Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.
BACKGROUND
In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.


RESULTS
We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.


CONCLUSIONS
TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.


BACKGROUND
URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
Division of General Internal Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA (D.E.S.).
Daniel E
DE
Singer
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (A.S.H., Y.L., M.R.P., J.P.P.).
Anne S
AS
Hellkamp
Janssen Pharmaceuticals, Raritan, NJ (Z.Y., C.C.N.).
Zhong
Z
Yuan
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (A.S.H., Y.L., M.R.P., J.P.P.).
Yuliya
Y
Lokhnygina
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (A.S.H., Y.L., M.R.P., J.P.P.).
Manesh R
MR
Patel
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (A.S.H., Y.L., M.R.P., J.P.P.).
Jonathan P
JP
Piccini
School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (G.J.H.).
Graeme J
GJ
Hankey
Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany (B.).
Günter
G
Breithardt
Mount Sinai Medical Center, The Cardiovascular Institute, New York, NY (J.L.H.).
Jonathan L
JL
Halperin
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH (R.C.B.).
Richard C
RC
Becker
Ruprecht-Karls-University, Heidelberg, Germany (W.H.).
Werner
W
Hacke
Janssen Pharmaceuticals, Raritan, NJ (Z.Y., C.C.N.).
Christopher C
CC
Nessel
Department of Medicine, Stanford University, Stanford, CA (K.W.M.).
Kenneth W
KW
Mahaffey
University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, UK (K.A.F.).
Keith A A
KA
Fox
Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC (R.M.C.).
Robert M
RM
Califf
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001208:Asia; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D001777:Blood Coagulation / Q000187:drug effects*; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods*; D004617:Embolism / Q000209:etiology / Q000517:prevention & control; D005060:Europe; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D007843:Latin America; D008297:Male; D009656:North America; D011237:Predictive Value of Tests; D013019:South Africa; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D014859:Warfarin
anticoagulants; arrhythmia; embolism; prevention; risk factors