高齢者の心房細動抗凝固治療のinr目標値は？ -...

Clinical Question 2014.6.1 JHOSPITALIST Network

分野：循環器テーマ：治療

亀田総合病院　総合内科　佐田竜一

高齢者の心房細動抗凝固治療のINR目標値は？

症例：７９歳女性• ADL/IADL共に完全自立。５年ぶりに受けた検診で不整脈を指摘されたために精査目的で受診。糖尿病、高脂血症、腎・肝機能障害は指摘されていない

• 既往歴：高血圧（60歳～）、肺結核（35歳）　　　　虫垂炎手術（18歳）

• 内服薬：アムロジピン5mg

• BT36.8℃、BP128/62mmHg、PR72/分・irreg-irreg、RR16、頸静脈怒張無し・胸部に明らかな心雑音無し

以前から指摘されていたそうだが、『無治療でよい』と言われていた・・・

クリニカルクエスチョン臓器障害や弁膜症などの合併症がない

高齢女性の慢性心房細動に対して

① 抗凝固療法は必要か？ ② 抗凝固療法のINR目標値は？ ③ 治療を躊躇する症例は？

（以下、ワーファリン=Vitamin K Antagonist; VKAと略）

① 抗凝固治療が必要か？⇒ まずは塞栓症のリスクを必ず評価する

CHADS スコア

C CHF/LV dysfunction

心不全左室機能不全 1

H Hypertension

高血圧 1A Age≧75 年齢≧75 1D DM 糖尿病 1S Stroke/TIA 脳梗塞/TIAの既往 2

合計 0-6１点以上：抗凝固治療の弱い推奨２点以上：抗凝固治療の強い推奨

CHA スコア

C CHF/LV dysfunction

心不全左室機能不全

1

H Hypertension

高血圧 1A Age≧75 年齢≧75 2D DM 糖尿病 1S Stroke/TIA 脳梗塞/TIAの既往 2V Vascular

disease血管疾患（心筋梗塞、

PAD、大動脈プラーク） 1A Age:

65-74y年齢：65-74歳 1

Sc Sex category

女性 1合計 0-9

１点以上：抗凝固治療の弱い推奨２点以上：抗凝固治療の強い推奨

高齢女性、且つ高血圧治療中なら抗凝固療法は必須Chest 2010; 137(2):263–272

JAMA. 2001;285(22):2864-2870.

② 抗凝固療法のINR目標値は？海外と日本のガイドラインの違い

2014 米国心臓病学会/米国心臓協会/米国不整脈学会

・・・＞全ての年齢で INR2.0～3.0 を推奨

2010 欧州心臓病学会

・・・＞全ての年齢で INR2.0～3.0 を推奨

2013 日本循環器学会

・・・＞７０歳以上で INR1.6～2.6 を推奨

Eur Heart J. 2010 Oct;31(19):2369-429.

J Am Coll Cardiol. 2014 PMID: 24685669

日本循環器学会心房細動治療（薬物）ガイドライン（2013年改訂版）

日本人AF患者７９３７人による前向き観察試験 INR＝1.6-2.6なら血栓イベント減少、INR≧2.0なら出血イベント増加

Circ J 2013; 77: 2264–2270.

高齢者はINR目標値が“甘め”がいい？

VKA治療時の、INR毎のイベントハザード比年齢

発生イベント

non-VKA

VKA therapy（INR）≦1.59 1.6-1.99 2.0-2.59 2.6-2.99 ≧3.0

≧70血栓 1.00 0.63

(0.21-1.31)0.42

(0.23-0.76)0.39

(0.20–0.75)0.23

(0.20–1.01)0.78

(0.23–2.65)

出血 1.00 1.82(0.68-4.88)

1.59(0.61-4.16)

2.87(1.12-7.35)

3.99(2.33-11.89

)

7.02(2.23-22.13)

INR至適値＝1.6～2.6！

しかし…… INR数値の間隔がやや恣意的？　INR至適上限＝2.6と定めた理由は？患者の３割近くがCHADS2 score0-1点だが、VKAで本当にいいの？

AFに対してVKA治療を行った前向きコホートATRIA studyのサブ解析（平均年齢77歳）

血栓症の発症患者、及び脳出血の発症患者それぞれをもとに症例対象研究を行ったところ、、、

Cardiovasc Qual Outcomes. 2009;2:297-304.

and only 1 category for INR values above 3.5 (ie, INR !3.6).Figure 1B plots the odds ratios of TE and of ICH relative toINR 2.0 to 2.5 as a function of this set of 6 INR categories forthe entire set of cases and controls. As is evident, the mainfeatures of the INR/outcomes relationships are preserved.

For patients with and without a history of prior ischemicstroke, we again observed a significant increase in odds of TEat INR levels below 2.0 (Figure 2). Compared with INR 2.0to 2.5, the odds of TE were more than doubled in the INR 1.5to 1.9 range for those with (OR, 2.34; 95% CI, 1.17 to 4.66)

International Normalized Ratio (INR) Level

Odd

s R

atio

s0

1

2

3

4

5

6

7

8

9

≤ 1.3 1.4-1.7 1.8-1.9 2.0-2.5 2.6-3.0 3.1-3.5 3.6-4.5 > 4.5

=

12.3

27.6

=

10.9ThromboembolismIntracranial Hemorrhage

102 115 32 73 41 14 11 8TE cases101 230 190 544 280 114 79 43TE controls

9 9 16 45 34 15 14 22ICH cases35 70 80 252 119 68 22 10ICH controls


Odd

s R

atio

s

0

1

2

3

4

5

6

7

8

9

< 1.5 1.5-1.9 2.0-2.5 2.6-3.0 3.1-3.5 ≥ 3.6

ThromboembolismIntracranial Hemorrhage

=

10.2

=

11.1

128 121 73 41 14 19TE cases132 389 544 280 114 122TE controls10 24 45 34 15 36ICH cases41 144 252 119 68 32ICH controls

A

B

Figure 1. A, ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CIs. The numbers of cases and controls for each INRcategory are given below the figure. B, ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adultswith nonvalvular AF, with 6 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CIs. The numbers of casesand controls for each INR category are given below the figure.

300 Circ Cardiovasc Qual Outcomes July 2009

by guest on February 3, 2014http://circoutcomes.ahajournals.org/Downloaded from




Odd

s R

atio

s0

1

2

3

4

5

6

7

8

9

≤ 1.3 1.4-1.7 1.8-1.9 2.0-2.5 2.6-3.0 3.1-3.5 3.6-4.5 > 4.5

=

12.3

27.6

=





Odd

s R

atio

s

0

1

2

3

4

5

6

7

8

9

< 1.5 1.5-1.9 2.0-2.5 2.6-3.0 3.1-3.5 ≥ 3.6


=

10.2

=

11.1


A

B







Odd

s R

atio

s0

1

2

3

4

5

6

7

8

9

≤ 1.3 1.4-1.7 1.8-1.9 2.0-2.5 2.6-3.0 3.1-3.5 3.6-4.5 > 4.5

=

12.3

27.6

=





Odd

s R

atio

s

0

1

2

3

4

5

6

7

8

9

< 1.5 1.5-1.9 2.0-2.5 2.6-3.0 3.1-3.5 ≥ 3.6


=

10.2

=

11.1


A

B






INR<2.0：血栓症↗INR≧3.5：脳出血↗

７５歳以上の高齢AF患者に対するVKA vs. AspirinのRCTINRは2.5を目標とする（許容範囲2.0-3.0）

VKAの方が、死亡/障害を起こす脳卒中を有意に減少させた

Lancet 2007;370:493–503.

VKA（488人） Aspirin（485人） VKA vs. Aspirin

Primary Events Total リスク/年 Total リスク/年 VKA vs. Aspirin

脳卒中 21 1.6% 44 3.4% RR=0.46 (95% C.I. 0.26-0.79)

臓器塞栓 1 0.1% 3 0.2% 有意差無し

脳卒中、臓器塞栓の複合発症率

24 1.8% 48 3.8% RR=0.48 (95% C.I. 0.28-0.80)

BAFTA study



③ 治療を躊躇する症例は？

HAS-BLED score スコア

H Hypertension 高血圧（sBP>160mmHg） 1

A Abnormal renal & liver function

例：Cre＞2.26mg/dl T-bil＞基準値の2倍

AST/ALT/ALP＞基準値の3倍 2

S Stroke 脳卒中 1B Bleeding 出血歴/出血傾向 1

L Labies INRs不安定なINR

至適治療域達成期間＜60％1

E Elderly (Age≧65) 65歳以上 1

D Drugs or alcohol抗血小板薬/NSAIDs併用アルコール依存

2

合計０点：低リスク　１−２点：中等度リスク

≧３点：高リスク

J Am Coll Cardiol. 2011 Jan 11;57(2):173-80.　Am J Med. 2011 Feb;124(2):111-4.

2

4

6

8

10

0 1 2 3 4

8.7

3.74

1.881.021.13

100人・年あたりの出血イベント率(件/１００人・年)

score

３点以上だと治療の定期的な見直しが必要

HAS-BLED scoreで出血リスクを評価する！

◯ 転倒のリスクが高い患者（転倒に伴う出血を助長）

◯ 誤った服用を起こすリスクが高い患者（例）患者個人の認知機能の問題　　家族のサポート力が弱い、ないしは独居　　　サポートするはずの家族が認知機能にトラブルを抱える、等々

◯ VKAとの相互作用が多い薬剤を既に多く内服している患者

◎ 現時点でのADL/IADLが著しく低い患者

出血イベントを懸念する場合

抗凝固治療によるメリットそのものに疑念を持つ場合

③ 治療を躊躇する症例は？その他にも、当科では・・・

本症例での対応① CHADS2 ＝２点、CHA2DS2-VASc ＝４点　なので、抗凝固療法は強い推奨

② HAS-BLED score＝１点（or 高血圧で＋１点＝２点）　なので出血リスクは高くないと判断した

③ INRは2.0-3.0を目標としてVKAを開始した

が、次の外来でINRが5.0まで上昇した！！どうする？(Circulation. 2012;125:2944-2947)

入院のうえで１）Vitamin K 10mg/30分毎２）新鮮凍結血漿　　（15-30mg/kg）３）プロトロンビン複合体製剤　　（25-50IU/kg）

VKAを中止して１）Vit.K 2.5-5mg内服２）短期的な経過観察

VKAを中止して短期的な経過観察のみないしは下記を考慮

・Vit.K 1-2.5mg内服（Vit.Kは恐らく出血リスク　のある患者の助けになる）

Yes

No出血症状がある？INR＞10

INRの値は？INR 4-10

Take Home MessageAFの患者を診たら、まずは塞栓リスクの評価を！高齢者・且つ女性は既にHigh-risk！

INR至適値には諸説あるが、出血リスクが低ければ2.0～3.0で良いのではないか？（出血リスクが高ければ1.6～2.6でもよいか……）

出血リスクだけでなく、各患者固有の背景をとらえ抗凝固治療が生む利益を熟考してから処方すべし！

おまけ：Warfarin vs. NOAC単一凝固因子を抑制して効果を発揮するNew Oral Anticoaglant＝NOAC。2014年5月現在、ダビガトラン/リバロキサバン/アピキサバンが使用可能

stroke or systemic embolism in elderly adults with AF.NOACs were also more effective than conventional ther-apy for the reduction of the risk of VTE or VTE-relateddeath.

A similar profile was also found for the effectivenessof the individual NOACs. Rivaroxaban, apixaban, and da-bigatran were more or as effective and safe as conven-tional therapy or pharmacologically active agents.

Concerns About Bleeding

Several recent reports have raised concerns regarding thesafety profile of NOACs in the elderly population.15–17

Reports initially suggested that NOACs may cause morebleeding events, including life-threatening or fatal bleedingin elderly adults.15,16 Case reports suggest that majorbleeding events can occur with even a modified (lower)dose of NOACs in elderly adults.15 A 2-month audit con-ducted by the Haematology Society of Australia and NewZealand identified 78 episodes of bleeding in dabigatran-treated individuals, and participant age was one of thefour major factors that contributed to these episodes.16

Two-thirds of the participants were aged 80 and older,and 58% had moderate or severe renal impairment.

One of the major arguments for the findings16 wasthat the mean age of the trial population (RE-LY trial)was lower (71), and data from that trial may not beextrapolated into clinical practice in this case, but the cur-rent analysis for individuals aged 75 and older, includingdata from 10 RCTs, did not show excess bleeding withNOACs or with dabigatran specifically (data pooled from2 RCTs). The data also showed that NOACs are signifi-cantly more effective than conventional therapy in thispopulation.

Recent detailed analysis of bleeding related to rivarox-aban and apixaban in elderly adults in two large random-ized trials also did not show excess bleeding with thesedrugs.32,33 The reasons frequently suggested for the greaterrisk of bleeding in elderly adults are renal function impair-ment, low body weight, drug interactions, and unavailabil-ity of reliable coagulation tests to monitor blood level ofNOACs.1,14 Almost all previous articles reporting greaterbleeding in elderly adults included individuals who hadcomorbidities, mainly coexisting renal failure,15,16 but allof the reports were from small observational studies orcase reports, and no randomized data are available. A pos-sible explanation for the contrasting results of the currentstudy might be that the chances of bleeding with NOACs

Figure 2. New oral anticoagulants versus conventional therapy for participants aged 75 and older: major or clinically relevantbleeding. CI = confidence interval.

JAGS MAY 2014–VOL. 62, NO. 5 NEW ORAL ANTICOAGULANTS IN ELDERLY ADULTS 861

J Am Geriatr Soc. 2014: 62: 857-864.

are more related to associated comorbidities than the ageof the individual per se.

Implications for Practice

The benefit of antithrombotic therapy is well established inelderly adults, including those who are at high risk of fall-ing or bleeding.10,11 The current study suggests thatNOACs are more effective than conventional anticoagu-lants in elderly adults. Old age per se should not be acriterion for withholding anticoagulation with NOACs.

The recommended dose of apixaban is lower (2.5 vs5 mg) in elderly adults with at least one comorbidity inaddition to older age (i.e., a lower dose is recommended inthose with ≥2 of aged ≥80, body weight ≤60 kg, or serumcreatinine ≥1.5 mg/dL).3 For individuals with AF, 110 mgof dabigatran twice a day is recommended for aged 80and older in the European Union, rather than a 150-mgtwice-a-day regular dose, although the Food and DrugAdministration (FDA) does not recommend a routine dosemodification for dabigatran in elderly adults.3,34 Dosemodification for rivaroxaban is also not recommended forelderly adults, but a lower dose of dabigatran and rivarox-aban is recommended in individuals with moderate renalimpairment.3,34

A recent FDA postmarketing report of bleeding withdabigatran did not identify any unrecognized risk factorsfor bleeding.35 A large propensity score–matched

nationwide cohort study from Denmark supports the FDAreport (which does not adjust for comorbidities).36

Another report showed no greater risk of bleeding withdabigatran in VKA-naive individuals.37

These arguments do not contradict the fact that cau-tion should still be taken with NOACs in elderly adultswith other comorbidities (mainly renal impairment) andvery low body weight. Lack of a reversal agent for theanticoagulant effects of NOAC should also be kept inmind while prescribing these agents.3 Thus, an individual-ized case-by-case approach might be best for elderlyadults, with proper judgment of risk of bleeding andassociated comorbidities rather than a generalized “onedrug fits all” approach. Prospective, randomized con-trolled trials of NOACs in elderly populations are alsoneeded.

LIMITATIONS

The current results are subject to the intrinsic limitationsof meta-analyses: pooling of data from different trials withdifferent study protocols, definitions of efficacy and safetyoutcomes, and baseline participant characteristics. Theparticipant population in the included trials was healthier,with less comorbidity, better cognitive and physical func-tion, and less polypharmacy, which is different from thetypical elderly adult population in practice. Although

Figure 3. New oral anticoagulants versus conventional therapy for participants aged 75 and older: stroke or systemic embolism.

862 SARDAR ET AL. MAY 2014–VOL. 62, NO. 5 JAGS

Warfarin vs. NOACのRCT10本から75歳以上の患者を抽出したメタアナリシス。VKAと比べてNOACは塞栓リスクが少なく、出血リスクは同等

（注） NOACのデメリット① 急な腎障害時に著明なINR延長を来す恐れ！　（例：脱水、敗血症など）② VKAと比べてかなり高額！　ワーファリン®1mg＝9.6円、5mgでも9.9円　プラザキサ®・イグザレルト®・エリスキュース®

　どれも通常使用量で１日あたり530.4円

患者さんの身体・社会背景に則してどちらか良い方を選ぶべし！！

高齢者の心房細動 抗凝固治療のinr目標値は？ -...

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高齢者の心房細動抗凝固治療のinr目標値は？ -...