Appropriateness of Oral Anticoagulants for Long-Term Treatment of Atrial Fibrillation in Older People: Results of a Systematic Literature Review and International Consensus Validation Process (OAC-FORTA 2016)
Drugs & Aging
Martin Wehling , Ronan Collins , Victor M. Gil , Olivier Hanon , Roland Hardt , Martin Hoffmeister , Pedro Monteiro , Terence J Quinn, Dieter Ropers , Giuseppe Sergi, Freek W.A. Verheugt
Martin Wehling; Prof. Dr. med.
Institute for Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology Mannheim
Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg
Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Tel: +49 621 383 9631, Fax: +49 621 383 9632
E-Mail:
Supplementary Table 1
Part 1: Warfarin
PMID, first author, year: / Warfarin vs / Patients on Warfarin >65 / Patients on Warfarin >75 / Patients on Warfarin >80 / Efficacy Strokes/primary efficacy endpoint[OR/HR] and/or event rates
Changes with age / Safety
Major Bleeding
[OR/HR] and/or event rates
Changes with age / Safety
ICB
[OR/HR] and/or event rates
Changes with age / Duration / Info on Geriatric syndromes or other info relating to problems in the elderly / Comments concerning particular study
25399274, Reddy VY, 2014 / Device / 115 / 0,63 (0,35-1,14) vs
0.67 (0.32-1.41)
Events/Patients
≥ 75 y
22/190 22/115
< 75 y
17/273 12/129
Device/Warfarin / 3.8y
24895454, Halperin JL, 2014 / Rivaroxaban / 3109 / ≥ 75 y
2,29 vs 2,85 %/y
0.80 (0.63–1.02)
< 75 y
2,00 vs 2,10 %/y
0.95 (0.76–1.19)
Rivaroxaban/Warfarin / ≥ 75 y
4,86 vs 4,40 %/y 1.11 (0.92–1.34)
< 75 y
2,69 vs 2,79 %/y
0.96 (0.78–1.19)
Rivaroxaban/Warfarin / ≥ 75 y
0,66 vs 0,83 %/y
0.80 (0.50–1.28)
< 75 y
0,37 vs 0,68 %/y 0.54 (0.33–0.89)
Rivaroxaban/Warfarin / 19.4 m
24755126, Liu X, 2014 / <100
24744272, Di Biase L, 2014 / Off warfarin / Unknown, total 794 / 48h
24705469, Hori M, 2014 / Rivaroxaban / 246 / ≥ 75 y
2,18 vs 4,25 %/y
0.51; 95% CI: 0.20–1.27
< 75 y
0,72 vs 1,67 %/y
0.44; 95% CI: 0.13–1.42
Rivaroxaban/Warfarin / ≥ 75 y
5,01 vs 3,29 %/y
1.51 (0.68-3.32)
< 75 y
1,83 vs 3,76 0.49 (0.23-1.05)
Rivaroxaban/Warfarin / ≥ 75 y
4 vs 6
< 75 y
1 vs 4
Rivaroxaban/Warfarin (absolute numbers) / Max 30 month / Japanese patients
24692475, Mavaddat N, 2014 / Aspirin / 488 / 2.7 y / MMSE no difference between warfarin and ASS though trend
1.48 (0.56–3.91) p = 0.42
24561548, Halvorsen S, 2014 / Apixaban / 7052/2 / 5678/2 / 2436/2 / > 80 y
1.53 vs 1.9%/y
0.81, 95% CI 0.51–1.29
> 75 y
1,56 vs 2,19 %/y
0.71(0.53-0.95)
> 65 y
1,25 vs 1,73 %/y, 0.72(0.54-0.96)
Apixaban vs warfarin / > 80 y
3.55 vs 5.41 %/y
0.66, 95% CI 0.48–0.90
> 75 y
3,33 vs 5,19 %/y
0.64(0.52-0.79)
> 65 y
1,99 vs 2,82 %/y
0.71(0.56-0.89)
Apixaban vs warfarin / > 80 y
0.47 vs 1.32 %/y
0.36, 95% CI 0.17–0.77
> 75 y
0,43 vs 1,29 %/y
0.34(0.20-0.57)
> 65 y
0,28 vs 0,81 %/y
0.35(0.20-0.60)
Apixaban vs warfarin / 1.8 y
24315894, Goodman SG, 2014 / Rivaroxaban / 4733/2 / 6164/2 / > 75 y
4,86 vs 4,40 %/y 1.11(0.92-1.34)
> 65 y
3,03 vs 3,24 %/y 0.94(0.73-1.21) Rivaroxaban vs warfarin / 2 y
24251359, Giugliano RP, 2013
+ suppl / Edoxaban high/low / 2820 / >75 y
1,91 vs 2,31 %/y;
0.83 high
2,55 vs 2,31 %/y;
1.10 low
<75 y
1,35 vs 1,48 %/y;
0.91 high
1,71 vs 1,48 %/y;
1.16 low
Edoxaban vs warfarin / >75 y
4,01 vs 4,83 %/y;
0.83 high
2,26 vs 4,83 %/y;
0.47 low
<75 y
2,02 vs 2,62 %/y;
0.77 high
1,23 vs 2,62 %/y;
0.47 low
Edoxaban vs warfarin / 2.8 y
24048467, Apostolakis S, 2013 / No age data
23325525, Reddy VY, 2013
Same study as 25399274, Reddy VY, 2014 / Number assumed to be below 100 (300/3?)
22118824, Roy B, 2012 / Placebo / 616 >70 y / 334 / Total mortality
>75 y
39/110 vs 72/334 events/patients
0.65(0.44-0.96)
<75 y
35/117 vs 40/282 events/patients
0.47(0.30-0.75)
Ischemic stroke
>70 y
17/227 vs 26/616 events/patients
0.57(0.31-1.01)
warfarin /placebo / >70 y
22/227 vs 44/616 events/patients 0.73(0.44-1.22)
warfarin /placebo / 3.4 y
21870978, Granger CB, 2011
Same as 24561548, Halvorsen S, 2014
21830957, Patel MR, 2011
+ suppl
Same as 24315894, Goodman SG, 2014 / Rivaroxaban / 3082 / ≥ 75 y
4,06 vs 5,00 %/y
0.80; 95% CI: 0.63–1.02
< 75 y
3,60 vs 3,79 %/y
0.95; 95% CI:
0,76–1.19
Rivaroxaban/Warfarin / „Safety on treatment“
≥ 75 y
2,67 vs 4,03 %/y
0.67; 95% CI: 0.51–0.88
< 75 y
2,68 vs 2,97 %/y 0.91; 95% CI: 0,7–1.19
Rivaroxaban/Warfarin / 2 y
21576658, Eikelboom JW, 2011 / Dabigatran 110/150 mg / 7884/3
<75 y
10855/3 / 7258/3 / 722x2/3>85 / For 110 mg
>75 y
0.88(0.66-1.17)
<75 y
0.93(0.70-1.22)
For 150 mg
>75 y
0.67 (0.49–0.90)
<75 y
0.63 (0.46–0.86)
>75 y
2.14 1.89 1.43 %/y
<75 y
1.43 1.32 0.90 %/y
War/110/150mg / For 110 mg
>75 y
1.01 (0.83–1.23)
<75 y
0.62 (0.50–0.77)
For 150 mg
>75 y
1.18 (0.98–1.42)
<75 y
0.70 (0.57–0.86)
>75 y
4.43 5.1 4.37%/y
>65-<74 y
1.89 2.12 3.04%/y
Risk 110/150mg/war / For 110 mg
>75 y
0.37 (0.21–0.64)
<75 y
0.22 (0.11–0.45)
For 150 mg
>75 y
0.42 (0.25–0.70)
<75 y
0.43 (0.25–0.74)
>75 y
1.00 0.37 0.41 %/y
<75 y
0.61 0.14 0.26 %/y
War/110/150mg / 2 y
21415134, Lane DA, 2011 / + antithrombotic
VKA (warfarin or aceno-coumarol) / 1501 / 1279 / >75 y
59 (3.7) events(%); HR 4.72 (2.34-9.52)
65-74 y
(35 (1.9) events(%); HR 2.38 (1.14-4.94)
<65 y as comparator / More analyses on age for all patients
20961244, Matchar DB, 2010 / Self testing vs clinic testing / 1773 / Primary endpoint: death, stroke or major bleeding
0.89 in favor of self testing / Contained in primary endpoint, not distinguishable
20694273, Weitz JI, 2010 / No age data
20076843, Pengo V, 2010 / Standard vs lower intensity / 267 / Primary endpoint: thromboembolism and major bleeding 0.7, 95% CI 0.4-1.1 in favor of lower intensity / 0.6, 95% CI 0.3-1.2 / 5.1 y / From abstract
19683639, Holmes DR, 2009 / Device / 305/3 / >75 y
0,74 (0,29–1,90)
<75 y
0,57 (0,24–1,34) / 1.5 y
18294998, Amadeus Investigators, 2008 / Idraparinux, prematurely stopped / unknown / Clinically relevant bleeding
>75
2,4 (1,8–3,1)
< 75
1,5 (1,2–1,8)
idraparinux vs warfarin / 10.7 m
18266660, Lip GY, 2008 / Pooled with/wo warfarin
17885258, Ford GA, 2007 / ximelagatran / 1385 / >75 y
2.23%/y
(95% CI, 1.60-2.86) vs
2.27%/y (95% CI, 1.63-2.91)
<75 y
1.25%/y (95%
CI, 0.87-1.62) vs 1.28%/y
(95% CI, 0.91-1.66)
ximelagatran
/warfarin / >75 y
2.7 vs 3.6 %/y
<75 y
1.4 vs 1.8 %/y
ximelagatran
/warfarin / >75 y
5 vs 6
<75 y
1 vs 5
ximelagatran
/warfarin / 18.3 m
17693178, Mant J, 2007 / Aspirin / 197 / 196 + 95 > 85 / For all ischemic stroke
0.8 vs 2.5%/y
0.30(0.13-0.63)
Primary event
>85 y
0,50 (0,17–1,31)
80-84 y
0,30 (0,10–0,77)
75-79 y
0,71 (0,29–1,65)
warfarin vs aspirin / >85 y
0,77 (0,24–2,32)
80-84 y
0,96 (0,39–2,33)
75-79 y
1,44 (0,34–6,95)
warfarin vs aspirin / For all hemorrhagic stroke
0.5 vs 0.4%/y 1.15(0.29-4.77)
warfarin vs aspirin / 2.7 y
16774980, Gomberg-Maitland M, 2006
And 16636210, Douketis JD, 2006 / Subgroup on gender, or primary analysis on bleeding
contained in 17885258, Ford GA, 2007
15911734, Sherman DG, 2005 / All encouraged to be on anticoagulant, no comparator, rate vs rhythm control / 703 >70 / Reasons for withdrawal for all, those < 70 y vs > 70 y and p-value:
Bleeding 285 (20.9) 126 (19.0) 159 (22.6) .10
Frailty/risk of falls 96 (7.0) 21 (3.2) 75 (10.7) .001
Physician refusal 169 (12.4) 77 (11.6) 92 (13.1) .42
Patient refusal 113 (8.3) 65 (9.8) 48 (6.8) .045
Surgery† 153 (13.1) 86 (15.4) 67 (11.0) .03
Other 82 (6.0) 47 (7.1) 35 (5.0) .10 / No endpoints over age, but geriatric information
15071259, Matchar DB, 2003 / Abstract, no clinical endpoints
12466506, Wyse DG, 2002 / No active control, rythm vs rate / 3091 / Mortality >65
Rate control better, < 65 trend towards rhythm control better / MMSE „similar in both groups“ / Age-related data on mortality only, but not related to anticoagulation which could be stopped in the rhythm controll group, also anticoagulant not specified
12106622, Matchar DB, 2002 / Intervention or control to improve anticoagu-lation quality vs placebo / 507 / In control sites
11 (4 [1–6]) vs 8 (3 [1–5]) warfarin vs no treatment
In intervention sites
14 (7 [3–11]) vs 6 (3 [1–5]) / In control sites
5 (2 [0–3]) vs 1 (0 [0–1]) warfarin vs no treatment
In intervention sites
3 (2 [0–3]) vs 1 (0 [0–1]) / 9 m
11074901, Beyth RJ, 2000 / Multicom-ponent program of management of warfarin therapy vs standard care / 325 / 12% vs. 5.6%; P = 0.0498 / Abstract only
10356104, Hart RG, 1999 / Aspirin + subtherapeutic warfarin
8607726, No authors listed, 1996 / Aspirin / 197 / 4.2(2.5-6.8) vs 1.6(0.7-3.6)%/y warfarin vs Aspirin / 1.8(0.9-3.8) vs 0.8(0.3-2.5)%/y warfarin vs aspirin / 2.0 y / More bleeding at higher INR in >75 only
7907677, No authors listed, 1994 / Aspirin / 197 / >75 y
3.6 vs 4.8%/y, 0.73(0.37-1.5)
<75 y
1.3 vs 1.9%/y, 0.67(0.34-1.3)
warfarin vs aspirin / <75 y
0.5 vs 0.2
warfarin vs aspirin / Contained in 8607726
23929423, Mao L, 2014 / Rivaroxaban / 254/2 / >75 y
0.85 0.73–1.08
< 75 y
0.84 0.71–1.05
Rivaroxaban vs warfarin / ? event rate / y given / Chinese patients
1406859, Ezekowitz MD, 1992 / Placebo / >70 220/2 / Thereof 88/2 / >70 0.9 vs 4.8%/y, risk reduction 0.79(0.34-0.93) warfarin vs placebo / 2 in each group / 1.8 y
SmPC Info / Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3)]. COUMADIN is contraindicated in any unsupervised patient with senility. Observe caution with administration of COUMADIN to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and
maintenance doses of COUMADIN in elderly patients.
No dosage adjustment is necessary for patients with renal impairment / Interpretatory summary for other findings of particular geriatric relevance
High risk for interactions
Low renal risk
Part 2: Acenocoumarol
PMID: / Acenocoumarol vs / Patients on Acenocoumarol >65 / Patients on Aceno-coumarol >75 / Patients on Aceno-coumarol >80 / Efficacy Strokes/primary efficacy endpoint[OR/HR] and/or event rates
Changes with age / Safety
Major Bleeding
[OR/HR] and/or event rates
Changes with age / Safety
ICB
[OR/HR] and/or event rates
Changes with age / Dura-tion / Info on Geriatric syndromes or other info relating to problems in the elderly / Comments concerning particular study
12669133, Pengo V, 2003 / Acenocoumarol or warfarin
SmPC / Elderly patients (≥65), patients with liver disease or severe heart failure with hepatic congestion or malnourished patients may require lower doses during treatment initiation and maintenance (see section 4.4 Special warnings and precautions for use).
Elderly: A dose lower than the recommended adult dose may be sufficient in elderly patients. Caution and more frequent monitoring of prothrombin time and INR is recommended (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties).
In paediatric and elderly patients (≥65 years), caution and more frequent monitoring of prothrombin time and INR is recommended (see Sections 4.2 Posology and method of administration and 5.2 Pharmacokinetic properties). / Interpretatory summary for other findings of particular geriatric relevance
High risk for interactions
Renal risk: low
Part 3: Fluindione
PMID: / Fluindione vs / Patients on Fluindione >65 / Patients on Fluindione >75 / Patients on Fluindione >80 / Efficacy Strokes/primary efficacy endpoint[OR/HR] and/or event rates
Changes with age / Safety
Major Bleeding
[OR/HR] and/or event rates
Changes with age / Safety
ICB
[OR/HR] and/or event rates
Changes with age / Duration / Info on Geriatric syndromes or other info relating to problems in the elderly / Comments concerning particular study
SmPC / Posologie chez le sujet âgé et très âgé
Le traitement doit être débuté par une dose plus faible. En effet, la dose moyenne d'équilibre est plus faible chez le sujet âgé que chez le sujet jeune, habituellement 1/2 à 3/4 de la dose (voir rubrique 4.4).
Précautions d'emploi
Chez le sujet âgé et très âgé, le risque hémorragique est élevé. Aussi, l'instauration d'un traitement antivitamine K, de même que la poursuite de ce traitement, ne devra se faire qu'après une évaluation soigneuse du rapport bénéfice/risque. La décision d'un traitement et son suivi doivent notamment prendre en compte les risques particuliers liés au terrain :
fréquence des pathologies associées et des associations thérapeutiques,
fréquence et gravité des accidents hémorragiques, liés en particulier au risque de chute,
risque d'altération des fonctions cognitives entraînant un risque d'erreur de prise.
Le risque de surdosage, en particulier en début de traitement, doit être particulièrement surveillé.
En cas d'insuffisance rénale sévère, ce médicament est généralement déconseillé. Cependant, dans les cas où il est utilisé, les doses initiales administrées devront être plus faibles et la surveillance de l'INR plus rapprochée.
Translation:
Dosage in the elderly and very elderly
Treatment should be started with a lower dose. Indeed, the average balance dose is lower in the elderly than in young subjects, usually 1/2 to 3/4 of the dose (see section 4.4).
Precautions
In the elderly and very elderly, the bleeding risk is high. Also, the establishment of an anti-vitamin K treatment, as well as the continuation of this process, shall be made only after careful evaluation of the benefit / risk. The decision for treatment and monitoring should in particular take into account the particular risks related to the plot:
• frequency of associated diseases and therapeutic associations,
• frequency and severity of bleeding, particularly related to the risk of falling,
• risk of cognitive impairment leading to a risk of making errors.
The risk of overdose, especially early in treatment, should be particularly monitored.
In severe renal impairment, the drug is generally not recommended. However, in cases where it is used, the initial doses administered will be lower and monitoring the earliest INR. / Interpretatory summary for other findings of particular geriatric relevance
High risk for interactions
Renal risk: low
Part 4: Phenprocoumon