The use of point of care coagulometers in clinical trials
It is with concern that we read the Editorial in the BMJ (1) regarding the ROCKET-AF trial comparing rivaroxaban (Xarelto®) with a warfarin treated control group. It has been brought forth that the warfarin-managed group had their INR measured on a coagulometer, which has some serious drawbacks. Here we will focus on the point of care coagulometer (POCT) used in the trial; discuss the impact on the results and the requirements for the use of a POCT in trials.
Generally, in order to provide solid evidence in terms of non-inferiority (or even superiority) of rivaroxaban compared with warfarin, the latter needs to have a sufficiently high time within therapeutic target range (TTR) – preferably ≥70%. In the ROCKET-AF trial (2) the TTR in the warfarin group was merely 55%, which reflects a suboptimal quality of oral anticoagulant therapy (3). Using patient self-testing and self-management a higher quality of treatment can be achieved for selected patients. (4) High TTR has been linked to improved efficacy and safety outcomes.(5)
In a previous paper we concluded, that the precision of the POCT coagulometers was generally adequate for clinical use, but their performance in terms of accuracy has to be viewed in the context of the inherent inaccuracies in INR measurements. The overall accuracy of POCT coagulometers seems, in this respect, to be generally acceptable for everyday clinical practice and they may be used in a clinical setting.(6) We also showed that the HemoSense (INRatio®) had not been investigated in any high quality studies and the precision and accuracy of that specific coagulometer was lower compared to some of the other coagulometers on the market. Therefore, one may wonder from an analytical perspective why the investigators of the ROCKET-AF study choose to use HemoSense (INRatio®) in a clinical trial?
A potential underestimation of the INR value compared with a laboratory standard is the concern. This could potentially lead to a higher risk of bleeding in the warfarin group and subsequently misleadingly favour rivaroxaban over warfarin in a direct comparison on safety outcomes. The authors of the ROCKET-AF trial have responded that INR values were merely low in patients with certain conditions in terms of e.g. chronic inflammation, acute inflammation, or hematocrit levels out of range. Furthermore, it is advocated, that this did not influence the conclusions of the study regarding safety endpoints.(7) It should be emphasized that a statistical insignificant result may still be regarded as a clinical relevant result. Additionally, it can be seen that the previous statistically significant and clinically relevant reduction in intracerebral haemorrhage for the rivaroxaban arm was not observed in the group with the conditions mentioned above. For the outcome of major bleeding the subgroup of patients with none of the conditions favoured treatment with rivaroxaban compared with warfarin, hazard ratio 0.87 (95% CI, 0.70-1.08); while patients with any of the conditioned displayed a hazard ratio of 1.18 (95% CI, 0.98-1.42).7 These results are counterintuitive with the hypothesis that patients with the mentioned conditions could have received a higher dose of warfarin resulting in an increased risk of bleeding. It could also indicate that:
1) This subgroup is not the patients causing problems in relation to INR measurements,
2) The analytical error does not affect the over all conclusion.
However, the overall statement that the results of the coagulometer (and conditions) had no influence on the outcome is somewhat speculative, and further enhances the doubt on the conclusions from the trial that has already been raised.(1)
It has been argued that a quality control of these coagulometers is necessary, which can be performed using several different setups.(8) Hereby, flaws in INR measurements than can be attributed to analytical variations would probably be detected, but these quality controls would not predict flaws attributable to the biological deviations in the individual patient as those described above.
In a clinical trial there must be transparency regarding which type of coagulometer is used, and the quality of INR measurement should be high and precise. This could have been fortified in the ROCKET-AF trial by using a more validated coagulometer and quality control of the INR values, e.g. by using INR measured in a certified laboratory.
We recommend that coagulometers used in a clinical study should be those with the evidence of the best performance in terms of accuracy and precision. Otherwise, the obtained results should be interpreted with caution and may limit the clinical impact in terms of changing treatment strategies.
1 D Cohen. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575
2 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
3 Christensen TD, Larsen TB, Hasenkam JM. Results of Vitamin K antagonist treatment in patients with atrial fibrillation depends on the type of management. Circulation 2012;126:e45.
4 Nilsson H, Grove EL, Larsen TB, et al. Sex differences in treatment quality of self-managed oral anticoagulant therapy: 6,900 patient-years of follow-up. PLoS One 2014;9:e113627.
5 De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013;110:1087-107.
6 Christensen TD, Larsen TB. Precision and accuracy of point-of-care coagulometers used for self-testing and self-management of oral anticoagulation therapy. Journal of Thrombosis and Haemostasis 2012;10:251-260.
7 Patel MR, Hellkamp AS, Fox KAA, et al. Point-of-Care Warfarin Monitoring in the ROCKET AF Trial. N Engl J Med 2016 Feb 3 [Epub ahead of print].
8 L Poller. Precision and accuracy of CoaguChek S and XS monitors: The need for external quality assessment. Thromb Haemost 2009;101:419–421.
Competing interests: Peter Brønnum Nielsen has been on the speaker bureaus for Boehringer Ingelheim. Torben Bjerregaard Larsen has served as an investigator for Janssen Scientific Affairs, LLC and Boehringer Ingelheim and has been on the speaker bureaus for Bayer, BMS/Pfizer, Roche Diagnostics, Takeda and Boehringer Ingelheim. Thomas Decker Christensen has been on the speaker bureaus for AstraZeneca, Boehringer Ingelheim, Pfizer, Takeda, Bristol-Myers Squibb and Roche Diagnostics.