Department of Cardiology, Shin-Oyama City Hospital, Tochigi, Japan. ClinicalTrials.gov Identifier: NCT

Transcription

1 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: NCT

2 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: FDA 2014 Available from: 2

3 Study design: Prospective Randomized Open Blinded Endpoint (PROBE) Patients aged 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

4 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

5 Timing of final analyses Sample size determination for final analyses Target: 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: ) 5

6 Study flow 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

7 Baseline demographics Aspirin (n = 7220) No aspirin (n = 7244) Age, Disease mean risk ± factors SD, years for vascular events 70 Men Hypertension (HT) 706 ± (552) (849) (423) 705 ± (550) (848) (424) Body Dyslipidemia mass index, (DL) mean ± SD, kg/m (720) ± (718) ± 34 Diabetes 25 mellitus (DM) (339) (366) (339) (359) Currently HT and DL smoking (133) (592) (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

8 Primary endpoint: Kaplan Meier estimate Proportion of patients with primary endpoint event (%) Aspirin No aspirin p = 0544 HR 094 (95% CI: ) Time to event (years) 5 6 Number at risk Aspirin No aspirin

9 Primary endpoint: observed events Aspirin (n = 7220) No aspirin (n = 7244) Total events Fatal events Cerebral infarction 2 7 Intracranial hemorrhage 5 5 Subarachnoid hemorrhage 2 4 MI 7 9 Other fatal CV events Non-fatal events Cerebral infarction Intracranial hemorrhage Subarachnoid hemorrhage 8 4 MI Undefined cerebrovascular events 3 5 9

10 Primary endpoint: disease risk factor subgroups Overall population n = HR (95% CI) 094 ( ) Hypertension No: n = 2186 Yes: n = ( ) 095 ( ) Dyslipidemia No: n = 4066 Yes: n = ( ) 091 ( ) Diabetes mellitus No: n = 9561 Yes: n = ( ) 089 ( ) Family history of premature CV disease No: n = 8144 Yes: n = 3963 Unknown: n = ( ) 119 ( ) 082 ( ) Favors aspirin Favors no aspirin 10

11 Primary endpoint: demographic risk factor subgroups Overall population n = HR (95% CI) 094 ( ) Sex Female: n = 8341 Male: n = ( ) 087 ( ) Age < 70 years: n = years: n = ( ) 092 ( ) Body mass index < 25 kg/m 2 : n = kg/m 2 : n = ( ) 108 ( ) Smoking No: n = Yes: n = ( ) 105 ( ) Favors aspirin Favors no aspirin 11

12 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 ( ) 277% [n = 193] 296% [n = 207] Secondary endpoints Death from CV disease 103 ( ) 086% [n = 58] 078% [n = 57] Non-fatal stroke (ischemic or hemorrhagic) 104 ( ) 165% [n = 117] 164% [n = 114] Non-fatal MI 053 ( ) * 030% [n = 20] 058% [n = 38] *p = 0019 Favors aspirin Favors no aspirin 12

13 Secondary efficacy endpoints: other Composite secondary endpoint Any cause of death HR (95% CI) 089 ( ) 099 ( ) 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 ( ) 346% [n = 239] 336% [n = 246] TIA Angina pectoris 057 ( ) Arteriosclerotic disease requiring surgery of intervention Serious extracranial hemorrhage * 086 ( ) 089 ( ) 185 ( ) ** 026% [n = 19] 066% [n = 46] 108% [n = 75] 086% [n = 62] 049% [n = 34] 081% [n = 54] 124% [n = 85] 051% [n = 34] *p = 0044 **p = 0004 Favors aspirin Favors no aspirin 13

14 Incidence of pre-specified gastrointestinal events of interest Event Aspirin (n = 7323) No aspirin (n = 7335) p value Stomach/abdominal discomfort 335 (457) [ ] 175 (239) [ ] < 0001 Heartburn 202 (276) [ ] 137 (187) [ ] < 0001 Gastroduodenal ulcer 191 (261) [ ] 91 (124) [ ] < 0001 Stomach/abdominal pain 168 (229) [ ] 81 (110) [ ] < 0001 Reflux esophagitis 160 (218) [ ] 125 (170) [ ] 0036 Gastrointestinal hemorrhage 103 (141) [ ] 31 (042) [ ] < 0001 Erosive gastritis 89 (122) [ ] 40 (055) [ ] < 0001 Nausea 79 (108) [ ] 50 (068) [ ] 0010 Stomach/abdominal pressure 31 (042) [ ] 21 (029) [ ] 0168 Values are n (%) [95% CI] 14

15 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

16 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