Predictive power. Multiplate analyzer

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1 Predictive power Multiplate analyzer

2 Multiplate analyzer Strengthening Roche s hemostasis portfolio With a series of industry firsts and innovative applications for early disease detection and monitoring, Roche is introducing yet another novel product to its hemostasis portfolio. Whilst Roche`s responsive laboratory coagulation roadmap is going to deliver platforms with outstanding productivity, the Multiplate system focuses on addressing a significant unmet medical need. Improving the assessment of a patient s platelet function status is key for hematologists, cardiologists and anesthetists in order to support clinical decisions in cardiology, surgery and intensive care. With the acquisition of Verum Diagnostica GmbH Roche gains an innovative and unique platelet function testing solution. Carried by a strong medical momentum its best in class predictivity of thrombotic and bleeding risk allows to tailor anti-platelet therapy and stratify patients at risk for bleeding. Supported by a highly standardized testing technology the Multiplate system has the potential to set new standards in patient care. Therefore Multiplate is a perfect complement to Roche`s ambition to combine true innovation with proven medical and diagnostic expertise into a new hemostasis portfolio.

3 Predictive power Multiplate analyzer Medical momentum > 200 Medline-listed publications with Multiplate Consensus paper of Working Group on High-On-Treatment-Platelet-Reactivity featuring Multiplate Guidelines introducing recommendations for platelet function testing in CABG and PCI for patients treated with clopidogrel Best predictivity for tailored anti-platelet therapy Approx. 20% of patients do not respond adequately to clopidogrel Other potent drugs have been introduced, which have advantages and disadvantages compared to clopidogrel and which are up to fold more expensive compared to clopidogrel Patients showing a low-response to clopidogrel in Multiplate analysis have shown a 5-10 fold risk for ischemic complications Patients with a high response to clopidogrel have shown a 2.6 fold risk for major bleeding Successful experiences using the tailoring of anti-platelet therapy aided by Multiplate analysis have been reported by several groups Consistent results Standardised and fast test procedure utilizing whole blood, easy to use, low blood volume/test Broad menu of CE marked tests for various applications 5 channel analyzer with high throughput High sensitivity and dynamic range Twin sensors for quality control Best predictivity for stratification of bleeding risk Patients with impaired platelet function according to Multiplate analysis have an increased risk for intra- and postoperative bleeding complications and/or transfusion requirements Multiplate can contribute to an improved management of bleeding complications in surgical procedures

4 Platelet function testing Overview Blood platelets play a pivotal role in physiological hemostasis, but also in the development of arterial thrombosis (myocardial infarction and stroke). Platelet function testing is utilized in the analysis of inherited and acquired platelet function disorders, in the analysis of platelet function in anesthesia and intensive care, and for monitoring of platelet function antagonists. Analysis of platelet disorders Various drugs and diseases, as well as genetic factors can lead to platelet dysfunction, which may cause a transient or permanent bleeding tendency. The Multiplate analyzer can detect platelet dysfunction and thus aid in the therapeutic management of such patients. Platelet function in anesthesia and intensive care Platelet dysfunction can lead to severe bleeding complications. The detection or exclusion of platelet dysfunction before invasive procedures or in bleeding patients can support the risk stratification and management in these situations. Monitoring of anti-platelet therapy Anti-platelet drugs are among the most frequently administered drugs in modern medicine. A combination of aspirin with an ADP receptor antagonist (clopidogrel, prasugrel or ticagrelor) is the mainstay antiplatelet therapy for patients with acute coronary syndromes (ACS) and/or coronary interventions with stent placement. The challenge of compliance and low response In the increasingly elderly and multimorbid patient population the issue of adherence to prescribed medications is of crucial importance. Through the ability to monitor and thus control anti-platelet therapy the Multiplate system can support the management of these patients. In addition anti-platelet drugs do not always act properly, even when taken appropriately by the patient. Reduced absorption, as frequently witnessed in patients suffering from cardiac shock, as well as an impaired metabolisation of the drug (especially clopidogrel) due to genetic factors, comedications or other confounders can lead to a diminished anti-platelet response to the medication ( low response ). In large prospective evaluations it was shown with Multiplate results that up to 20% of patients do not respond adequately to clopidogrel treatment. These patients have a 5-10 fold increased risk for stent thrombosis, stroke and q-wave myocardial infarction 1-4 following percutaneous coronary interventions (PCI). Novel ADP P2Y12 receptor antagonists Prasugrel and ticagrelor are novel P2Y12 receptor antagonists that act more potently and more consistently than clopidogrel. This includes an enhanced risk of fatal bleedings (prasugrel) and higher risk for non-cabg related major bleedings and dyspnea (ticagrelor). 5,6 At the expense of a higher rate of bleeding or undesired side effects not all patients are likely to benefit from the use of these drugs compared to the standard therapy with clopidogrel. In addition prasugrel and ticagrelor are up to times more expensive than clopidogrel. 7 In summary, the question of which ADP receptor inhibitor to use has pharmacological as well as socio-economic implications with advantages and disadvantages for all three available drugs.

5 Best predictivity for tailored anti-platelet therapy Adequate platelet inhibition is of pivotal importance for the clinical management of patients at high risk of arterial thrombosis, e.g. after stent placement or in acute coronary syndrome (ACS). Clopidogrel or Aspirin low-response (reduced effect of the prescribed drug in the patient) is associated with a significantly increased risk of arterial thromboembolism. Clopidogrel low-response is found in approximately 20% of patients. The Multiplate system is highly sensitive for the detection of response to Aspirin, clopidogrel, prasugrel, IIbIIIa receptor antagonists and other platelet inhibitors. Multiple prospective studies have shown the Multiplate analysis best predicitivity to determine patients at risk of atherothrombotic events: A large (n=1608) prospective study evaluating the clinical impact of clopidogrel reponse in the setting of PCI has shown that clopidogrel low-responders exhibited a 9.4 fold increased risk of early stent thrombosis 1 whereas a regular responders risk of stent thrombosis was very low (0,2%) The Multiplate system better predicts stent thrombosis compared to the flow cytometric VASP assay, 4 and stent thrombosis compared to genetic testing of polymorphisms of CYP2C19 gene alleles 8 The prognostic value of Multiplate analysis was also demonstrated in neuroradiology 9 In a consensus publication the Multiplate test is listed with unmatched odds ratios to determine risk enhancement in clopidogrel low responders 10 Multiplate analysis is predictive for both thrombotic and bleeding risk after PCI 11 Evidence is available confirming that low-response to clopidogrel is a modifiable risk factor and Multiplate guided antiplatelet therapy has the potential to improve patient outcome: Routine PF testing [with Multiplate ] is useful for guidance of tailored antiplatelet treatment and switching to prasugrel markedly reduces stent thrombosis risk in high platelet reactivity patients on clopidogrel. 12 Routine tailoring of antiplatelet therapy with MEA [Multiplate ] is capable of eradicating early definite stent thrombosis 13 tailoring the dose of clopidogrel with the Multiplate analyzer significantly reduced the risk of ischemic complications as compared to a uniform dosing strategy of 75 mg clopidogrel in an all-comer cohort of patients after PCI. 14 Recent PCI guidelines are supporting PFT with a class IIb recommendation: In patients treated with clopidogrel with high platelet reactivity, alternative agents, such as prasugrel or ticagrelor, might be considered (Level of evidence: C) 15

6 Best predictivity for stratification of bleeding risk Blood platelet function plays a pivotal role in hemostasis during surgery and following traumatic injuries. Platelet dysfunction can lead to bleeding complications, increased transfusion of blood products and occasionally the need for surgical re-exploration. Therefore, in patients undergoing surgery the ability to assess platelet function before, during and after the intervention is desirable. Causes of platelet dysfunction Platelet dysfunction may be caused by the ingestion or administration of anti-platelet drugs, concomitant medications such as antibiotics or anti-rheumatics, or by patient comorbidities. Stratification of bleeding risk Several studies have shown the ability of the Multiplate analyzer to detect patients with an increased risk for bleeding complications and/or transfusion requirements during surgery Testing the effects of anti-platelet drugs Aspirin and ADP receptor antagonists can be sensitively assessed using the Multiplate analyzer. Patients undergoing cardiac surgery who demonstrate a strong anti-platelet effect of clopidogrel have a significantly higher risk to experience major bleeding compared to individuals who express a weak or lack of anti-platelet effect. 16 Several studies have shown that Multiplate analysis can effectively determine the recovery from the effects of anti-platelet drugs such as aspirin 21,22 clopidogrel and prasugrel. 23 Reduced need for preoperative waiting periods Clopidogrel should normally be discontinued for 5 days before a surgical procedure.. According to the 2011 blood conservation clinical practice guidelines platelet function testing may be used to detect clopidogrel non-responders who may not require a preoperative waiting period after clopidogrel discontinuation. 24 This can lead to reduced hospitalization times and considerable cost savings. Citations from studies using the Multiplate analyzer: The multiple electrode aggregometry ADP test in patients under thienopyridine treatment and undergoing cardiac surgery is associated with postoperative bleeding and platelet transfusion and provides an accurate preoperative prediction of postoperative bleeding risk. Ranucci et al. Ann Thorac Surg 2011;91: The inclusion of MEA in our POC supported algorithm allowed for timely and specific detection of platelet dysfunction. Goerlinger K et al. Anesthesiology Dec;115(6): POC-guided therapy was associated with lower Fresh Frozen Plasma and Platelet Concentrates usage and costs as well as an improved clinical outcome in this prospective randomized single-center study. Weber CF et al. Anesthesiology in press

7 Consistent results The Multiplate analyzer is an easy to use, compact system. It deploys a Windows based interface programmed with a comprehensive menu of whole blood platelet function assays. Its flexible design allows for a fast turn around time of 10 minutes per test a period. Combined with its 5 channels, this permits the processing of up to 30 tests per hour that require only 300 µl blood per analysis. Broad menu of tests for a wide spectrum of applications With its menu of six CE marked procedures (ADPtest, ASPItest, TRAPtest, COLtest, RISTOtest, ADPtest HS) the Multiplate system is sensitive for the monitoring of platelet function inhibitors determines platelet dysfunction before invasive procedures and in bleeding patients is suitable for the detection of hereditary or acquired platelet function disorders 25 is sensitive for von Willebrand Disease (comparable to optical aggregometry) 26 is used in various research models, the functional determination of Heparin induced thrombocytopenia in whole blood and various animal models Patented Detection Technology The signal reaction in the Multiplate analyzer is triggered by the adhesion of activated platelets to the surfaces of the sensor electrodes that induces an increase of electrical resistance. Each test cell incorporates two pairs of sensors (multiple electrode aggregometry = MEA), serving as a built-in quality control. Citations from studies using the Multiplate analyzer: MEA is a fast and standardized method to individually assess platelet function prior to and after clopidogrel treatment. Sibbing D et al. Thromb Haemost 2008; 99: As a whole blood method, Multiplate avoids the handling of blood samples, with the advantage that the cellular environment remains unchanged, and allows rapid evaluation of platelet aggregation by ready-to-use test cuvettes with 2 independent sensor units. In addition, the use of whole blood tests platelet function under more physiologic conditions. Paniccia R et al. Am J Clin Pathol Jun;131(6): The effect size by use of multiple electrode aggregometry (MEA) was consistently greater for clopidogrel and aspirin as compared to other methods. Siller-Matula JM et al. Thromb Haemost Aug;102(2): MEA accurately detected the time-dependent antiplatelet effect of aspirin and provided reproducible platelet aggregation results. Jambor C et al. Anesth Analg 2009;109: A further advantage of this method [Multiplate ] allows the clinician to use small amounts of whole blood. Halimeh S et al. Klin Padiatr 222(3), 2010;

8 Medical momentum With its introduction to the market in 2005, the Multiplate analyzer has witnessed great momentum in terms of adoption and medical consensus on its value. Since that time over 200 medline listed publications have been generated with the Multiplate system, validating the growing interest and adoption of the Multiplate analyzer in clinical practice. The MEA principle of the Multiplate analyzer has been incorporated into the 2008 revision of the Clinical and Laboratory Standards Institute (CLSI) approved guideline on platelet function testing. 36 Large prospective studies such as that performed by the ISAR group in a cohort of 1608 patients associated Multiplate results with risk for stent thrombosis and other ischemic events in PCI patients. 1 The JACC consensus paper of the high on treatment platelet reactivity working group made reference to the Multiplate analyzer with unmatched odds ratios to determine patients at enhanced thrombotic risk. 10 Platelet function testing is further supported by guidelines. The 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions Guideline for Percutaneous Coronary Intervention 15 includes platelet function testing for anti-platelet drug selection with a class IIb recommendation: Platelet function testing may be considered in patients at high risk for poor clinical outcomes. (Level of Evidence: C). In patients treated with clopidogrel with high platelet reactivity, alternative agents, such as prasugrel or ticagrelor, might be considered. (Level of Evidence: C) Platelet function testing has also received a Class IIb recommendation by the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists in their 2011 blood conservation clinical practice guidelines. 24 Point-of-care testing for platelet ADP responsiveness might be reasonable to identify clopidogrel nonresponders who are candidates for early operative coronary revascularization and who may not require a preoperative waiting period after clopidogrel discontinuation. (Level of evidence C). As more evidence is gathered to demonstrate the benefits of anti-platelet therapy aided by the use of the Multiplate analyzer, there is further room for guidelines recommendations to become stronger.

9 Multiplate analyzer Strengthening Roche s hemostasis portfolio Platelet function testing Extended routine testing Multiplate analyzer cobas t 411 coagulation analyzer cobas t 611 coagulation analyzer Patient and professional monitoring cobas IT applications Routine and special testing CoaguChek XS system CoaguChek XS Plus system CoaguChek XS Pro system Next generation coagulation analyzers Laboratory automation cobas p 612 pre-analytical system MODULAR PRE-ANALYTICS EVO

10 References 1 Sibbing, D., Braun, S., Morath, T., Mehilli, J., Vogt, W., Schömig, A., Kastrati, A., von Beckerath, N. (2009). Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. Mar 10;53(10): Sibbing, D. et al. (2010). Clopidogrel response status assessed with Multiplate point-ofcare analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost. Jan;103(1): Schulz, S. et al. (2010). Platelet response to clopidogrel and restenosis in patients treated predominantly with drug-eluting stents. Am Heart J. Aug;160(2): Siller-Matula, J.M. et al. (2010). Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay. J Thromb Haemost. Feb;8(2): Wiviott, S.D. et al. (2007). N Engl J Med; 357: Wallentin, L. et al. (2009). N Engl J Med; 361: NHS - New drug evaluation: No 109, 01 (2011). Regional Drug and Therapeutics Centre, 8 Siller-Matula, J.M. et al. (2012). Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost. Apr;10(4): Müller-Schunk, S. et al. (2008). Monitoring of clopidogrel-related platelet inhibition: correlation of nonresponse with clinical outcome in supra-aortic stenting. Am J Neuroradiol.; 29(4): Bonello, L. et al. (2010). Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol Sep 14;56(12): Sibbing, D. et al. (2010). Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol. Jul 20;56(4): Sibbing, D. et al. (2012). J Am Coll Cardiol;59;E Christ, G. et al. (2011). Eurointervention; Vol 7;Suppl M. 14 Hazarbasanov, D. et al. (2012). Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. J Thromb Thrombolysis. Jan 15. [Epub ahead of print]. 15 Levine, G.N. et al. (2011). ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. Dec 6;124(23): Ranucci, M. et al. (2011). Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines. Ann Thorac Surg. Jan;91(1): Wang, H., Leff, J., Nair, S., Shore-Lesserson, L. (2012). Use of multiple electrode aggregometry (MEA) in predicting postoperative bleeding and transfusion requirements after cardiopulmonary bypass surgery, a prospective observational study. Anesth Analg;114(suppl); Reece, M.J. et al. (2011). Near-patient platelet function testing in patients undergoing coronary artery surgery: a pilot study. Anaesthesia. Feb;66(2): Rahe-Meyer, N. et al. (2008). An evaluation of cyclooxygenase-1 inhibition before coronary artery surgery: aggregometry versus patient self-reporting. Anesth Analg. Dec;107(6): Rahe-Meyer, N. et al. (2009). Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand. Feb;53(2): Jámbor, C. et al. (2009). Whole blood multiple electrode aggregometry is a reliable point-of-care test of aspirin-induced platelet dysfunction. Anesth Analg.;109(1): Jámbor, C. et al. (2011). Multiple electrode whole blood aggregometry, PFA-100, and in vivo bleeding time for the point-of-care assessment of aspirin-induced platelet dysfunction in the preoperative setting. Anesth Analg. Jul;113(1): Bernlochner, I. et al. (2012). A prospective randomized trial comparing the recovery of platelet function after loading dose administration of prasugrel or clopidogrel. Platelets. Feb Ferraris, V.A. et al. (2011). update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. Mar;91(3): Awidi, A. et al. (2009). Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia. Platelets. Aug;20(5): Valarche, V. et al. (2011). Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. J Thromb Haemost. Aug;9(8): Ferrer-Marin, F. et al. (2011). Effects of in vitro adult platelet transfusions on neonatal hemostasis. J Thromb Haemost. May;9(5): Sibbing, D. et al. (2010). Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. Feb 2;121(4): Morel-Kopp, M.C. et al. (2012). Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study. Thromb Haemost. Mar;107(3): Elalamy, I. et al. (2009). Heparin-induced multiple electrode aggregometry: a potential tool for improvement of heparin-induced thrombocytopenia diagnosis. J Thromb Haemost. Nov;7(11): Kalbantner, K. et al. (2010). Measurement of platelet function in dogs using a novel impedance aggregometer. Vet J. Aug;185(2): Baumgarten, A. et al. (2010). Measurement of platelet aggregation in ovine blood using a new impedance aggregometer. Vet Clin Pathol. Jun;39(2): Czura, C.J. et al.(2010). Vagus nerve stimulation regulates hemostasis in swine. Shock. Jun;33(6): Kirkeby, A. et al. (2008). High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO). Thromb Haemost. Apr;99(4): Fröbert, O. et al. (2010). Platelet function in brown bear (Ursus arctos) compared to man. Thromb J. Jun 2;8: Clinical and Laboratory Standards Institute (CLSI) document H58-A. (2008). Platelet Function Testing by Aggregometry; Approved Guideline. ISBN

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