I nvasive versus Conservative Strategy in Patients Over 8 0 Years w ith Non ST-Elevation Myocardial I nfarction or Unstable Angina Pectoris: A Random ized Multicenter Study After Eighty Study Nicolai Kloumann Tegn, Michael Abdelnoor, Lars Aaberge, Knut Endresen, Pål Smith, Svend Aakhus, Erik Gjertsen, Ola Dahl-Hofseth, Anette Hylen Ranhoff, Lars Gullestad, Bjørn Bendz, for the After Eighty Study Investigators Oslo University Hospital, Rikshospitalet, Norway Presenter disclosure information: Funded by the Norwegian Health Association
Background • Elderly patients counts for approximately one third of all patients with Non ST-Elevation Myocardial Infarction (NSTEMI) and Unstable Angina Pectoris (UAP). Patients ≥ 80 years are under-represented in clinical • trials. • The role of an early invasive strategy, and even an invasive strategy at all, remains a subject of debate. • According to WHO / US National Center for Health Statistics, the life expectancy at the age of 80 years is ~ 9 years.
RCTs w ith early invasive treatm ent Trial Num ber of Average Num ber ( % ) Num ber ( % ) ≥ 7 5 years ≥ 8 0 years patients age FRI SC I I 2 4 5 6 6 5 4 6 6 ( 1 9 ) I CTUS 1 2 0 0 6 1 3 6 ( 1 3 ) I talian 3 1 3 8 2 3 1 3 ( 1 0 0 ) 1 9 6 ( 6 3 ) Elderly ACS RI TA 3 1 8 1 0 6 3 2 1 7 ( 1 2 ) 4 6 ( 2 .5 ) TACTI CS 2 2 2 0 6 2 2 6 6 ( 1 2 .5 ) VANQW I SH 9 2 0 6 1 7 3 ( 8 )
Aim of the study • The aim of the present clinical trial was to investigate whether patients ≥80 years would benefit from an early invasive versus a conservative strategy when initially stabilized after NSTEMI or UAP . • The primary endpoint was a composite of myocardial infaction, need of urgent revascularization, stroke and death.
Study centers Oslo 17 hospitals in the South-East Health Region of Norway covering a population of 2.7 mill.
I nclusion and exclusion criteria I nclusion Exclusion Patients ≥ 80 years. • • Clinical unstable. • NSTEMI or UAP , with/ without • Ongoing bleeding problems. ST-segment depression in • Short life expectancy (less ECG, and normal/ elevated than 12 months) due to levels of troponin T or I. serious comorbidity. • No chest pain or other • Significant mental disorder. ischaemic symptoms/ signs after medical treatment and mobilization.
Sam ple size calculation • This was an open label dynamic randomized trial. • Previous studies targeting this population were lacking when planning this study. • Considering the TACTICS study (Cannon et al NEJM 2001) for a comparable population there was an incidence of composite endpoint (Death + MI) of 10.8% at 6 months. • A prior power analysis was performed based on the TACTICS study. Considering a type I error of 5% and a power of 80% to detect an absolute 10% reduction in composite endpoint, we calculated a need of 2* 206 = 412 patients.
I nclusion flow -chart 4187 patients with NSTEMI or UAP Not included; n= 3730 • Short life expectancy; n= 825 • Ongoing or recent bleeding; n= 183 • Unable to comply with protocol; n= 409 • Clinical unstable incl. ongoing ischemia; n= 560 • Refused to participate; n= 402 • Logistic reasons; n= 1011 • Other reasons; n= 103 457 randomized 229 assigned the 228 assigned the invasive group conservative group 5 dropouts 1 dropout 229 included in the 228 included in the intention-to-treat analysis intention-to-treat analysis
I nclusion flow -chart Randomization Conservative group Invasive group Transported to the PCI centre the day after inclusion No PCI: PCI: Returned to the Returned to community community hospital after hospital after ~ 4-6 hours ~ 6-18 hours Optimal medical treatment in the Optimal medical treatment in the community hospitals before discharge community hospitals before discharge
Baseline characteristics I nvasive Strategy Conservative Strategy Characteristics ( N= 2 2 9 ) ( N= 2 2 8 ) Mean age ( range) – years 8 4 .7 ( 8 0 - 9 3 ) 8 4 .9 ( 8 0 - 9 4 ) Fem ale n ( % ) 1 0 4 ( 4 5 ) 1 2 8 ( 5 6 ) Previous MI n ( % ) 1 0 7 ( 4 7 ) 9 0 ( 4 0 ) Previous angina n ( % ) 1 2 3 ( 5 5 ) 1 1 5 ( 5 1 ) Previous PCI n ( % ) 5 4 ( 2 4 ) 4 6 ( 2 0 ) Previous CABG n ( % ) 4 3 ( 1 9 ) 3 2 ( 1 4 ) Hypertension n ( % ) 1 3 0 ( 5 8 ) 1 3 8 ( 6 1 ) Diabetes typeI I n ( % ) 4 5 ( 2 0 ) 3 2 ( 1 4 ) COPD n ( % ) 2 4 ( 1 1 ) 1 8 ( 8 ) Apoplexia cerebri n ( % ) 3 9 ( 1 7 ) 2 9 ( 1 3 ) Atrial fibrillation n ( % ) 4 8 ( 2 1 ) 5 2 ( 2 3 ) Sm oking; cur. or prev. n ( % ) 1 1 2 ( 5 0 ) 1 0 9 ( 4 8 % ) Troponin elevation n ( % ) 2 1 2 ( 9 5 ) 2 0 9 ( 9 2 ) Atrial fibrillation n ( % ) 4 9 ( 2 2 ) 4 2 ( 1 9 ) ST depression n ( % ) 4 2 ( 1 9 ) 4 0 ( 1 8 ) Left Bundle Branch Block n ( % ) 2 2 ( 1 0 ) 2 4 ( 1 1 ) GFR m L/ m in/ 1 ,7 3 m 2 5 2 ± 1 2 5 4 ± 1 1 GRACE score 1 3 8 1 3 5 P values are ns
Medical treatm ent during index I nvasive Strategy Conservative Strategy Characteristics n( % ) ( N= 2 2 9 ) ( N= 2 2 8 ) Acetylsalisylic acid ( 7 5 m g) 2 2 3 ( 9 7 ) 2 2 2 ( 9 7 ) ADP-inhibitor Clopidogrel 1 9 5 ( 8 5 ) 1 8 8 ( 8 2 ) Ticagrelor 1 1 ( 5 ) 1 2 ( 5 ) ACE inhibitor / ARB 9 9 ( 4 3 ) 1 1 5 ( 5 0 ) Beta blocker 1 9 0 ( 8 3 ) 1 9 6 ( 8 5 ) Statins 2 0 5 ( 9 0 ) 1 9 3 ( 8 5 ) Loop or thiazide diuretics 9 4 ( 4 1 ) 7 6 ( 3 3 ) Calcium channel blocker 4 5 ( 2 0 ) 4 7 ( 2 1 ) Nitrates 1 0 4 ( 4 5 ) 1 2 6 ( 5 5 ) Anticoagulation W arfarin 3 8 ( 1 7 ) 2 1 ( 9 ) Heparin ( LMW H) 1 7 3 ( 7 6 ) 1 7 3 ( 7 6 ) Anti-I I a ( dabigatran) 1 1
Medical therapy at discharge I nvasive Strategy Conservative Strategy Characteristics ( N= 2 2 9 ) ( N= 2 2 8 ) Acetylsalisylic acid ( 7 5 m g) 2 1 2 ( 9 3 ) 2 1 1 ( 9 3 ) ADP-inhibitor Clopidogrel 1 6 4 ( 7 2 ) 1 6 5 ( 7 2 ) Ticagrelor 9 ( 4 ) 8 ( 4 ) ACE inhibitor / ARB 1 1 8 ( 5 2 ) 1 2 2 ( 5 4 ) Beta blocker 1 9 2 ( 8 4 ) 1 9 2 ( 8 4 ) Statins 2 0 6 ( 9 0 ) 1 9 1 ( 8 6 ) Loop or thiazide diuretics 1 0 4 ( 4 5 ) 8 6 ( 3 8 ) Calcium channel blocker 5 4 ( 2 4 ) 5 3 ( 2 3 ) Nitrates 7 7 ( 3 4 ) 1 0 9 ( 4 8 ) Oral anticoagulation W arfarin 4 8 ( 2 1 ) 3 2 ( 1 4 ) Anti-Xa ( rivaroxaban) 3 3 Anti-I I a ( dabigatran) 1 6
Results Freedom of compocite endpoints Rate Ratio, 0.48 (95% CI, 0.37-0.63); p<0.00001
Results I nvasive Conservative Endpoint ( N= 2 2 9 ) ( N= 2 2 8 ) Rate Ratio P value* Prim ary Endpoint Com posite Endpoint 9 3 ( 4 1 % ) 1 4 0 ( 6 1 % ) 0 .4 8 ( 0 .3 7 - 0 .6 3 ) < 0 .0 0 0 1 Com ponents of the Prim ary EP Myocardial infarction 3 9 ( 1 7 % ) 6 9 ( 3 0 % ) 0 .5 0 ( 0 .3 3 - 0 .7 5 ) 0 .0 0 0 3 Need of urgent revasc. 5 ( 2 % ) 2 4 ( 1 1 % ) 0 .1 9 ( 0 .0 5 - 0 .5 2 ) 0 .0 0 0 1 Stroke 8 ( 3 % ) 1 3 ( 6 % ) 0 .6 1 ( 0 .2 2 - 1 .6 0 ) 0 .2 6 Death of any cause 5 7 ( 2 5 % ) 6 2 ( 2 7 % ) 0 .8 7 ( 0 .5 9 - 1 .2 7 ) 0 .5 3 Com posite of death + MI 8 1 ( 3 5 % ) 1 0 9 ( 4 8 % ) 0 .5 4 ( 0 .4 0 – 0 .7 3 ) < 0 .0 0 0 1 Median follow -up of 1 .5 1 years * P-values are two-tailed
Bleeding com plications I nvasive Conservative Strategy Strategy ( N= 2 2 9 ) ( N= 2 2 8 ) Major 4 4 Gastro intestinal 2 2 Percardial tam ponade 1 0 Traum atic epidural hem atom a 1 0 Traum atic subdural hem atom a 0 1 Subarachnoid hem orrhage 0 1 Minor 2 3 1 6 Gastro intestinal 1 4 1 1 Other 9 5 P values are ns
Conclusions • We have demonstrated that an invasive strategy is superior to a conservative strategy in patients ≥ 80 years with NSTEMI or UAP. • No differences in complication rates (i.e. bleedings) were seen between the two strategies.
After Eighty Study investigators Steering com m ittee Nicolai K. Tegn, Michael Abdelnoor, Lars Aaberge, Knut Endresen, Pål Smith, Svend Aakhus, Erik Gjertsen, Lars Gullestad, Bjørn Bendz (Chairman). Data and safety m onitoring board Theis Tønnessen and Rune Wiseth Acknow ledgem ents Aker Hospital, Akershus University Hospital, Bærum Hospital, Diakonhjemmet Hospital, Drammen Hospital, Elverum Hospital, Fredrikstad Hospital, Gjøvik Hospital, Hamar Hospital, Kongsberg Hospital, Lillehammer Hospital, Moss Hospital, Notodden Hospital, Ringerike Hospital, Skien Hospital and Vestfold Hospital.
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