1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2012 年 6 月 28 日 8:30-8:55 ８階 医局 Ogawa H, Kim-Mitsuyama S, Matsui K, Jinnouchi T, Jinnouchi H, Arakawa K; OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study Group. Angiotensin II Receptor Blocker-based Therapy in Japanese Elderly, High-risk, Hypertensive Patients. Am J Med. 2012 Apr 14. [Epub ahead of print]

2. doi:10.1016/j.amjmed.2011.12.010 http://www.oscar-study.jp/

3. BACKGROUND: It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker ＋ calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients.

4. METHODS: The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker ＋ 20 mg/d olmesartan (angiotensin II receptor blocker ＋ calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death.

6. ARB ＝ angiotensin II receptor blocker; CCB ＝ calcium channel blocker; BMI ＝ body mass index; BP ＝ blood pressure; eGFR ＝ estimated glomerular filtration rate (men: 194 × Cr － 1.094 × age － 0.287 ; women: 194 × Cr － 1.094 × age － 0.287 × 0.739); HDL ＝ high-density lipoprotein. Data are mean ± standard deviation for continuous variables and number (%) for categoric variables. P values were calculated using t tests for continuous variables and chi-square tests for categoric variables.

8. Figure 2 Time course of systolic and diastolic blood pressure in the 2 groups (A) and difference in blood pressure between the 2 groups (B) during follow-up. Blue values show mean systolic and diastolic blood pressure of high- dose ARB group, while red values show those of ARB plus CCB group. BP ＝ blood pressure; ARB ＝ angiotensin II receptor blocker; CCB ＝ calcium channel blocker. * P ＜.05, †P ＜.01 statistically significant difference between the 2 treatment groups at each time point.

9. Figure 3 Kaplan-Meier curves for primary composite endpoint during the follow-up period in overall patients (A), patients with cardiovascular disease at baseline (B), and patients without cardiovascular disease at baseline (with only type 2 diabetes) (C). In (A), there were 58 patients with events (10.03%) in the high-dose ARB group, compared with 48 patients with events (8.19%) in the ARB ＋ CCB group. The number of patients with cardiovascular disease in (B) was 405 and 407 in high-dose ARB and ARB ＋ CCB combination groups, respectively, and the number of patients without cardiovascular disease in (C) was 173 and 179 in high-dose ARB and ARB ＋ CCB combination groups, respectively. ARB ＝ angiotensin II receptor blocker; CCB ＝ calcium channel blocker; HR ＝ hazard ratio; CI ＝ confidence interval.

12. Adverse Events The number of serious adverse events, one of the secondary end points in this study, was 47 (8.1%) in the high-dose angiotensin II receptor blocker group and 51 (8.7%) in the angiotensin II receptor blocker ＋ calcium channel blocker group, with no significant difference between the 2 groups (P ＝.75). New cancer diagnosis was not significantly different between the treatment groups (10 [1.7%] in the highdose angiotensin II receptor blocker group vs 21 [3.6%] in the angiotensin II receptor blocker ＋ calcium channel blocker combination group; P ＝.07).

13. Study Limitations The OSCAR study has several limitations. The first limitation is the use of the Prospective Randomized Open Blinded End-point (PROBE) method. The PROBE method has the potential drawback of investigator bias. However, we believe that aggressive treatment for blood pressure control was similarly performed in both groups, as shown by the high percentage of patients who achieved target blood pressure control and good compliance in both groups. Therefore, the use of PROBE design appeared not significantly to affect the main outcomes in this study. The second limitation might be sample size. It is possible that the absence of difference in the primary outcome in the OSCAR study may be attributed to an underpowered sample size. However, the number of primary end points in the OSCAR study was close to the expected number of events. Therefore, the absence of difference in the primary outcome between the groups seems to be explained by the heterogeneity of treatment effects between 2 subgroups of patients, those with cardiovascular disease and those without as discussed above, although the possibility of insufficient sample size in the OSCAR study cannot be completely excluded.

14. RESULTS: During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker ＋ calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker ＋ calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker ＋ calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89- 1.92; P ＝.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P ＝.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P ＝.14). This treatment-by- subgroup interaction was significant (P ＝.02).

15. CONCLUSION: The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.

16. Message 高齢のハイリスク日本人高血圧患者を対象に、高用量の ARB 投与と ARB と Ca 拮抗薬併用のどちらが、心血管系疾患発症抑制において有用か検討する目的で 実施された初めての大規模臨床研究。試験は PROBE 法で行われた。登録期間 は、 2005 年６月～ 07 年 5 月までで、日本国内の 134 施設から登録された。 対象は、少なくとも心血管系疾患発症リスク（脳血管疾患、心疾患、血管疾患、 腎疾患、２型糖尿病）を１つ以上もつ 65 ～ 84 歳の外来高血圧患者で、オルメ サルタン 20mg/ 日を単独投与されている 1164 例。 ①オルメサルタン高用量（ 40mg/ 日）群 578 例 ②オルメサルタン 20mg/ 日 +Ca 拮抗薬（アゼルニジピンまたはアムロジピ ン）投与群 586 例 ―― の２群に分け、治療効果を比較した。主要評価項目は、致死性または非致 死的心血管系イベントの複合（脳血管疾患、心血管系疾患、心不全、そのほか アテローム血栓症、糖尿病性微小血管障害、腎疾患） + 総死亡。 ITT 解析を行ったところ、主要評価項目は、 ARB 高用量群で 58 例、 ARB+Ca 拮抗薬併用群では 48 例に発生し、ハザード比は 1.31 で両群間に有意差はみら れなかった（ 95 ％ CI ： 0.89 ～ 1.92 、 P 値＝ 0.1717 ）。なお、血圧値は ARB と Ca 拮抗薬併用群で、 ARB 高用量群に比べ、有意に低かった（ P 値＜ 0.05 ）。

17. Message ◎心血管系疾患の有無で最適な治療異なる可能性も サブグループ解析の結果、心血管系疾患の既往例では、主要評価項目の発生が ARB 高用量群（ 405 例）では 51 例、 ARB ＋ Ca 拮抗薬併用群（ 407 例）では 34 例で、 ARB 高用量群で有意に高い結果となった（ P 値＝ 0.0261 ）。 一方で、心血管系疾患の既往がなく、糖尿病だけを合併する患者では、主要評 価項目が、 ARB 高用量群（ 173 例）の７例に対し、 ARB ＋ Ca 拮抗薬群（ 179 例）では 14 例発生し、 ARB 高用量群で低い結果となった（ P 値＝ 0.1445 ）。 高齢者のハイリスク高血圧患者における治療戦略として「 ARB 高用量群と ARB と Ca 拮抗薬併用群で有意な差はみられなかった」と結論付けた。その上 で、心血管系疾患の既往があるかないか（２型糖尿病のみを合併）により、 「２つの治療の効果が相対的に異なる」可能性を示唆した。 http://www.mixonline.jp/Article/tabid/55/artid/40615/Default.aspx