ESTES PARK, COLO. – Largely overlooked in all the hubbub over the new oral anticoagulants and their evolving role in stroke prevention in patients with atrial fibrillation has been an unrelated significant change in the 2012 American College of Chest Physicians guidelines on antithrombotic therapy.
The latest ACCP guidelines chart a new course in managing patients with a CHADS2 score of 0 – that is, those patients under age 75 with none of the major risk factors included in the CHADS2 rating system. For the first time, the recommended antithrombotic regimen in such patients is ... nothing.
That’s right. Nada. Not aspirin, not aspirin plus clopidogrel, not warfarin or its new alternatives.
"For patients with AF, including those with paroxysmal AF, who are at low risk of stroke ... the expert panel suggests no therapy rather than antithrombotic therapy," the guidelines state (CHEST 2012;141[Suppl. 2]:7S-47S).
The American College of Chest Physicians (ACCP) expert panel was influenced by calculations that 1 year of prophylactic aspirin in patients with a CHADS2 score of 0 may prevent 2 nonfatal strokes per 1,000 treated patients at the expense of 3 additional nonfatal major extracranial bleeding events.
This is an evolution of therapy. Earlier editions of the ACCP guidelines recommended aspirin in patients under age 65 with a CHADS2 score of 0, and either aspirin or warfarin in those aged 65-75 years, noted Dr. Kathryn Hassell, a hematologist and professor of medicine at the University of Colorado, Denver.
The CHADS2 scoring system assigns 1 point each for atrial fibrillation (AF) patients who have Congestive heart failure, Hypertension, Age of 75 years or more, or Diabetes mellitus, and 2 points for a history of Stroke or TIA.
The 2012 ACCP guidelines recommend that patients with a CHADS2 score of 1 or more receive oral anticoagulation, with the novel agent dabigatran (Pradaxa) favored over warfarin. For patients who are not oral anticoagulation therapy candidates, combination prophylaxis with aspirin and clopidogrel is recommended.
The ACCP’s recommendation for preferential use of dabigatran over warfarin has become controversial. Dabigatran was the first of the new anticoagulants to come to the market. It did so with much fanfare on the basis of its far greater convenience, as well as its small, but statistically significant reductions in stroke or systemic embolism and intracranial hemorrhage compared with warfarin in the randomized, 18,000-plus patient RE-LY trial (N. Engl. J. Med. 2009;361:1139-51).
But then came a December 2011 Food and Drug Administration safety announcement of postmarketing reports of serious bleeding events in patients on dabigatran, along with a recommendation to assess renal function prior to treatment and adjust the dabigatran dosing depending upon the creatinine clearance rate.
FDA warnings are always a boon to the legal profession. The TV airwaves are now filled with commercials for ‘The Pradaxa Side Effects Lawyer,’ whose zingy motto is, "Over 130,000 clients can’t be wrong."
Serious bleeding problems arose because physicians aren’t used to thinking about creatinine clearance when anticoagulating patients for AF, Dr. Hassell said at a conference on internal medicine sponsored by the University of Colorado. Creatinine clearance is simply not an issue for warfarin, whose clearance is unaffected by renal function. In contrast, dabigatran’s elimination is 80% renal. Clearance of the drug is considerably slowed in the elderly, even the healthy elderly. And neither the pharmaceutical company nor the FDA did a good job initially of getting the word out to physicians regarding the short list of drug interactions with dabigatran, she said.
"Many of the cardiologists I work with were surprised to learn dabigatran even has drug interactions," she recalled at the conference.
Strong inducers of dabigatran metabolism include St. John’s wort, rifampin, carbamazepine, and phenytoin. "You think you’re giving a full dose of dabigatran to patients on one of those drugs, but you’re not," the hematologist observed.
On the other hand, patients on a strong inhibitor of dabigatran metabolism, such as verapamil, experience rising blood concentrations of the anticoagulant, setting them up for severe bleeding.
Rivaroxaban (Xarelto), the other novel oral anticoagulant marketed in the United States, also is cleared predominantly by the kidneys. Dr. Hassell said she’s looking forward to the widely expected eventual approval of a third oral agent, apixaban, which has only 25% renal elimination, meaning it’s likely to be better tolerated than dabigatran or rivaroxaban in patients having a glomerular filtration rate (GFR) on the low side.
The new anticoagulants share a number of attractive characteristics that make them "a huge step forward" compared with warfarin, Dr. Hassell said. Their onset of activity is 2-4 hours rather than the days it takes for warfarin to build up in the patient’s system. There are no interactions with leafy green vegetables or any other foods. No monitoring of INR (International Normalized Ratio) is required or even possible; all humans take the same once-daily dose provided they’re not renally impaired or on an interacting drug. The potential drug interactions are relatively few in number.