低危房颤患者不需任何抗凝治疗

科罗拉多州埃斯蒂斯帕克——美国胸内科医师协会(ACCP)的2012年抗血栓治疗指南首次建议不对CHADS2评分为0的患者(即无任何主要危险因素的75岁以下患者)进行任何抗血栓治疗(CHEST 2012;141[Suppl. 2]:7S-47S)。新版指南称，对于卒中风险低的房颤(包括阵发性房颤)患者，不需进行任何治疗。

ACCP专家组的建议主要基于以下计算结果：对CHADS2评分为0的患者预防性使用阿司匹林，每治疗1,000例患者可预防2例非致死性卒中，但同时额外导致3例非致死性主要颅外出血事件。此前的ACCP指南建议对CHADS2评分为0的65岁以下患者使用阿司匹林，对65~75岁以下患者使用阿司匹林或华法林。在CHADS2评分系统中，如果房颤患者合并充血性心力衰竭、高血压、糖尿病或年龄≥75岁，则各计1分，如具有卒中或TIA病史，则计2分。

2012新版指南建议CHADS2评分≥1分的患者接受口服抗凝药物治疗，并建议在新型药物达比加群(Pradaxa)和华法林之间，优先考虑使用前者。对于不适合接受口服抗凝治疗的患者，建议预防性合用阿司匹林和氯吡格雷。

新版指南优先考虑使用达比加群的建议已引起争议，因为2011年12月美国食品药品管理局(FDA)发布的上市后安全性报告显示这一新型抗凝药物可引起严重出血事件，并建议在治疗前进行肾功能检查及基于肌酐清除率调整达比加群剂量。

达比加群80%的剂量通过肾脏清除，并且清除速率在老年患者中明显较慢，甚至在健康老年人中亦是如此。而华法林的清除不受肾功能影响，因此无肌酐清除的问题。此外，不少药物可与达比加群发生相互作用，而药企和FDA并未很好地向临床医生传达这方面的信息。达比加群代谢的强诱导剂包括圣约翰草、利福平、卡马西平和苯妥英。达比加群代谢的强抑制剂包括维拉帕米等。合用维拉帕米的患者可出现达比加群血液浓度升高，从而增加发生严重出血的风险。

在美国上市的另一种新型口服抗凝药——利伐沙班(Xarelto)也主要通过肾脏清除。第三种新型口服抗凝药为阿哌沙班，其肾脏清除率仅为25%，这意味着在肾小球滤过率(GFR)偏低的患者中，阿哌沙班的耐受性可能优于达比加群和利伐沙班。

与华法林相比，新型抗凝药具有一些共同的优点，如起效快(2~4 h，华法林为数天)；不与绿叶蔬菜或任何其他食物发生相互作用；不需监测国际标准化比值(INR)；如果无肾功能损害或未合用其他可发生相互作用的药物，则每日只需服用1次相同的剂量。此外，近期对3项涉及约45,000例患者的关键随机临床试验进行Meta分析发现，与华法林相比，达比加群、利伐沙班和阿哌沙班这些新型抗凝药共计使卒中或全身栓塞风险降低22%、血管死亡率降低13%、全因死亡率降低12%、颅内出血风险降低51%，所有差异均具有显著性。此外，与华法林相比，新型抗凝药使用者的大出血发生率较少，胃肠道出血发生率较高，差异均无显著性(Am. J. Cardiol. 2012;110:453-60)。

Kathryn Hassell博士

科罗拉多大学丹佛分校的内科教授Kathryn Hassell博士表示，在有更多的临床治疗经验发表之前，其不准备常规使用这些新型药物代替华法林。目前，他主要对以下患者使用新型抗凝药：肾功能正常、出血风险低、华法林治疗期间INR不稳定、用药依从性相当好、未合并其他可能发生相互作用的药物。对于以下患者，则使用华法林：GFR低于60 ml/min或INR在较长时间内稳定在治疗范围内；出血风险高；依从性差；使用新型抗凝药后12~24 h内效力丧失。对于具有多发性出血或凝血事件史的患者，如需通过测定INR监测抗凝程度，则华法林是唯一用药选择。Hassell博士声明无经济利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: BRUCE JANCIN, Cardiology News Digital Network

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 haveCongestive 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.

Moreover, key clinical outcomes are modestly, but significantly, better than with warfarin, as demonstrated in a recent meta-analysis of three pivotal randomized clinical trials of dabigatran, rivaroxaban, and apixaban involving nearly 45,000 patients. Compared with warfarin, the new agents collectively showed reductions of 22% in the risk of stroke or systemic embolism, 13% in the risk of vascular mortality, 12% in all-cause mortality, and 51% in intracranial hemorrhage, all of which were significant. In addition, there were nonsignificant trends for less major bleeding and more GI bleeding (Am. J. Cardiol. 2012;110:453-60).

Nonetheless, Dr. Hassell isn’t prepared to routinely substitute the new agents for warfarin. She’s waiting to see reports of more extensive experience with them in everyday clinical practice. For the time being, the patients in her practice who get one of the new anticoagulants instead of warfarin are those with normal renal function, low bleeding risk, unstable INRs on warfarin, and reasonably good medication adherence, and who are not taking any of the interacting drugs.

She sticks with warfarin in patients with a GFR below about 60 mL/minute or a stable INR in therapeutic range a great deal of the time. If they’re at high bleeding risk they get warfarin, which is readily reversible, unlike the novel anticoagulants. If they have problems with adherence, warfarin is the best option because missing a dose of warfarin causes less harm; loss of activity occurs within 12-24 hours with the new agents. And if Dr. Hassell thinks she wants to monitor the degree of anticoagulation by measuring INR, as in a patient with a history of multiple bleeding or clotting events, warfarin is the sole option.

She reported having no financial conflicts.