Robbert J. Slingerland

Six of Eight Hemoglobin A1c Point-of-Care Instruments Do Not Meet the General Accepted Analytical Performance Criteria

BACKGROUND Hemoglobin A(1c) (Hb A(1c)) point-of-care (POC) instruments are widely used to provide rapid-turnaround results in diabetic care centers. We investigated the conformance of various Hb A(1c) POC instruments (In2it from Bio-Rad, DCA Vantage from Siemens, Afinion and Nycocard from Axis-Shield, Clover from Infopia, InnovaStar from DiaSys, A1CNow from Bayer, and Quo-Test from Quotient Diagnostics) with generally accepted performance criteria for Hb A(1c). METHODS The CLSI protocols EP-10, EP-5, and EP-9 were applied to investigate imprecision, accuracy, and bias. We assessed bias using 3 certified secondary reference measurement procedures and the mean of the 3 reference methods. Assay conformance with the National Glycohemoglobin Standardization Program (NGSP) certification criteria, as calculated from analyses with 2 different reagent lot numbers for each Hb A(1c) method, was also evaluated. RESULTS Because of disappointing EP-10 results, 2 of the 8 manufacturers decided not to continue the evaluation. The total CVs from EP-5 evaluations for the different instruments with a low and high Hb A(1c) value were: In2it 4.9% and 3.3%, DCA Vantage 1.8% and 3.7%, Clover 4.0% and 3.5%, InnovaStar 3.2% and 3.9%, Nycocard 4.8% and 5.2%, and Afinion 2.4% and 1.8%. Only the Afinion and the DCA Vantage passed the NGSP criteria with 2 different reagent lot numbers. CONCLUSIONS Only the Afinion and the DCA Vantage met the acceptance criteria of having a total CV <3% in the clinically relevant range. The EP-9 results and the calculations of the NGSP certification showed significant differences in analytical performance between different reagent lot numbers for all Hb A(1c) POC instruments.

Prognostic Value of Admission Glycosylated Hemoglobin and Glucose in Nondiabetic Patients With ST-Segment–Elevation Myocardial Infarction Treated With Percutaneous Coronary Intervention

Background— In nondiabetic patients with ST-segment–elevation myocardial infarction, acute hyperglycemia is associated with adverse outcome. Whether this association is due merely to hyperglycemia as an acute stress response or whether longer-term glycometabolic derangements are also involved is uncertain. It was our aim to determine the association between both acute and chronic hyperglycemia (hemoglobin A1c [HbA1c]) and outcome in nondiabetic patients with ST-segment–elevation myocardial infarction. Methods and Results— This observational study included consecutive patients (n=4176) without known diabetes mellitus admitted with ST-segment–elevation myocardial infarction. All patients were treated with primary percutaneous intervention. Both glucose and HbA1c were measured on admission. Main outcome measure was total long-term mortality; secondary outcome measures were 1-year mortality and enzymatic infarct size. One-year mortality was 4.7%, and mortality after total follow-up (3.3±1.5 years) was 10%. Both elevated HbA1c levels (P<0.001) and elevated admission glucose (P<0.001) were associated with 1-year and long-term mortality. After exclusion of early mortality (within 30 days), HbA1c remained associated with long-term mortality (P<0.001), whereas glucose lost significance (P=0.09). Elevated glucose, but not elevated HbA1c, was associated with larger infarct size. After multivariate analysis, HbA1c (hazard ratio, 1.2 per interquartile range; P<0.01), but not glucose, was independently associated with long-term mortality. Conclusions— In nondiabetic patients with ST-segment–elevation myocardial infarction, both elevated admission glucose and HbA1c levels were associated with adverse outcome. Both of these parameters reflect different patient populations, and their association with outcome is probably due to different mechanisms. Measurement of both parameters enables identification of these high-risk groups for aggressive secondary risk prevention.

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial on Benfotiamine Treatment in Patients With Diabetic Nephropathy

OBJECTIVE To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes and UAE equivalent to 15–300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43). RESULTS Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P < 0.001). Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion. CONCLUSIONS In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status.

Three of 7 Hemoglobin A1c Point-of-Care Instruments Do Not Meet Generally Accepted Analytical Performance Criteria

BACKGROUND In 2009, we investigated the conformance of 8 hemoglobin A(1c) (Hb A(1c)) point-of-care (POC) instruments. Since then, instruments have improved and new devices are available on the market. In this second study, we evaluated the performance of DCA Vantage, Afinion, InnovaStar, Quo-Lab, Quo-Test, Cobas B101, and B-analyst Hb A(1c) POC instruments. METHODS Clinical and Laboratory Standards Institute protocols EP-5 and EP-9 were applied to investigate imprecision, accuracy, and bias. We assessed bias using the mean of 3 certified secondary reference measurement procedures (SRMPs). Assay conformance with the National Glycohemoglobin Standardization Program (NGSP) certification criteria was also evaluated. Interference of common Hb variants was investigated for methods that could work with hemolysed material. RESULTS The total CVs for all instruments, except for the DCA Vantage at a high Hb A(1c) value, were ≤3.1% in SI units and ≤2.1% in Diabetes Control and Complications Trial (DCCT) units. Afinion, DCA Vantage, B-analyst, and Cobas B101 instruments passed the NGSP criteria with 2 different reagent lot numbers. Quo-Test, Quo-Lab, and InnovaStar instruments had a negative bias compared to the mean of the 3 SRMPs and failed NGSP criteria. Most of the common Hb variants did not interfere with the investigated instruments, except Hb AE for the Cobas B101. CONCLUSIONS Afinion, DCA Vantage, Cobas B101, and B-analyst instruments met the generally accepted performance criteria for Hb A(1c). Quo-Test, Quo-Lab, and InnovaStar met the criteria for precision but not for bias. Proficiency testing should be mandated for users of Hb A1c POC assays to ensure quality.

Pre- and Postoperative Accuracy and Safety of a Real-Time Continuous Glucose Monitoring System in Cardiac Surgical Patients: A Randomized Pilot Study

BACKGROUND Our objective was to evaluate the accuracy and safety of a real-time (RT) continuous glucose monitoring system (CGMS) in patients before and after cardiothoracic surgery and to investigate whether activation of the alarm function of the RT-CGMS had an effect on glucose control. METHODS Patients scheduled for elective cardiothoracic procedures, without a history of insulin-requiring diabetes, were perioperatively monitored with RT-CGMS for 72 h and were randomized into two groups: with or without the alarm function (set at 4 and 10 mmol/L) of the device activated. Sensor values were compared with capillary, arterial, and venous blood glucose values. Percentages of time spent in various glucose ranges were compared between groups. RESULTS There were no adverse effects of the RT-CGMS. Of the 1,001 sensor value comparisons with capillary or arterial measurements, 96.6% fell within Clarke Error Grid zones A and B, with relative absolute differences ranging from 15% (preoperative period) to 12% (intensive care unit period) to 14% (postoperative period on the ward). Seventeen (7.9%) arterial and 16 (2.0%) capillary comparisons fell within zone D or E. Whether or not the alarm function, as used in this pilot study, was activated did not affect time spent in different glucose ranges. CONCLUSIONS Although the RT-CGMS is safe and accurate according to accepted standards, there are still small aberrations, which in our opinion preclude unlimited use in its present form in a clinical setting. The effect of the alarm function at different glucose levels remains to be investigated.

Self-Monitoring of Blood Glucose: The Use of the First or the Second Drop of Blood

OBJECTIVE There is no general agreement regarding the use of the first or second drop of blood for glucose monitoring. This study investigated whether capillary glucose concentrations, as measured in the first and second drops of blood, differed ≥10% compared with a control glucose concentration in different situations. RESEARCH DESIGN AND METHODS Capillary glucose concentrations were measured in two consecutive drops of blood in the following circumstances in 123 patients with diabetes: without washing hands, after exposing the hands to fruit, after washing the fruit-exposed hands, and during application of different amounts of external pressure around the finger. The results were compared with control measurements. RESULTS Not washing hands led to a difference in glucose concentration of ≥10% in the first and in the second drops of blood in 11% and 4% of the participants, respectively. In fruit-exposed fingers, these differences were found in 88% and 11% of the participants, respectively. Different external pressures led to ≥10% differences in glucose concentrations in 5–13% of the participants. CONCLUSIONS We recommend washing the hands with soap and water, drying them, and using the first drop of blood for self-monitoring of blood glucose. If washing hands is not possible, and they are not visibly soiled or exposed to a sugar-containing product, it is acceptable to use the second drop of blood after wiping away the first drop. External pressure may lead to unreliable readings.

Comparison of usefulness of C-reactive protein versus white blood cell count to predict outcome after primary percutaneous coronary intervention for ST elevation myocardial infarction

White blood cell (WBC) count and high-sensitive C-reactive protein (hs-CRP) are both used as markers of inflammation and prognosis after an ST elevation myocardial infarction (STEMI), but it is unknown whether they have independent prognostic value. We investigated the association and independent prognostic importance of WBC and hs-CRP after STEMI. In this subanalysis of the On-TIME trial, in 490 of 507 (97%) patients, either WBC count or CRP, and in 362 (71%) patients, both WBC count and CRP, were measured on admission before primary percutaneous coronary intervention. There was no significant correlation between WBC count and CRP (R = 0.080). Higher levels of CRP were associated with a reinfarction or death within 1 year (mean hs-CRP 14.2 +/- 20.4 vs 6.1 +/- 14.2, p = 0.006), but CRP was not associated with enzymatic infarct size (lactate dehydrogenase, LDHQ48) or left ventricular ejection fraction. A higher baseline WBC count was associated with larger LDHQ48 and lower left ventricular ejection fraction but not with 1-year reinfarction or death. In conclusion, although both WBC count and CRP are markers of inflammation and predictors of outcome after STEMI, we did not find a correlation between baseline WBC count and CRP levels in patients treated with primary percutaneous coronary intervention for STEMI. The mechanisms by which WBC counts predict outcome were related to myocardial infarct size whereas CRP were not.

Prehospital triple antiplatelet therapy in patients with acute ST elevation myocardial infarction leads to better platelet aggregation inhibition and clinical outcome than dual antiplatelet therapy

Objective To assess whether prehospital initiation of high-dose tirofiban in addition to high-dose clopidogrel results in more adequate inhibition of platelet aggregation (IPA) and better clinical outcome after primary percutaneous coronary intervention (PCI). Methods Prespecified two-centre substudy of the prospective, international, multicentre, placebo controlled Ongoing Tirofiban in Myocardial Infarction Evaluation trial 2 (On-TIME-2 trial). 648 of 964 (67%) patients in the On-TIME-2 trial with ST elevation myocardial infarction undergoing primary PCI were studied. Pre-PCI IPA after early prehospital initiation of high-bolus dose (25 μg/kg) tirofiban was compared to placebo in addition to acetylsalicylic acid, unfractionated heparin and 600 mg clopidogrel. Results IPA was measured at a median of 60 min after study medication administration. In all four tests: Fe induced platelet aggregation, ADP induced platelet aggregation, platelet function analyser (PFA)-100 (collagen–epinephrine and collagen–ADP cartridge) IPA was higher in patients pretreated with high-dose tirofiban (p<0.001 for all tests), even after >74 min of pretreatment. Patients in the highest quartile of IPA had less residual ST segment deviation 1 h post-PCI (p value for trend: p=0.001, 0.004, 0.001, 0.002 respectively). There was a significant relationship between PFA-100 (both cartridges) and major adverse cardiovascular events (MACE, p=0.028, p=0.035) and early thrombosis (p=0.009, p=0.007). Conclusions 60 min of prehospital initiated antiplatelet treatment including high-dose tirofiban resulted in higher levels of IPA compared to pretreatment with acetylsalicylic acid and high-dose clopidogrel alone, even after longer pretreatment times. Levels of IPA were significantly related to ST resolution and MACE, including stent thrombosis. This substudy confirms the main findings of the On-TIME2 trial that clopidogrel alone is suboptimal, even at high dose and administered well in advance of primary PCI.

Hemoglobin A1c determination in the A1C-Derived Average Glucose (ADAG) study.

Abstract Background: The A1C-Derived Average Glucose (ADAG) study was commenced to gain a better understanding of the relationship between HbA1c and average blood glucose and to investigate if HbA1c could be expressed in the same units as day-to-day glucose monitoring. Owing to the impact of the outcome of this study it was very important to determine HbA1c values with a minimum of uncertainty and as close as possible to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) primary reference method, which is the only valid anchor of HbA1c standardization. Methods: Approximately 2300 samples were analyzed with four IFCC secondary reference methods. Additional off-line calibration with IFCC secondary reference material with assigned IFCC values was performed to improve the uncertainty in the HbA1c value determination. Results: Additional off-line calibration improved the 95% confidence interval between the four different HbA1c methods at HbA1c of 6.00% from ±0.28% (5.72%–6.28%) to ±0.20% (5.80%–6.20%) and at HbA1c of 9.00% from ±0.43% (8.57%–9.43%) to ±0.24% (8.76%–9.24%). Conclusions: The HbA1c results used in the ADAG study were determined with the lowest uncertainty technically feasible by using four certified IFCC secondary reference methods and additional off-line calibration with IFCC secondary reference material. Clin Chem Lab Med 2008;46:1617–23.

Performance of the FreeStyle Libre Flash glucose monitoring system in patients with type 1 and 2 diabetes mellitus

Objective To evaluate the performance of the FreeStyle Libre Flash continuous glucose monitoring (FSL-CGM) system against established central laboratory methods. Research design and methods 20 subjects (8 type 1 diabetes mellitus, 12 type 2 diabetes mellitus) were analyzed. FSL-CGM sensor measurements (inserted in arm and abdomen) were compared with capillary blood glucose results analyzed with StatStrip as semigold standard. The glucose response after a standardized oral glucose load was measured by FSL-CGM and capillary samples analyzed by perchloric acid hexokinase (PCA-HK) method, StatStrip and FSL test strip (FSLC), and a commonly used CGM system (iPro2). Results FSL-CGM arm sensor readings showed 85.5% of paired readings falling within Clarke Error Grid (ISO 15197:2013) zone A when compared with StatStrip. For FSL-CGM abdomen and FSLC, these percentages were 64% and 98%, respectively. The overall correlation of FSL-CGM in the arm and the StatStrip indicates a performance with lower results with the FSL-CGM in the arm than expected based on the StatStrip in the lower glucose ranges, and higher results than expected in the higher ranges. Following a standardized glucose load, a slower rise in glucose level was observed for FSL-CGM arm as compared with PCA-HK, StatStrip, FSLC, and iPro2 during the first 45–60 min after glucose load ingestion. Conclusions Certain matters need attention while using the FSL-CGM in daily life including the observed lower values in the lower ranges, and the underestimation of the effect of a meal on glucose response. These effects of such deviations can partly be overcome by optimizing the available user instructions. Trial registration number TC5348; results.