Johnson & Johnson and Bayer suffered a major setback as the U.S. Food and Drug Administration (FDA) has once again denied approval of the blood thinner Xarelto, a product aimed at those who suffer from the heart condition acute coronary syndrome (ACS).

The FDA issued its first rejection in June, due to concern over bleeding caused by the drug.

"While we saw an increase in major bleeding, there was no increase in fatal bleeding," said Johnson & Johnson's Janssen Research & Development LLC Vice President Christopher Nessel in a press release on Monday. "We will continue to work with the FDA to address their questions."

Johnson & Johnson markets Xarelto in the U.S., while Bayer markets the product overseas. It is part of a new group of drugs designed to take the place of warfarin, an older blood thinner that has been at times difficult to administer. The FDA first approved Xarelto in 2011 for blood clot prevention after knee- or hip-replacement surgery. It has since approved an expanded use of the drug for the treatment of certain blood clots.

Use of Xarelto for the treatment of ACS initially looked promising. In 2011, the ATLAS ACS 2-TIMI 51 trial was announced to much adulation. Expectations were fueled in February 2012, when the FDA allowed priority review of the ACS indication. But questions about the ATLAS trial surfaced just a few months later, resulting in the FDA's Cardiovascular and Renal Drugs Advisory Committee voting against the ACS indication.

Nevertheless, Johnson & Johnson and Bayer stand by their product.

"We remain confident in the robustness and results of the ATLAS ACS 2 TIMI 51 trial," Nessel said, "evidenced by a significant reduction in cardiovascular events, including a clinically important decrease in cardiovascular death, as published in the New England Journal of Medicine."

On Monday shares of Johnson & Johnson and Bayer closed at $77.20 and $99.06, respectively.