Antonsen, Jacob

Bundgaard, Nina

Engstrøm, Thomas

Holmvang, Lene

Iversen, Kasper

English

Copenhagen University Research Information System

u n i ve r s i t y  o f  co pe n h ag e n  Københavns UniversitetPosture changes platelet inhibition time after ingestion of prasugrelAntonsen, Jacob; Bundgaard, Nina; Holmvang, Lene; Engstrøm, Thomas; Iversen, KasperPublished in:Danish Medical JournalPublication date:2018Document versionPublisher's PDF, also known as Version of recordDocument license:UnspecifiedCitation for published version (APA):Antonsen, J., Bundgaard, N., Holmvang, L., Engstrøm, T., & Iversen, K. (2018). Posture changes plateletinhibition time after ingestion of prasugrel. Danish Medical Journal, 65(10), [A5504].Download date: 03. Feb. 2020Dan Med J 65/10  October 2018 1DANISH MEDICAL JOURNALPosture changes platelet inhibition time  after ingestion of prasugrelJacob Antonsen1, Nina Bundgaard1, Lene Holmvang2, Thomas Engstrøm2 & Kasper Iversen3The use of percutaneous coronary intervention (PCI) over fibrinolysis has been proven to reduce the mortal-ity and morbidity for patients with acute myocardial in-farction [1]. For PCI to have a positive effect on mortal-ity, it needs to be conducted no longer than 90-120 min. after the first medical contact [2].Numerous studies have proven the importance of reducing pre- as well as post-procedural platelet reac-tivity in patients undergoing PCI [3, 4]. Efforts have been put into finding a “cut-off” target value for point-of-care (POC) assays of platelet reactivity used to evalu ate the risk of complications after PCI [5-7]. The oral thienopyridine, prasugrel, has been proven to be superior to clopidogrel in the treatment of pa-tients with acute coronary syndrome due to a faster and more consistent platelet inhibition [8]. Prasugrel is ORIgINAL ARtICLE1) Department of Surgery,  Bispebjerg Hospital2) Department  of Interventional Cardiology,  Rigshospitalet3) Department of Cardiology,  Herlev Hospital, DenmarkDan Med J 2018;65(10):A5504ABSTRACTInTRoduCTIon: Several studies have suggested that supine posture during pill ingestion prolongs oesophageal transit time. Whether ingesting prasugrel in an upright position leads to reduced platelet reactivity during percutaneous coronary intervention remains unclear.MeThodS: A total of 20 people were randomly assigned to ingest 60 mg of prasugrel in either the supine or upright position. Platelet reactivity was analysed using the point-of-care assay VerifyNow. ReSulTS: In the upright position, the velocity of platelet inhibition was highest between 20 and 40 min. (Δ = 101.9 P2Y12 reaction units (PRU)). In the supine position, the highest value was seen between 40 and 60 min. (Δ = 56.85 PRU). Time to reach the cut-off for reducing peri- and post-operative risk of thrombosis showed a mean difference of 8 min. in favour of the upright group.ConCluSIonS: A trend towards faster reduction of platelet reactivity was seen when ingesting prasugrel in the upright position compared with the supine position.FundIng: This work was supported by Oda and Hans Svenningsens Foundation (grant number: BOF-10109). The foundation had no part in the collection, analysis or interpretation of data, or in the writing of the report or the decision to submit the work for publication. TRIAl RegISTRATIon: This trial was registered with clinicaltrials.gov (NCT01365741). a prodrug that is metabolised to one active metabolite (R-138727) and numerous inactive metabolites by  the hepatic cytochrome P450, isoenzymes CYP3A4, CYP2B6 and, to a lesser extent, CYP2C9 and CYP2C19. The active metabolite binds irreversibly to the platelet P2Y12 ADP receptor and inhibits platelet aggregation.Previous studies have shown that the passage of tablets through the upper gastrointestinal tract is highly variable and dependent on multiple factors in-cluding body posture at the time of ingestion [9-12].  In one study [10], 58% of tablets swallowed in the su-pine position stayed in the oesophagus for more than 5 min. Posture may influence the pharmacokinetics of orally administered drugs by affecting the rate of gas-tric emptying, intestinal motility, absorption, splanch-nic-hepatic blood flow, renal elimination, plasma vol-ume and metabolism [13].The purpose of this study was to investigate the dif-ference in degree and velocity of thrombocytic inhibi-tion between two different postures at the time of in-gestion of 60 mg prasugrel. MeThodSA total of 20 non-smoking, healthy males with no previ-ous medical history aged 20-30 years participated in this study. All participants gave their written informed consent, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The Danish National Committee on Biomedical Research Ethics and the Danish Data Protection Agency ap-proved the study (identification number H-15011038). Blood sampling: Before each experiment, a 1.7 mm (16 gauge) plastic indwelling catheter was inserted into the v. mediana cubiti and connected to a three-way stopcock and a shielded blood-collecting needle via a 10-cc plastic tube. At 20-min. intervals after ingestion of 60 mg of prasugrel, 2 ml of blood was drawn for VerifyNow anal-ysis using a citrate Vacuette. Before sampling for analy-sis, 4 ml of blood were drawn on a K3 ethylenediamine-tetraacetic acid (EDTA) tube, and after sampling the system was flushed with 0.9% saline.Ingestion: A randomised cross-over trial with two phases and a two-week washout period was conducted. Participants were randomised at their first visit to ei-ther the supine or the upright position, and thus the re- Dan Med J 65/10  October 20182DANISH MEDICAL JOURNALverse position at their next visit. Participants random-ised to the supine position were laying on a hospital bed with no head elevation. They were instructed to swallow 6 × 10 mg of prasugrel with the use of 50 ml of water, through a straw. Thereafter, they were in-structed to lie as still as possible for the duration of the experiment.The participants who were randomised to the up-right position followed the same instructions, but in-gested the pills sitting in an upright position. They maintained the upright position for 120 sec. and were then invited to lie down. Platelet function testing: The antiplatelet activity of prasugrel was tested with turbidimetric optical detec-tion (VerifyNow P2Y12 test; Accumetrics, San Diego, CA, USA) in citrate- anticoagulated whole-blood sam-ples collected every 20 min. up to 100 min. The ADP-activated platelets aggregated in the test channel on fi-brinogen-coated microbeads, and the resultant change in optical signal was measured and expressed as P2Y12 reaction units (PRU). In the control channel, platelets were activated with thrombin receptor-activating pep-tides, and the baseline maximal aggregation was meas-ured. Statistical analysis: The data were analysed using SPSS 20 software (SPSS Inc., Chicago, IL, USA). Re-peated ANOVA measures were performed based on the difference calculated between the results for degree and velocity of thrombocytic inhibition in the supine and the upright position. The Wilcoxon signed rank test was used for calculation of differences in time to reach cut-off for PRU. A cut-off value for avoiding complica-tions was set to ≤ 240 PRU. A p-value of < 0.05 was considered significant.We also looked for the velocity of inhibition, being the delta values between two measurements (i.e. ∆T0-T20, ∆T20-T40 etc.) to see how change in posture could affect the time to maximum velocity. The delta values were calculated, and the results from the supine group were subtracted from the results from the up-right group. Power calculation: We expected a difference in time to inhibition of 15 min., a standard deviation of 10 min., risk of type 1 error of 0.05 and risk of type 2 error of 0.1. This yielded a sample size of seven. To reduce the risk of type 2 error, we chose to investigate 20 subjects. Trial registration: This trial has been registered with clinicaltrials.gov (NCT01365741).ReSulTSThe baseline characteristics and values of the test group showed similarity (Table 1). The mean PRU value at baseline (T0) was 286 in the supine position and 272 in the upright position, (p = 0.6 for differ-ence). The inhibition of thrombocyte function for the upright and the supine position appears from Figure 1 and Figure 2. There was a statistically significant in-crease in inhibition of the ADP receptor in both the su-pine and the upright group from T = 40 to T = 100, when compared to T = 0 (p = 0.03 at T = 40 and p = 0.000 at T = 60/80/100). When comparing the two groups, supine and up-right, we saw a non-significant difference in baseline values of 15 PRU (standard error of mean = 26; p = 0.6). Since we were interested in the difference be-tween the supine and the upright position, we adjusted for this difference. Thus, we found a significant differ-ence between the supine and the upright group at T = 40 min. (p = 0.050) but a non-significant difference  at T = 60 min. and T = 80 min. (p = 0.052, and p = 0.066, respectively) (Table 2). Our analysis of the difference in velocity of throm-bocytic inhibition between the two postures showed the largest difference at T40-T20 (48 PRU) and a spike at T100-T80 (10 PRU). This means that the maximum effect of posture change was seen at 20-40 min. after ingestion. When looking at each group in isolation, the biggest change in PRU values was seen in the 40-60-min. range in the supine group (∆56.85 PRU) and in the 20-40-min. range in the upright group (∆101.9 PRU).TABle 1Baseline characteristics (n = 20).Gender: male, % 100Age, mean (range), yrs 23 (20-29)Weight, mean (range), kg 74.7 (68-90)Height, mean (range), cm 179.5 (176-190)BMI, mean (range), kg/m2 22.8 (20.7-24.9)Ethnicity, %Caucasian of Danish descent 90Danish of Persian descent 10TABle 2The difference between supine and upright position after adjust-ing for baseline differences. time, min. Difference in PRU, mean ± SEM (95% CI) p-valueT0  65.76 ± 26.10 (–65.76-36.36) 0.570T20  53.91 ± 26.05 (–53.91-48.21) 0.913T40 102.11 ± 26.05 (–102.11-0.14) 0.050T60 101.76 ± 26.05 (–101.76-0.36) 0.052T80  98.91 ± 26.05 (–98.91-3.21) 0.066T100  88.66 ± 26.05 (–88.66-13.46) 0.149CI = confidence interval; PRU = P2Y12 reaction units; SEM = standard error of the mean.Dan Med J 65/10  October 2018 3DANISH MEDICAL JOURNALComparing the mean PRU values between the two groups, it was seen that at T = 40 min., the PRU values in both groups were below the cut-off of 240 (229 PRU in the supine group versus 178 in the upright group). The mean time to reach the PRU cut-off of ≤ 240 was 40 min. in the upright position and 48 min. in the supine position. The difference, however, did not reach statistical significance (p > 0.05). dISCuSSIonOur data showed a statistically significant difference in the time to inhibition of thrombocytic ADP receptors when comparing ingestion in the upright and the su-pine position. We also observed a non-significant trend towards a faster likelihood of reaching the cut-off be-fore interventional procedures. It has been shown that pre- and post-procedural platelet reactivity measured by VerifyNow has a prognostic significance for the de-velopment of procedural complications [5, 14-16]. The consensus reached concerning the VerifyNow machine is that a pre- and post PRU of ≥ 240 increases the risk of post- and perioperative complications [5, 6, 8, 14, 17]. Sibbing et al investigated thrombocytic inhibition using a somewhat similar POC assay (Multiplate, Roche Diagnostics Limited) to define a cut-off for procedural complications. They: “did not observe a gradual in-crease of events across quintiles but a significant accu-mulation of stent thrombosis in patients belonging to the upper quintile of MEA (Multiple Electrode Aggre-gometry) measurements” [15], underlining the import-ance of proper thrombocytic inhibition prior to PCI. VerifyNow was chosen because of its rapid results, easy handling and proven prognostic value in the evalu ation of PCI patients [5, 6, 14, 16, 17]. VerifyNow has a good correlation to light transmission aggregom-etry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation. It is shown to be reliable in the evalu-ation of platelet inhibition [18, 19], even in the upper and lower quartiles of inhibition.One of the potential strengths of this study is the use of prasugrel instead of clopidogrel as the drug of choice. Prasugrel has a more consistent pharmaco-dynamics profile with improved efficacy and less inter individual variability. Studies have shown a non-responder rate using clopidogrel in the 0-52% range, but only about 3% have been reported to be non-re-sponders to prasugrel [20]. In our study, 15% of sam-ples (three measurements in the upright group and three measurements in the supine group) did not reach the cut-off during the 100 min. Had the sam-pling con tinued, the test subject might have had shown sensitivity to the drug later, but with regards to this study, they were “non-responders”, thus weaken-ing our result. Cur rently, a newer platelet inhibitor, ticagrelor (Bril ique), has been introduced to the Danish market, but at the time of protocol approval, prasugrel was the preferred agent and, as described above, it showed potential strengths compared with clopidogrel and was thus our drug of choice for this randomised study.  The weakness of this study is first and foremost the small sample size. Using a cross-over study has poten-tially limited the effect of this weakness and increased the study’s statistical strength. Prasugrel is a pro-drug needing gastric absorption and hepatic metabolism to become activated, but our subjects did not fast before the experiment, which might have influenced our re-sults. Our test subjects were all young, healthy males. FIguRe 2Mean difference in P2Y12 reaction units (PRU) between supine and upright with standard  error of the mean.140100120604020800PRUT0 T20 T40 T60 T80 T100Time, min.FIguRe 1Mean P2Y12 reaction unit (PRU) values adjusted for baseline difference.350250300150100502000PRUT0 T20 T40 T60 T80 T100Time, min.Upright Supine Dan Med J 65/10  October 20184DANISH MEDICAL JOURNALTherefore, the results cannot be directly transferred to patients with acute cardiac ischaemia.  Seeing that prasugrel is prone to give PRU values in the upper quartiles of inhibition, one might suspect that the VerifyNow would be less reliable due to its nar-row dynamic range. Studies have been conducted showing a good correlation between LTA and Verify-Now using prasugrel [19], even in the upper and lower quartiles of inhibition. This could possibly constitute a confounder in our study when looking at the overall difference between the supine and the upright position. Nevertheless, when looking at the velocity of inhibition in the mid quartiles of inhibition, this should have no effect on our results. ConCluSIonSOur study showed a non-significant trend towards a faster reduction of platelet reactivity when ingesting prasugrel in the upright position than in the supine po-sition. Larger clinical trials would be needed to confirm and assess the impact of posture on pharmacokinetics and its variability.CoRReSPondenCe: Jacob Antonsen. E-mail: jacobantonsen@dadlnet.dk ACCePTed: 16 July 2018ConFlICTS oF InTeReST: none. Disclosure forms provided by the authors are available with the full text of this article at Ugeskriftet.dk/dmjlITeRATuRe1. Andersen HR, Nielsen TT, Rasmussen K et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction.  N Engl J Med 2003;349:733-42. 2. McNamara RL, Wang Y, Herrin J et al. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006;47:2180-6. 3. Schomig A, Neumann FJ, Kastrati A et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coron-ary-artery stents. N Engl J Med 1996;334:1084-9. 4. Bertrand ME, Legrand V, Boland J et al. Randomized multicenter com-parison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. 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Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-elut-ing stent thrombosis. J Am Coll Cardiol 2009;53:849-56. 16. Siller-Matula JM, Christ G, Lang IM et al. Multiple electrode aggregom-etry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay. J Thromb Haemost 2010;8:351-9. 17. Breet NJ, van Werkum JW, Bouman HJ et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754-62. 18. Chen F, Maridakis V, O’Neill EA et al. A randomized clinical trial compar-ing point-of-care platelet function assays and bleeding time in healthy subjects treated with aspirin or clopidogrel. Platelets 2011. doi: 10.3109/09537104.2011.604806. 19. Jakubowski JA, Li YG, Small DS et al. A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis. J Cardiovasc Pharmacol 2010;56:29-37. 20. Jernberg T, Payne CD, Winters KJ et al. Prasugrel achieves greater in-hibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable cor-onary artery disease. Eur Heart J 2006;27:1166-73. 

Posture changes platelet inhibition time after ingestion of prasugrel

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Posture changes platelet inhibition time after ingestion of prasugrel

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