Dissertation

Below you will find the outline of my dissertation.
It will give you an idea about the structure of my thesis, and will give you access to the appendices.

Chapters

  1. Introduction
  2. Choosing between continuing VKA or switching to a DOAC in currently well-controlled patients on VKA for atrial fibrillation: a randomised controlled trial (GAInN)
  3. Quality of life after switching from well-controlled vitamin K antagonist to direct oral anticoagulant: little to GAInN
  4. Clinical usefulness of the SAMe-TT2R2 score: a systematic review and simulation meta-analysis
  5. Is the time in therapeutic range on coumarins predicted by previous time in therapeutic range?
  6. An easy-to-use tool to flag patients at risk of poor INR control: a streak of subtherapeutic INRs
  7. More precise dosing of acenocoumarol for better control in patients aged above 80 years, a randomised controlled pilot study
  8. Effect of switching from acenocoumarol to phenprocoumon on time in therapeutic range and INR variability: a cohort study
  9. Discussion

Choosing between continuing VKA or switching to a DOAC in currently well-controlled patients on VKA for atrial fibrillation: a randomised controlled trial (GAInN)

Published in modified form as British Journal of Haematology. 2019 Aug 6;186(3):e21–3; I will publish my thesis’ version here when it is approved.

Study protocol

The study protocol can be found here.

Outcome definitions

Outcome Definition
Stroke A sudden focal neurological deficit of presumed cerebrovascular etiology that persisted beyond 24 hours, or was treated (e.g. by thrombolysis or thrombectomy) to avoid persistence beyond 24 hours, and was not due to another identifiable cause. Brain imaging (computer tomography or magnetic resonance imaging) is recommended for all suspected strokes.
Systemic embolism An abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of another likely mechanism (e.g. atherosclerosis, instrumentation, or trauma).
Myocardial infarction The occurrence of a percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In the absence of PCI or CABG, myocardial infarctions is defined by typical symptoms and cardiac biomarker elevation (troponin I or T, creatine kinase-MB) above the upper limit of normal, new pathological Q waves in at least 2 contiguous electrocardiogram leads, or confirmed by autopsy.
Vascular death Death due to vascular causes e.g. stroke, systemic embolism or acute myocardial infarction.
Major bleeding According to the ISTH criteria(Schulman & Kearon, 2005): A clinically overt bleeding with fatal outcome, a fall in hemoglobin of at least 2 g/dL, leading to transfusion ≥2 units of packed red blood cells or occurring at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal).
Non-major clinically relevant bleeding overt bleeding not meeting the above mentioned criteria for major bleeding, but resulting in a medical intervention, unscheduled contact with health care provider (visit or phone) and/or temporary interruption of study treatment

Clinical endpoints in the per-protocol analysis

Endpoint DOAC (N = 121) VKA (N = 120) ARD HR
Net clinical benefit 4 4 0.0 (-4.5 to 4.6) 1.04 (0.26–4.17)
Efficacy 3 4 0.9 (-3.4 to 5.1) 0.78 (0.18–3.50)
  Stroke 2 0 -1.7 (-3.9 to 0.6)
  Systemic embolism 0 1 0.8 (-0.8 to 2.5)
  Myocardial infarction 1 2 0.8 (-2.0 to 3.6) 0.53 (0.05–5.81)
  Vascular death 1 1 0.0 (-2.3 to 2.3) 1.04 (0.07–16.64)
Safety 12 12 0.1 (-7.5 to 7.6) 1.04 (0.47–2.31)
  Major bleeding 2 0 -1.7 (-3.9 to 0.6)
  Clinically relevant non-major bleeding 9 10 0.9 (-5.9 to 7.7) 0.93 (0.38–2.30)
  All-cause mortality 2 2 0.0 (-3.2 to 3.2) 1.05 (0.15–7.42)

Serious adverse events

SAE Reason Event VKA DOAC
Hospitalisation Ablation 2 0
Hospitalisation Cardioversion 1 1
Hospitalisation Heart failure 2 0
Hospitalisation Intervention 7 4
Hospitalisation Observation 2 1
Hospitalisation Other 0 2
Hospitalisation; Life-threatening Intervention 0 1
Life-threatening Cancer 0 4

Sex differences

Quality of life after switching from well-controlled vitamin K antagonist to direct oral anticoagulant: little to GAInN

Published in Thrombosis Research. 2020 Jun;190:69–75.

Study protocol

The study protocol can be found here (and is the same as the one above).

Table S1: Baseline values for excluded SF-36 scales

DOAC VKA
Bodily Pain 74 [62 – 100] 84 [70 – 100]
Physical Functioning 75 [50 – 85] 85 [65 – 95]
Role Emotional 100 [67 – 100] 100 [67 – 100]
Role Physical 75 [25 – 100] 100 [50 – 100]

Clinical usefulness of the SAMe-TT2R2 score: a systematic review and simulation meta-analysis

Published in PLOS ONE. 2018 Mar 13;13(3):e0194208.

PRISMA checklist

The PRISMA checklist can be downloaded here.

S1 Table

Quality assessment of studies. QUADAS-2 rating.

S2 Table

Results from individual studies

S3 Table

Sensitivity analyses. Shows how different indications or methods of TTR measurement change the results.

S1 Figure

Bland Altman plot. Shows the difference between the simulated and original values.

S2 Figure

Forest plots showing sensitivity, specificity and power of separation (PSEP) of the SAMe-TT2R2 score. Uses cutoffs of ≥2 and ≥3 to predict a TTR <70%.

S3 Figure

Sensitivity analyses. Shows how different indications or methods of TTR measurement change the results. Dotted lines represent confidence intervals that were too wide to be displayed properly.

Is the time in therapeutic range on coumarins predicted by previous time in therapeutic range?

Published in Research and Practice in Thrombosis and Haemostasis. 2020 May 30;4(4):604–9.

Supplementary Table

Table S1: Patient characteristics by baseline TTR stratum.
This table includes patients who were included in the 180-day analysis.
Target range Variable G1 G2 G3 G4 G5
2-3 N 3538 3638 3639 3548 3668
2-3 Age, years – mean (SD) 78.4 ± 11.5 78.4 ± 11.3 78.0 ± 11.2 77.7 ± 10.8 77.8 ± 10.4
2-3 Female sex – n (%) 1763 (50%) 1852 (51%) 1767 (49%) 1744 (49%) 1729 (47%)
2-3 VKA experience, years – mean (SD) 5.7 ± 5.2 5.6 ± 5.2 5.7 ± 5.2 5.6 ± 5.2 5.6 ± 5.1
2-3 Atrial Fibrillation – n (%) 2996 (85%) 3093 (85%) 3065 (84%) 2976 (84%) 3137 (86%)
2-3 Mechanical valve – n (%) 20 (1%) 29 (1%) 33 (1%) 31 (1%) 26 (1%)
2-3 VTE – n (%) 606 (17%) 618 (17%) 659 (18%) 637 (18%) 599 (16%)
2-3 Mean acenocoumarol dose, mg – mean (SD) 2.2 ± 1.1 2.2 ± 1.0 2.3 ± 1.0 2.3 ± 1.0 2.3 ± 1.0
2-3 Follow-up duration in days, median (IQR) 675 [345 – 720] 690 [435 – 720] 690 [450 – 705] 690 [480 – 705] 690 [525 – 705]
2-3 Time within range (%), median (IQR) 37 [29 – 43] 54 [50 – 57] 66 [63 – 69] 77 [74 – 80] 91 [87 – 99]
2-3 TTR >70% – n (%) 0 (0%) 0 (0%) 386 (11%) 3548 (100%) 3668 (100%)
2-3 Time below range (%), median (IQR) 14 [1 – 31] 12 [2 – 24] 9 [0 – 19] 6 [0 – 14] 0 [0 – 5]
2-3 Time above range (%), median (IQR) 49 [31 – 61] 34 [22 – 43] 25 [15 – 32] 17 [9 – 22] 3 [0 – 10]
2.5-3.5 N 161 159 160 157 164
2.5-3.5 Age, years – mean (SD) 77.0 ± 11.5 76.1 ± 11.9 79.6 ± 10.9 77.2 ± 11.5 77.4 ± 10.4
2.5-3.5 Female sex – n (%) 64 (40%) 57 (36%) 56 (35%) 51 (32%) 66 (40%)
2.5-3.5 VKA experience, years – mean (SD) 10.6 ± 6.2 11.0 ± 7.0 10.7 ± 6.1 10.0 ± 6.5 10.3 ± 6.0
2.5-3.5 Atrial Fibrillation – n (%) 137 (85%) 130 (82%) 139 (87%) 121 (77%) 133 (81%)
2.5-3.5 Mechanical valve – n (%) 16 (10%) 25 (16%) 22 (14%) 33 (21%) 20 (12%)
2.5-3.5 VTE – n (%) 22 (14%) 15 (9%) 17 (11%) 16 (10%) 25 (15%)
2.5-3.5 Mean acenocoumarol dose, mg – mean (SD) 2.1 ± 1.1 2.2 ± 1.1 2.1 ± 1.0 2.4 ± 1.0 2.3 ± 1.0
2.5-3.5 Follow-up duration in days, median (IQR) 690 [405 – 720] 705 [502 – 720] 690 [401 – 705] 690 [540 – 720] 690 [656 – 705]
2.5-3.5 Time within range (%), median (IQR) 24 [16 – 31] 44 [41 – 48] 56 [54 – 60] 69 [65 – 72] 86 [81 – 93]
2.5-3.5 TTR >70% – n (%) 0 (0%) 0 (0%) 0 (0%) 64 (41%) 164 (100%)
2.5-3.5 Time below range (%), median (IQR) 64 [46 – 75] 43 [31 – 52] 32 [23 – 40] 22 [13 – 30] 7 [0 – 15]
2.5-3.5 Time above range (%), median (IQR) 11 [0 – 25] 12 [1 – 26] 13 [2 – 22] 7 [0 – 18] 0 [0 – 8]

Figure S1

Median (interquartile range) of TTR by baseline TTR group, over time, in target range 2.5-3.5. The panels indicate the duration of TTR calculation; the vertical line indicates when no INRs overlap between current TTR and baseline TTR.

Figure S2

Probabilities to obtain a time in the therapeutic range (TTR) > 70%, conditional on baseline TTR, in target range 2.5-3.5

An easy-to-use tool to flag patients at risk of poor INR control: a streak of subtherapeutic INRs

Published in Thrombosis Research. 2019 Sep;181(June):46–51.
No supplements.

More precise dosing of acenocoumarol for better control in patients aged above 80 years, a randomised controlled pilot study

Submitted. More information will follow after acceptance.

Study protocol

The study protocol is available here.

Effect of switching from acenocoumarol to phenprocoumon on time in therapeutic range and INR variability: a cohort study

Published in PLOS ONE. 2020 Jul 10;15(7):e0235639.

  • S1 Table. Patient characteristics from all potential controls.
  • S2 Table. Direct effect of switching in subgroups.
    See also S6 Table.
  • S3 Table. Coefficients from logistic regression used in the propensity score matching.
  • S4 Table. Patient characteristics from switchers and selected non-switchers.
  • S5 Table. Patient characteristics from switchers and selected non-switchers in subgroups.
  • S6 Table. Effect of switching from acenocoumarol to phenprocoumon, compared with non-switchers.
    Estimate with 95% confidence interval. An asterisk indicates that values were log-transformed in the analyses.