Low-dose aspirin for primary prevention of cardiovascular events in elderly Japanese patients with atherosclerotic risk factors: a randomized clinical trial Yasuo Ikeda, Kazuyuki Shimada, Tamio Teramoto, Shinichiro Uchiyama, Tsutomu Yamazaki, Shinichi Oikawa, Masahiro Sugawara, Katsuyuki Ando, Mitsuru Murata, Kenji Yokoyama, Takuro Shimbo, Naoki Ishizuka Department of Cardiology, Shin-Oyama City Hospital, Tochigi, Japan ClinicalTrialsgov Identifier: NCT00225849 1
Introduction and objective Prevention of cardiovascular (CV) diseases is an important public health priority both worldwide and in Japan The role of aspirin in the primary prevention of CV disease has been hotly debated for several years Meta-analyses indicate benefits as well as risks 1 Recently, the US Food and Drug Administration cautioned against the general use of aspirin for the primary prevention of heart attacks and strokes 2 Japanese Primary Prevention Project (JPPP) Study objective To determine whether daily, low-dose aspirin reduces the incidence of CV events compared with no aspirin in elderly Japanese patients with atherosclerotic risk factors 1 Raju NC et al Curr Opin Cardiol 2012;27:499 507 2 FDA 2014 Available from: http://wwwfdagov/drugs/resourcesforyou/consumers/ucm390574htm 2
Study design: Prospective Randomized Open Blinded Endpoint (PROBE) Patients aged 60 85 years Hypertension Dyslipidemia Diabetes mellitus (one or more condition) Eligible 1:1 randomization 1007 clinics (all 47 prefectures) Enteric-coated aspirin 100 mg/day No aspirin Ongoing medications to control underlying disease(s) 3
Primary and secondary endpoints Outcome measure Death from CV causes: myocardial infarction (MI), stroke and other CV causes Composite primary endpoint Composite secondary endpoint Individual secondary endpoints Non-fatal stroke (ischemic or hemorrhagic) Non-fatal MI Transient ischemic attack (TIA) Angina pectoris Arteriosclerotic disease requiring surgery or intervention Death from causes other than CV disease Any cause of death Serious extracranial hemorrhage requiring transfusion or hospitalization 4
Timing of final analyses Sample size determination for final analyses Target: 15 000 patients for 624 primary endpoint events to occur 80% power to detect a 20% reduction in annual frequency of events, from 0874% without aspirin to 0698% with aspirin (two-sided α = 005) Independent Data Monitoring Committee (DMC) recommended to discontinue the study prematurely owing to futility The DMC believed that statistical power would not be reached, and that continuing the study might put patients at unnecessary risk of adverse events Median duration of patient follow-up at final analysis was 502 years (interquartile range: 455 533) 5
Study flow 14 658 randomized 7323 aspirin 100 mg/day 7335 no aspirin 103 excluded from analyses 55 major protocol violation 30 entry criteria not met 14 withdrawal of consent 4 clinic closure/investigator death 91 excluded from analyses 59 major protocol violation 25 entry criteria not met 1 withdrawal of consent 6 clinic closure/investigator death 7220 included in analyses Including 791 lost to follow-up 7244 included in analyses Including 753 lost to follow-up 6
Baseline demographics Aspirin (n = 7220) No aspirin (n = 7244) Age, Disease mean risk ± factors SD, years for vascular events 70 Men Hypertension (HT) 706 ± 62 3986 (552) 6133 3055 (849) (423) 705 ± 62 3985 (550) 6145 3068 (848) (424) Body Dyslipidemia mass index, (DL) mean ± SD, kg/m 2 5198 242 (720) ± 35 5200 242 (718) ± 34 Diabetes 25 mellitus (DM) 2445 2644 (339) (366) 2458 2604 (339) (359) Currently HT and DL smoking 4276 959 (133) (592) 4264 934 (129) (589) DL and DM 1794 (248) 1798 (248) HT and DM 1932 (268) 1939 (268) HT, DL and DM 1446 (200) 1442 (199) Family history of premature CV disease No 4058 (562) 4086 (564) Yes 1981 (274) 1982 (274) Unknown 1181 (164) 1176 (162) Values are n (%) unless otherwise stated 7
Primary endpoint: Kaplan Meier estimate Proportion of patients with primary endpoint event (%) 5 4 3 2 1 0 0 1 Aspirin No aspirin p = 0544 HR 094 (95% CI: 077 115) 2 3 4 Time to event (years) 5 6 Number at risk Aspirin 7220 7021 6771 6583 6322 3639 169 No aspirin 7244 7073 6861 6645 6359 3711 182 8
Primary endpoint: observed events Aspirin (n = 7220) No aspirin (n = 7244) Total events 193 207 Fatal events 56 56 Cerebral infarction 2 7 Intracranial hemorrhage 5 5 Subarachnoid hemorrhage 2 4 MI 7 9 Other fatal CV events 40 31 Non-fatal events 137 151 Cerebral infarction 83 94 Intracranial hemorrhage 23 10 Subarachnoid hemorrhage 8 4 MI 20 38 Undefined cerebrovascular events 3 5 9
Primary endpoint: disease risk factor subgroups Overall population n = 14 464 HR (95% CI) 094 (077 115) Hypertension No: n = 2186 Yes: n = 12 278 090 (049 163) 095 (077 117) Dyslipidemia No: n = 4066 Yes: n = 10 398 102 (071 148) 091 (072 115) Diabetes mellitus No: n = 9561 Yes: n = 4903 099 (076 130) 089 (066 118) Family history of premature CV disease No: n = 8144 Yes: n = 3963 Unknown: n = 2357 087 (066 115) 119 (082 172) 082 (054 126) 025 050 100 200 400 Favors aspirin Favors no aspirin 10
Primary endpoint: demographic risk factor subgroups Overall population n = 14 464 HR (95% CI) 094 (077 115) Sex Female: n = 8341 Male: n = 6123 103 (077 137) 087 (067 114) Age < 70 years: n = 6493 70 years: n = 7971 100 (068 146) 092 (073 116) Body mass index < 25 kg/m 2 : n = 9216 25 kg/m 2 : n = 5248 088 (069 112) 108 (077 150) Smoking No: n = 12 571 Yes: n = 1893 091 (073 114) 105 (068 161) 025 050 100 200 400 Favors aspirin Favors no aspirin 11
Secondary efficacy endpoints: primary endpoint components HR (95% CI) 5-yr event rate [number of events] Aspirin (n = 7220) No aspirin (n = 7244) Primary endpoint 094 (077 115) 277% [n = 193] 296% [n = 207] Secondary endpoints Death from CV disease 103 (071 148) 086% [n = 58] 078% [n = 57] Non-fatal stroke (ischemic or hemorrhagic) 104 (080 134) 165% [n = 117] 164% [n = 114] Non-fatal MI 053 (031 091) * 030% [n = 20] 058% [n = 38] 025 050 100 200 400 *p = 0019 Favors aspirin Favors no aspirin 12
Secondary efficacy endpoints: other Composite secondary endpoint Any cause of death HR (95% CI) 089 (075 104) 099 (085 117) 5-yr event rate [number of events] Aspirin (n = 7220) 400% [n = 280] 429% [n = 297] No aspirin (n = 7244) 459% [n = 319] 411% [n = 303] Non-CV death 099 (082 118) 346% [n = 239] 336% [n = 246] TIA Angina pectoris 057 (032 099) Arteriosclerotic disease requiring surgery of intervention Serious extracranial hemorrhage * 086 (058 128) 089 (065 121) 185 (122 281) ** 026% [n = 19] 066% [n = 46] 108% [n = 75] 086% [n = 62] 049% [n = 34] 081% [n = 54] 124% [n = 85] 051% [n = 34] 025 050 100 200 400 *p = 0044 **p = 0004 Favors aspirin Favors no aspirin 13
Incidence of pre-specified gastrointestinal events of interest Event Aspirin (n = 7323) No aspirin (n = 7335) p value Stomach/abdominal discomfort 335 (457) [411 508] 175 (239) [205 276] < 0001 Heartburn 202 (276) [240 316] 137 (187) [157 220] < 0001 Gastroduodenal ulcer 191 (261) [226 300] 91 (124) [100 152] < 0001 Stomach/abdominal pain 168 (229) [196 266] 81 (110) [088 137] < 0001 Reflux esophagitis 160 (218) [186 255] 125 (170) [142 203] 0036 Gastrointestinal hemorrhage 103 (141) [115 170] 31 (042) [029 060] < 0001 Erosive gastritis 89 (122) [098 149] 40 (055) [039 074] < 0001 Nausea 79 (108) [085 134] 50 (068) [051 090] 0010 Stomach/abdominal pressure 31 (042) [029 060] 21 (029) [018 044] 0168 Values are n (%) [95% CI] 14
Summary and conclusions This seminal study indicates that primary prevention with daily low-dose aspirin does not reduce the overall risk of atherosclerotic events in elderly Japanese patients with CV risk factors However, the study was discontinued prematurely before the study reached statistical power Therefore, lack of power or absence of a beneficial effect of aspirin may account for the non-significant outcome Irrespective, the clinical importance of aspirin in the primary prevention of CV events is less than originally anticipated in this patient population Aspirin significantly reduced the incidence of non-fatal MI and TIA, while it increased the risk of serious extracranial bleeding Further analyses are planned 15
Ikeda and coauthors Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years and Older With Atherosclerotic Risk Factors: A Randomized Clinical Trial Published online November 17, 2014 Available at jamacom and on The JAMA Network Reader at mobilejamanetworkcom jamanetworkcom 16