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Results from a retrospective, nationwide study of close to 40,000 veterans challenge the idea that nonobstructive coronary artery disease (CAD) is a clinically benign condition.

Veterans with evidence of nonobstructive CAD on elective coronary angiography had a 2- to 4.5-fold greater risk for myocardial infarction compared with those with no evidence of CAD, and 1-year MI risk was found to increase progressively by CAD extent, rather than increasing abruptly when CAD became obstructive.

"The results of this study support the concept that nonobstructive CAD is not 'insignificant' but rather is associated with a significant and quantifiable risk for cardiovascular morbidity and mortality," researcher of the VA Eastern Colorado Health Care System, and colleagues wrote in the Nov. 5

In an interview with 番茄社区, Maddox said he does not believe many cardiologists and vascular biologists will be surprised by the finding that CAD risk follows a linear path and that there is clinically meaningful risk associated with nonobstructive CAD.

"This fits with how we believe the disease works, but we have been unable to make this definitive link by showing this in a big group like the VA cohort until now," he said.

Cardiologist Clyde W. Yancy, MD, who was not involved in the research, said the study findings should change the conversation between clinicians and patients with evidence of nonobstructive coronary artery lesions.

Yancy is chief of the division of medicine-cardiology at Chicago's Northwestern University Feinberg School of Medicine and a spokesman for the American Heart Association.

"These patients are often told their coronaries are fine and they have nothing to worry about," he told 番茄社区. "That is bad messaging. Instead the message should be 'There is evidence of atherosclerosis and while there is no need to panic, we need to address it.'"

Yancy added that the study "debunks the argument that there is such a thing as mild coronary artery disease."

Up to 1 in 4 Angiograms Show Minimal Plaque

Nonobstructive CAD refers to the presence of atherosclerotic plaque revealed during coronary angioplasty that does not appear to obstruct blood flow or result in anginal symptoms.

These nonobstructive lesions occur in between 10% and 25% of patients undergoing elective angiography, and their presence has historically been characterized as "insignificant" or "no significant CAD" in the medical literature even though multiple studies have shown plaque ruptures leading to MI commonly come from nonobstructive plaques, Maddox and colleagues wrote.

Maddox said little is known about the clinical impact of stable nonobstructive CAD because very few studies have included these patients and most coronary angiography registries include obstructive, but not nonobstructive CAD.

The VA Clinical Assessment, Reporting, and Tracking (CART) program is one of the only registries in the nation to include data on nonobstructive CAD, including long-term patient outcomes. The program uses a clinical software application embedded in the VA electronic health record (EHR) to capture standardized patient and procedural data for all coronary procedures performed in VA catheterization laboratories nationwide.

The newly published study examined the researchers' hypothesis that increasing CAD severity across the continuum of nonobstructive and obstructive CAD is associated with increasing MI and death risk.

The analysis included all U.S. veterans with no history of prior CAD undergoing elective coronary angiography for CAD between October of 2007 and September of 2012 at any of the nation's 79 VA cardiac catheterization laboratories. The primary outcome was one-year hospitalization for nonfatal MI after the index angiography, and secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality.

For patients receiving more than one coronary angiogram during the study period, the first angiogram was used to characterize CAD extent.

Just Over 1 in 5 Patients Had Nonobstructive CAD

Among 37,674 patients, 8,384 (22.3%) had nonobstructive CAD, defined as a coronary artery stenosis 20% or greater but less than 50% in the left main coronary artery, or a stenosis 20% or greater but less than 70% in any other epicardial coronary artery. Another 20,899 patients (55.4%) had obstructive CAD, defined as any stenosis 50% or greater in the left main coronary artery, 70% or greater in any other coronary artery, or both.

The remaining 8,391 patients (22.3%) had no apparent CAD, defined as all coronary stenoses less than 20% or luminal irregularities.

During the year following index coronary angiography, 845 patients had died and 385 had been rehospitalized for MI. Among patients with no apparent CAD, just eight patients had MIs (0.11%, 95% CI 0.10%-0.20%).

MI incidence increased progressively with CAD extent in patients with both nonobstructive and obstructive disease, ranging from a 0.24% rate in the lowest CAD obstruction group to 2.47% in those with the most obstructive CAD:

• 1-vessel nonobstructive CAD -- 0.24% (95% CI 0.10%-0.49%)
• 2-vessel nonobstructive -- 0.56% (95% CI 0.30%-1.00%)
• 3-vessel nonobstructive -- 0.59% (95%CI 0.30%-1.30%)
• 1-vessel obstructive -- 1.18% (95% CI 1.00%-1.40%)
• 2-vessel obstructive -- 2.18% (95%CI 1.80%-2.60%)
• 3-vessel or LM obstructive -- 2.47% (95%CI 2.10%-2.90%)

Cox regression modeling was used in the adjusted analysis. After adjustment, 1-year MI rates were found to increase with increasing CAD extent.

Compared with patients with no apparent CAD, the hazard ratio for 1-year MI was:

• 1-vessel nonobstructive CAD -- HR 2.0 (95% CI 0.8-5.1)
• 2-vessel nonobstructive -- HR 4.6 (95% CI, 2.0-10.5)
• 3-vessel nonobstructive -- HR 4.5 (95%CI, 1.6-12.5)
• 1-vessel obstructive -- HR 9.0 (95%CI, 4.2-19.0)
• 2-vessel obstructive -- HR 16.5 (95%CI 8.1-33.7)
• 3-vessel or LM obstructive -- HR 19.5 (95%CI, 9.9-38.2)

One-year mortality rates also increased with increasing CAD extent, ranging from 1.38% in patients without apparent CAD to 4.30% in those with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD.

Study limitations cited by the researchers included the possibility of selection bias for patients chosen to undergo coronary angiograms and a lack of data of cardiac-specific mortality. The fact that the overwhelming majority of patients included in the study were male and white also limited the generalizability of the findings to other populations, they noted.

"To our knowledge, this study provides the most comprehensive assessment of the risks associated with nonobstructive CAD demonstrated during elective coronary angiography," Maddox and colleagues wrote, adding that the results complement the majority of prior cardiac CT studies which suggests a significant, progressive increase in the risk of adverse cardiac events with increasing CAD extent.

'Nonobstructive Label Misleads Patients'

They added that the findings "reveal the limitations of a dichotomous characterization of angiographic CAD into 'obstructive' and 'nonobstructive' to predict MI and highlight the importance of preventive strategies such as pharmacotherapy treatments and lifestyle modifications to mitigate these risks."

Yancy said just like patients with obstructive CAD, patients with minimal CAD should be urged to take appropriate preventive medications and make lifestyle changes to reduce their risk of disease progression.

He agreed with Maddox that the term 'nonobstructive CAD' may mislead patients.

"We should simply tell patients they have coronary artery disease, because that is, in fact, what they have," he said.

From the American Heart Association:

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