DES Can't Outmuscle Harmful CAC Effects in Women: Study

NEW YORK, NY — A pooled analysis shows moderate or severe coronary artery calcification (CAC) dramatically increases the risk for hard adverse events in women undergoing PCI even with newer drug-eluting stents (DES)^[1].

At 3 years of follow-up, women with moderate or severe target lesion CAC were at higher adjusted risk than those with no or mild CAC for the composite of death, MI, or target lesion revascularization (TLR) (hazard ratio [HR] 1.56; 95% CI 1.33–1.84; P<0.0001) and death, MI, or stent thrombosis (HR 1.48; 95% CI 1.21–1.80; P=0.0001).

"This adverse effect was consistent across all the subsets and even with the new-generation DES, which have overcome a lot of the bad outcomes," senior investigator Dr Roxana Merhan (Ichan School of Medicine, Mount Sinai, NY) told heartwire from Medscape.

Calcification is known to confer increased risk for worse outcomes in the general population, but she noted that its role in women undergoing PCI has been unclear due in part to historical underrepresentation in randomized clinical trials.

"One of the reasons that women get excluded from these trials is because they have severe calcification. Nobody wants bad results, so nobody wants severely calcified lesions to come in," Mehran said. "This to me is a call to action to actually study women with calcific lesions and better understand how best to treat these women; I think at the moment we really don't have clear answers."

The investigators, led by Dr Gennaro Giustino (Ichan School of Medicine), observe that even with meticulous lesion preparation, optimal stent expansion and strut apposition are not always achieved. The ORBIT-II trial suggested a benefit to atherectomy with DES in patients with severely calcified lesions, but appropriately designed randomized clinical trials are still needed to show whether routine lesion decalcification can improve PCI outcomes.

The present analysis, published online September 26, 2016 in JACC: Cardiovascular Interventions, examined individual patient-level data from 11,557 women in 26 randomized DES trials pooled as part of the Women in Innovation and Drug-Eluting Stents (WIN-DES) collaboration.

DES used in the trials were classified as early-generation (Cypher, Cordis; Taxus, Boston Scientific) and new-generation (Xience, Abbott Vascular; Promus, Boston Scientific; Endeavor, Medtronic; Resolute, Medtronic; Biomatrix, Biosensors; Nobori, Terumo; and Yukon, Translumina). CAC status was available in 6371 women.

Moderate to severe CAC was present in 25.5%, but "real-world rates" could be even higher because some trials may have excluded heavy calcification or lesions requiring atherectomy, Dr Cindy Grines (Detroit Medical Center Heart Hospital, MI) and Dr Kimberly Skelding (Geisinger Medical Center, Danville, PA) echoed in an accompanying editorial^[2].

They write that the women did "relatively well" out to 3 years of follow-up, with a TLR rate of only 6.7% compared with 18% TLR at 9 months in ROTAXUS" and a stent-thrombosis rate of 1.5%, "suggesting this population of women was highly selected."

The study also aimed to identify independent clinical correlates of CAC in the all-female population. As expected, they were the traditional risk factors of hypertension, hypercholesterolemia, previous bypass surgery, smoking, worse left ventricular and renal function, and advancing age.

"It comes back again to primary and secondary prevention for women first and foremost and avoiding them needing to get to this level of such complex disease with increased coronary calcification, which really puts them at very high risk for ill events and poor outcomes," Mehran said.

The editorialists observe that women have smaller vessels that may be more prone to restenosis and stent thrombosis, especially if calcified, but also point to the very strong correlation between osteoporosis, vascular calcification, and cardiovascular events. Women are often prescribed calcium supplements starting well before menopause, and studies suggest high-dose calcium supplements, particularly in the setting of vitamin D deficiency, may increase the risk of MI and CV events.

"Unfortunately, recommendations for calcium supplements and warfarin for atrial fibrillation (female sex is an independent risk factor in the CHA ₂DS₂-VASc risk calculation) may further women's risk. Additional studies to determine prevention and treatment of cardiovascular calcification in women are desperately needed," Grines and Skelding write.

Mehran reported receiving institutional research grants from the Medicines Company, Bristol-Myers Squibb, Sanofi, Eli Lilly, and AstraZeneca; consulting fees from AstraZeneca, Bayer, CSL Behring, Janssen Pharmaceuticals, Merck, Osprey Medical, and Watermark Research Partners; and serving on the advisory boards of Abbott Laboratories, Boston Scientific, Covidien, Janssen, the Medicines Company, and Sanofi. Giustino reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Grines reported no relevant financial relationships. Skelding reported consulting for Abbott and serving as a proctor for Medtronic.

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