ISCHEMIA: ESTRATÉGIA INVASIVA

OU CONSERVADORA INICIAL PARA

DOENÇA CORONARIANA ESTÁVEL
RENATO MACIEL DE ARANTES – R1 CARDIOLOGIA
ISCHEMIA Research Question
• Em paciente estáveis com isquemia pelo menos moderada em um
teste de estresse, há benefício para adicionar cateterismo cardíaco e,
se possível, revascularização à terapia médica ideal?
 Desenho do estudo
Stable Patient
Moderate or severe ischemia
(determined by site; read by core lab)

CCTA not required, e.g., Blinded CCTA

eGFR 30 to <60 or coronary
anatomy previously defined NO
Core lab anatomy eligible? Screen failure
YES
RANDOMIZE

INVASIVE Strategy CONSERVATIVE Strategy

OMT + Cath + OMT alone
Optimal Revascularization Cath reserved for OMT failure

Maron DJ, et al. American Heart Journal. 2018; 201;124-135.

Desenho do estudo
• Inicialmente submetidos a algum tipo de exame de estresse funcional:
ecocardiograma TT com estresse, cintilografia miocárdica, RNM cardíaca e Teste
ergométrico** (incluído posteriormente devido a dificuldade de recrutamento
dos pacientes). Esses testes eram refeitos por um segundo centro,
posteriormente.
• Posteriormente esses pacientes selecionados (cerca de 70%) foram submetidos a
angiotomografia de coronárias afim de descartar lesões de alto risco (tronco de
coronária esquerda/proximais) e também excluir falso-positivos.
• Excluídos os pacientes com clearence de creatininda entre 30 e 60
• Anatomia previamente definida.
• Desse modo os pacientes foram divididos em dois grupos
• Tratamento conservador (medicamentoso)
• Tratamento medicamentoso + terapia invasiva
DESFECHOS:
• Desfecho primário (composto):
• Tempo para morte cardiovascular, infarto do miocárdio (IM), internação por
angina instável, insuficiência ou parada cardíaca ressuscitada.
• Principais desfechos secundários:
• Tempo para morte CV ou IM
• Qualidade de vida
• Outros desfechos incluem
• Morte de todas as causas
• Benefício clínico líquido (AVC adicionado ao ponto final primário)
• Componentes do ponto final primário.
 Critérios de Elegibilidade
Critérios clínicos e de isquemia para elegibilidade CCTA Eligibility Criteria
Inclusion Criteria Critério de inclusão:
• Idade maior ou igual a 21 anos • ≥50% stenosis in a major epicardial vessel
• Moderate or severe ischemia* (stress imaging participants)
• Cintilografia miocardica com mais do 10% de isquemia (SDS ≥7) • ≥70% stenosis in a proximal or mid vessel
• ECO: 3 segmentos ou mais com evidência de moderada/severa hipocinesia ou acinesia. (ETT participants)
• RNM cardíaca
• Perfusão: ≥12% miocardio e/ou Major Exclusion Criteria
• Análise contrátil: ≥3/16 segmentos com hipocinesia severa ou acinesia induzidas pelo • ≥50% stenosis in unprotected left main
estresse.
• Teste ergométrico (ETT) >1.5mm depressão de ST in >2 derivações or >2mm ST
depressão de ST em uma única derivação atingindo menos de 7 METs, com angina.

Critérios de exclusão:
• IC NYHA Classe III-IV
• Angina refratária ao tratamento clínico
• FE < 35%
• SCA recente (menos de 2 meses)
*Ischemia eligibility determined by sites. All stress tests interpreted at core labs.
• Abordagem < de 1 ano (PCI ou CRVM)
• Clcr < 30 ou hemodiáliose
Maron DJ, et al. American Heart Journal. 2018; 201;124-135.
Fluxo do estudo Screen Failure (3339)
Major Reasons:
• Insufficient ischemia (N = 1350)
Enrolled (8518) • No obstructive CAD (N = 1218)
• Unprotected LMD (N =434)

Randomized (5179)
Study CCTA in 73% of randomized participants

Randomized to INV (2588) Randomized to CON (2591)

Median follow-up for survivors 3.3 years Median follow-up for survivors 3.3 years
(IQR 2.2 to 4.3 years) (IQR 2.2 to 4.4 years)
Proportion of follow-up completed: 99.4% Proportion of follow-up completed: 99.7%
Características dos grupos:
Characteristic Total INV CON
Clinical
Age at Enrollment (yrs.)
Median 64 (58, 70) 64 (58, 70) 64 (58, 70)
Female Sex (%) 23 23 22
Hypertension (%) 73 73 73
Diabetes (%) 42 41 42
Prior Myocardial Infarction (%) 19 19 19
Ejection Fraction, Median (%) (n=4637) 60 (55, 65) 60 (55, 65) 60 (55, 65)
Systolic Blood Pressure, Median (mmHg) 130 (120, 142) 130 (120, 142) 130 (120, 142)
Diastolic Blood Pressure, Median (mmHg) 77 (70, 81) 77 (70, 81) 77 (70, 81)
LDL Cholesterol, Median (mg/dL) 83 (63, 111) 83 (63, 111) 83 (63, 109.5)
History of Angina 90% 90% 89%
Angina Began or Became More Frequent Over the Past 3 Months 29% 29% 29%
Stress Test Modality
Stress Imaging (%) 75 75 76
Exercise Tolerance Test (ETT) (%) 25 25 24

Hochman JS et al. JAMA Cardiology. 2019 Mar 1;4(3):273-86.

Interpretação da severidade da isquemia:

Characteristic Total INV CON

Baseline Inducible Ischemia*

Severe 54% 53% 55%
Moderate 33% 34% 32%
Mild/None 12% 12% 12%
Uninterpretable 1% 1% 1%

Hochman JS et al. JAMA Cardiology. 2019 Mar 1;4(3):273-86.

 ANATOMIA CORONARIANA:

100 100
90 90 87 87
80 80
68 67 70 68
70 70
60 60
50 47 50 46 47
44
40 34 40
29
30 24 30
22
20 20
10 10
1 1
0 0
1 2 ≥3 Left Main Left Anterior Proximal LAD Left Circumflex Right Coronary
Descending Artery
# of Vessels with >50 % Stenosis (%)
Specific Vessels with > 50% Stenosis (%)
N=2982 (% of total) N=3739

Hochman JS et al. JAMA Cardiology. 2019 Mar 1;4(3):273-86.

 Manejo dos fatores de risco
Entrada vs Última visita
100 100 96 97
95 95 Baseline Average
90 88 90
90
Last Visit Average
80 77
80 70 65
70 59
60
70 66 66
50
41
60 40
32
% AT GOAL

30
50 20
41 20

% at goal
40 10

30 0

20

10

0
Any Statin High-Intensity Statin ACE Inhibitor/ARB Among All
Participants

Axis Title

High Level of Medical Therapy Optimization is defined as a participant meeting all of the
following goals: LDL < 70 mg/dL and on any statin, systolic blood pressure < 140 mm/Hg, on
aspirin or other antiplatelet or anticoagulant, and not smoking. High level of medical
therapy optimization is missing if any of the individual goals are missing.

Cardiovascular Clinical Research Center

 Coronariografia e Revascularização
Cardiac Catheterization Revascularization
96%
95%

76% 79% 80%

28%
23%

9% 12%
Indications for cath in CON 7%
Suspected/confirmed event 13.8%
OMT Failure 3.9%
Non-adherence 8.1%

Cardiovascular Clinical Research Center

 Desfecho primário: Morte CV, IM, Hospitaliazação por AI, IC ou
30% PCR revertida
Adjusted Hazard Ratio = 0.93 (0.80, 1.08)
25% P-value = 0.34
Cumulative Incidence (%)

Absolute Difference INV vs. CON

20%
CON
6 months: 15.5%
INV
15% Δ = 1.9% (0.8%, 3.0%)

13.3%
10%

5%
4 years:
Δ = -2.2% (-4.4%, 0.0%)
0%
0 1 2 3 4 5

Follow-up (years)
Subjects at Risk

CON 2591 2431 1907 1300 733 293

INV 2588 2364 1908 1291 730 271

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 DESFECHO SECUNDÁRIO: MORTE CV E IM
30%
Adjusted Hazard Ratio = 0.90 (0.77, 1.06)
25% P-value = 0.21
Cumulative Incidence (%)

Absolute Difference INV vs. CON

20%

13.9% CON
15% 6 months:
Δ = 1.9% (0.9%, 3.0%) INV

10% 11.7%

5% 4 years:
Δ = -2.2% (-4.4%, -0.1%)
0%
0 1 2 3 4 5

Follow-up (years)
Subjects at Risk
CON 2591 2453 1933 1325 746 298
INV 2588 2383 1933 1314 752 282

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 All-Cause Death

The probability of at least a 10% relative risk reduction of INV on

all-cause mortality is <10%, based on pre-specified Bayesian analysis.

6.5%

6.4%

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 Procedural MI Spontaneous MI
Type 4a or 5 MI Types 1, 2, 4b, or 4c MI

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Hospitalization for Unstable Angina Hospitalization for Heart Failure

Resuscitated Cardiac Arrest Stroke

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 Primary endpoint
Pre-specified Important Subgroups
There was no heterogeneity of treatment effect

High degree of medical therapy optimization

N=3739 for Prox LAD Y/N

N=2982 for # diseased vessels
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Hospitalization for Unstable Angina Hospitalization for Heart Failure

Resuscitated Cardiac Arrest Stroke

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 Limitações
 Unblinded trial – no sham procedure
 Based on exclusion criteria, the trial results do not apply to patients with:
 Acute coronary syndromes within 2 months
 Highly symptomatic patients
 Left main stenosis
 LVEF <35%

 Trial findings may not be generalizable to centers with higher procedural

complication rates
 Completeness of revascularization has not yet been assessed
 Women were enrolled in the trial but more often excluded from randomization
compared to men due to less ischemia and more non-obstructive CAD

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 Sumário
 The curves cross for the primary endpoint and the major secondary
endpoint at approximately 2 years from randomization
 ~2 in 100 higher estimated rate with INV at 6 months
 ~2 in 100 lower estimated rate with INV at 4 years

 Procedural MIs were increased with an invasive strategy

 Spontaneous MIs were reduced with an invasive strategy
 Low all-cause mortality in both groups despite high-risk clinical
characteristics, high-risk ischemia and extensive CAD
 No heterogeneity of treatment effect, including by type of stress test,
severity of ischemia or extent of CAD
 Very low rates of procedure-related stroke and death.

Cardiovascular Clinical Research Center

 Conclusões
 ISCHEMIA is the largest trial of an invasive vs conservative strategy for
patients with SIHD
 Overall, an initial INV strategy as compared with an initial CON strategy
did not demonstrate a reduced risk over median 3.3 years for
 Primary endpoint - CV death, MI, hospitalization for UA, HF, RCA
 Major Secondary endpoint - CV death or MI

Cardiovascular Clinical Research Center

E se estendermos um pouco mais o tempo de
seguimento, será mesmo que esses pacientes
submetidos a revascularização miocárdica não se
beneficiariam no estudo ISCHEMIA a longo prazo?

Cardiovascular Clinical Research Center

 ISCHEMIA - Extendend

A revascularização miocárdica não é superior à estratégia

inicial de se manter tratamento clínico otimizado, mas pode
ajudar os médicos na tomada de decisão compartilhada sobre
quando avaliarem a anatomia coronária em pacientes selecionados
com doença arterial coronariana crônica e isquemia moderada

Cardiovascular Clinical Research Center