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PINNACLE-AF Registry Suggests Slow Uptake of New Anticoagulants


August 16, 2012 (Washington, DC) — Preliminary data from the PINNACLE registry focusing on patients with atrial fibrillation (AF) suggest that just under half of patients with AF are treated with anticoagulants [1]. Interestingly, of patients in the registry who received oral anticoagulation, 87.4% were treated with warfarin in 2011 while just 12.6% were prescribed one of the two newly available oral anticoagulants.
"We were a little bit surprised," said Dr William Oetgen (Georgetown University, Washington, DC) in reference to the relatively high number of patients who remained on warfarin. "The efficacy and the safety of the novel oral anticoagulants, the two of them that are on the market, are better than Coumadin. The ease of administration is much better than Coumadin. . . . On balance, the drugs seem to be a therapeutic advancement, but the uptake has been slower than we thought it would be."
The PINNACLE-AF registry is part of the American College of Cardiology (ACC) National Cardiovascular Data Registry (NCDR) and is designed to determine how the next generation of anticoagulants is being used in clinical practice. Like PINNACLE, which is the largest cardiovascular outpatient database in the US, the PINNACLE-AF registry is focused on improving quality of care and clinical outcomes in patients with AF. As reported previously by heartwire , treatment of AF patients has altered dramatically in recent years with the emergence and approval of the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) and the oral factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson).
To date, 121 000 unique AF patients are included in the registry. Of these, 50% were treated with anticoagulants in 2011. To heartwire , Oetgen, the senior vice president of science and quality at the ACC, said this number is in line with a previous analysis of AF patients treated in the PINNACLE registry. In that report, 55.1% of patients were treated with anticoagulation. In addition, the 50% anticoagulation rate is in line with other studies that assessed performance measures in patients with cardiovascular disease. For example, during the 1990s, the initial level of treating MI patients with beta blockers was approximately 45%.
"We're just starting to measure [anticoagulation rates], and there has not been time for dissemination of knowledge or for raising awareness among physicians and patients," said Oetgen. Regarding the 12.6% uptake of new oral anticoagulants, he added that physicians can be slow to change treatment patterns and are skeptical of new drugs, particularly in a therapeutic area that is fraught with danger such as AF.
"You can overdo anticoagulation and the patient gets into trouble," Oetgen told heartwire . "You can underdo it and the patient can get into trouble, too. There is a natural hesitancy. The other thing is that there have been a rash of press reports about untoward effects, or bad results, such as bleeds, probably in the range of what would be expected, but they've gotten a huge amount of press. So there's a little bit of a fear factor there."
Bristol-Myers Squibb and Pfizer provide financial support for the PINNACLE-AF registry.

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Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . 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Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. 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