The US Food and Drug Administration (FDA) said it wanted further analysis of existing drugs studies.
Brilinta, which is already approved in Europe, is expected to reach $2bn (£1.3bn) sales in the US once approved.
The FDA had already postponed its review of the heart drug since September after patients in a North American trial of the drug failed to show significant benefits.
AstraZeneca is hoping Brilinta will challenge Plavix produced by rivals Bristol-Myers Squibb and Sanofi-Aventis, which is the second best-selling drug in the world with over $9.5bn sales last year.
The UK company is about to see patents on some of its other major brands expire, including schizophrenia drug Seroquel and heartburn relief Nexium.