Mortality Benefit with ACE Inhibitors in Nonobstructive CAD

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Among patients with acute coronary syndromes (ACS), even those who have nonobstructive coronary artery disease (CAD) reap reduced mortality at 6 months with use of an ACE inhibitor, according to a registry study published online March 3, 2014, ahead of print in the American Journal of Cardiology. However, the study also found that this population is less likely to be prescribed the preventive therapy than patients with obstructive CAD.

For the EMMACE-2 (Evaluation of Methods and Management of Acute Coronary Events) registry, researchers led by Raffaele Bugiardini, MD, of the University of Bologna (Bologna, Italy), examined evidence-based therapies prescribed at discharge for 1,602 patients who had been hospitalized for ACS and undergone cardiac catheterization. Patients were divided into 2 groups:

  • Nonobstructive CAD (< 50% stenosis in all vessels; n = 350)
  • Obstructive CAD (≥ 50% stenosis in 1 or more vessels; n = 1,252)

ACE Inhibitors Protective But Less Frequently Prescribed

Overall, 15% of patients with nonobstructive CAD and 25% of those with obstructive CAD were not prescribed aspirin at discharge (P < 0.001). However, since clopidogrel was recommended for patients who were unable to take aspirin or for use in combination, all patients received at least one recommended antiplatelet therapy. At discharge, nonobstructive CAD patients were more likely to be given prescriptions for beta-blockers and statins but less likely to be prescribed ACE inhibitors compared with obstructive CAD patients (table 1).

Table 1. Preventive Therapies Prescribed at Discharge


(n = 350)

(n = 1,252)

P Value




< 0.001

ACE Inhibitors








At 6 months, 16.9% of patients had died. Compared with the obstructive CAD group, patients in the nonobstructive group had markedly lower cardiovascular mortality (3.1% vs 20.7%; P < 0.001). Furthermore, men and women with nonobstructive CAD had similar risk of death (OR 0.99; 95% CI 0.95-1.04). Conversely, women with obstructive CAD had a higher unadjusted risk of death than their male counterparts (OR 1.12; 95% CI 1.05-1.19).

In nonobstructive CAD, use of ACE inhibitors was the only independent variable with a protective effect on mortality risk (OR 0.31; 95% CI 0.03-0.78; P = 0.004); whereas older age was the only independent variable predisposing to death at 6-month follow-up (OR 1.01; 95% CI 1.03-1.19; P = 0.007). There was no association between beta-blocker or statin use and death (P = 0.31 and P = 0.28, respectively).

In contrast, among obstructive CAD patients, 6-month mortality was linked to use of beta-blockers (OR 0.47; 95% CI 0.32-0.67; P < 0.001), ACE inhibitors (OR 0.47; 95% CI 0.26-0.87; P = 0.01), and statins (OR 0.52; 95% CI 0.36-0.74; P < 0.001). STEMI as index event was the strongest independent predictor of death in this group (OR 1.92; 95% CI 1.33-2.77; P = 0.001).

New Incentive for Preventive Therapy

“These new findings provide an additional argument to treat patients with nonobstructive coronary lesions with ACE inhibitors,” Dr. Bugiardini and colleagues say, even though the prescription pattern for ACE inhibitors and beta-blockers for patients with nonobstructive disease seen in the study is consistent with guideline recommendations.

Although the authors offer no definitive explanation of why ACE inhibitors are protective in patients with nonobstructive disease, they say one answer may lie in the drugs’ anti-atherosclerotic and antithrombotic properties. “Blunting the renin-angiotensin system may decrease plaque size, cholesterol content, and macrophage accumulation,” they suggest. “These effects may in turn contribute to plaque stabilization by inhibition of metalloproteinase.”

As to why beta-blockers failed to protect patients with nonobstructive CAD, Dr. Bugiardini and colleagues say the impact of beta-blocker usage may not have been captured in this database as the effectiveness of such drugs is small. Secondly, the heterogeneous grouping of nonobstructive disease may have favored finding an effect of ACE inhibitor use, they say.

Study Details

Compared with those with obstructive disease, patients with nonobstructive CAD were approximately 10 years younger (for both sexes) and had less history of lipid disorders, diabetes, and hypertension. Additionally, STEMI as index event occurred less frequently in patients with nonobstructive vs obstructive CAD. In gender analysis, apart from age (men were younger than women; P < 0.001), there were no significant differences in cardiovascular risk factors, nor in the incidence of STEMI as index event in nonobstructive CAD.


Manfrini O, Morrell C, Das R, et al. Effects of angiotensin-converting enzyme inhibitors and beta-blockers on clinical outcomes in patients with and without coronary artery obstructions at angiography (from a register-based cohort study on acute coronary syndromes). Am J Cardiol. 2014;Epub ahead of print.



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  • Dr. Bugiardini reports no relevant conflicts of interest.