Key learnings from ISCHEMIA, ISCHAEMIA-CKD, & Interim Analysis

M3 India Newsdesk Dec 09, 2019

Here are the major highlights and key takeaways from ISCHAEMIA, ISCHEMIA-CKD trials, and the Interim Analysis that were presented at the 2019 annual meeting of the American Heart Association (AHA), held this year.

ISCHEMIA

The interpretation of the ISCHEMIA trial was not entirely positive since it showed that routine invasive therapy, when compared to optimal medical therapy in stable patients with moderate ischaemia was not associated with lesser major adverse ischemic events. The angina burden and background medical therapy needs to be carefully considered in stable ischaemic heart disease patients before considering invasive therapy as it may be possible that optimal coronary revascularisation be attained with lesser procedural complications. Patients with current/recent acute coronary syndrome, highly symptomatic patients, left main stenosis, or left ventricular ejection fraction <35% are not included as being represented by these findings or suggestions.

Background

Trial investigators had to change the primary endpoint of cardiovascular death and myocardial infarction (MI) to include resuscitated cardiac arrest, hospitalisation for unstable angina, and hospitalisation for heart failure. The study protocol was also changed to re-define inclusion ischaemia from 10% or more on nuclear perfusion imaging to patients with 5% ischaemic burden at low levels of exertion and patients with ECG changes during exercise tolerance testing without imaging with approval of the independent data and safety monitoring board.

These controversial changes led to questioning the baseline characteristics and risk profiles of ISCHEMIA participants after they were published earlier in 2019. The Seattle Angina Questionnaire (SAQ) Summary Score was assigned to be the primary outcome of health status benefits rather than the SAQ Angina Frequency and Quality of Life scales which was now the secondary outcome. This protocol tweaking was exposed in an "Ischemia Trial Update" in September.

Patients with stable ischaemic heart disease and moderate to severe myocardial ischaemia on noninvasive stress testing were enrolled to evaluate and compare routine invasive therapy with optimal medical therapy in this randomized, parallel study.

The inclusion criteria were,

Patients >20 years of age, and moderate to severe ischaemia on noninvasive stress testing (nuclear ≥10% ischaemia; echo ≥3 segments of ischaemia; cardiac magnetic resonance ≥12% ischaemia and/or ≥3 segments with ischaemia; exercise treadmill test ≥1.5 mm ST depression in ≥2 leads or ≥2 mm ST depression in single lead at <7 METs with angina).
Patients with ≥50% left main stenosis (from blinded computed tomography), advanced chronic kidney disease (estimated glomerular filtration rate <30 ml/min), recent myocardial infarction, left ventricular ejection fraction <35%, left main stenosis >50%, unacceptable angina at baseline

New York Heart Association class III-IV heart failure, and prior PCI or CABG within last year were excluded from the study.

Randomisation of 5,179 patients with stable ischaemic heart disease and moderate to severe ischaemia led a group of those on routine invasive therapy (n = 2,588) and a group of those on medical therapy (n = 2,591). In the routine invasive therapy group, subjects were offered either coronary angiography, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) as was considered appropriate, whereas subjects underwent coronary angiography only for failure of medical therapy in the medical therapy group.

The mean patient age was 64 years, 23% were female and 41% had diabetes. At baseline, the frequency of angina was none, 34%; several times per month, 44%; and daily/weekly, 22%. The duration of follow-up was for 3.3 years.

Salient features/characteristics found were that cardiac catheterization was done in 96% of the invasive group vs. 28% of the medical therapy group over the complete follow-up period and that coronary revascularization was done in 80% of the invasive group vs. 23% of the medical therapy group over the complete follow-up period.

Key findings:

13.3% of the routine invasive group met the primary outcome of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, or hospitalisation for unstable angina or heart failure at 3.3 years compared with 15.5% of the medical therapy group (p = 0.34) and multiple subgroups showed the same findings.
Harm (~2% absolute increase) within the first 6 months and benefit within 4 years (~2% absolute decrease) was associated with invasive therapy.
11.7% of the routine invasive group met the secondary outcomes of cardiovascular death or myocardial infarction compared with 13.9% of the medical therapy group (p = 0.21)
6.4% of the routine invasive group compared with 6.5% of the medical therapy group suffered all-cause death (p = 0.67)
Periprocedural myocardial infarction (invasive/conservative hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.87-4.74) and spontaneous myocardial infarction (invasive/conservative HR 0.67, 95% CI 0.53-0.83) were also observed.
The quality of life (QoL) outcomes showed symptom betterment in patients with daily/weekly/monthly angina, but this was lacking in patients not having angina.

ISCHEMIA-CKD

Coronary angiography followed by revascularisation does not impart any betterment on clinical outcomes or quality of life in this high-risk population of suitable patients with chronic kidney disease (CKD) as well as stable ischaemic heart disease and at least moderate ischaemia on stress testing.

The ISCHEMIA-CKD trial was done in a classically much higher-risk population of 777 adults with CKD and moderate or severe ischaemia as defined by exercise or pharmacologic stress testing. Patients were randomly assigned to receive an initial invasive strategy of optimal medical therapy (OMT) plus diagnostic cardiac cath, with revascularisation as appropriate in one group, or the second group which adopted a conservative strategy that offered invasive therapy only if symptoms occurred despite OMT.

Angiography was ultimately done in about 85% of the 388 patients during the study's 3 years in the initial invasive strategy group with 50% of the group ending up with percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG).

In contrast, angiography was ultimately done in about 22% of the 389 patients during the study's 3 years in the conservatively managed patients group with 12% of the group ending up with percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG).

To lower the risk for acute kidney injury (AKI) from contrast exposure, customised hydration and low- or zero-contrast-agent procedure techniques training was imparted to interventional personnel at the investigator sites all around the globe.

Key findings:

The primary endpoint of death or nonfatal MI was not significantly different with the invasive strategy. The hazard ratio (HR) over 3 years was 1.01 (95% CI, 0.79 - 1.29; P = .95).
On evaluation in a prospectively defined secondary analysis, neither the angina severity and frequency, nor other quality-of-life (QoL) issues differed with the invasive strategy. Across subgroups, results were consistent.
For 61.9% patients with moderate baseline ischaemia, the primary-endpoint HR was 1.30 (95% CI, 0.94 - 1.79) and in 38.1% patients when ischaemia was severe, the primary-endpoint HR was 0.70 (95% CI, 0.46 - 1.05). Significant interaction between ischaemia severity and outcomes was evident P = .02.
In the invasive group, the risk for stroke was higher by more than threefold when compared to the conservative strategy group. Also, the invasive group had significantly more combined endpoint of death or initiation of dialysis. The HRs for invasive group versus the conservative management group were as follows:
- HR for stroke = 3.76 (95% CI, 1.52 - 9.32; P = .004)
- HR for death or new dialysis = 1.48 (95% CI, 1.04 - 2.11; P = .02)
- HR for unstable angina = 0.15 (95% CI, 0.02 - 1.37; P = .09)
The requirement for first-time dialysis escalated soon after intervention in the invasive strategy group as expected, but even the conservative group showed statistically similar rates at 3 years: HR, 1.47 (95% CI, 0.88 - 2.44; P = .13).
AKI rates at were consistently low across the various centers. In the invasive group, 7.8% was the rate of AKI after PCI or CABG whereas in the conservatively managed patients, it was 5.4% with eventually crossing over later. Correspondingly, the new need for dialysis within 30 days of the procedure were only 2.1% and 0.6%, respectively.

Interim ISCHEMIA Analysis

Based on an interim analysis, the only moderate success from the highly anticipated ISCHEMIA trial may be in giving clues about patients that may achieve their cholesterol and blood pressure goals.

The complete baseline and 1-year low-density-lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) data of 3984 (78% of the 5179 ISCHEMIA) participants as of January 28, 2019 was analysed.

Patients got a median of two antihypertensive drugs. A statin was used by 95%, and a medication donation or reimbursement was had by 20%. Less than 70 mg/dL was the OMT LDL-C goal. The goal for SBP was less than 140 mm Hg at trial launch but this was revised downward as per the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guidelines to less than 130 mm Hg in April 2018.

Key findings:

At 1 year, the ISCHEMIA investigators reported that the proportion of participants at goal for LDL-C increased from 35% to 52% and that the proportion of participants at goal for SBP increased from 65% to 75%.
Women were almost a third less likely to attain LDL-C 1-year goals than men (odds ratio [OR]. 0.68; 95% CI, 0.58 - 0.80) and they trended toward lower odds of attaining the SBP goal (OR, 0.87; 95% CI, 0.73 - 1.04) in multivariate analysis.
Older age (per 10-unit increase; OR, 1.11), lower baseline LDL-C (per 10-unit lower LDL-C; OR, 1.19), high-intensity statin use (OR, 1.30), and enrollment at a North American site (OR, 1.32) were the other predictors of attaining the LDL-C target.
SBP goal attainment was predicted by lower baseline SBP (per 10-unit lower SBP; OR, 1.27) and North American enrollment (OR, 1.35).
Remarkably, the likelihood of meeting goals for LDL-C (OR, 0.97; 95% CI, 0.83 - 1.14) or SBP (OR, 1.00; 95% CI, 0.84 - 1.20) was not increased by adherence to lipid-lowering or antihypertensive medications.

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