ISCHEMIA trial : what's new for stable ischemic heart disease patients ?

Selected in NEJM by F. Burzotta , C. Trani

The ISCHEMIA trial was designed to evaluate the clinical impact of systematic invasive management in patients with stable ischemic heart disease and significant inducible ischemia. Read this review by guest expert reviewers Francesco Burzotta and Carlo Trani.

Reviewers

Francesco Burzotta

@burzotta_f

Interventional cardiologist / Cardiologist

Policlinico Universitario Agostino Gemelli - Roma, Italy

Carlo Trani

Interventional cardiologist / Cardiologist

Fondazione Policlinico Universitario Agostino Gemelli - Roma, Italy

Our Comment

Why this study – the rationale/objective?

The ISCHEMIA trial was designed to evaluate the clinical impact of systematic invasive management, as compared with conservative approach, in patients with stable ischemic heart disease and significant inducible ischemia.

How was it executed – the methodology?

The ISCHEMIA trial was an international multicenter NHLBI-supported trial.

Key inclusion criteria were stable (symptomatic or asymptomatic) ischemic heart disease and instrumental documentation of at least moderate ischemia on a qualifying stress test.

An extensive series of exclusion criteria were adopted and included severe angina, heart failure, low ejection fraction, concerns by patients' physicians regarding the possibility to have left main disease.

As a result of these criteria, among the wide population of suspected or known stable ischemic heart disease, only a subgroup of patients have been enrolled (see figure 1).

Selection and management tree in the ISCHEMIA trial

After having selected possible candidates for randomisation, all participants with normal renal function first underwent blinded coronary computed tomography angiography (CCTA). Such CCTA was performed with the aim of excluding patients with left main coronary artery disease and those without obstructive atherosclerosis. A series of patients were also excluded for other (non-anatomical) reasons as shown in Figure 1. In particular, from July 2012 to January 2018, out of 26000, 5179 (around 20%) patients were randomised (Figure 1) to an initial invasive or conservative treatment strategy.

All included patients received optimal medical therapy (OMT).

Patients randomised to the conservative strategy had to undergo cardiac catheterisation only for failure of OMT or suspected adverse events occurrence.

The invasive strategy consisted of routine cardiac catheterisation followed by revascularisation with PCI or CABG as selected by the local Heart Team. Of note, FFR was recommended for stenosis <50% if PCI was considered and stress imaging showed ischemia in the corresponding territory. FFR was also recommended for stenosis <80% if PCI was considered and stress imaging did not show ischemia in the corresponding territory. Use of instantaneous wave-free ratio instead of FFR was permitted (cut-off for revascularization: ≤0.89).

All patients were followed up during the trial at 1.5, 3, 6, and 12 months after randomisation and every 6 months thereafter to detect clinical changes.

The study primary / secondary endpoints as well as the target study population size changed during the study conduction and the final definitions came out respectively on June 2017 and August 2016. The primary study end-point was a composite of cardiovascular death, non-fatal myocardial infarction, hospitalisation for unstable angina, hospitalisation for heart failure or resuscitated cardiac arrest.

What is the main result?

A total of 2588 patients were randomised to invasive management and 2591 to OMT. Baseline characteristics were well balanced and included 41.8% of diabetic and 35.4% of asymptomatic patients.

The primary outcome occurred in 318 patients in the invasive-strategy group and in 352 patients in the conservative-strategy group. In covariate-adjusted Cox model analysis, the estimated hazard ratio with the invasive strategy as compared with the conservative strategy was 0.93 (95% confidence interval: 0.80 to 1.08; P = 0.34).

The main secondary end-point (death from cardiovascular causes or myocardial infarction) occurred in 276 patients of the invasive-strategy group and in 314 patients of the conservative-strategy group. At 5 years, the estimated death from cardiovascular causes or myocardial infarction rate was 14.2% in the invasive-strategy group and 16.5% in the conservative-strategy group (difference, −2.3 percentage points; 95% CI, −5.0 to 0.4). Total mortality did not differ.

When looking at the event occurrence over time, trends toward early hazards and later benefits with the invasive strategy were suggested for composite primary end-point as well as for cardiac death or myocardial infarction or myocardial infarction alone.

As a final remark, the angina and quality of life ISCHEMIA substudy was contemporary published (Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMoa1916370) and showed that patients randomly assigned to the invasive strategy had (up to 36-month evaluation) greater improvement in angina-related health status than those assigned to the conservative strategy. This was driven by minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline.

Critical reading and the relevance for clinical practice

ISCHEMIA trial represents a large, important trial that is expected to help physicians in their clinical practice.

Two main questions may help physicians translating the trial findings into the clinical practice:

• How to recognise patients similar to the ISCHEMIA trial study population?
• How to apply the ISCHEMIA trial findings when considering to refer patients to cardiac catheterisation and revascularisation?

Figure 1 may help in recognising the stable ischemic heart disease patients enrolled in the ISCHEMIA : they represent a subset of the entire population today undergoing ischemia tests. To become part of randomisation, patients had also to undergo CCTA (unless not feasible due to renal failure). This looks really remarkable since CCTA was proven to be feasible in such a large population and allowed, despite ischemia documentation, to exclude many patients due to the opposite features of no obstructive or left main coronary disease. Thus, a possible important message might be that coronary anatomy assessment by CCTA might find increasing space in the modern management of stable ischemic heart disease.

Moving to the critical issue of deciding whether and when invasive management should be advised, the ISCHEMIA trial documented that if the patient has inducible ischemia but no suspect of left main disease, an initial OMT might be equally effective in terms of hard adverse events. Yet, to achieve this, strict clinical follow-up (comparable to the scheduling of this trial) is needed since many patients (about 1 out of 4 at 5 years) are expected to deserve crossover to cardiac catheterisation and myocardial revascularisation (figure 1). Finally, with regards to the symptoms and quality of life, invasive management was proven to have significant and durable benefits. This aspect, together with the possible risk of invasive procedures, can be the object of informative discussion in the individual patient decision-making process.

Five questions and answers about the ISCHEMIA Trial

Read interview with Francesco Burzotta

References

1. Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O'Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020; 382:1395-1407.
2. Spertus JA, Jones PG, Maron DJ, O'Brien SM, Reynolds HR, Rosenberg Y, Stone GW, Harrell FE Jr, Boden WE, Weintraub WS, Baloch K, Mavromatis K, Diaz A, Gosselin G, Newman JD, Mavromichalis S, Alexander KP, Cohen DJ, Bangalore S, Hochman JS, Mark DB; ISCHEMIA Research Group. Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease. N Engl J Med 2020; 382:1408-1419.