Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis The APPAC Randomized Clinical Trial
JAMA. 2015;313(23):2340-2348.
Patients
Patients aged 18 to 60 years admitted to the emergency department with a clinical suspicion of uncomplicated acute appendicitis confirmed by a CT scan were enrolled in the study. Patients with complicated appendicitis, which was defined as the presence of an appendicolith, perforation, abscess, or suspicion of a tumor on the CT scan, were excluded. Other exclusion criteria were age younger than 18 years or older than 60 years, contraindications for CT (eg, pregnancy or lactating, allergy to contrast media or iodine, renal insufficiency with serum creatinine level >150 μmol/L, actively taking metformin), peritonitis, unable to cooperate and provide informed consent, and the presence of serious systemic illness.
18歳から60歳の合併症のないCTで確定した虫垂炎患者．
糞石，穿孔，膿瘍，腫瘍が疑われる患者は除外．その他，CT撮影できない，造影できない，状態が悪すぎるなどは除外
Intervention:
Antibiotic Therapy
Ertapenem was chosen as the antibiotic for this study because of its efficacy as a monotherapy for serious intra- abdominal infections,18 requiring only a single, daily dose. Intravenous ertapenem sodium (1 g/d) was administered for 3 days to patients in the antibiotic group, with the first dose given in the emergency department. The clinical status of patients in the antibiotic group was reevaluated within 12 to 24 hours after admission by the surgeon on call. If the sur- geon suspected progressive infection, perforated appendici- tis, or peritonitis, the patient underwent appendectomy. Intravenous antibiotic treatment was followed by 7 days of oral levofloxacin (500 mg once daily) and metronidazole (500 mg 3 times per day).
Control:
Surgical Treatment
Open appendectomy was performed using a McBurney right- lower quadrant muscle-splitting incision technique. Some sur- geons performed laparoscopic appendectomy. Prophylactic an- tibiotics (1.5 g of cefuroxime and 500 mg of metronidazole) were administered approximately 30 minutes before the in- cision was made. No further antibiotics were given to pa- tients in the surgical group unless a wound infection was sus- pected postoperatively. Appendicitis was confirmed if there was histopathological evidence of transmural neutrophil in- vasion involving the appendiceal muscularis layer.
抗生剤割り付け：エルタペネム 1g×3日間 → レボフロキサシン 500mg/日＋ メトロニダゾール 500mg×３/日×7日間
手術割り付け：開腹虫垂切除はマクバーニー切開法を使用。一部、腹腔鏡下虫垂切除
Outcome Measures
The primary end point for patients in the antibiotic group was resolution of acute appendicitis, resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of 1 year (treatment efficacy). Treatment success in the appendec- tomy group was defined as a patient successfully undergoing an appendectomy. Secondary end points included overall postintervention complications, late recurrence (after 1 year) of acute appendi- citis after conservative treatment, length of hospital stay and the amount of sick leave used by the patient, postinterven- tion pain scores (VAS score range, 0-10; a score of 0 indicates no pain and 10 indicates the worst possible pain), and the use of pain medication. Postintervention complications included clinical wound infection (surgical site infection) occurring within 30 days after the operative procedure as diagnosed by a surgeon or with a positive bacterial culture,19 other general postoperative complications (eg, pneumonia), adverse ef- fects of the antibiotic treatment (eg, diarrhea), incisional her- nia, possible adhesion-related problems (eg, bowel obstruc- tion), and persistent abdominal or incisional pain.
primary end pointは、虫垂炎治療成功かつ，1年以内の再発率．
secondary end pointは介入後の合併症、保存的治療後に遅発性に（1年後に）急性虫垂炎が再発すること、入院日数と患者の病気休暇の量、介入後の痛み得点：VAS得点、痛み止めの使用。
介入後合併症は、外科医によって虫垂炎と診断するまたは血液培養陽性になってから３０日以内に術後感染（傷感染）がおこること。他の介入後合併症は（例えば、肺炎）、抗生物質治療による副作用（例えば、下痢）、瘢痕ヘルニア、接着の問題（例えば、腸閉塞）、しつこい切開部の腹痛。
Randomization
Patients were randomized by a closed envelope method either to undergo open appendectomy or to receive antibi- otic therapy with intravenous ertapenem. The randomiza- tion was performed with a 1:1 equal allocation ratio. There were 610 opaque, sealed, and sequentially numbered ran- domization envelopes. The envelopes were shuffled and then distributed to each participating hospital. To random- ize a patient, the surgeon on duty in each participating hos- pital opened a consecutively numbered envelope that con- tained information regarding the randomization group assignment for the patient. Most of the treating surgeons were not part of the core study team and provided care as they did in their normal clinical practice.
ランダム化は、envelopeによる1:1の等しい配分比率で実行
施設によるstratifyは行っていない．
虫垂炎なのでopeによる差はないか．
characteristicsは同等
blind
Most of the treating surgeons were not part of the core study team and provided care as they did in their normal clinical practice.
open-labelなので患者・医師はどちらを選択したか知っている。多くの，外科医はstudyの中心スタッフには加わらないことになっていた．
ITT
primary outcomeに関しては，intention-to-treat．追跡不能に関しては，地域の病院での追加手術がないかなど調べている．
治療は両グループで同様に行われたか
抗生剤群は，所定の抗生剤で改善ない，再発すれば虫垂切除となっている．
SSIの治療に関する抗菌薬は記載無し．
size
手術成功率99%，抗生剤治療奏効率 75%，non-inferiority marginを24％と見積り，片側検定でα=0.05, β=0.10，lost follow-upが10%で，610人必要．
途中で思ったより集まらなかったのでβ=0.86にはなるが，530人で妥協した．
結果
primary
手術群 273名、 抗生剤群 253名。手術群273名のうち、1例を除き手術成功、成功率 99.6％ (95% CI, 98.0% to 100.0%)。抗生剤群において、虫垂炎所見から1年内に虫垂切除を施行したのは256名中70 名(27.3%; 95% CI, 22.0% to 33.2%) 。186名 (72.7%; 95% CI, 66.8% to 78.0%) は手術不要であった。ITT解析にて群間治療効果差 27.0% (95% CI, −31.6% to ∞) (P = .89)であった。事前設定非劣性マージン24％とすると、抗生剤治療の手術に対する非劣性確認できなかった。
その後の虫垂切除術施行された抗生剤治療70名中58名 (82.9%; 95% CI, 72.0% to 90.8%) は合併症無しの虫垂炎で、合併症有りは 7 名(10.0%; 95% CI, 4.1% to 19.5%) 、再発疑いで手術されたが虫垂炎でなかったのは 5名 (7.1%; 95% CI, 2.4% to 15.9%)であった。抗生剤治療ランダム化患者での虫垂切除遅れによる腹腔内膿瘍や他の重大合併症は認めなかった。
secondary
抗生剤グループ（6/216の患者）で2.8%（95%のCI、1.0%- 6.0%）の複雑化率は、外科的なグループ（45/220の患者）の20.5%（95%のCI、15.3%-26.4%）の率より17.7%（95%のCI（11.9%-23.4%））低かった（P < .001）。
病院滞在日数の長さは、外科的なグループの方が短かった（P < .001）。外科処置群（中央値、3日;25—75パーセンタイル、2日—3日、それぞれ）、抗生処置群で（中央値、3日;25—75パーセンタイル、3日—3日）。
VASスコアは退院時３点と２点、１週間２点と１点でそれぞれ抗生剤投与群の方が低かった、２ヶ月は１点同士で差がなかった
病気休暇の長さは１９日と７日で抗生剤投与群の方が短かった．
読んでみて．
1年で25%近い再発率をどう考えるか．どうしても手術が嫌ならしょうがないし，外科医が必要ないと言ってしまえば，しょうがないが，やっぱり切除がよいと思う．