Interim ISCHEMIA Analysis: Uphill Fight to Hit Treatment Targets

Patrice Wendling

November 15, 2019

PHILADELPHIA — An interim analysis ahead of the highly anticipated ISCHEMIA trial points to only moderate success in achieving cholesterol and blood pressure goals and offers clues as to which patients are more likely to get to goal.

The trial is assessing a fundamental question in cardiovascular medicine of whether patients with stable moderate to severe ischemia on stress testing have fewer adverse cardiovascular events when managed with an initial invasive approach with revascularization on top of optimal medical therapy (OMT) or with conservative management on a background of OMT.

COURAGE and BARI 2D showed that invasive revascularization plus OMT did not reduce the rate of MI or death, compared with OMT alone, although other analyses have suggested a benefit with revascularization over OMT alone in patients with greater ischemic burden. The first sham-controlled PCI trial, ORBITA, however, cast doubt on the belief that PCI delivers better relief of angina than OMT alone.

The present analysis focused on 3984 (78% of the 5179 ISCHEMIA) participants who had complete baseline and 1-year low-density-lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) data, as of January 28, 2019. At baseline, patients were receiving a median of two antihypertensive medications, 95% were on a statin, and 20% were receiving a medication donation or reimbursement.

The OMT LDL-C goal was less than 70 mg/dL. For SBP, it was less than 140 mm Hg at trial launch and for this analysis, but was revised downward to less than 130 mm Hg in April 2018 in alignment with the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guidelines.

The proportion of participants at goal for LDL-C and SBP increased from 35% to 52% and from 65% to 75%, respectively, at 1 year, the ISCHEMIA investigators reported November 13 in Circulation: Cardiovascular Quality and Outcomes.

In multivariate analysis, women were nearly a third less likely to reach 1-year goals for LDL-C than men (odds ratio [OR]. 0.68; 95% CI, 0.58 - 0.80), and trended toward lower odds of reaching the SBP goal (OR, 0.87; 95% CI, 0.73 - 1.04).

Other predictors of achieving the LDL-C target were 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).

Lower baseline SBP (per 10-unit lower SBP; OR, 1.27) and North American enrollment (OR, 1.35) predicted SBP goal attainment.

Notably, adherence to lipid-lowering or antihypertensive medication did not increase 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).

"We made some progress but it certainly illustrates the challenges of aggressive medical therapy and goal attainment, even in the context of a clinical trial," study author Jonathan D. Newman, MD, MPH, New York University School of Medicine, told theheart.org | Medscape Cardiology.

"To give you context, over half of participants got to an LDL of less than 70, and that really had not been done in COURAGE or BARI 2D or FREEDOM," he said. "Our 1-year goal attainment of going from 65% to 75% systolic blood pressure is competitive and I think compares well to where these other trials ended up with their medical therapy management. But again, this is an interim result at 1 year and not the final goal attainment."

Multiple strategies for OMT and lifestyle goal attainment were used in the trial, including medication reimbursement at 30% of centers, algorithms to help sites reach LDL-C/SBP goals and manage angina, and direct contact from senior investigators to counsel sites if LDL-C/SPB targets were not being attained, Newman said.

"I think that is a very admirable approach to make sure medical therapy is done correctly and one we haven't seen in trials of this size before," ORBITA principal investigator Rasha Al-Lamee, MBBS, Imperial College London, told theheart.org | Medscape Cardiology.

Nevertheless, she noted that the gains were "only modest" and that comparisons with previous trials must take into account that OMT targets vary between trials. For example, COURAGE used a more lenient LDL-C target (<100 mg/dL) than ISCHEMIA, but a more stringent SBP target (<130/85 mm Hg) than was used in this analysis.

Al-Lamee also cautioned that these are interim findings and that data on antianginal therapy were not available. Antianginal OMT is relevant when quantifying the symptomatic benefit of revascularization beyond placebo, as in ORBITA, whereas optimum risk-reduction therapy is the only OMT that matters for the primary end point of ISCHEMIA of cardiovascular death, myocardial infarction (MI), resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure.

In an accompanying editorial, Al-Lamee and colleagues argue that OMT is a "catch-all" term that is often not informative and that accurate quantification of medical therapy in a clinical trial is crucial because it affects the end points and contextualizes the results.

"As a community we must move away from routinely framing medical therapy under the simplistic banner of 'OMT,' and work to establish more descriptive and representative terms," they write. "We should ask for rigorous application and testing and insist that a realistic gold standard is reached before calling it optimum'."

When ISCHEMIA is presented Saturday at the AHA Scientific Sessions 2019, Al-Lamee and colleagues suggest considering the 'Golidlocks phenomenon,' in which trial results are often filtered through a lens of whether OMT is considered too little, too much, or just right. Critics, for example, questioned whether antianginal therapy in ORBITA was reflective of real-world clinical practice, while some, including Al-Lamee, contend antianginal therapy in FAME-2 was too little.

"It may be that ISCHEMIA is as good as we can get, but I think we'll have to think about that when we see the results," she told theheart.org | Medscape Cardiology. "What's important is that we don't allow the results to color how we judge medical therapy because I think we often do that. We kind of go backwards; we go from the results and go backwards trying to find a reason for the results that we found unexpected."

ISCHEMIA is supported by a grant from the National Heart, Lung, and Blood Institute and financial donations from Arbor Pharmaceuticals and AstraZeneca; devices and medications were provided by Abbott Vascular/St. Jude Medical, Medtronic, Volcano, Arbor Pharmaceuticals, AstraZeneca, Merck Sharp & Dohme, and Omron Healthcare. Newman and the editorialists report no relevant conflicts of interest.

Circ Cardiovasc Qual Outcomes. 2019;12:e006002 and 12:e006265. Full text, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook.

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