Original Investigation | Less Is More

Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome:  Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome–2 (BIOMArCS-2) Glucose Trial

Maarten de Mulder, MD1; Victor A. Umans, MD, PhD1; Jan H. Cornel, MD, PhD1; Friso M. van der Zant, MD, PhD2; Frank Stam, MD, PhD3; Rohit M. Oemrawsingh, MD4,5; K. Martijn Akkerhuis, MD, PhD4; Eric Boersma, Msc, PhD4
[+] Author Affiliations
1Department of Cardiology, Medical Center Alkmaar, Alkmaar, the Netherlands
2Department of Nuclear Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands
3Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, the Netherlands
4Department of Cardiology, Erasmus Medical Centre, Rotterdam, the Netherlands
5Interuniversity Cardiology Institute Netherlands, Utrecht
JAMA Intern Med. 2013;173(20):1896-1904. doi:10.1001/jamainternmed.2013.10074.
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Importance  Elevated plasma glucose levels in patients with acute coronary syndrome (ACS) on hospital admission are associated with increased mortality. Clinical trials of glucose regulation have provided inconsistent results with respect to cardiovascular outcomes, perhaps because target glucose levels have been suboptimal.

Objective  To study the effectiveness and safety of intensive glucose management in patients with ACS who have hyperglycemia, aiming at strict blood glucose normalization.

Design, Setting, and Participants  Single-center, prospective, open-label, randomized clinical trial in a large teaching hospital. Patients with ACS with an admission plasma glucose level of 140 to 288 mg/dL were eligible for inclusion and enrolled from July 23, 2008, to February 8, 2012. Patients with insulin-dependent diabetes mellitus were excluded. Informed consent was obtained from 294 patients, who were randomized. Of these, 93.6% received percutaneous coronary intervention (PCI).

Interventions  Intensive glucose management strategy, aiming at a plasma glucose level of 85 to 110 mg/dL by using intravenous insulin, or to conventional expectative glucose management.

Main Outcomes and Measures  End points were assessed according to the intention-to-treat principle. The primary end point was high-sensitivity troponin T value 72 hours after admission (hsTropT72); secondary end points, area under the curve of creatine kinase, myocardial band (AUC–CK-MB), release and myocardial perfusion scintigraphy findings at 6 weeks’ follow-up.

Results  In the intensive management arm, median hsTropT72 was 1197 ng/L (25th and 75th percentiles of distribution, 541-2296 ng/L) vs 1354 ng/L (530-3057 ng/L) in the conventional arm (P = .41). Median AUC–CK-MB was 2372 U/L (1242-5004 U/L) vs 3171 U/L (1620-5337 U/L) (P = .18). The difference in median extent of myocardial injury measured by myocardial perfusion scintigraphy was not significant (2% vs 4%) (P = .07). Severe hypoglycemia (<50 mg/dL) was rare and occurred in 13 patients. Before discharge, death or a spontaneous second myocardial infarction occurred in 8 patients (5.7%) vs 1 (0.7%) (P = .04).

Conclusions and Relevance  Intensive glucose regulation did not reduce infarct size in hyperglycemic patients with ACS treated with PCI, and was associated with harm. Future studies should focus on patients with ACS who have persistently elevated blood glucose after PCI, and should evaluate alternative strategies for optimizing glycemia.

Trial Registration  www.trialregister.nl Identifier: NTR1205

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Figure 1.
Flowchart of Randomization

aPatients withdrew consent after randomization, before further study procedures.bPatients were withdrawn from the study by the investigators within 1 hour because of absence of acute coronary syndrome (ACS) (n = 6) or immediate transfer to another hospital. No data were obtained in these individuals.

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Figure 2.
Median Glucose Values per Treatment Arm

Median glucose values per time point after admission. At 6, 12, 24, and 36 hours, there was a significant difference between treatment arms (all P < .001). To convert glucose levels to micromoles per liter, multiply by 0.0555. Horizontal lines indicate medians; upper and lower limits of the boxes, 25th and 75th percentiles; and whiskers, 5th and 95th percentiles.

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Figure 3.
Treatment Effect for Different Prespecified Subgroups

Infarct size was dichotomized by dividing patients above (large infarction) or below (small infarction) the median troponin T values determined 72 hours after admission (hsTropT72) value. In 10 patients the hsTropT72 value was missing; therefore, they were not included in this analysis. To convert glucose levels to micromoles per liter, multiply by 0.0555. NSTEMI indicates non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation MI.

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