Triage® BNP Test Product Insert - Drug testing supplies from CLIA
Contents
1. Perez A Kazanegra R Herrmann H C McCullough P A Breathing Not Properly Multinational Study Investigators Rapid measurement of B type natriuretic peptide in the emergency diagnosis of heart failure N Engl J Med 347 161 167 2002 McCullough P A Nowak R M McCord J Hollander J E Herrmann H C Steg P G Duc P Westheim A Omland T Knudsen C W Storrow A B Abraham W T Lamba S Wu A H Perez A Clopton P Krishnaswamy P Kazanegra R and Maisel A S B type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure analysis from Breathing Not Properly BNP Multinational Study Circulation 106 416 422 2002 Maisel A S Koon J Krishnaswamy P Kazanegra R Clopton P Gardetto N Morrisey R Garcia A Chiu A and De Maria A Utility ot B natriuretic peptide as a rapid point of care test for screening patients undergoing echocardiography to determine left ventricular dysfunction Am Heart J 144867 3 74F2001 Lubien E DeMaria A Krishnaswamy PA Clopton P s K on J Kazanegra R Gardetto N Wanner E and Maisel A S Utility of B natriuretic peptide in detecting diastolic dysfunction Circulation 05 595 601 2002 Krishnaswamy P Lubien E Clopton P Koon J Kazanegra R Wanner E Gardetto N Garcia A DeMaria A and Maisel A S Utility of B natriuretic peptide in identifying patients with left ventricular systolic or d2. Triage BNP Test Product Insert Rapid Quantitative Test for B type Natriuretic Peptide pall Triage BNP Test w Product Insert Product Insert Catalog 98000XR Intended Use The Alere Triage BNP Test is a rapid point of care fluorescence immunoassay to be used with the Alere Triage Meters for the quantitative measurement of B type natriuretic peptide BNP in EDTA anticoagulated whole blood or plasma specimens The test is intended to be used as an aid in the diagnosis and assessment of severity of congestive heart failure also referred to as heart failure The test also is used for the risk stratification of patients with acute coronary syndromes and for the risk stratification of patients with heart failure Summary and Explanation of the Test Itis estimated that 5 8 million people in the United States have heart failure with approximately 670 000 new cases occurring each year Congestive heart failure CHF occurs when the heart cannot deliver a sufficient amount of blood to the body This condition can occur at any age but is most prevalent in an aged population Symptoms of GHF include shortness of breath fluid retention and respiratory distfess These symptoms are often vague and nonspecific for deteGting early stages of CHEZ B type natriuretic peptide BNP is a member of a class of hormones that regulate blood pressure The heart issthe main source of circulating BNP in bumans Sp The molecule is rel
3. Median 12 3 7 7 11 1 17 9 19 8 53 9 9h 73 5 39 6 64 5 76 1 84 7 179 4 Percentile Percent lt o a e o e 100 pg mL 98 0 99 5 99 2 97 4 96 9 84 2 Minimum 5 0 5 0 5 0 5 0 5 0 5 0 Maximum 252 0 251 3 252 0 207 7 197 9 218 5 N Median 95th 56 9 23 8 39 0 72 4 62 7 77 9 Percentile Percent lt 98 9 98 9 199 5 98 3 98 9 95 8 100 pg mL Minimum 5 0 5 0 5 0 5 0 5 0 5 0 Maximum 252 0 251 3 252 0 207 7 127 3 218 5 N Females Age Age Age All Age lt 45 45 54 55 64 65 74 Age 75 Median 18 5 11 6 17 7 28 2 27 6 67 1 oe 84 2 47 4 71 7 80 5 95 4 179 5 Percentile Percent lt 97 2 100 0 98 9 96 4 95 1 75 8 100 pg mL Minimum 5 0 50 5 0 5 0 5 0 5 0 Maximum 197 9 92 6 142 8 143 2 197 9 194 1 N 676 240 189 111 103 33 2011 Alere All rights reserved 13 Individuals with CHF Blood samples were obtained from 804 patients diagnosed with CHF 246 women and 558 men The descriptive statistics for BNP concentrations in patients with CHF are presented in the table below These values are representative of the values obtained from clinical studies Each laboratory should establish a reference range that represents the patient population that is to be evaluated In addition laboratories should be aware of their respective institutions current practice for the evaluation of patients with CHF CHF Population All NYHA Functional
4. S Shirakami G Jougasaki M and Imura H Increased human brain natriuretic peptide in congestive heart failure New Engl J Med 323 757 758 1990 Sagnella G A Measurement and significance of circulating natriuretic peptides in cardiovascular disease Clin Science 95 519 529 1998 McDonagh T A Robb S D Murdoch D R Morton J J Ford l Morrison C E Tunstall Pedoe H McMurray J J V and Dargie H J Biochemical detection of left ventricular systolic dysfunction Lancet 351 9 13 1998 Mair J Friedl W Thomas S and Puschendorf B Natriuretic Peptides in assessment of left ventricular dysfunction Scand J Clin Lab Invest 59 132 142 1999 20 2011 Alere All rights reserved 15 16 17 18 19 20 21 22 23 24 25 26 Muders F Kromer E P Griese D P Pfeifer M Hense H W Riegger G A J and Elsner D Evaluation of plasma natriuretic peptides as markers for left ventricular dysfunction Am Heart J 134 442 449 1997 Cowie M R Struthers A D Wood D A Coats A J S Thompson S G Poole Wilson P A and Sutton G C Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care Lancet 350 1347 1351 1997 Maisel A S Krishnaswamy P Nowak R M McCord J Hollander J E Duc P Omland T Storrow A B Abraham W T Wu A H Clopton P Steg P G Westheim A Knudsen C W
5. 0 930 with a 95 confidence interval of 0 902 0 958 Prognostic Utility in Patients with Acute Coronary Syndromes BNP concentrations measured in patients with acute coronary syndromes ACS or cardiovascular disease provide prognostic information about the patient s risk for death and the development of CHF 2226 Statistically significant increases in death future myocardial infarction and CHF have been associated with higher BNP concentrations measured within the first 72 hours after the onset of ACS symptoms In a recent clinical study BNP concentrations were evaluated in an observational retrospective manner in patients with ACS consisting of unstable angina myocardial infarction with ST segment elevation or myocardial infarction without ST segment elevation BNP measurements were performed on specimens obtained within 72 hours after the onset of ischemic discomfort from a population of 2525 high risk ACS patients that met standard diagnostic criteria for ACS Patients whose BNP concentration was at least 80 pg mL had higher rates of death myocardial infarction and CHF both at 30 days and at 10 months after presentation than 18 2011 Alere All rights reserved patients whose BNP concentration was below 80 pg mL In this population of patients with ACS BNP measurements within the first 72 hours after the onset of symptoms provide useful predictive information to aid in the risk stratification of patients with ACS Prognostic Ut
6. Class All CHF Il Median 359 5 95 4 221 5 459 1 1006 3 an S 22 3 14 8 9 9 37 6 147 2 Percentile Percent gt 5 e 6 100 pg mL 80 6 48 3 76 6 86 0 96 3 Minimum 5 0 5 0 5 0 5 2 5 0 Maximum gt 5000 904 6 4435 8 gt 5000 gt 5000 N 804 118 197 300 187 CHF Population Males NYHA Functional Class All CHF m Median 317 8 87 8 232 6 458 9 1060 3 a 21 9 16 8 10 7 25 0 196 5 Percentile Percent gt z e Iodoa 78 9 46 5 78 8 85 2 97 2 Minimum 5 0 5 0 5 0 5 2 5 0 Maximum gt 5000 904 6 2710 6 gt 5000 gt 5000 N 558 101 146 203 106 14 2011 Alere All rights reserved CHF Population Females NYHA Functional Class All CHF Wl Median 499 7 114 7 191 2 469 2 996 5 ath F 30 7 6 8 9 7 45 6 121 0 Percentile Percent gt 6 100 pg mL 84 6 58 8 70 6 87 6 95 1 Minimum 5 0 5 0 5 0 11 7 15 5 Maximum gt 5000 519 6 4435 8 4582 0 4706 5 N 246 17 51 97 81 2 CHF with unknown NYHA Functional Class male The New York Heart Association NYHA developed a four stage functional classification system for CHF that is based on a subjective interpretation of the severity of a patient s clinical signs and symptoms Class patients have no limitations of physical activity and have no symptoms with ordinary physical activity Class Il patients have a slight limitation of physical activi
7. Device testing Refer to the Quality Control Considerations section e Frozen plasma and refrigerated whole blood or plasma specimens must be allowed to reach room temperature and be mixed thoroughly before testing e Mix whole blood specimens by gently inverting the tube several times e Mix plasma specimens by vortexing or inverting the tube several times STEP 1 Add Patient Specimen 1 Open the pouch and label the Test Device with the patient identification number 2 Place the Test Device on a level horizontal surface 3 Using the transfer pipette squeeze the larger top bulb completely and insert the tip into the specimen 4 Release the bulb slowly The transfer pipette barrel should fill completely with some fluid flowing into the smaller lower bulb 5 Place the tip of the transfer pipette into the sample port of the Test Device and squeeze the larger bulb completely The entire volume of fluidyin the transfer pipette barrel must flow into the sample port The specimen in the smaller_ lower bulb will not be expelled 6 Remove the transfer pipette tip from the Sample port and then release the larger top bulb K Discard the transfer pipette Allow specimen toxa sorb completely before moving the Test Device STEP 2 Run Test als From the main screen select Run Test and press Enter 2 Select Patient Sample and press Enter 3 Enter the patient identification number and press Enter 4 Confirm that the numb
8. Once removed from refrigeration the pouched Test Device is stable for up to 14 days at room temperatur but not beyond the expiration date printed on the pouch With a soft felt tip marker gently write the date and time of removal from the refrigerator on the pouch and cross out the manufacturer expiration date printed on the pouch Care must be taken to document the time the product is at room temperature Once equilibrated to room temperature do not return the Test Device to refrigeration Before using refrigerated Test Devices allow individual foil pouches to reach operating temperature 20 24 C or 68 75 F This will take a minimum of 15 minutes If a kit containing multiple Test Devices is removed from refrigeration allow the kit to reach room temperature before use This will take a minimum of 60 minutes Do not remove the Test Device from the pouch until prepared for immediate use 2011 Alere All rights reserved 3 Specimen Collection and Preparation A venous whole blood or plasma specimen using EDTA as the anticoagulant is required for testing with this product Other blood specimen types have not been evaluated Use of plastic blood draw tubes containing K2 EDTA as an anticoagulant for sample collection permits an accurate measurement of plasma BNP concentrations Davidson et al Circulation 91 1276 1995 For sample collection follow the sample tube manufacturer s recommended procedure Blood and plasma specimens ma
9. a more useful marker than ANP to distinguish between normal subjects and patients in the earlier stages of CHF BNP is more sensitive and specific than ANP for detecting decreases in LVEF Additionally there is a positive correlation between blood BNP concentrations and left ventricular end diastolic pressure and inverse correlation to left ventricular function following acute myocardial infarction Blood BNP concentrations represent an independent assessment of ventricular function without the use of other invasive or expensive diagnostic tests There is an association with elevated BNP concentrations and alterations in hemodynamic parameters including raised atrial and pulmonary wedge pressures reduced ventricular systolic and diastolic function left ventricular hypertrophy and myocardial infarction Numerous reports in the scientific literature have described the utility of BNP as a diagnostic marker for CHF and left ventricular dysfunction S These observations are supported by an analysis of the clinical study data The Receiver Operating Characteristic ROC Curve of BNP cut offs versus clinical sensitivity and specificity from the clinical study data is provided below The area under the curve is 0 955 0 005 The clinical utility of the Alere Triage BNP Test also has been confirmed and described in detail in the scientific literature 1718 ROC Curve 100 0 90 0 80 0 4 499 125 150 180 200 70 0 60
10. of Substance 50 ng mL Recovery Aldosterone 1 g mL 104 Angiotensin 600 pg mL 108 Angiotensin II 600 pg mL 108 Endothelin 20 pg mL 101 Adrenomedullin ADM 1000 pg mL 97 Alpha Atrial Natriuretic polypeptide 1 28 1000 pg mL 104 Prepro BNP 22 46 1000 pg mL 104 Prepro BNP 1 21 1000 pg mL 106 Arg Vasopressin 1000 pg mL 96 C type Natriuretic Peptide 53 1000 pg mL 106 Prepro ANF 56 92 1000 pg mL 104 Prepro ANF 104 123 1000 pg mL 97 Urodilatin CCD ANP 95 126 1000 pg mL 100 Angiotensin III 1000 pg mL 108 Prepro ANF 26 55 1000 pg mL 107 2011 Alere All rights reserved 17 Precision The average within day and total precision were determined using the ANOVA model by testing control materials that had BNP added at concentrations near the decision points of the assay and throughout the range of the standard curve The study was conducted over 12 days testing each control 10 times per day Each Test Device was read on five Triage Meters Of particular note the use of different Meters does not significantly affect the test precision Average Within Day Imprecision Mean Standard cv pg mL Deviation pg mL 71 3 6 3 8 8 629 9 69 1 11 0 4087 9 475 5 11 6 Average Total Imprecision Mean Standard cv pg mL Deviation pg mL 71 3 7 0 9 9 629 9 75 5 12 0 4087 9 500 1 12 2 Whole Blood vs Plasma Correl
11. 0 50 0 Sensitivity 40 0 500 30 0 20 0 1 1000 10 0 0 0 T T T T 0 0 20 0 40 0 60 0 80 0 100 0 1 Specificity 16 2011 Alere All rights reserved A box and whiskers plot for the clinical study population is provided below with a horizontal dashed line representing the suggested cutoff of 100 pg mL 1 400 T 1 300 7 1 200 1 100 1 000 900 800 700 BNP pg mL 600 500 400 300 200 HOT HU MED N 1 286 804 Non CHF CHF The clinical sensitivity and specificityof the Alere Triage BNP Test using a cutoff of 100 pg mL for various age groups within achigender is described in the table below Males Age lt 45 Age 45 54 Age 55 64 Age 65 74 Age 75 Sensitivity 81 6 76 0 75 6 79 3 82 4 95 Confidence Interval 70 8 92 5 67 5 84 6 68 2 82 9 72 6 86 76 1 88 7 Specificity 98 9 99 5 98 3 98 9 95 8 95 Confidence Interval 97 4 100 0 98 5 100 0 97 7 98 9 98 4 99 4 94 7 96 9 2011 Alere All rights reserved 17 Females Age lt 45 Age 45 54 Age 55 64 Age 65 74 Sensitivity 82 1 69 0 82 4 97 9 91 9 95 Confidence Interval 68 0 96 3 57 1 80 9 71 9 92 8 93 7 100 0 85 2 98 7 Specificity 100 0 98 9 96 4 95 0 75 7 95 Confidence Interval 100 0 100 0 97 5 100 0 95 5 97 4 93 4 96 7 72 2 79 2 It has been reported that BNP has excellent util
12. 7 Logeart et al found that admitted heart failure patients with pre discharge BNP concentrations of 350 700 pg mL had a hazard ratio of 5 4 for death or readmission for heart failure within 6 months and patients withya pre dischatge BNP Concentration greater than 700 pg mL had a hazafd ratio of 15 2 forthe same endpoint compared to patients with a pre dischargesBNP concentration less than 350 pg mL Taken together these studies indicate that higher BNP concentrations or the lack of a decrease in the BNP concentration from hospital admissiOnsto discharge indicate an increased risk of hospitalization or death in patients with heart failure 2011 Alere All rights reserved 19 Bibliography of Suggested Reading 1 2 10 11 12 13 14 http www cdc gov dhdsp data statistics fact sheets fs heart failure htm Wu A B Type natriuretic peptide and its clinical utility in patients with heart failure Medical Laboratory Observer 10 10 14 2001 Bonow R O New insights into the cardiac natriuretic peptides Circulation 93 1946 1950 1996 McDowell G Shaw C Buchanan K and Nicholls D The natriuretic peptide family Eur J Clin Invest 25 291 298 1995 Yandle T Biochemistry of natriuretic peptides J Internal Med 235 561 576 1994 Mukoyama M Nakao K Hosoda K Suga S Saito Y Ogawa Y Shirakami G Jougaski M Obata K Yasue H Kambayashi Y Inouye K and Imura H Brain natriu
13. CIES REQUIRED FOR THE SALE OF PRODUCTS FOR THEIR INTENDED USE the LIMITED WARRANTY IF THE PRODUCT FAILS TO MEET THE REQUIREMENTS OF THE LIMITED WARRANTY THEN AS CUSTOMER S SOLE REMEDY ALERE SHALL EITHER REPAIR OR REPLACE AT ALERE S DISCRETION THE PRODUCT EXCEPT FOR THE LIMITED WARRANTY STATED IN THIS SECTION ALERE DISCLAIMS ANY AND ALL WARRANTIES EXPRESS OR IMPLIED INCLUDING BUT NOT LIMITED TO ANY WARRANTY OF MERCHANTABILITY FITNESS FOR A PARTICULAR PURPOSE AND NON INFRINGEMENT REGARDING THE PRODUCT ALERE S MAXIMUM LIABILITY WITH ANY CUSTOMER CLAIM SHALL NOT EXCEED THE NET PRODUCT PRICE PAID BY CUSTOMER NEITHER PARTY SHALL BE LIABLE TO THE OTHER PARTY FOR SPECIAL INCIDENTAL OR CONSEQUENTIAL DAMAGES INCLUDING WITHOUT LIMITATION LOSS OF BUSINESS PROFITS DATA OR REVENUE EVEN IF A PARTY RECEIVES NOTICE IN ADVANCE THAT THESE KINDS OF DAMAGES MIGHT RESULT The Limited Warranty above shall not apply if the Customer has subjected the Product to physical abuse misuse abnormal use use inconsistent with the Product Manual or Insert fraud tampering unusual physical stress negligence or accidents Any warranty claim by Customer pursuant to the Limited Warranty shall be made in writing within the applicable Limited Warranty period Protected by US patent numbers 5 763 189 5 885 527 6 074 616 16 194 222 6 238 931 6 251 687 6 391 265 6 392 894 6 544 797 and 6 764 510 The Alere Loop Alere Triage Code Chip and Mete
14. ation A comparison study was performed on EDTA whole blood vs plasma The correlation data shows r 0 9878 y 0 925x 13 439 Data from Clinical Studies Individuals Without CHF The circulating BNP concentration was determined from 1286 individuals without CHF 676 women and 610 men using the Alere Triage BNP Test This population included individuals with hypertension diabetes renal insufficiency and chronic obstructive pulmonary disease There are no statistically significant changes in BNP concentration associated with hypertension diabetes renal insufficiency and chronic obstructive pulmonary disease The descriptive statistics for BNP concentrations in individuals without CHF are shown in the table below The values are representative of the values obtained from clinical studies The decision threshold was determined by the 95 confidence limit of BNP concentration in the non CHF population age 55 and older The most appropriate decision threshold apparent from these distributions is 100 pg mL This value translates into a general specificity of the test of 98 i e less than 2 expected false positives in individuals without CHF Each laboratory should establish a reference range that represents the patient population that is to be evaluated 12 2011 Alere All rights reserved Descriptive Statistics BNP Concentration pg mL Non CHF Population Age Age Age Al Age lt 45 45 54 55 64 65 74 A9975t
15. e the following slope 1 01 with 95 Confidence Interval 0 97 to 1 04 intercept 0 4 with 95 Confidence Interval 0 4 to 1 1 The average coefficient of variation for the two measurements on each sample by the POL employees for the BNP range of 5 pg mL to 78 pg mL was 13 5 Limitations of the Procedure e Test results should be evaluated in the context of all the clinical and laboratory data available In those instances where test results do not agree with the clinical evaluation additional tests should be performed accordingly e Severely hemolyzed specimens should be avoided When a sample appears to be severely hemolyzed another specimen should be obtained and tested 8 2011 Alere All rights reserved e This test has been evaluated with venous whole blood and plasma using EDTA as the anticoagulant Other specimen types draw methods or anticoagulants have not been evaluated Use standard venipuncture techniques Follow the sample collection recommendations of the sample tube manufacturer e There is the possibility that factors such as technical or procedural errors as well as interfering or cross reacting substances in patient specimens may impact the test and cause erroneous results e These assays are fluorescence immunoassays and may be affected by environmental conditions Therefore it is important for each laboratory to establish its own reference range based on the laboratory conditions and procedures Expected Value
16. eased into the blood in response to increased heart pressure Various studies have demonstrated that increased levels of circulating BNP are found in early stages of CHF The level of BNP in the blood continues to increase as the CHF disease advances The Alere Triage BNP Test offers an objective noninvasive measurement for assessing patients for CHF and risk stratification in patients with acute coronary syndromes ACS 7 Principles of the Procedure The Alere Triage BNP Test is a single use fluorescence immunoassay device designed to determine the concentration of BNP in EDTA anticoagulated whole blood or plasma specimens The test procedure involves the addition of several drops of an EDTA anticoagulated whole blood or plasma specimen to the sample port on the Test Device After addition of the specimen the whole blood cells are separated from the plasma using a filter contained in the Test Device The specimen reacts with fluorescent antibody conjugates and flows through the Test Device by capillary action Complexes of each fluorescent antibody conjugate are captured on discrete zones specific to the analyte The Test Device is inserted into the Alere Triage Meter hereafter referred to as Meter The Meter is programmed to perform the BNP analysis after the specimen has reacted with the reagents within the Test Device The concentration of BNP in the specimen is directly proportional to the fluorescence detected The results are disp
17. er was entered correctly by selecting Confirm Patient ID and pressing Enter If the number was not entered correctly select Correct Patient ID press Enter and repeat the previous step 5 Holding the Test Device by the edges insert the Test Device into the Meter and press Enter The result will be displayed when the analysis is complete Note The Test Device must be inserted into the Meter within 30 minutes from the time the patient specimen was added A delay longer than 30 minutes may cause the results to be invalid and blocked out on the printout STEP 3 Read the Results dr Results may be printed by pressing the Print button 2 Discard the Test Device after release from the Meter 3 A blocked out result indicates the result was invalid and the test should be repeated 2011 Alere All rights reserved 5 Results The Meter measures the target analyte automatically The result is displayed on the screen The operator has the option to print the results A number in pg mL represents the amount of BNP present in the sample For additional information refer to the Alere Triage Meter User Manual e The BNP range reported by the test system is 5 pg mL to 5000 pg mL Standardization The Alere Triage BNP Test has been standardized using a purified protein preparation of BNP based on the mass concentration of the analyte present in EDTA anticoagulated plasma Quality Control Considerations Every Alere Triage BNP Test i
18. esult will be displayed printed when complete Each parameter should pass before patient testing is performed 7 Remove the QC Device from the Meter and place in the QC Device Box DO NOT DISCARD THE QC DEVICE Note If the QC Device or external controls do not perform as expected review the above instructions to see if the test was performed correctly repeat the test or contact Alere or your local Alere representative refer to Contact Alere section Refer to the Alere Triage Meter User Manual for a complete description of the quality control system CLIA Considerations The Alere Triage BNP Test is a CLIA waived test system for whole blood only Each laboratory or testing site using the Alere Triage BNP Test must have a CLIA Certificate of Waiver before starting testing To obtain a Certificate of Waiver call your state department of health or contact Alere for an application Form CMS 116 Alere San Diego Inc can provide the phone number of your state department of health and assist you in filling out the application 2011 Alere All rights reserved 7 The Alere Triage BNP Test is a waived test so long as it is used according to the instructions set in the Package Insert Any modification by the laboratory to the test system or the test system instructions will result in this test no longer meeting the requirements for waived categorization A modified test is considered to be high complexity and is subject to all applicab
19. g foil pouch Lele Use EDTA whole blood or plasma sample only Add sample here GER Peel open here 2011 Alere All rights reserved 23 Contact Alere Alere Product Support Contact one of the following Alere Product Support Care Centers or your local distributor if you have any questions regarding the use of your Alere product You may also contact us at www alere com Region E Mail Address Europe amp Middle East 44 161 483 9032 EMEproductsupport alere com Asia Pacific 61 7 3363 7711 APproductsupport alere com Africa Russia amp CIS 972 8 9429 683 ARCISproductsupportQalere com Latin America 57 01800 094 9393 LAproductsupport alere com Canada 1 613 271 1144 CANproductsupport alere com US 1 877 308 8287 USproductsupport alere com Alere Customer Service Contact the following Alere Service Care Center or your local distributor for order and billing assistance You may also contact us at www alere com Phone 1 877 441 7440 24 2011 Alere All rights reserved E Mail Address GlientservicesQalere com Limited Warranty FOR THE APPLICABLE WARRANTY PERIOD ALERE WARRANTS THAT EACH PRODUCT SHALL BE I OF GOOD QUALITY AND FREE OF MATERIAL DEFECTS Il FUNCTION IN ACCORDANCE WITH THE MATERIAL SPECIFICATIONS REFERENCED IN THE PRODUCT MANUAL AND III APPROVED BY THE PROPER GOVERNMENTAL AGEN
20. iastolic dysfunction Am J Med 111 274 279 2001 Omland T Aakvaag A Bonarjee V V S Caidahl K Lie R T Nilsen D W T Sundsfjord J A and Dickstein K Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long term survival after acute myocardial infarction Circulation 93 1963 1969 1996 Richards A M Nicholls M G Yandle T G Ikram H Espiner E A Turner J G Buttimore R C Lainchbury J G Elliott J M Frampton C Crozier G and Smyth D W Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction Heart 81 114 120 1999 Stein B C and Levin R I Natriuretic peptides physiology therapeutic potential and risk stratification in ischemic heart disease Am Heart J 135 914 923 1998 Wallen T Landahl S Hedner T Nakao K and Saito Y Brain natriuretic peptide predicts mortality in the elderly Heart 77 264 267 1997 Darbar D Davidson N C Gillespie N Choy A M J Lang C C Shyr Y McNeill G P Pringle T H and Struthers A D Diagnostic value of B type natriuretic peptide concentrations in patients with acute myocardial infarction Am J Cardiol 78 284 287 1996 2011 Alere All rights reserved 27 27 Doust J A Pietrzak E Dobson A and Glasziou P How well does B type natriuretic peptide predict death and cardiac events in patients with heart failure systematic
21. ility in Patients with Heart Failure BNP concentrations measured at admission and or discharge in patients with heart failure provide prognostic information about the patient s risk for death or rehospitalization A systematic review of studies investigating BNP for prognostic utility in patients with heart failure concluded that every 100 pg mL increase in BNP concentration was associated with a 35 increase in the relative risk of death and that admitted heart failure patients whose BNP values did not decrease over the course of their treatment are at a particularly high risk of death or a cardiovascular event The authors also found that higher BNP concentrations in asymptomatic patients were prognostic for future death or cardiovascular events Vrtovec et al and Harrison et al studied heart failure patients at the time of presentation and found that patients with higher BNP concentrations gt 1 000 pg mL and gt 480 pg mL respectively had a significantly higher risk of all cause cardiac and pump failure death and cardiac related readmissions 8 9 Cheng et al and Bettencourt et al studied admitted heart failure patients receiving treatment and found that patients who did not experience death or readmission within 30 days or 6 months exhibited a decrease in BNP concentrations from admission to discharge while patients whose BNP concentration did not decrease from admission to discharge were at significantly higher risk for adverse events 0
22. ini M Ravkilde Y Main J Wu A H Tate J Pagani F Christenson R H Jaffe A S Committee on Standardization of Markers of Cardiac Damage of the IFCC Quality specifications for B type natriuretic peptide assays Clin Chem 51 486 496 1995 Wilkins M Red do J and Brown L The natriuretic peptide family Lancet 349 1307 1310 1997 Stein B and Levin R Natriuretic peptides physiology therapeutic potential and risk stratification in ischemic heart disease Am Heart J 135 914 923 1998 Davidson N C Struthers A D Brain natriuretic peptide J Hypertension 12 No 4 329 336 1994 Espiner E A Richards M Yandle T G Nicholls M G Natriuretic Hormones Clinical Disorders of Fluid and Electrolyte Metabolism 24 481 509 1995 Guyton Arthur C Textbook of Medical Physiology Philadelphia W B Saunders Co 1991 pp 205 219 Espiner E A Physiology of natriuretic peptides J Internal Med 235 527 541 1994 22 2011 Alere All rights reserved Glossary of Symbols GG LOT YYYYMMDD Do not reuse Use by Batch code Catalog number SES CSC Manufacturer for use Authorized representative in In Vitro diagnostic medical Bi Store at 2 8 C the European Community device TEST DEVICE CONT a en Test Device Contents Transfer pipette fy Patient number oO D Printer paper CODE CHIP module SL Add sample immediately after openin
23. iration date printed on the outside of the box e Carefully follow the instructions and procedures described in this insert and the quick 2 2011 Alere All rights reserved reference instruction Optimal results will be achieved by performing testing at temperatures between 20 24 C 68 75 F If results from multiple specimens from the same patient will be compared it is recommended to maintain a consistent sample type whole blood or plasma Sample dilution is not recommended The use of non Alere Controls and Calibration Verification materials is not recommended Keep the Test Device in the sealed pouch until ready for immediate use Discard after single use The transfer pipette should be used for one patient specimen only Discard after single use Patient specimens used Test Devices and used transfer pipettes may be potentially infectious Proper handling and disposal methods should be established by the laboratory in accordance with local state and federal regulations The Alere Triage BNP Test should not be used as absolute evidence for CHF The results should be interpreted along with clinical findings and other laboratory test results Blood concentrations of BNP may be elevated in patients who are experiencing a heart attack patients that are candidates for renal dialysis and patients that have had renal dialysis Storage and Handling Requirements Store the Test Devices in a refrigerator at 248 C 35 46 F
24. ity as an aid in the diagnosis of patients with CHF and preserved systolic function CHF PSF generally referred to as diastolic dysfunction 2 The diagnostic utility of BNP in CHF PSF patients was determined from the clinical study data by determining the area under the ROC curve for individuals without CHF versus 155 individuals with CHF that had ejection fractions gt 50 The area under the curve is 0 934 0 012 which indicates that the test is effective as an aid in the diagnosis of CHF in patients with preserved systolic function An age matched analysis of the clinical data was performed with thefollowing common age distribution in the groups offindividuals with and withouteCHF individuals less than 35 years old comprise 3 of the total number of observations individuals age 35 to 44 comprise 6 of the total individuals age 45 to 54 comprise 11 of the total individuals 55 to 64 years old comprise 22 of the total individuals 65 to 74 years old comprise 26 of the total and individuals 75 years and older comprise 32 of the total This age distribution reflects the prevalence of CHF within the age groups and genders according to data published by the American Heart Association in the 2000 Heart and Stroke Statistical Update and also reflects the age structure of the United States population according to data published by the National Center for Health Statistics in Health United States 2000 The resulting area under the ROC curve is
25. layed on the Meter screen in approximately 15 minutes from the addition of specimen The analysis is based on the 2011 Alere All rights reserved 1 amount of fluorescence the Meter detects within a measurement zone on the Test Device A greater amount of fluorescence detected by the Meter indicates a higher BNP concentration in the specimen All results are stored in the Meter memory to display or print when needed If connected the Meter can transmit results to the lab or hospital information system Reagents and Materials Provided The Alere Triage BNP Test contains all reagents necessary for the quantification of BNP in EDTA anticoagulated whole blood or plasma specimens The Test Device contains e Murine monoclonal antibodies and polyclonal antibodies against BNP e Fluorescent dye Stabilizers Alere Triage BNP Test Catalog 98000XR Kit contains TEST DEVICE 25 Test Devices 25 Transfer Pipettes 1 Reagent CODE CHIP Module 1 Printer Paper Roll Materials Required but Not Provided Alere Triage MeterPro Catalog 55070 or 55071 Triage MeterPlus Catalog 55040 or 55041 Alere Triage BNP Control 1 Catalog 98013XR Alere Triage BNP Control 2 Catalog 98014XR OR Alere Triage Total 5 Control 1 Catalog 88753 Alere Triage Total 5 Control 2 Catalog 88754 Warnings and Precautions For In Vitro Diagnostic Use e For use by healthcare professionals Do not use the kit beyond the exp
26. le CLIA requirements Results of Untrained User Study An untrained user study was conducted in which participants were given only the test instructions and asked to perform testing of three 3 prepared samples at three different BNP levels low medium and high in random order The participants were not given any training on the use of the test A total of 65 participants were enrolled from 3 sites representing a diverse demographic educational age gender population The table below presents the summary of the performance by the untrained users Level 1 Level 2 Level 3 Low Medium High Concentration 45 6 227 2244 Number of 65 65 65 Measurements Average 95 44 8 218 2166 Confidence Interval 43 7 45 8 213 223 2105 2227 Standard Deviation 4 1 21 7 247 CV 9 2 10 0 11 4 Observed Range 37 2 64 1 166 273 1570 2730 Concentration of BNP in a sample was an average of total number of 20 measurements by a trained laboratory professional using the Triage BNP Test A physician office laboratory POL study was conducted at four physician offices using 60 EDTA anticoagulated whole blood samples from apparently healthy volunteers Each sample was tested by two physician office employees and by a trained laboratory professional Results from the POL employees were compared to the trained laboratory professional s results using a Deming regression The results of the regression analysis wer
27. ne measurements are shown below Percent Recovery Donor 1 Donor 2 Donor 3 Donor 4 Level 1 94 1 95 9 91 8 100 4 Level 2 85 6 97 0 90 1 94 2 Level 3 104 7 101 7 97 8 105 0 Level 4 102 8 93 8 98 9 105 8 2011 Alere All rights reserved 9 Percent Recovery Donor 1 Donor 2 Donor 3 Donor 4 Level 5 92 0 86 4 94 3 99 0 Level 6 102 7 108 3 100 1 93 7 Level 7 110 7 106 5 110 3 104 6 Level 8 101 2 111 8 123 4 105 0 Level 9 106 3 98 6 93 1 92 3 Analytical Sensitivity The analytical sensitivity or lowest detectable concentration that is distinguishable from zero for the Alere Triage BNP Test was determined by testing a zero calibrator 20 times each using 3 lots of reagents and 5 Meters on 5 days The average 95 confidence limit of the analytical sensitivity of the Alere Triage BNP Test was less than 5 pg mL Interfering Substances Hemoglobin up to 1 000 mg dL lipids cholesterol up to 1 000 mg dL and triglycerides up to 1 000 mg dL or bilirubin up to 20 mg dL added to plasma specimens containing BNP did not interfere with the recovery of BNP The hematocrit was varied between 27 and 51 with no significant effect on the recovery of BNP Analytical Specificity Pharmaceuticals The following drugs were evaluated for potential cross reactivity and interference in the Alere Triage BNP Test All drugs were tested at concentration
28. rPro are trademarks of the Alere group of companies 2011 Alere All rights reserved 25 TM Distributed by CLiAwalved com San Diego CA 82121 tel 858 481 5031 toll free 886 882 7738 www cliawaived com Made in USA ENSRC26159enA 2011 Alere All rights reserved PN 26159en Rev A 2011 03 CE MDSS GmbH Schiffgraben 41 30175 Hannover Germany
29. retic peptide as a novel cardiac hormone in humans Evidence for an exquisite dual natriuretic peptide system atrial natriuretic peptide and brain natriuretic peptide J Clin Invest 87 1402 1412 1991 Clerico A lervasi G Del Chicca M G Emdin M Maffei S Nannipieri M Sabatino L Forini F Manfredi C and Donato L Circulating levels of cardiac natriuretic peptides ANP and BNP measured by highly sensitive and specific immunoradiometric assays in normal subjects and in patients with different degrees of heart failure J Endocrinol Invest 21 170 179 1998 deLemos J A Morrow D A Bentley J H Omland T SabatinesM S McCabe C H Hall C Cannon C P and Braunwald E The prognostic value of B type natriuretic peptide in patients with atut eoronary syndromes New Engl J Med 345 1014 1021 2001 Maeda K Tsutamoto T Wada A Hisanaga T and Kinoshita M Plasma brain natriuretic peptide_as biochemical marker of high left ventricular end diastolic pressure inmpatients with symptomatic left ventricular dysfunction Am Heart J 135 825 832 1998 Dao Q Krishnaswamy P Kazanegra R Harrison A Amirnovin R Lenert L Clopton P Alberto J Hlavin P and Maisel A Utility of B type natriuretic peptide in the diagnosis of congestive heart failure in an urgent care setting J Am Coll Cardiol 37 379 385 2001 Mukoyama M Nakao K Saito Y Ogawa Y Hosoda K Suga
30. review BMJ 330 625 633 2005 28 Vrtovec B Delgado R Zewail A Thomas C D Richartz B M and Radovancevic B Prolonged QTc interval and high B type natriuretic peptide levels together predict mortality in patients with advanced heart failure Circulation 107 1764 1769 2003 29 Harrison A Morrison L K Krishnaswamy P Kazanegra R Clopton P Dao Q Hlavin P and Maisel A S B type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea Ann Emerg Med 39 131 138 2002 30 Cheng V Kazanegra r Garcia A Lenert L Krishnaswamy P Gardetto N Clopton P and Maisel A A rapid bedside test for B type natriuretic peptide predicts treatment outcomes in patients admitted for decompensated heart failure a pilot study J Am Coll Cardiol 37 386 391 2001 31 Bettencourt P Ferreira S Azevedo A and Ferreira A Preliminary data on the potential usefulness of B type natriuretic peptide levels in predicting outcome after hospital discharge in patients with heart failure Am J Med 2002 113 215 219 2002 32 Logeart D Thabut G Jourdain P Chavelas C Beyne P Beauvais F Bouvier E and Solal A C Predischarge B type natriuretic peptide assay for identifying patients at high risk of re admission after decompensated heart failure J Am Coll Cardiol 43 635 41 2004 Other Suggested Reading Apple F S Pantegh
31. s e BNP results less than or equal to 100 pg mL are representative of normal values in patients without CHF e BNP results greater than 100 pg mL are considered abnormal and suggestive of patients with CHF e BNP results of gt 5000 pg mL are considered very high values for BNP and exceed the upper limits of the BNP test Higher BNP concentrations measured in the first 72 hours after an acute coronary syndrome are associated with an increased risk of death myocardial infarction and CHF e Higher BNP concentrations or the lack of a decreasesintthe BNR eoncentration from hospital admission to discharge indicate an increased risk of hospitalization or death in patients with heart failure Each laboratonf should establish a reference range that is representative of the patient population to be evaluated Additionally each laboratory should consider the current practice in the evaluation of patients experiencing symptoms at each institution Performance Characteristics Linearity Plasma specimens anticoagulated with EDTA from four apparently healthy individuals were spiked with purified BNP to final concentrations of 5000 pg mL Each spiked plasma specimen was diluted gravimetrically with unspiked plasma to obtain BNP values throughout the range of the Alere Triage BNP Test Linear regression analysis of the data indicates that the assay is linear throughout the measurable range of the test Recovery data representing results from ni
32. s a quantitative test that includes two internal control materials of different concentrations that are run automatically with every patient specimen external liquid control solution or proficiency testing sample If the automatic check of these built in controls shows that the control value results are within the limits set during manufacturing the Meter will report a result for the specimen being tested If the automatic check of these built in controls shows that the control value results are not within the limits set during manufacturing a test result will not be reported Instead the Meter will display a warning or error message that is described in the Alere Triage Meter User Mantal Good Laboratory Practice suggests that external controls should be tested with each new lot or shipment of test materials or every 30 days and as otherwise required by your laboratory s standard quality control procedures Controls should be tested in the same manner as if testing patient specimens Wien running patient specimens or external controls if an analyte fails for any reason built in control failure or an external control out of range no patient results will be reported Users should foll6w government guidelines for example federal state or local and or accreditation requirements for quality control Performing Alere Triage System Quality Control QC Device Use the QC Device to ensure proper function of the Meter Perform QC Device
33. s representing the blood concentrations that would result from a maximal therapeutic dose and at least twice the maximal therapeutic dose There was no significant interference with the BNP measurement nor was there any assay cross reactivity Abciximax Dopamine Nitroglycerin Acetaminophen Enalapril Maleate Noraminopyrine Acetylsalicylic acid Dipyridamole Oxazepam Activase Erythromycin Oxytetracycline Allopurinol Furosemide Phenobarbital Amiodarone Eptifibatide Phenytoin Ampicillin Hydralazine Probenecid Ascorbic Acid Hydrochlorothiazide Procainamide Amlodipine Besylate Heparin Propanolol Atenolol Isosorbide dinitrate Quinidine 10 2011 Alere All rights reserved Caffeine Indomethacin Simvastin Captopril Lisinopryl Sulfamethoxazole Cyclosporine Lovastatin Theophylline Chloramphenicol Methyldopa L thyroxine Clopidogrel Bisulfate Mirinone lactate Trimethoprim Proteins and Peptides Diclofenac Nicotine Verapamil Digoxin Nicotinic Acid Warfarin Diltiazem Niphedipine Digitoxin Nitrofurantoin The following proteins and peptides were evaluated for potential cross reactivity and interference with the Alere Triage BNP Test at the concentrations indicated below There was no significant interference with the BNP measurement nor was there any significant assay cross reactivity Reactivity with Related Proteins and Peptides Substance Concentration
34. testing for the following conditions Upon initial setup of the Meter e Each day of patient testing e When the Meter has been transported or moved Whenever there is uncertainty about the performance of the Meter e Whenever required by your laboratory s quality control requirements Do not discard the Alere Triage QC Device and associated CODE CHIP module Store them in the QC Device Box Refer to the Alere Triage User Manual for complete instructions on use of the QC Device 1 The first time a new QC Device is run in the Meter install the QC Device CODE CHIP module The QC Device CODE CHIP module data is stored in the Meter memory The QC Device CODE CHIP module does not need to be reinstalled after the first time 6 2011 Alere All rights reserved 77 Ka QC Device CODE CHIP Module a From the main screen select Install New Code Chip and press Enter b Place the QC Device CODE CHIP module into the lower left front corner of the Meter Follow the prompts on the screen c Remove the QC Device CODE CHIP module from the Meter when data transfer is complete d Place the QC Device CODE CHIP module back into e OC Device Box for storage From the main creen select Run Test and press Enter If User ID is enabled enter your User ID number and press Enter Select OG Devioe and press Enter Insert QC Device into the Meter and press Enter ER E Ze S h A Pass or Fail r
35. ty and have symptoms with ordinary physical activity Class III patients have a marked limitation of physical activity andyhave symptoms with less than ordinary physical activity but not at rest Class V patients are winable to perform any physical activity without discomfort Reports nthe scientifie literature have indicated that there is a relationship between BNP and the severity of CHF 2 7 An analysis of NYHA classificationfand BNP concentrations from the clinical study data indicate that there is a relationship between be severity of the clinical signs and symptoms of CHF and BNP concentration These data are consistent with the previous reports in the literature and further demonstrate that BNP measurements along with NYHA classification can provide additional objective information to the physician about the patient s CHF severity BNP vs NYHA Classification 1200 1000 oo Q CH 400 200 Median BNP Concentration pg mL O CH CH Non NYHA NYHA NYHA NYHA CHF Class Class II Class Ill Class IV 2011 Alere All rights reserved 15 Diagnostic Utility Various studies have demonstrated that circulating BNP concentrations increase with the severity of CHF based on the NYHA classification BNP concentrations are much lower than ANP concentrations normally but as the severity of CHF advances according to the NYHA classification plasma BNP increases progressively more than respective ANP values S Therefore BNP is
36. y be stored at room temperature or chilled for testing within 7 hours of collection Plasma specimens may be stored chilled for testing within 24 hours of collection Transport specimens at room temperature or chilled and avoid extreme temperatures If testing cannot be completed within 24 hours the plasma should be separated and stored at 20 C until it can be tested Avoid using severely hemolyzed specimens whenever possible If a specimen appears to be severely hemolyzed another specimen should be obtained and tested Test Procedure Lot Calibration Using the Reagent CODE CHIP Module When a new lot of Test Devices is opened the calibration and expiration data for that lot of Test Devices must be transferred to the Meter before patienttesting Use the Reagent CODE CHIP module supplied with the new lot of lest Devices to transfer the data to the Meter Reagent CODE CHIP Module Perform one time for each new lot of Test Devices i 2 From the main screen select Install New Code Chip Press Enter Place the Reagent CODE CHIP module into the lower left front corner of the Meter and follow the prompts on the screen Remove the Reagent CODE CHIP module from the Meter when data transfer is complete Place the Reagent CODE CHIP module back into its original container for storage 4 2011 Alere All rights reserved Testing Patient Specimens Procedural Notes For each day of patient testing perform QC
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