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高齢者への薬剤

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高齢者への薬剤

  1. 1. 高齢者への薬剤投与の注意点
  2. 2. 高齢者への投薬 Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121• 高齢者(≥65歳)では慢性疾患が多く, 内服している薬剤も多い • 米国では≥65歳の12%が10種類以上, 23%が5種類以上の薬剤が処方. 市販薬(OTC)も含めるともっと多くなる. • 若年と比較し, 3倍以上の薬剤使用量となる.
  3. 3. 薬物動態の変化 Southern Medical Journal 2012;105:437-445• 薬物動態は, 吸収, 分布, 代謝, 排泄の4つで規定される.• 吸収; 加齢に伴い消化管蠕動, 血流は低下する.  胃酸の分泌も低下し, 胃内のpHは上昇する. • 血流低下, pH上昇により, 経口摂取された薬剤の吸収率は低下. • 一方で, 蠕動運動の低下は消化管通過時間が延長するため, 吸収率は上昇し, 血中濃度ピークまでの時間も延長.
  4. 4. Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121• 分布容積の変化; 高齢者の体格, 組成の変化 • 高齢者では, 体重, Total body water(TBW)は低下し, 相対的に脂質の割合は増加. >65yでは毎年0.5%体重低下する. • 例えば80kgの75歳では体脂肪率29%, 一方で20歳の場合は15%のみ Med Clin N Am 95 (2011) 579–593 •  → Hydrophilic drugs(親水性の薬剤)の分布容積は低下する.   親水性薬剤であるジゴキシンやリチウム,   エタノールは同じ量でも血中濃度が増加する.  → Lipophilic drugs(脂質溶解性の薬剤)は脂肪組織へ分布し,   Vdは増加するものの蓄積による効果遷延のリスクが上昇   (ベンゾジアゼピン系)• 分布; アルブミン値の低下 • アルブミン結合性の薬剤では遊離体の増加を来たし, 作用が増強 (フェニトイン, テオフィリン, ワーファリン, ジゴキシン)
  5. 5. 体格に応じた薬剤調節• 例えば, 90kg, 190cmの患者は, 56kg, 150cmの患者と比較して約2倍の体積を有する. • 熱病では決まった投与量のみ記載されているが, 日本人との対格差, 近年の肥満患者の増加に対応できていない • 肥満患者と非肥満患者では薬剤の吸収率に差はないが, タンパク結合率, 分布体積は肥満患者で大きい. • また, 肥満患者では肝代謝が亢進する傾向にある Lancet 2010;375:248-51
  6. 6. Hydrophilic(親水性) Lipophilic(親脂質性) βラクタム系 キノロン  ペニシリン, セフェム, マクロライド  モノバクタム, カルバペネム Lincosamides グリコペプチド テトラサイクリン アミノグリコシド チゲサイクリン ポリミキシン Co-trimoxazole フォスフォマイシン リファンピシン• 各抗生剤の親和性 クロラムフェニコール • 高齢者では親水性の薬剤のVdは減少 → 血中濃度が上昇し易い 新脂質性の薬剤のVdは増加するが, 蓄積し排泄は低下する. • 90歳の羸痩の強い寝たきり高齢者の誤嚥性肺炎, 例え予測ClCr >50だとしても, ABPC/SBT 3g q6hで投与するのはどうなんだろう? Lancet 2010;375:248-51
  7. 7. • 代謝の変化; 肝臓容積, 肝血流の低下 Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121 • 高齢者ではCytochrome P450も低下しており, 肝で代謝される薬剤は少量でも効果を示す様になる. (β阻害薬, TCA, Nitrateなど)• 排泄の変化; 腎機能(30台半ばからGFRは6-12mL/min/10y低下する) • Cockcroft-GaultのCCr計算式; (140-年齢)xWt / 72xCr (女性x0.85) 体重は理想体重を用いる • 日本人 70-74歳の平均身長は男性163.7cm, 女性151.4cm ここから理想体重を求めると男性59.6kg, 女性44.6kg • 高齢女性ではCre<1でも Cre 0.2 0.4 0.6 0.8 1.0 1.2 男性 281 141 94 70 56 47 腎機能は悪いかもしれない 女性 179 90 60 45 36 30
  8. 8. • 他のClCr推定方法Table 1. Formulas available for estimating creatinine clearance1,14,15,17,18 Southern Medical Journal 2012;105:437-445Creatinineclearance estimate Formula CommentsCockcroft-Gault formula Estimated creatinine clearance (mL/min) = Widely used; Cockroft-Gault equation is used to make dosage adjustments, [140 j age (y) Â weight (kg)]/(72 Â SCr) because this is how drug manufacturers establish their dosing recommendations. This is mandated by the FDA. Multiply by 0.85 if female Use ideal body weight: The process of rounding the SCr concentration up by 1.0 mg/dL is not Men = 50 + (2.3 Â number of inches over 5 ft) supported by medical evidence. Women = 45.5 + (2.3 Â number of inches over 5 ft)Abbreviated Estimated glomerular filtration rate May be most effective in patients with diabetic kidney disease, patients MDRD equation (mL/min/1.73 m2) = 186 Â serum creatinine with chronic kidney disease in middle age (average age 51 y), black (mg/dL) Y 1.154 Â age (y) Y 0.203: patients with hypertensive chronic kidney disease, and patients with & Â (0.742 if female) preexisting kidney disease. The MDRD equation is often used to stage patients’ degree of kidney dysfunction. & Â (1.210 if African American)Actual 24-h Time-consuming and increases work for nursing Pregnant women, patients with extremes of age and weight, patients with creatinine collection malnutrition, patients with skeletal muscle diseases, patients with paraplegia or quadriplegia, patients consuming a vegetarian diet and with rapidly changing kidney functionCircumstances under which these equations are not effective for estimating renal function: extreme body weight: body mass index G19 or 935 kg/m2, significantmuscle mass abnormality (amputations, loss of muscle mass, muscle disease, or paralysis), acute kidney failure, pregnancy, severe hepatopathy, generalized edema,or ascites.FDA, Food and Drug Administration; MDRD = modification of diet in renal disease; SCr = serum creatinine.commonly used calculation, although many practitioners prefer what would provide the most accurate estimation of a patient’sthe MDRD formula, which may prove to be more accurate than creatinine clearance.20,21other formulas even though it has not been used for as long as In summary, the altered pharmacokinetics observed inCockroft-Gault. In elderly adults, a low serum creatinine is not most elderly patients significantly affect the particular phar-always indicative of normal renal function. Because older adults macokinetics of a drug. These changes are summarized inhave lower muscle mass than younger people, low serum cre- Table 2. Although drug absorption is probably least affected
  9. 9. • 日本とアメリカの平均体重, 慎重の比較 年齢 男性 女性 65-69歳 62.95kg 164.5cm 53.04kg 152.4cm 70-74歳 62.27kg 163.7cm 51.34kg 151.4cm 75-79歳 60.16kg 162.0cm 50.18kg 149.7cm 平成22年度 体力, 運動能力調査 年齢 男性 女性 60-69歳 90.0kg 175.4cm 77.30kg 161.8cm 70-79歳 85kg 173.8cm 70.60kg 159.2cm ≥80歳 76.3kg 170.7cm 64.5kg 156.0cm CDC http://www.cdc.gov • このような母集団で評価されたRCT, trialsで投与量が決定されている これが日本人にそのまま当てはまるものか?
  10. 10. Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121• 薬剤作用の減弱, 増強 • 加齢とも無い, 各組織での受容体数の変化, 感受性の変化があり, 作用が減弱, 増強することも分かっている. β阻害薬や刺激薬の効果は減弱し, ワーファリンやオピオイドの効果は増強することが判明している.
  11. 11. • 高齢者の薬物動態のまとめ Southern Medical Journal 2012;105:437-445 Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121 変化 結果 胃酸分泌低下, pHの上昇 吸収 薬剤吸収率の低下 消化管血流の低下 消化管運動の低下 消化管内薬物残存, 吸収増加 分布 Total body water 低下, 体重減少 親水性薬剤のVd低下 親脂質性薬剤のVd上昇 脂肪組織の占める割合の上昇 排泄遅延 アルブミン低下 遊離体薬物の上昇 代謝 酵素誘導の低下, 肝組織減少, 肝血流低下 肝代謝の低下 Oxydase system活性の低下 排泄 GFRの低下, 腎血流低下 腎排泄の低下
  12. 12. 高齢者で特に問題となりやすい薬剤 薬剤 問題 SU剤, インスリン 低血糖リスク ワーファリン 出血リスク 10歳加齢毎に0.5mg程度必要量が減る* ジゴキシン 食欲低下, 不整脈 ベンゾジアゼピン 意識障害, 転倒 高齢者では排泄遅延 抗ヒスタミン 意識障害, 尿閉 H2阻害薬 意識障害, 昏迷, 抑うつ 抗精神病薬 意識障害, 死亡リスク 抗うつ薬 意識障害, 便秘, 低血圧 抗てんかん薬 意識障害, 肝障害, 腎障害 NSAID 消化管出血, 腎不全 降圧薬 失神, 徐脈, 低血圧 利尿薬 脱水, 低血圧, 電解質異常 甘草 低K血症, 高血圧JAMA 2010;304:1592-1601, Southern Medical Journal 2012;105:437-445 *Chest 2005;127:2049-56MOUNT SINAI JOURNAL OF MEDICINE 78:613–626, 2011 • 反対に, 意識障害, 低血糖, 尿閉, 便秘, 低血圧, 不整脈, 出血, 腎不全, 脱水, 電解質異常があれば薬剤性を先ず疑うべし.
  13. 13. • 健康食品による副作用 MOUNT SINAI JOURNAL OF MEDICINE 78:613–626, 2011 健康食品, サプリ 問題 相互作用 HMG-CoA reductase inhibitors, CoQ10 悪心, 下痢, 食欲低下 warfarin, 化学療法 エキナセア 頭痛, めまい, 悪心, 便秘, 肝障害 CYP3A4誘導 アスピリン, HIV protease阻害薬 ニンニク 出血, 低血糖, 消化管症状 CYP2E1阻害作用, CYP3A4誘導 抗凝固/抗血小板薬, Trazodone, イチョウ 出血, 悪心, 頭痛, 下痢, 動悸, 不安 NSAID, MAOI, 抗精神病薬, インスリン, CYP3A4と2C19阻害 インスリン, SU剤, 抗凝固薬, チョウセンニンジン 高血圧, 頻脈, 下痢, 低血糖 MAOI, イマチニブ, CYP3A4阻害 グルコサミン 消化管症状, 頭痛, 浮腫 不明 ベンゾジアゼピン, バルビツレート カバカバ(コショウ科) 鎮静, 肝障害, 意識障害 CYP2E1, 1A2, 2C8, 2C9, 2C19, 2D6, 3A4阻害 ノコギリヤシ 頭痛, 悪心, 下痢, 出血 抗凝固薬 ジルチアゼム, ニフェジピン, 下痢, 頭痛, 悪心, 昏迷, 西洋オトギリ草 ワーファリン, SSRI, TCA, 経口避妊薬, 不眠, 日光過敏 テオフィリン, CYP3A4, 2C9, 2C19, 2E1誘導 ベンゾジアゼピン, ハロペリドール セイヨウカノコソウ 鎮静, 頭痛, 離脱症状 CYP450, 2D6, 3A4阻害
  14. 14. Polypharmacy Drugs Aging 2003;20:817-832• Polypharmacy; 多剤服用 には主に3つのタイプがある. • Appropriate polypharmacy; 患者本人の疾患, 病態に対して  妥当といえる処方のみだが, 総量が多い場合 • Inappropriate polypharmacy; 疾患, 病態に対して  妥当とは言えない, 過度な処方がされている場合. • Redundant pseudopolypharmacy; 実際使用しているよりも多く,  患者が報告しているケース.  患者の誤解, 医師のカルテの記載ミス  (前のカルテを参照し続けているなど)が原因となる.
  15. 15. Journal of Clinical Pharmacy and Therapeutics (2007) 32, 113–121• 多剤となる理由; • 高齢者の多彩な慢性疾患, 訴えに応じて処方されるパターン. • 複数の医師に処方され, しばしば同じ作用の薬剤が 処方されているパターン. • 薬剤の副作用を更に薬剤で対応されているパターン • アドヒアランス低下を効果不十分と判断され, 増量されているパターン.
  16. 16. Drugs Aging 2003;20:817-832• 多剤の使用の問題点は6つ. • 副作用の増加, アドヒアランスの低下, 薬剤間相互作用, Medication Errors  上記による入院率の増加, 医療費の増大. • 2剤使用すると副作用のリスクは13%, 4剤の使用では38%, 7剤以上の使用では82%まで上昇する. • 多剤では当然アドヒアランスも低下する.
  17. 17. • イタリアのRetrospective study Drug Aging 2010;27:1019-1028 • ≥65yの887165名のうち, 平均薬剤使用数は6.3±4.2 1-4剤使用例が39.3%, 5-7剤使用例が28.4%, 8-10剤使用例が17.4%, 11-14剤が10.2%, 15剤以上が4.7% • 高齢者ほどPolypharmacyのリスクは高い 65-74歳をReferenceとした時, 75-84歳ではOR 1.76[1.74-1.78] ≥85歳ではOR 1.83[1.80-1.85]
  18. 18. 薬剤による副作用• 内科入院の2.4-6.7%が薬剤の副作用によるもの. その大半が高齢者. • 高齢者の薬剤副作用のリスクは全体の3倍. 高齢者の再入院の20%は薬剤による副作用が原因との報告もある. その75%は薬剤を適切に使用すれば予防可能であった.
  19. 19. 投薬のチェック方法• Beers’ criteria;   • Beersが1991年に提唱した, 高齢者に害を及ぼす可能性のある 薬剤のリスト. 2012年にUpdateが発表されており, 以下のURLでDL可能 (http://www.americangeriatrics.org/health_care_professionals/clinical_practice/ clinical_guidelines_recommendations/2012) • 大量のため, 割愛. ポケットブックもDL可能であり, ポケットデバイスに入れておくと便利.
  20. 20. Table 1 (continued from page 1)AGS BEERS CRITERIA TABLE 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Organ System/ Recommendation, Rationale,FOR POTENTIALLY INAPPROPRIATE Therapeutic Category/Drug(s) Quality of Evidence (QE) & Strength of Recommendation (SR) Antispasmodics Avoid except in short-term palliative care to decreaseMEDICATION USE IN OLDER ADULTS n Belladonna alkaloids oral secretions. n Clidinium-chlordiazepoxideFROM THE AMERICAN GERIATRICS SOCIETY n Dicyclomine Highly anticholinergic, uncertain effectiveness. n HyoscyamineThis clinical tool, based on The AGS 2012 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older n Propantheline QE = Moderate; SR = StrongAdults (AGS 2012 Beers Criteria), has been developed to assist healthcare providers in improving medication safety in n Scopolamineolder adults. Our purpose is to inform clinical decision-making concerning the prescribing of medications for olderadults in order to improve safety and quality of care. Antithrombotics Dipyridamole, oral short-acting* (does not Avoid.Originally conceived of in 1991 by the late Mark Beers, MD, a geriatrician, the Beers Criteria catalogues medications apply to the extended-release combination with May cause orthostatic hypotension; more effective alternativesthat cause adverse drug events in older adults due to their pharmacologic properties and the physiologic changes of aspirin) available; IV form acceptable for use in cardiac stress testing.aging. In 2011, the AGS undertook an update of the criteria, assembling a team of experts and funding the develop- QE = Moderate; SR = Strongment of the AGS 2012 Beers Criteria using an enhanced, evidence-based methodology. Each criterion is rated (qual- Ticlopidine* Avoid.ity of evidence and strength of evidence) using the American College of Physicians’ Guideline Grading System, which Safer, effective alternatives available.is based on the GRADE scheme developed by Guyatt et al. QE = Moderate; SR = StrongThe full document together with accompanying resources can be viewed online at www.americangeriatrics.org. Anti-infective Nitrofurantoin Avoid for long-term suppression; avoid in patients withINTENDED USE CrCl <60 mL/min.The goal of this clinical tool is to improve care of older adults by reducing their exposure to Potentially Inappropri- Potential for pulmonary toxicity; safer alternatives available; lack ofate Medications (PIMs). n This should be viewed as a guide for identifying medications for which the risks of use in older adults outweigh concentration in the urine. QE = Moderate; SR = Strong n These criteria are not meant to be applied in a punitive manner. n This list is not meant to supersede clinical judgment or an individual patient’s values and needs. Prescribing and Cardiovascular managing disease conditions should be individualized and involve shared decision-making. Alpha1 blockers Avoid use as an antihypertensive. n These criteria also underscore the importance of using a team approach to prescribing and the use of non- n Doxazosin High risk of orthostatic hypotension; not recommended as routine n Prazosin treatment for hypertension; alternative agents have superior risk/ pharmacological approaches and of having economic and organizational incentives for this type of model. n Implicit criteria such as the STOPP/START criteria and Medication Appropriateness Index should be used in n Terazosin a complementary manner with the 2012 AGS Beers Criteria to guide clinicians in making decisions about safe QE = Moderate; SR = Strong medication use in older adults. Alpha agonists - n Clonidine ers as listed.The criteria are not applicable in all circumstances (eg, patient’s receiving palliative and hospice care). If a clinician is n Guanabenz* High risk of adverse CNS effects; may cause bradycardia and n Guanfacine* orthostatic hypotension; not recommended as routine treatmentof the medication as potentially inappropriate can serve as a reminder for close monitoring so that the potential for n Methyldopa* for hypertension.an adverse drug effect can be incorporated into the medical record and prevented or detected early. n Reserpine (>0.1 mg/day)* QE = Low; SR = Strong Antiarrhythmic drugs (Class Ia, Ic, III) n AmiodaroneTABLE 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults n Dofetilide n Dronedarone Organ System/ Recommendation, Rationale, n Flecainide harms than rhythm control for most older adults. Therapeutic Category/Drug(s) Quality of Evidence (QE) & Strength of Recommendation (SR) n IbutilideAnticholinergics (excludes TCAs) n Procainamide Amiodarone is associated with multiple toxicities, including thyroidFirst-generation antihistamines (as single Avoid. n Propafenone disease, pulmonary disorders, and QT interval prolongation.agent or as part of combination products) n Quinidine QE = High; SR = Strongn Brompheniramine Highly anticholinergic; clearance reduced with advanced age, and n Sotaloln Carbinoxamine tolerance develops when used as hypnotic; increased risk of confu- Disopyramide* Avoid.n Chlorpheniramine sion, dry mouth, constipation, and other anticholinergic effects/ Disopyramide is a potent negative inotrope and therefore mayn Clemastine toxicity. induce heart failure in older adults; strongly anticholinergic; othern Cyproheptadine antiarrhythmic drugs preferred.n Dexbrompheniramine Use of diphenhydramine in special situations such as acute treat- QE = Low; SR = Strongn Dexchlorpheniramine ment of severe allergic reaction may be appropriate.n Diphenhydramine (oral) Dronedaronen Doxylamine heart failure. QE = High (Hydroxyzine and Promethazine), Moderate (All others); SRn Hydroxyzine = Strongn Promethazine Worse outcomes have been reported in patients taking drone-n Triprolidine general, rate control is preferred over rhythm control for atrialAntiparkinson agents Avoid.n Benztropine (oral) QE = Moderate; SR = Strongn Trihexyphenidyl Not recommended for prevention of extrapyramidal symptoms Digoxin >0.125 mg/day Avoid. with antipsychotics; more effective agents available for treatment of In heart failure, higher dosages associated with no additional Parkinson disease. may increase risk of toxicity. QE = Moderate; SR = Strong QE = Moderate; SR = Strong
  21. 21. Table 1 (continued from page 2) Table 1 (continued from page 3) TABLE 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults TABLE 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Organ System/ Recommendation, Rationale, Organ System/ Recommendation, Rationale, Therapeutic Category/Drug(s) Quality of Evidence (QE) & Strength of Recommendation (SR) Therapeutic Category/Drug(s) Quality of Evidence (QE) & Strength of Recommendation (SR) Nifedipine, immediate release* Avoid. Nonbenzodiazepine Avoid chronic use (>90 days) hypnotics Benzodiazepine-receptor agonists that have adverse events similar Potential for hypotension; risk of precipitating myocardial ischemia. n Eszopiclone to those of benzodiazepines in older adults (e.g., delirium, falls, QE = High; SR = Strong n Zolpidem fractures); minimal improvement in sleep latency and duration. n Zaleplon QE = Moderate; SR = StrongSpironolactone >25 mg/day Avoid in patients with heart failure or with a CrCl <30 mL/min. Ergot mesylates* Avoid. Isoxsuprine* In heart failure, the risk of hyperkalemia is higher in older adults if QE = High; SR = Strong taking >25 mg/day. QE = Moderate; SR = Strong Endocrine Androgens Avoid unless indicated for moderate to severeCentral Nervous System n Methyltestosterone* hypogonadism.Tertiary TCAs, alone or in combination: Avoid. n Testosterone Potential for cardiac problems and contraindicated in men withn Amitriptyline prostate cancer.n Chlordiazepoxide- Highly anticholinergic, sedating, and cause orthostatic hypotension; QE = Moderate; SR = Weak amitriptyline Desiccated thyroid Avoid.n Clomipramine to that of placebo. Concerns about cardiac effects; safer alternatives available.n QE = Low; SR = Strongn Imipramine QE = High; SR = Strongn Perphenazine-amitriptyline Estrogens with or without progestins Avoid oral and topical patch.Topical vaginal cream: Ac-n Trimipramine management of dyspareunia, lower urinary tract infec- - tions, and other vaginal symptoms.ond- (atypical) generation (see online for full list) non-pharmacologic options have failed and patient is Evidence of carcinogenic potential (breast and endometrium); lack threat to self or others. of cardioprotective effect and cognitive protection in older women. Evidence that vaginal estrogens for treatment of vaginal dryness is Increased risk of cerebrovascular accident (stroke) and mortality in safe and effective in women with breast cancer, especially at dos- persons with dementia. QE = Moderate; SR = Strong QE = High (Oral and Patch), Moderate (Topical); SR = Strong (Oral andThioridazine Avoid. Patch),Weak (Topical)Mesoridazine Growth hormone Avoid, except as hormone replacement following pituitary Highly anticholinergic and greater risk of QT-interval prolongation. gland removal. QE = Moderate; SR = Strong Effect on body composition is small and associated with edema, arthralgia, carpal tunnel syndrome, gynecomastia, impaired fastingBarbiturates Avoid. glucose.n Amobarbital*n Butabarbital* QE = High; SR = Strongn Butalbital greater risk of overdose at low dosages. Insulin, sliding scale Avoid.n Mephobarbital* Higher risk of hypoglycemia without improvement in hyperglyce-n Pentobarbital* QE = High; SR = Strong mia management regardless of care setting.n Phenobarbital QE = Moderate; SR = Strongn Secobarbital* Megestrol Avoid.Benzodiazepines - Minimal effect on weight; increases risk of thrombotic events andShort- and intermediate-acting: nia, agitation, or delirium. possibly death in older adults. n Alprazolam QE = Moderate; SR = Strong n Estazolam Older adults have increased sensitivity to benzodiazepines and Sulfonylureas, long-duration Avoid. n decreased metabolism of long-acting agents. In general, all ben- n Chlorpropamide Chlorpropamide: prolonged half-life in older adults; can cause nOxazepam zodiazepines increase risk of cognitive impairment, delirium, falls, n Glyburide prolonged hypoglycemia; causes SIADH nTemazepam fractures, and motor vehicle accidents in older adults. Glyburide: higher risk of severe prolonged hypoglycemia in older nTriazolam adults.Long-acting: May be appropriate for seizure disorders, rapid eye movement QE = High; SR = Strong n Chlorazepate sleep disorders, benzodiazepine withdrawal, ethanol withdrawal, n Chlordiazepoxide severe generalized anxiety disorder, periprocedural anesthesia, Gastrointestinal n Chlordiazepoxide-amitriptyline end-of-life care. Metoclopramide Avoid, unless for gastroparesis. n Clidinium-chlordiazepoxide Can cause extrapyramidal effects including tardive dyskinesia; risk n Clonazepam QE = High; SR = Strong may be further increased in frail older adults. n Diazepam QE = Moderate; SR = Strong n Flurazepam n Quazepam Mineral oil, given orally Avoid. Potential for aspiration and adverse effects; safer alternatives avail-Chloral hydrate* Avoid. able. QE = Moderate; SR = Strong light of overdose with doses only 3 times the recommended dose. Trimethobenzamide Avoid. QE = Low; SR = Strong One of the least effective antiemetic drugs; can cause extrapyrami-Meprobamate Avoid. dal adverse effects. High rate of physical dependence; very sedating. QE = Moderate; SR = Strong QE = Moderate; SR = Strong
  22. 22. Table 1 (continued from page 4) Table 2 (continued from page 5) TABLE 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults TABLE 2: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug- Organ System/ Recommendation, Rationale, Disease or Drug-Syndrome Interactions That May Exacerbate the Disease or Syndrome Therapeutic Category/Drug(s) Quality of Evidence (QE) & Strength of Recommendation (SR) Disease or Drug(s) Recommendation, Rationale, Quality of Evidence Syndrome (QE) & Strength of Recommendation (SR) Pain Medications Syncope Acetylcholinesterase inhibitors (AChEIs) Avoid. Meperidine Avoid. Peripheral alpha blockers Not an effective oral analgesic in dosages commonly used; may n Doxazosin Increases risk of orthostatic hypotension or brady- cause neurotoxicity; safer alternatives available. n Prazosin cardia. QE = High; SR = Strong n Terazosin QE = High (Alpha blockers), Moderate (AChEIs,TCAs andNon-COX-selective NSAIDs, oral Avoid chronic use unless other alternatives are not effec- Tertiary TCAs antipsychotics); SR = Strong (AChEIs and TCAs),Weakn Aspirin >325 mg/day tive and patient can take gastroprotective agent (proton- (Alpha blockers and antipsychotics)n Diclofenac Chlorpromazine, thioridazine, and olan-n zapinen Etodolac Increases risk of GI bleeding/peptic ulcer disease in high-risk Central Nervous Systemn Fenoprofenn Ibuprofen corticosteroids, anticoagulants, or antiplatelet agents. Use of pro- Chronic Bupropion Avoid.n Ketoprofen ton pump inhibitor or misoprostol reduces but does not eliminate seizures or Chlorpromazinen Meclofenamate risk. Upper GI ulcers, gross bleeding, or perforation caused by epilepsy Clozapinen Mefenamic acid Maprotiline patients with well-controlled seizures in whom alter-n Meloxicam months, and in about 2%–4% of patients treated for 1 year. These Olanzapine native agents have not been effective.n Nabumetone trends continue with longer duration of use. Thioridazinen Naproxen Thiothixene QE = Moderate; SR = Strongn Oxaprozin QE = Moderate; SR = Strong Tramadoln Piroxicam Delirium All TCAs Avoid.n Sulindac Anticholinergics (see online for full list)n Tolmetin Benzodiazepines Avoid in older adults with or at high risk of delirium Chlorpromazine because of inducing or worsening delirium in olderIndomethacin Avoid. Corticosteroids adults; if discontinuing drugs used chronically, taper toKetorolac, includes parenteral Increases risk of GI bleeding/peptic ulcer disease in high-risk H2-receptor antagonist avoid withdrawal symptoms. groups (See Non-COX selective NSAIDs) Meperidine Of all the NSAIDs, indomethacin has most adverse effects. Sedative hypnotics QE = Moderate; SR = Strong QE = Moderate (Indomethacin), High (Ketorolac); SR = Strong ThioridazinePentazocine* Avoid. Dementia Anticholinergics (see online for full list) Avoid. Opioid analgesic that causes CNS adverse effects, including confu- & cognitive Benzodiazepines Avoid due to adverse CNS effects. sion and hallucinations, more commonly than other narcotic drugs; impairment H2-receptor antagonists Avoid antipsychotics for behavioral problems of is also a mixed agonist and antagonist; safer alternatives available. Zolpidem dementia unless non-pharmacologic options have QE = Low; SR = Strong Antipsychotics, chronic and as-needed use failed and patient is a threat to themselves or others.Skeletal muscle relaxants Avoid. Antipsychotics are associated with an increased riskn Carisoprodol Most muscle relaxants poorly tolerated by older adults, because of of cerebrovascular accident (stroke) and mortality inn Chlorzoxazone anticholinergic adverse effects, sedation, increased risk of fractures; persons with dementia.n Cyclobenzaprine effectiveness at dosages tolerated by older adults is questionable. QE = High; SR = Strongn Metaxalone QE = Moderate; SR = Strong History Anticonvulsants Avoid unless safer alternatives are not avail-n Methocarbamol of falls or Antipsychoticsn Orphenadrine fractures Benzodiazepines*Infrequently used drugs. Table 1 Abbreviations: ACEI, angiotensin converting-enzyme inhibitors; ARB, angiotensin Nonbenzodiazepine hypnotics Ability to produce ataxia, impaired psychomotor n Eszopiclone function, syncope, and additional falls; shorter-actingreceptor blockers; CNS, central nervous system; COX, cyclooxygenase; CrCl, creatinine clearance; GI, gastroin- n Zaleplon benzodiazepines are not safer than long-acting ones. n Zolpidemsecretion; SR, Strength of Recommendation; TCAs, tricyclic antidepressants; QE, Quality of Evidence QE = High; SR = Strong TCAs/SSRIsTABLE 2: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug-Disease or Drug-Syndrome Interactions That May Exacerbate the Disease or Syndrome Insomnia Oral decongestants Avoid. n PseudoephedrineDisease or Drug(s) Recommendation, Rationale, Quality of Evidence n Phenylephrine Stimulants CNS stimulant effects.Syndrome (QE) & Strength of Recommendation (SR) n AmphetamineCardiovascular n Methylphenidate QE = Moderate; SR = StrongHeart failure NSAIDs and COX-2 inhibitors Avoid. n Pemoline Theobromines n Theophylline Nondihydropyridine CCBs (avoid only for - n Caffeine systolic heart failure) bate heart failure. Parkinson’s All antipsychotics (see online publica- Avoid. n Diltiazem disease tion for full list, except for quetiapine and Dopamine receptor antagonists with potential to n Verapamil QE = Moderate (NSAIDs, CCBs, Dronedarone), High (Thia- clozapine) worsen parkinsonian symptoms. zolidinediones (glitazones)), Low (Cilostazol); SR = Strong Pioglitazone, rosiglitazone Antiemetics Quetiapine and clozapine appear to be less likely to n Metoclopramide precipitate worsening of Parkinson disease. Cilostazol n Prochlorperazine Dronedarone n Promethazine QE = Moderate; SR = Strong
  23. 23. Table 2 (continued from page 6) Table 2 (continued from page 7) TABLE 2: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug- TABLE 2: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug- Disease or Drug-Syndrome Interactions That May Exacerbate the Disease or Syndrome Disease or Drug-Syndrome Interactions That May Exacerbate the Disease or Syndrome Disease or Drug(s) Recommendation, Rationale, Quality of Evidence Disease or Drug(s) Recommendation, Rationale, Quality of Evidence Syndrome (QE) & Strength of Recommendation (SR) Syndrome (QE) & Strength of Recommendation (SR) Gastrointestinal Inhaled anticholinergic agents Avoid in men. Chronic Oral antimuscarinics for urinary inconti- Avoid unless no other alternatives. urinary tract constipation nence symptoms, Strongly anticholinergic drugs, except - n Darifenacin Can worsen constipation; agents for urinary incon- benign antimuscarinics for urinary incontinence tion. n Fesoterodine tinence: antimuscarinics overall differ in incidence of prostatic (see Table 9 for complete list). n Oxybutynin (oral) constipation; response variable; consider alternative hyperplasia QE = Moderate; SR = Strong (Inhaled agents),Weak (All n Solifenacin agent if constipation develops. others) n Tolterodine Stress or Alpha-blockers Avoid in women. n Trospium QE = High (For Urinary Incontinence), Moderate/Low (All mixed n Doxazosin Others); SR = Strong urinary in- n Prazosin Aggravation of incontinence. Nondihydropyridine CCB continence n Terazosin n Diltiazem QE = Moderate; SR = Strong n Verapamil Table 2 Abbreviations: CCBs, calcium channel blockers; AChEIs, acetylcholinesterase inhibitors; CNS, central ner- First-generation antihistamines as single - agent or part of combination products tion; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; QE, Quality of Evidence n Brompheniramine (various) n Carbinoxamine n Chlorpheniramine TABLE 3: 2012 AGS Beers Criteria for Potentially Inappropriate Medications to Be Used with Caution in n Clemastine (various) Older Adults n Cyproheptadine Drug(s) Recommendation, Rationale, Quality of Evidence (QE) & Strength of Recommenda- n Dexbrompheniramine tion (SR) n Dexchlorpheniramine (various) Aspirin for primary preven- n Diphenhydramine tion of cardiac events n Doxylamine n Hydroxyzine QE = Low; SR = Weak n Promethazine n Triprolidine Dabigatran Anticholinergics/antispasmodics (see online for full list of drugs with strong anticholinergic properties) QE = Moderate; SR = Weak n Antipsychotics Prasugrel n Belladonna alkaloids n Clidinium-chlordiazepoxide n Dicyclomine risk older patients (eg, those with prior myocardial infarction or diabetes). n Hyoscyamine QE = Moderate; SR = Weak n Propantheline n Scopolamine Antipsychotics Use with caution. n Tertiary TCAs (amitriptyline, clomip- Carbamazepine Carboplatin May exacerbate or cause SIADH or hyponatremia; need to monitor sodium level ramine, doxepin, imipramine, and trimip- Cisplatin closely when starting or changing dosages in older adults due to increased risk. ramine) MirtazapineHistory of Aspirin (>325 mg/day) Avoid unless other alternatives are not ef- SNRIs QE = Moderate; SR = Stronggastric or Non–COX-2 selective NSAIDs fective and patient can take gastroprotective SSRIsduodenal TCAsulcers Vincristine May exacerbate existing ulcers or cause new/addi- Vasodilators Use with caution. tional ulcers. QE = Moderate; SR = Strong May exacerbate episodes of syncope in individuals with history of syncope.Kidney/Urinary Tract QE = Moderate; SR = WeakChronic kid- NSAIDs Avoid. Table 3 Abbreviations: CrCl, creatinine clearance; SIADH, syndrome of inappropriate antidiuretic hormoneney disease secretion; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin–norepinephrine reuptake inhibitors;stages IV May increase risk of kidney injury. SR, Strength of Recommendation; TCAs, tricyclic antidepressants; QE, Quality of Evidenceand V Triamterene (alone or in combination) May increase risk of acute kidney injury. The American Geriatrics Society gratefully acknowledges the support of the John A. Hartford Foundation, QE = Moderate (NSAIDs), Low (Triamterene); SR = Strong Retirement Research Foundation and Robert Wood Johnson Foundation. (NSAIDs),Weak (Triamterene) AGSUrinary Estrogen oral and transdermal (excludes Avoid in women.incontinence intravaginal estrogen) THE AMERICAN GERIATRICS SOCIETY(all types) in Aggravation of incontinence. Geriatrics Health Professionals.women QE = High; SR = Strong www.americangeriatrics.org
  24. 24. アドヒアランスのチェック MANAGING MEDICATIONS IN CLINICALLY COMPLEX ELDERS• アドヒアランスを障害する因子 JAMA. 2010;304(14):1592-1601 g Table 1. Barriers to Medication Adherence and Targeted Solutions i Barriers Potential Solutions a Forgetting to take; Use pill organizers, medication calendars, blister limited organizational packs, electronic dispensing devices; simplify c skills regimen and reduce pill burden; encourage i active family/caregiver involvement; use Internet-linked or electronic adherence aids e and reporting systems m Patient believes drug is Work collaboratively with patient to address c not needed, is concerns and establish shared goals of care; ineffective, or that provide educational (including literacy- p too many drugs appropriate) materials using teach-back c are being taken approach; assess drug effectiveness; simplify m regimen and reduce pill burden Difficulty taking Substitute with easier-to-use medications (eg, p (eg, opening pill liquid if trouble swallowing; ordering easy-off g bottles, swallowing) caps); simplify regimen and reduce pill i burden; use pill cutters, oral dosing syringes, insulin syringe magnification, spacer for i inhalers Cost Substitute with lower-cost medications (eg, G generic vs brand name) and reduce unnecessary ones; assess prescription drug M insurance and direct patient to apply for t low-income subsidy and prescription drug assistance programs h
  25. 25. どの薬剤を切るべきか?creased compared with the control group. The present studytests the feasibility of applying the same algorithm in com- Discuss the following with the patient/guardian • 各患者背景,munity-dwelling elderly patients. An evidence-based consensus exists for using the Yes drug for the indication given in its current dosing rate リスク-ベネフィットを考慮し, METHODS in this patient’s age group and disability level, and the benefit outweighs all possible known adverse effects No/Not sure 中止,STUDY PARTICIPANTS 変更を決める. No Indication seems valid and relevant in this patient’s age S group and disability level TThis prospective cohort study included consecutive elderly pa- Otients referred by their family physician or family for compre- Yes P Dhensive geriatric assessments from February 2005 through June Yes R2008 and excluded patients with advanced disease (cancer or Do the known possible adverse reactions of the drug U outweigh possible benefit in old, disabled patients? Gnoncancer) in whom the initial estimate of life expectancy wasless than 3 months and patients in whom follow-up availabil- No • 入院というイベントはity was shorter than 4 months. Participants were assessed and Yesrecommendations were made on medications based on the Good Any adverse symptoms or signs that may be related to S the drug? H 薬剤調節の最も良い機会とPalliative–Geriatric Practice (GP-GP) algorithm (Figure).12 As-sessments were performed either at the day care center for se- No I F Tnior citizens in Pardes Hana or at the patient’s home in Israel. T 捉えるべし.The rationale for recommendations was then explained and dis- Is there another drug that may be superior to the one in question? Yes Ocussed in detail with each patient and/or guardian/family. They A Nwere informed of the pros and cons of each medication pre- No Oscribed, the level of evidence for a positive benefit to risk ratio T Can the dosing rate be reduced with no significant risk? Hand its possible impact on longevity and quality of life. Fol- Elowing this discussion and based on patient and/or guardian/ Rfamily preferences and consent, detailed letters were sent to the No Yes D Rfamily physicians with recommendations to stop as many “non– U Continue with the same dosing rate Reduce dose Glife saving drugs” as possible for at least 3 months. When stop-ping a Intern Med. 2010;170(18):1648-1654 appropriate, dose Arch drug therapy was not considered
  26. 26. • その患者背景, 状態に一致した 母集団での明確なEvidenceあり → 薬剤は継続. (実際殆ど無し) • 患者背景, 状態を考慮し, 妥当ではないと判断 → 中止. • 副作用が利点を上回る → 中止. • 副作用が認められるが, 利点が大きい場合 → 薬剤を変更 • 他の薬剤でもっと効果が高いものがる場合 → 変更 • 投薬を減量しても不利益が無いと考えられる場合 → 減量Arch Intern Med. 2010;170(18):1648-1654
  27. 27. 患者に応じた薬剤の調節 • ① 患者背景, 状態, 年齢, 余命を考慮し,  それぞれのプロブレム毎のゴールを決める(アウトカム設定) • ② 各プロブレムに対して投与されている薬剤が  そのアウトカムに沿っているか?   → 沿っていないならば変更, 中止すべき.   → プロブレムと投与薬剤が合っていない場合も中止 • ③ 薬剤の副作用のアセスメントし,  副作用と薬剤投与の利益を比較.   → 副作用の方が大きいならば中止 or 減量 or 変更Arch Intern Med. 2010;170(18):1648-1654を一部改変
  28. 28. palliative m medications Less Time Palliative those addre toms. Exam targets includ vention of m Trea maintenance efit tmen y l Ben tion, and tre tanc Goal t Tar xpec Unti s of get CA E Time Care Life WITH g ainin Rem These conce nents in a Appropriate prescribing l Medications expectancy More Time Curative goals of care (Figure 3) components Figure 3. The model shows that the 4 steps in medication decision making form a pyramid, visually representing the appropriate medications at any level. At the top are represented patients for whom others, yield• どの薬剤が必要になるかはそれぞれの患者で異なる. remaining life expectancy is limited, drugs should have the shortest time until benefit, goals of care are palliative, and treatment targets are focused on symptom management. Moving toward the bottom, the propriate m able limitatio base of appropriate medications expands as the patient’s life expectancy is longer, time until benefit may be longer, goals of care are more aggressive, and treatment targets are aimed more at preventive be made to d strategies. The bottom of the pyramid therefore contains all medications that are otherwise appropriate cations ident • 余命, 治療のゴール, 目的, 薬剤開始∼効果発現までの時間の4軸で according to existing criteria for patients 65 years and older. components 考える方法もある. (REPRINTED) ARCH INTERN MED/ VOL 166, MAR 27, 2006 WWW.ARCHINTERNMED.COM 606 ©2006 American Medical Association. All rights reserved. • 例えば余命が2年なのに効果発現まで2年以上かかる治療は無意味Downloaded From: http://archinte.jamanetwork.com/ by JUNKO NAGASUE on 11/29/2012 Intern Med 2006;166:605-609 Arch
  29. 29. • Case 1; 75歳女性, HT, 変形性関節症, 2型DM. • ADLは自立しており, 余命は17年程度と予測(life tableより)  → 各問題点においてしっかりとマネージメントし,   Strokeや虚血性心疾患の予防, 変形性関節症の予防,   転倒リスクの回避, 骨粗鬆症のチェック, 治療などキッチリ必要 • DMに関しては低血糖リスクが低い薬剤の選択. Arch Intern Med 2006;166:605-609
  30. 30. • Case 2; 72歳男性, 重度心不全, COPDでHOT導入. • 予測余命は数ヶ月∼1年程度. この状態でいろいろ精査し, それぞれの病態に対応しても 効果発現までの期間も長く, 意味は乏しい. • むしろ緩和ケア, 対症療法を中心とすべきと言える. 呼吸苦や不安を緩和する為の薬剤, 気管支拡張薬など. Arch Intern Med 2006;166:605-609
  31. 31. 例題• 80歳男性, 脳 塞後, 認知症(血管性疑い)で寝たきり. 食事摂取は可能だがムセが多い. 2型糖尿病, 高血圧, 高脂血症の既往あり, かかりつけは他院. • そんな患者が誤嚥性肺炎にて入院. • 入院時の内服薬は, バルプロ酸, セロクエル, SU剤, CCB, スタチン, PPI, アスピリン, サアミオン • 薬剤調節をどう行う?
  32. 32. • (使用薬剤に対する)プロブレムを挙げよう • #糖尿病, #高血圧, #高脂血症 #脳血管性認知症, #脳 塞後• それぞれのプロブレムに対応する薬剤は? プロブレム 使用薬剤 コメント 糖尿病 SU剤 高血圧 CCB 高脂血症 スタチン アスピリン 脳血管性認知症 ASAの潰瘍予防にPPI サアミオン 脳 塞後 アスピリン 上記と同じ バルプロ酸 その他 対応するプロブレムが無い? セロクエル
  33. 33. • ① それぞれのアウトカムは? • 前提として, この患者さんの状況は, 80歳寝たきりで, 余命も数年あるかどうか. コミュニケーションは困難で, かろうじて食事可能. プロブレム アウトカム(建前) 状況に合わせたアウトカム(本音) キッチリとHbA1cを押さえる 高齢, 余命も数年 糖尿病 (HbA1c 7%前後) 低血糖だけは起こさない様にしたい... キッチリとBP <130/90へ 高血圧 あまり頑張りすぎて低血圧になっても... 降圧薬は(Level 1A) LDL-chol<80にしたいところ 高脂血症 スタチンは14%再発を減らす, けど... スタチンは(Level 1B)脳血管性認知症 脳 塞予防 アスピリンは 抗血小板薬は必須 1000人に7名で再発を減らす 脳 塞後 (Level IA) 死亡率は1000人に4名減らす 出血は1000人に2名 Lancet Neurol 2011;10: 357–71
  34. 34. • ② アウトカムと薬剤の関係プロブレム 状況に合わせたアウトカム(本音) 使用薬剤 アセスメント 高齢, 余命も数年 SU剤は低血糖の高リスク, 糖尿病 低血糖だけは起こさない様にした SU剤 高齢者での使用はどうか? い... あまり頑張りすぎて低血圧に CCB程度ならば問題無いかも. 高血圧 CCB なっても... 日頃の血圧をモニタリングし判断 効果的ではあるが, スタチンは14%再発を減らす,高脂血症 スタチン この患者に必須かと言われると微 けど... 妙脳血管性 一応, 誤嚥を減らすとの弱いエビ サアミオン 認知症 デンスはある* アスピリンは 1000人に7名で再発を減らす この数字と余命と出血リスクを脳 塞後 アスピリン 死亡率は1000人に4名減らす どう考えるか? 出血は1000人に2名 バルプロ酸 これについては情報が無く その他 セロクエル さらに聴取する必要がある *Medicine 2011;90: 279-283
  35. 35. • ここまでのアセスメントでの薬剤調節; • 糖尿病に対してはSU剤から低血糖リスクの少ない他のピオグリタゾ ンやメトフォルミンへ変更を試してみる方針とした. • 高血圧に対するCCBは継続. 高脂血症に対するスタチンは中止. • 脳 塞に対するアスピリンは迷ったあげく残し, サアミオン(Nicegoline)は誤嚥リスクが高いので, 藁へもすがる思いで残した. • 問題は投与理由が不明なバルプロ酸とセロクエル
  36. 36. • 薬剤の病歴を詳しく聴取(From 家族, 前医) • 認知症が特に増悪したのは2-3年前. その際 不穏, 昼夜逆転, 叫び声, 興奮が強く, 家族がかなり困った. 主治医に相談し, 眠剤や抗精神病薬が試され, その際バルプロ酸, セロクエルが開始. 痙攣はした事はありません • それら開始後から徐々に不穏や昼夜逆転は消失し, 活気も低下してきた気がする. • 誤嚥やムセがひどくなったのは1-2年前から, あ, そう言えばその薬が始まって落ち着いた時期だったかしら?
  37. 37. • 入院後, バルプロ酸, セロクエルは一旦中止し, 経過観察. • 誤嚥性肺炎治療と同時にSTリハビリも開始. • 入院後からは幾分活気が戻り, 問いかけ対する反応も良好に. STリハビリにて刻み食も良好に摂取できる様になり, 家人から見ても明らかに反応が良くなったと. • ムセも無く, 食事摂取良好となったが, 身体機能は廃用症候群にてあまり改善なく, 退院となった.• 今回の薬剤調節; • スタチン, バルプロ酸, セロクエル中止. (サアミオンも止められたかも...)
  38. 38. • Clinical pearl • 抗てんかん薬が入っている場合, 必ず, しつこく, 何時, どこで, どのタ イミングにてんかん発作があったのかは確認すべきである.  しばしばてんかんが無いのに他の理由で薬剤が入り, 中止できず に意識障害の原因となっていることがある. • 抗精神病薬も同様, 何故入っているのかは常に意識しなさい. Katsushige Takagishi
  39. 39. 反対に急に中止するとダメな薬剤は? 薬剤 理由 対応 抗パーキンソン薬* 悪性症候群のリスク 徐々に漸減させる ステロイド 副腎不全のリスク 徐々に漸減させる ベンゾジアゼピン(大量の) 離脱のリスク 徐々に漸減させる 心不全に対するβ阻害薬 心不全増悪のリスク 中止必要な場合は循環器併診虚血性心疾患に対する抗血小板薬§ 虚血性心疾患のリスク 中止必要な場合は循環器併診* Levodopa, Dopamine agonist, COMT阻害薬(Catechol-O-Methyl transferase)§ DES留置後12mo以内の2剤療法 → 1剤への変更と, 全期間における1剤療法 → 中止とする場合
  40. 40. 抗血小板薬中止による影響• Aspirin中止による心血管イベントリスクを評価したMeta. – 6 prospective cohort trialsのMeta-analysis, N=50279名. – 全体では, Aspirin中止による心血管イベントリスクRR 3.14[1.75-5.61] – 特に冠動脈ステント留置群では高リスクであり, RR89.78[29.9-269.6] European Heart Journal (2006) 27, 2667–2674• 心血管系イベントの10.2%が直前にAspirin中止歴がある. – 周術期におけるAspirin中止の影響を評価したMeta-analysisでは, Aspirin中止∼各イベント発症までの期間は, 急性冠動脈疾患 8.5±3.6d 脳血管疾患 14.3±11.3d 末梢血管疾患 25.8±18.1d となる. 早いものでは中止後5日で発症. Journal of Internal Medicine 2005; 257: 399–414

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