Aspirin: Good Drug, Bad Drug
Cover Story | Once a mainstay in the armamentarium of cardiologists, aspirin has morphed into a tricky drug to recommend. The generous response to give it to anyone with cardiovascular risk — acute or not — has proved, shall we say, problematic. Today, clinicians may be as likely to over-use aspirin as they are to under-use it.
Aspirin has been getting a bad rap these days … except when it’s heaped with praise. These use it/don’t use it messages seem confusing for sure, but the evidence being accumulated should assist clinical decision making and inform guidelines.
Take Two and Call Me… Wait, Don’t Take Any…
Certainly, we know about the several settings where the use of aspirin remains quite clear cut. We’ve cleaned up the primary prevention issue in terms of guidance — well, almost, since the Food and Drug Administration (FDA), American Heart Association (AHA), and U.S. Preventive Services Task Force all say something slightly different. In brief, as the FDA stated in May 2014 after reviewing the available data, the evidence does not support “…the general use of aspirin for primary prevention of a heart attack or stroke.” However, as reported recently, self-prescribing still occurs regularly, complicating the situation.1
It’s hardly news that someone in the throes of a heart attack might want to chew a baby aspirin or two. Well, actually, in Canada, that is news: Just a few weeks ago, Health Canada gave Bayer Inc. the okay to promote their drug as an emergency treatment for myocardial infarction (MI).2 It’s not that Canadians haven’t been using aspirin in acute MI for more than 15 years, but now the packaging can include instruction to consumers to chew two 81 mg aspirin tablets if they suspect they’re having an MI, providing Canucks a jumpstart on platelet inhibition before the paramedics arrive. File this under cutting edge science.
Given aspirin’s substantial ability to reduce periprocedural MI caused by thrombotic occlusion, one would also assume that periprocedural aspirin in patients undergoing percutaneous coronary intervention (PCI) also rates as a no brainer. Yes, but surprisingly it’s sometimes not being used prior to PCI when it should be. This is illustrated in a report published at the end of 2013 in the Journal of the American College of Cardiology showing a significant proportion of patients undergoing PCI are not receiving aspirin, and their subsequent rates of death and stroke were significantly higher than those who did receive periprocedural aspirin FIGURE.3
“We thought this would be an infrequent problem, but I was honestly shocked that just over 7% of patients were getting PCI without getting aspirin prior to the procedure,” said that study’s senior author, Hitinder Gurm, MD, in an interview with CardioSource WorldNews: Interventions.
“In almost all patients, we should be able to get aspirin on board before we take them to the lab,” he added. Dr. Gurm, who is from the University of Michigan Medical Center in Ann Arbor, thinks aspirin needs to be part of the pre-procedure “time-out” checklist.
The Two Sides of Aspirin and Warfarin in Stable CAD
The use of aspirin in secondary prevention in patients with established vascular disease is strongly supported by current guidelines due to its ability to produce a 25% reduction in the risk of cardiovascular death, MI, or stroke.4
Martial Hamon, MD, and colleagues at the Centre Hospitalier Universitaire de Caen in France recently looked at the little-studied prognostic impact of major bleeding in outpatients with stable coronary artery disease (CAD).5 While the deleterious effects of major bleeding in the setting of PCI has received tons of attention of late, few have studied the relatively rare phenomenon of major bleeding in an otherwise stable CAD patient.
In the CORONOR (Suivi d’une cohorte de patients COROnariens stables en region NORd-Pas-de-Calais) registry, Hamon and colleagues prospectively enrolled 4,184 CAD patients who were at least 1 year past any MI or coronary revascularization. The good news: during 2 years of follow-up, patients experienced only 51 major bleeding events, yielding a rate of 0.6% per year. Most were gastrointestinal bleeds (54.9%), with 19.6% being intracranial. Most of the bleeding events were classified as Bleeding Academic Research Consortium (BARC) type 3a bleeds, with 12 fatal bleeds (BARC type 5).
The usual list of suspects appeared as predictors of major bleeding: older age, diabetes, renal failure, and warfarin use.
However, in the case of warfarin (the strongest predictor with a hazard ratio (HR) of 4.69; p <0.0001), the increased risk of bleeding was only evident in patients who received a combination of warfarin and aspirin (VKA + APT in FIGURE 2). There was no significant increase in bleeding in patients on warfarin alone.
Here’s where things start getting messy. Although patients in CORONOR were, by protocol, at least 1 year past a recent coronary event, 21% were taking dual antiplatelet treatment with aspirin and clopidogrel. About 11% of the cohort was taking warfarin, mainly for atrial fibrillation (AF). Among the patients on warfarin, more than two-thirds were also taking aspirin. No patients were taking prasugrel, ticagrelor, or the novel oral anticoagulants (NOACs) at inclusion.
In patients taking both warfarin and aspirin, the hazard ratio for the cumulative risk of major bleeding soared to 7.30 (p < 0.05), as compared to just 1.69 (p = NS) among patients taking only warfarin and 1.58 (p = NS) for those taking clopidogrel and aspirin.
Moreover, this increased risk of bleeding came with no preventive benefit: researchers found no difference in the risk of the combined endpoint of cardiovascular death, MI, or nonhemorrhagic stroke in patients treated with warfarin and aspirin versus warfarin alone.
“Long-term oral anticoagulation (OAC) was the strongest risk factor for bleeding in this stable setting,” wrote Hamon et al. “In particular, we found that the combination of OAC with an antiplatelet agent was associated with a major increase in the number of bleeding episodes.”
Lest the consequences of major bleeding in stable CAD patients be underestimated, after multivariable adjustment, major bleeding was associated with an almost 3-fold greater risk of death (HR = 2.89; p < 0.0001).
The authors noted that although it remains common practice to treat AF patients with stable CAD with warfarin and aspirin, the 2010 European Society of Cardiology guidelines broadly suggest warfarin monotherapy, unless the patient suffers a subsequent cardiovascular event that might warrant concomitant aspirin.
“This [recommendation was made] on the basis of evidence that the addition of [aspirin] is associated with a substantial increase in bleeding, with no clear evidence for a decrease in ischemic events,” said Dr. Hamon. And now, adding in the new data from Hamon et al. on patients with stable CAD and wide use of coronary revascularization, including drug-eluting stent (DES) implantation, the picture grows ever clearer that aspirin should be avoided in CAD patients who warrant warfarin treatment for stroke prophylaxis.
“Recent guideline statements support the conclusions of the CORONOR registry: the coexistence of atrial fibrillation with CAD is neither an excuse for stopping OAC nor an indication for continuing antiplatelet therapy,” wrote Harold Dauerman, MD, from the University of Vermont College of Medicine in Burlington, in an editorial on CORONOR.6
1 + 1 = Too Much for AF Patients on OAC
The Hamon et al. findings in stable CAD patients come on the heels of several other recent studies that addressed the risk of aspirin combined with OAC, which taken together “seem to provide a clear message: stop worrying about platelet inhibition in patients with CAD who are taking oral anticoagulant agents,” said Dr. Dauerman.
One of those earlier studies was ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), a broadly inclusive U.S. multicenter observational registry that tracked 10,126 patients with AF, of whom 7,347 were taking OAC therapy.7 Of those, 35% were taking concomitant aspirin: 81 mg in 85% of patients and higher doses in the remainder.
Of some concern, atherosclerotic vascular disease was absent in 39% of ORBIT-AF patients prescribed OAC and aspirin, yet 25% had elevated bleeding risk and 17% were in the highest-risk category (ATRIA ≥5).
Both major bleeding and hospitalizations for bleeding were almost 50% higher in those on OAC and aspirin compared to OAC alone, with no apparent ischemic benefit. Low in both groups, crude MI rates did not differ with aspirin use or lack thereof.
“The use of OAC+ASA appears to persist despite increasing concerns about the true bleeding risk of ASA and its lack of incremental benefit in preventing stroke in patients with AF already on OAC,” wrote the ORBIT-AF investigators.
Despite the new message coming from several guideline committees and recent study data, the data remain somewhat weak, Dr. Dauerman noted in his editorial on CORONOR. He said he will likely continue to give aspirin 81 mg daily to “many” of his stable CAD with AF patients, particularly those implanted with first-generation DES.
“In selected CAD patients in stable condition with atrial fibrillation identified by CORONOR as at high risk for bleeding, these registry observations will be heeded: stop the aspirin, continue the warfarin, and use the art of clinical medicine to guide decisions where clear information remains wanting,” Dr. Dauerman concluded.
Triple Therapy: Triple Threat?
Every patient who comes in with an ACS and undergoes PCI should be discharged on lifetime aspirin, right? Hard and fast rules need to slow down a bit….
What about patients with AF who require PCI? (FIGURE 3) This is fast becoming an unavoidable question for clinicians, since about 1% to 2% of the population has AF and 80% of them have an indication for OAC.8 Also, up to 30% of patients with AF have coexistent vascular disease, with about 20% of those individuals requiring PCI over time. Before 2014, the guidelines recommended triple therapy with a vitamin K antagonist, aspirin, and clopidogrel. However, triple therapy is associated with an annual bleeding risk of up to 45% and increased mortality.9
While the 2011 AF management guidelines suggested that low-dose aspirin and/or clopidogrel could be given concurrently with anticoagulation,10 the newest iteration, released at the 2014 American College of Cardiology Scientific Session, has clearly downgraded aspirin use.11 The new 2014 AHA/ACC/HRS guidelines for the management of AF state: “Following coronary revascularization (surgical or percutaneous) in patients with AF and a CHA2DS2-VASc score of 2 or greater, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with OAC, but without aspirin.”
“New evidence, including a randomized controlled trial and a real-life nationwide registry of more than 12,000 patients, showed the great potential of the combination of vitamin K antagonist (VKA) and clopidogrel without aspirin to improve clinical outcomes in comparison with triple therapy,” wrote Willem J. M. Dewilde, MD, in a recent state-of-the-art review on triple therapy for AF patients undergoing PCI.9 Dr. Dewilde is from Amphia Hospital, Breda, the Netherlands.
Dr. Dewilde and colleagues tentatively suggest that a better option than dual therapy with warfarin and clopidogrel may exist for patients with AF undergoing PCI: warfarin and one of the new P2Y12 inhibitors, either ticagrelor or prasugrel, both of which inhibit platelets more potently and show less interindividual variability than clopidogrel.
They cautioned, however, that “we do not have any data yet on the combination of VKA plus prasugrel, VKA plus ticagrelor, or triple therapy (VKA plus ticagrelor plus aspirin) in AF patients undergoing PCI, but one could reasonably fear that combining these more potent platelet inhibitors with VKA could lead to more bleeding events.”
It so happens that the new 2014 AHA/ACC non-ST-elevation-acute coronary syndrome (NSTE-ACS) guidelines, published online September 23, 2014, for the first time recommend one antiplatelet inhibitor over another.12 (The guidelines are currently scheduled to be published in the December 23, 2014, issue of JACC.) Specifically, for early initial antiplatelet therapy in patients with NSTE-ACS, ticagrelor is given a class IIa recommendation over clopidogrel. Similarly, prior to PCI, both ticagrelor and prasugrel are given class IIa recommendations over clopidogrel, although prasugrel carries a caveat that it should not be used in patients who are at high risk for bleeding consistent with the findings of TRITON-TIMI 38 trial.
For patients taking warfarin, the NSTE-ACS guidelines suggest that triple therapy with warfarin, clopidogrel, and aspirin should be of limited duration to reduce bleeding risk, and that a proton pump inhibitor should be used for those with a history of gastrointestinal (GI) bleeding and considered for those without such a history.
The guidelines also recommend limiting the duration of triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a P2Y12 receptor inhibitor in patients with NSTE-ACS to reduce bleeding risk, adding that there is “sparse information” on the use of the newer P2Y12 inhibitors in patients receiving triple therapy.
Of note, ticagrelor carries a Black Box warning stating: “Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial loading dose, use with aspirin 75-100 mg/day.” For both prasugrel and clopidogrel, the package insert notes maintenance daily aspirin can be from 100 to 350 mg.
The NSTE-ACS guideline authors do specify that the recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg/day, and, elsewhere, state that after PCI, “it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses.”
New and Improved: Do NOACs and Aspirin Play Well Together?
At present, there are no published trials to have directly evaluated the use of NOACs in patients with acute coronary syndrome (ACS) and AF on dual antiplatelet therapy. Post hoc and planned analyses of the randomized controlled trials of NOACs in nonvalvular AF have indicated that bleeding risk is elevated in patients taking concomitant aspirin, consistent with the known risks of aspirin.13,14
However, as this issue of CSWN: Interventions was going to press, investigators reported in JAMA Internal Medicine a higher than expected risk of bleeding in patients recently initiated on dabigatran.15 Hernandez et al. used pharmacy and medical claims from a 5% random sample of Medicare beneficiaries who had initiated therapy with dabigatran or warfarin within 60 days of AF diagnosis. Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for GI bleeding. Dabigatran was consistently associated with an increased risk of major bleeding and GI hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. One piece of good news: risk of intracranial hemorrhage was lower with dabigatran.
In an accompanying commentary, journal editor-in-chief Rita Redberg, MD, wrote that these findings “give us cause for concern because it appears that the bleeding risk for dabigatran is higher than for warfarin and significantly greater than originally appeared at the time of the FDA approval.”16
Christopher Cannon, MD, Executive Director of Cardiometabolic Trials at Harvard Clinical Research Institute had a different take on the results. “On dabigatran, the news was higher bleeding – from one of 2 studies. The data were actually very reassuring (given that) the FDA safety review came to the opposite conclusion: dabigatran’s safety profile was reaffirmed.”
Having said that, he added, that since the results of the 2013 WOEST study,17 “I do think of clopidogrel and OAC much more without aspirin. We have all been searching for approaches to reduce the bleeding of triple therapy and WOEST gave the first glimmer of hope.” That trial showed clopiogrel without aspirin was associated with a significant reduction in bleeding complications but no increase in the rate of thrombotic events in patients on OAC who have undergone PCI.
One slight additional complicating factor: the increasing use of the new P2Y12 inhibitors “would be expected to expose the patients to an even higher risk of major bleeding,” compared to clopidogrel, according to a recent European “joint consensus statement” on the management of antithrombotic therapy in AF patients presenting with ACS and/or undergoing percutaneous coronary or valve interventions.8
As for the NOACs, they are considered a preferred alternative to warfarin for AF stroke prophylaxis based on recent clinical trials showing better similar or better ischemic outcomes and a decreased risk of bleeding. However, the consensus appears to be that more data are needed to determine how they’ll perform in patients with both AF and CAD.
The 2014 U.S. AF guidelines summarized the situation succinctly: “The novel oral anticoagulants have not been evaluated in the context of AF and ACS and thus no recommendation for their use can be made.”
Going one step further, they make a class I recommendation for anticoagulation with warfarin (unless contraindicated) for patients with ACS and AF.
The ongoing PIONEER AF-PCI trial will evaluate the safety of two different rivaroxaban treatment strategies and one VKA treatment strategy utilizing various combinations of dual antiplatelet therapy or low-dose aspirin or clopidogrel (or prasugrel or ticagrelor) in 2,100 patients with AF who undergo PCI with stent placement.
The much larger RE-DUAL PCI trial will evaluate dabigatran (110 mg or 150 mg bid) plus clopidogrel or ticagrelor versus the triple antithrombotic therapy regimen with warfarin plus clopidogrel or ticagrelor plus aspirin. The trial will enroll 8,500 AF patients who have undergone PCI with stent implantation at 700 sites in more than 40 countries worldwide.
Dr. Cannon, lead investigator of the study, told CSWN: Interventions, said this large scale multinational trial should help better determine ways to safely reduce bleeding risk. Besides evaluating dual therapy approach with two dabigatran doses, they will also be incorporating efforts to reduce bleeding risk into the control arm by shortening the duration of dual antiplatelet therapy to 1 month post bare-metal stenting (relatively standard now) and pushing duration of therapy down to just 3 months post drug-eluting stent placement. Also they will be dropping one of the two antiplatelets (dropping aspirin, not the P2Y12 inhibitor). Dr. Cannon said, “These strategies came after much discussion with the Steering Committee – and in full recognition that there are about 40 different possible combinations of agents, doses, and durations that might be tried. We have three promising approaches that we aim to test and hope that it can be useful information on how to manage this very tricky clinical scenario.”
Figures 1, 2 and 3 (click on image to expand)
- Kolber M, Sharif N, Marceau R, Szafran O. Can Fam Physician .2013;59:55-61.
- ASPIRIN® 81mg for Emergency Use during Heart Attacks: Approved in Canada (press release). http://www.newswire.ca/en/story/1431994/aspirin-81mg-for-emergency-use-during-heart-attacks-approved-in-canada. Accessed on October 28, 2014.
- Kenaan M, Seth M, Aronow HD, et al. J Am Coll Cardiol. 2013;62:2083-9.
- Weitz JI. 2015. Philadelphia: Elsevier, pp. 1819.
- Hamon M, Lemesle G, Tricot O, et al. J Am Coll Cardiol. 2014;64:1430-6.
- Dauerman HL. J Am Coll Cardiol. 2014;64:1437-40.
- Steinberg BA, Kim S, Piccini JP, et al. J Am Coll Cardiol. 2013;128:721-8.
- Lip GY, Windecker S, Huber K, et al. Eur Heart J. 2014 Aug 25. [Epub ahead of print]
- Dewilde WJ, Janssen PE, Verheugt FW, et al. J Am Coll Cardiol. 2014;64:1270-80.
- Fuster V, Ryden LE, Cannom DS, et al. J Am Coll Cardiol. 2011;57:101-98.
- January CT, Wann LS, Alpert JS, et al J Am Coll Cardiol. 2014 March 28. [Epub ahead of print]
- Amsterdam EA, Wenger NK, Brindis RG, et al. J Am Coll Cardiol. 2014 Sep 18. [Epub ahead of print]
- Alexander JH, Lopes RD, Thomas L, et al. Eur Heart J. 2014;35:224-32.
- Dans Al. Connolly SJ, Wallentin L, et al. Circulation. 2013;127:634-40.
- Hernandez I, Baik SH, Piñera A, Zhang Y. JAMA Intern Med. 2014 Nov 3. [Epub ahead of print]
- Redberg RF. JAMA Intern Med. 2014 Nov 3. [Epub ahead of print]
- Dewilde WJ, Oirbans T, Verheugt FW, et al. Lancet. 2013;381:1107-15.
Keywords: CardioSource WorldNews Interventions
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