The long awaited results of the ISCHEMIA trial were presented at this weekend’s American Heart Association’s annual scientific meeting in Philadelphia, Pennsylvania by the Principal Investigator Dr. Judith Hochman (1). This study was a randomized parallel multicenter study that had an aim to compare outcomes of patients with stable ischemic heart disease and had moderate to severe ischemia on non-invasive stress testing who underwent optimal medical therapy (conservative arm) compared with those who underwent initial routine invasive therapy (invasive arm).
The clinical and stress test eligibility criteria were:
- Age > 21 years
- The presence of moderate or severe ischemia is defined as:
- Nuclear > 10% left ventricular ischemia (summed difference score of > 7)
- Stress echo with > 3 segments with stress induced moderate to severe hypokinesis or akinesis.
- CMR with
- Perfusion > 12% myocardial ischemia and/or
- Wall motion > 3/16 segments with stress induced severe hypokinesis or akinesis.
- Exercise tolerance testing (ETT) with > 1.5 mm ST depression in > 2 leads or >2 mm ST depression in single lead at <7 METS with angina.
Ischemia eligibility was determined by sites. All stress tests were interpreted at core labs.
The major clinical exclusion criteria were:
- New York Heart Association Class III-IV functional class
- Unacceptable angina despite medical therapy
- Left Ventricular Ejection Fraction (LVEF) <35%.
- Acute coronary syndrome within the last 2 months
- Percutaneous coronary intervention or coronary artery bypass graft within the last 1 year
- eGFR <30ml/min on dialysis
The coronary CT angiogram Eligibility Criteria were:
- > 50% stenosis in a major epicardial vessel (stress imaging participants)
- > 70% stenosis in a proximal or mid vessel (ETT participants)
Major Exclusion Criteria:
- > 50% stenosis in unprotected left main disease.
This study initially enrolled 8518 patients of which 3339 were excluded due to screen failure due to insufficient ischemia (N=1350), nonobstructive coronary artery disease (CAD) (N=1218) and the presence of unprotected left main disease (N=434). The remaining 5179 patients were randomized either to the conservative arm (2591 patients) or to the invasive arm (2588 patients). The study follow up was over 3 years, the mean age of patients included in the study was 64 years and the number of women enrolled in the study was 23%. Forty-one percent of the study cohort had diabetes mellitus.
The primary outcomes of the study were:
- The primary outcome of cardiovascular death, myocardial infarction, resuscitated cardiac arrest or hospitalization for unstable angina or heart failure followed over a 3 year period occurred in 13.3% of the invasive group compared with 15.5% of the conservative arm (p=0.34) and this was seen across multiple sub-groups.
The secondary outcomes of the study were:
- Rates of cardiovascular death or myocardial infarction were similar in both the invasive and conservative arms (11.7% vs. 13.9%, p=0.21).
- Rates of all-cause deaths were similar in both arms (6.4% in the invasive arm vs. 6.5% in the conservative arm, p=0.67).
- Invasive arm was associated with a higher rate of periprocedural myocardial infarction within the first 6 months post coronary revascularization (invasive/conservative hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.87-4.74).
- There was a greater incidence of spontaneous myocardial infarction in the conservative arm compared with the invasive arm that was seen after 3 years (invasive/conservative HR 0.67, 95% CI 0.53-0.83).
Improvement in quality of life with regards to anginal symptoms was observed only in patients with daily, weekly or monthly angina.
The limitations of the study included the fact that this was an unblinded trial with no sham procedure. Based on exclusion criteria the trial results are not applicable to patients with left ventricular ejection fraction less than 35%, significant (> 50%) left main stenosis, very symptomatic patients and patients who have had acute coronary syndromes within the previous 2 months. Trial findings may not be extrapolated to centers with higher procedural complication rates. Completeness of revascularization has not yet been assessed. The other limitation was the limited amount of women enrolled in the study (23%) as many were excluded from randomization when compared to men due to less ischemia and more non-obstructive CAD.
The ISCHEMIA trial concluded that patients with stable CAD and moderate to severe ischemia had significant durable improvements in angina control and quality of life with an invasive strategy if they had angina occuring daily/weekly or monthly. Shared decision-making should be done to ensure alignment of treatment with patients’ goals and preferences for patients with angina. However, in patients without angina, an invasive strategy led to minimal symptom improvement or quality of life benefits as compared with a conservative strategy. An early invasive strategy was not associated with a significant reduction in clinical events.
Based on these study findings my take home messages of the ISCHEMIA trial are that:
- This study validates the importance of Optimal Guideline Directed Medical Therapy (GDMT) and the need to control cardiovascular risk factors and optimize anti-anginal therapy in this population. This is a potential area for improvement in daily clinical practice in caring for patients with stable ischemic heart disease. The challenges with real world clinical practice is ensuring patient compliance with medications and the patient’s ability to afford and access medical therapy. This is particularly relevant with regards to cholesterol management in patients in whom statin therapy is not sufficient in lowering cholesterol and PCSK9 inhibitors may have to be considered. It is yet to be determined if outcomes would be different with achievement of optimal GDMT.
- Due to the known disparities in health care with regards to race and socioeconomic status, there is a need to determine if outcomes would be similar in minority as well as underserved patient populations.
- Only 23 % of the study population were females as many females were excluded due to non-obstructive coronary artery disease. Therefore I believe that it is uncertain that these study findings can be extrapolated to females.
- It is also unclear the impact of adding cardiac rehabilitation and exercise therapy to GDMT on this study population with regards to their overall clinical outcomes.
- It is encouraging that 80% of the patients in the invasive arm who had moderate to severe ischemia on non-invasive stress tests were determined to require revascularization therapy due to significant CAD indicating good accuracy rates for stress testing. It would be interesting if this could be extrapolated to real world practice. This in my mind emphasizes the need for tools in stress testing to improve and maintain accuracy such as attenuation correction and use of prone imaging with SPECT imaging, the use of solid state CZT cameras for SPECT imaging, the value of cardiac positron emission tomography (PET) which has been shown to have greater accuracy when compared to SPECT (2) as well as the use of artificial intelligence to improve accuracy with nuclear stress testing (3).
- There was an increased incidence of periprocedural MI in the invasive arm which is not a surprising finding. However, I believe that this is thought provoking as it would be interesting to determine if these myocardial infarction events were due to in-stent restenosis or due to distal embolization within the stented vessel.
- While it may be reflexive to consider performing only Coronary CT angiogram in these patients with chest pain to rule out LM disease and deferring stress testing before determining management strategy, I do believe that it is important to have objective evidence of ischemia before deciding to prescribe potentially lifelong anti-anginal therapy. This is relevant for each patient as this may not align with their desires. Additionally, this would commit them and/or their insurers to this additional expense, therefore having a clinical indication for these medications is important.
- A longer period of follow up could potentially have different outcomes in the treatment arms of the study and it would be interesting to determine if there will be an ISCHEMIA Extend study to evaluate this further.
- The completeness of revascularization in the ischemic territory is an area of uncertainty based on these study findings. Therefore, further subgroup retrospective analysis of the invasive arm will hopefully be considered by the study investigators to further study this area.
- Patient centered shared-decision aid tools or applications will hopefully be developed to help the physician predict individual patient’s risks and benefits for each strategy. This will facilitate the patient -physician discussion to determine the patient’s overall desires and to determine treatment goals for the patient. This is important due to the fact that what may seem a reasonable management strategy to the physician may not be acceptable to the patient based on their desired lifestyle and/or treatment goals.
Overall, I believe the ISCHEMIA trial results validates the importance of optimal GDMT as well as the importance of shared decision making between the patient and the physician based on the overall clinical risk profile of each patient and the therapeutic goals for each patient. Hopefully, these trial results will not necessarily lead to a paradigm shift in clinical practice but will result in clinical practice improvement in delivering customized patient care based on individual patient’s clinical risks, treatment goals and patient desires.
- Takx, RAP, Blomberg BA, El Aidi H, Habets J, de Jong PA, et al. Diagnostic Accuracy of Stress Myocardial Perfusion Imaging Compared to Invasive Coronary ANgiography with Fractional Flow Reserve Meta-Analysis. Circ Cardiovasc Imaging. 2015;8:e002666
- Slomka PJ,Betancur J, Liang JX, et al. Rationale and design of the REgistry of Fast Myocardial Perfusion Imaging with NExt generation SPECT (REFINE SPECT). J Nucl Cardiol 2018; Jun 19:[Epub ahead of print]
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