received at least one dose or partial dose of study medication; the full analysis population included all randomized patients who received any study medication and who provided any efficacy data after the start of study medication. Following the principle of intention-to-treat, the full analysis TIMI 0/1 population were patients who were defined as the full analysis population who also recorded a TIMI 0/1 flow at entry.

Assuming SPECT infarct size standard deviation of 20%, and 20% of patients being unevaluable at Day 7/discharge, 240 patients with pre-PCI TIMI flow grade 0/1 provide a 80% power to detect a mean absolute difference of 10% in infarct size between caldaret and placebo. An estimated 60% of patients would have pre-PCI TIMI flow grade 0/1, giving a final sample size of ~400.

Analyses included pairwise comparisons between each active treatment group and placebo. Statistical tests were two-sided, at the 5% level of significance, and differences between treatment groups were presented with 95% confidence intervals. No adjustment was made for multiple comparisons, since this was an exploratory study—the emphasis was on estimation of differences vs. placebo.

Primary and secondary efficacy variables were log-transformed and analysed using analysis of covariance, including factors for centre, age, and treatment. Statistical analyses were performed with the SAS software Version 8.2. Further exploratory analysis was performed to identify other significant covariates (advanced age >70, gender, hypertension, diabetes mellitus, prior MI, angina, summed ST, location of infarct anterior/non-anterior) pre-specified in the analysis plan. No estimation of missing values was conducted. Efficacy data were missing due to deaths, withdrawals and non-evaluable SPECT, and numbers in each treatment group were similar; however, potential bias cannot be completely ruled out.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Appendix
 Acknowledgements
 References
 
Patient population
Figure 1 describes patient disposition. Of note was the ower number of patients with non-anterior MI in the HD group. Baseline characteristics were well balanced (Table 1). A higher incidence of pre-PCI TIMI flow grade of 0 in the placebo group was detected (Table 2).


Figure 3041
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  		Figure 1 Patient disposition (in farct location unknown in one patient).

 

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  		Table 1 Patient characteristics

 

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  		Table 2 Pre-procedure TIMI flow grades, full analysis population

 
Safety assessments
Mortality at Day 30 was 2.4%, with no difference between treatment groups (Table 3). The most frequently reported treatment-related TEAEs (possible or probable relationship to study drug) were hypotension, bradycardia, angina pectoris, headache and, vomiting; however, frequency of each was the same for drug and placebo groups.


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  		Table 3 Overview of AEs (safety population)

 
Three patients withdrew from the study due to adverse events (AEs)/medical conditions and 8% of patients had interruption or discontinuation of the study drug due to a TEAE. Only one AE was considered by the investigator to be ‘probably’ related to study drug, an SAE of cardiac failure in the placebo group.

The median time to stable ST-segment resolution of 1.6, 1.3, and 1.4 h were not significantly different for the LD, HD, and placebo groups, respectively. No differences in QTc or cardiac rhythm were observed.

Efficacy analyses
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 secondary 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 pressure at Day 7/discharge.


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  		Table 4 Myocardial infarct size at Day 7/discharge and at Day 30 in patients with pre-PCI TIMI flow grade 0/1 determined by SPECT

 

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  		Table 5 Cardiac markers of infarct size in patients with pre-PCI TIMI flow grade 0/1

 

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  		Table 6 LV function parameters determined by SPECT on Day 7/discharge and on Day 30 in patients with pre-PCI TIMI flow grade 0/1

 

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  		Table 7 Clinically adjudicated endpoints up to Day 30 in patients with pre-PCI TIMI flow grade 0/1

 
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 composite 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%).


Figure 3042
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  		Figure 2 Study outcomes in anterior infarct patients with pre-PCI TIMI flow grade 0/1.

 

Figure 3043
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  		Figure 3 Study outcomes in non-anterior infarct patients with pre-PCI TIMI flow grade 0/1.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Appendix
 Acknowledgements
 References
 
The CASTEMI study is the first human experience with caldaret in patients with large STEMI undergoing 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 setting, 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 location 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 mechanism 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 treatment prior to PCI. Thus, the ultimate contribution of such medical strategies for ‘facilitated PCI’ in STEMI to reduce infarct size remains controversial.4,17


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Appendix
 Acknowledgements
 References
 
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 anterior infarct patients may be viewed as chance findings or hypothesis generating worthy of further study.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
Acknowledgements
 References
 
List of primary investigators
Belgium
Boland J, Hopital de la Citadelle, Boulevard du 12ieme de Ligne 1, 4000 Liege; Convens C, AZ Middelheim, Lindenreef 1, 2020 Antwerpen; Heyndrickx G, Onze Lieve Vrouwziekenhuis, Moorselbaan 164, 9300 Aalst; Legrand V, CHU Sart Tilman, Domaine du Sart Tilman, 4000 Liege; Salembier J-P, Clinique St Elisabeth, Place Louise Godin 15, 5000 Namur; Vrolix M, Algemeen Ziekenhuis St Jan, Dienst Hartcatherterisatie. Schiepse Bos 2, B-3600 Genk.

Germany
Brachmann J, Klinikum Coburg gGmbH, II. Medizinische Klinik, Ketschendorfer Str. 33, 96450 Coburg; Koch K-C, Universitätsklinik um Aachen, Med. Klinik I, Pauwelsstrasse 30, 52074 Aachen; Zahn R, Klinik der Stadt Ludwigshafen, Bremerstr. 79, 67063 Ludwigshafen.

Israel
Beyar R, Rambam Medical Center, Invasive Cardiology Department, Bat Galim 8, 31096 Haifa; David D, Meir Hospital, Sapir Medical Centre, Department of Cardiology, 59 Tshernichovsky St, 44281 Kfar Saba; Gilon D, Hadassah Medical Organization, Department of Noninvasive C ardiology, PO Box 12000, 91120 Jerusalem; Guetta V, Chaim Sheba Medical Center, Centre of Invasive Cardiology, 52621 Tel Hashomer; Kracoff O, Kaplan Medical Center, ICCU, Hagalil St, PO Box 1, 76100 Rehovot; Marmor A, Rebecca Sieff Hospital, Department of Cardiology, 13000 Safed; Roguin N, Western Galilee Hospital—Nahariya, Heart Institute, PO Box 21, 22100 Nahariya; Roth A, Tel Aviv Sourasky Medical Center, Department of Cardiology, 6 Weizman Street, 64239 Tel Aviv; Tzivoni D, Shaarei Zedek Medical Center, Department of Cardiology, 12 Hans Bayth St, PO Box 3235, 91031 Jerusalem.

The Netherlands
Bär F, Academisch Ziekenhuis Maastricht, Afdeling Cardiologie, P. Debeyelaan 25, 6229 HX Maastricht; Koolen JJ, Catharina Ziekenhuis, Afdeling R&D Cardiologie, Michelangelolaan 2, 5623 EJ Eindhoven; Piek JJ, Academisch Medisch Centrum, Afdeling Cardiologie, Meibergdreef 9, 1105 AZ Amsterdam; Slagboom T, Onze Lieve Vrouwe Gasthuis, Oosterpark 279, 1090 HM Amsterdam; Suttorp MJ, Sint Antonius Ziekenhuis, Koekoekslaan 1, 3435 CM Nieuwegein; te Riele JAM, Amphia Ziekenhuis, Locatie Molengracht, Molengracht 21, 4818 CK Breda; van Boven AJ, Academisch Ziekenhuis Groningen, Cardioresearch, Hanzeplein 1, 9713 GZ Groningen.

Spain
Fernández Vázquez F, Complejo Hospitalario de León, Edificio Princesa Sofia,Servico de Hemodinámica (planta baja), C/Altos de Nava, s/n, 24008 León; Macaya C, Hospital Clinico San Carlos, Sección Hemodinámica Cardiaca, 2a Planta. Ala Norte, Dr Martin Lagos s/n, 28040 Madrid; Ma Hernández J., Hospital Virgen de la Victoria, Servicio de Hemodinámica, Campus Universitari Teatinos, s/n 29010 Malaga; Valdés Chavarri M, Hospital Virgen de la Arrixaca, Hemodinámica, Ctra. De Madrid-Cartagena Km 61.7, 30120 El Palmar, Murcia.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix
 Acknowledgements
References
 
Financial support from Mitsubishi Pharma Corporation.

Conflict of interest

F.W.B., J.B., A.F-O., G.R.H., M.G.H., M.W.K., J.H.C.R., D.T.: members of the CASTEMI study Steering Committee and received honoraria payments accordingly.

F.W.B., J.B., M.T.D., A.F.-O., G.R.H., D.T.: study investigators.

M.G.H.: consultant to Mitsubishi Pharma throughout the study.

N.A.: a full-time employee of Mitsubishi Pharma Europe Ltd, a 100% owned subsidiary of Mitsubishi Pharma Corporation of Japan (the study sponsor), at the time of the study and now a consultant to the company.

M.D.: a full-time employee of Mitsubishi Pharma Europe Ltd, a 100% owned subsidiary of Mitsubishi Pharma Corporation of Japan.

J.T.: a full-time employee of Mitsubishi Pharma Corporation of Japan, the sponsor of the study.


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 Results
 Discussion
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 Appendix
 Acknowledgements
 References
 

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M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker
Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies
Cardiovasc Res, June 1, 2007; 74(3): 343 - 355.
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