My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

Although there may always be hesitation in resuming anticoagulation (AC) in patients with non-valvular atrial fibrillation (NVAF) and recent fall(s), the weight of the evidence suggests that most patients are still more likely to benefit from AC than be adversely impacted by intracranial hemorrhage.
An often-quoted systematic review article on the risks and benefits of anti-thrombotic (AC or aspirin) therapy in patients with NVAF at risk estimated that persons taking warfarin must fall 295 times in 1 year for warfarin to not be the optimal therapy for reducing the risk of stroke (1). The authors concluded that “a history of and/or the presence of risk factors for falls should not be considered important factors in the decision whether to offer antithrombotic (especially warfarin) therapy to elderly patients with atrial fibrillation”.
In another study involving older adults with NVAF, although a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage, this risk did not differ among patients treated with warfarin, aspirin or no antithrombotic therapy (2).
Ultimately, the decision to prescribe AC in patients with NVAF at risk for falls should be made based on shared decision making with patients and caregivers. However, in the absence of absolute contraindications for AC in these patients (eg, intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders), perceived or actual risk of falls by itself should not automatically exempt a patient from receiving AC in NVAF (3).

 

Although much of the data on the relative risk of bleeding against prevention of strokes has been derived from studies involving warfarin, it is reassuring that the risk of intracranial bleed has been lower than that of warfarin for several newer non-vitamin K antagonist direct oral anticoagulants (NOACs or DOACs),  including dabigatran, rivaroxaban, edoxaban and apixaban (4). 

 

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References

1. Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patiets with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159:677-685.
2. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118:612-617.
3. Hagerty T, Rich MW. Fall risk and anticoagulation for atrial fibrillation in the elderly: a delicate balance. Clev Clin J 2017;84:35-40.

4. Lopez RD, Guimaraes PO, Kolls BJ, et al. Intracranial hemorrhage in patietns with atrial fibrillation receiving anticoagulation therapy. Blood 2017;129:2980-87. 

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

Although its mechanism is not full elucidated, fixed drug eruption (FDE) is thought to result from the drug-induced cytotoxic activation of CD8+ memory T cells.1 ,2

In this context, the culprit medication behaves as a hapten that adheres to basal keratinocytes which in turn results in the recruitment of T cells and inflammation.  However, as the inflammation resolves, CD8+  effector-memory T cells remain in the area in question,  setting the stage for more rapid immunologic reaction when the drug is reintroduced.

Why a systemic drug triggers a reaction only at specific sites in the body is a fascinating question. Prior herpes simplex virus (HSV) infection (eg, on the lips or genitalia) may explain some cases.1 Interestingly, despite the absence of prior herpetic lesions, most patients with FDE are seropositive for HSV. Previously traumatized body sites (e.g. from burns or insect bites) may also create an immune microenvironment conducive to FDE.

The classic presentation of FDE is reappearance of a rash in the genitals, perianal areas, hands, and feet within 30 min to 8 hours of taking the culprit medication.3 Look specifically for NSAIDs, tetracyclines, sulfonamides, and aspirin on the patient’s drug list. 4

References

  1. Shiohara, T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009; 9:316-21. https://www.ncbi.nlm.nih.gov/pubmed/19474709
  2. Butler, DF. Fixed Drug Eruptions. Medscape. http://emedicine.medscape.com/article/1336702-overview#a4. Accessed March 26, 2018.
  3. Korkij W, Soltani K. Fixed drug eruptions: A brief review. Arch Dermatol 1984;120:520. https://www.ncbi.nlm.nih.gov/pubmed/6231004
  4. Oakley, A. Fixed Drug Eruption. https://www.dermnetnz.org/topics/fixed-drug-eruption Accessed March 26, 2018.

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

 

Patients with atrial fibrillation (AF) who need percutaneous coronary intervention (PCI) after acute coronary syndrome or for stable angina pose a treatment challenge as oral anticoagulants (OACs) and dual antiplatelet therapy (DAPT) are often used concurrently to decrease the risk of systemic thromboembolism and stent thrombosis. However, “triple therapy”, including aspirin, a P2Y12 inhibitor, and an OAC (eg, warfarin or a direct oral anticoagulant-DOAC), also increases the risk of bleeding, necessitating several recent landmark trials to better address the subject.

Two modest-sized RCTs (WOEST and ISAR-TRIPLE) reported that when compared to triple therapy (DAPT plus warfarin), double therapy (single antiplatelet agent plus INR-targeted warfarin) is associated with reduced risk of bleeding complications without an increased risk of thrombotic events. 1,2

Two larger RCTs, PIONEER AF-PCI and RE-DUAL PCI, studied rivaroxaban and dabigatran, respectively, in patients with non-valvular AF undergoing PCI and found a reduction in bleeding events in patients receiving double therapy (single antiplatelet agent plus DOAC) compared to triple therapy (DAPT plus warfarin), without an increased risk of thrombotic complications. 3,4

Collectively, these studies suggest that it may be safe to treat patients with increased risk of bleeding with double therapy (even immediately following PCI) without an increase in thrombotic events. If triple therapy is elected, duration should be minimized, clopidogrel should be preferred over more potent P2Y12 inhibitors, and a PPI should be considered.

 

References:

  1. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381:1107-15. https://www.ncbi.nlm.nih.gov/pubmed/23415013
  2. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65:1619-29. https://www.ncbi.nlm.nih.gov/pubmed/25908066
  3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1611594
  4. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. Published online, Aug, 27, 2017. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708454

 

Contributed by Amulya Nagarur, MD, Mass General Hospital, Boston, MA

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

My patient with atrial fibrillation (AF) with a CHA2DS2-VASc score ≥2 is not a candidate for anticoagulation due to excessive bleeding risk. Does high-dose aspirin provide an effective alternative for stroke prevention in this setting?

 The SPAF (Stroke Prevention in Atrial Fibrillation) trial1 found a 42% reduction in overall risk of stroke with daily aspirin (325 mg). However, critics note that no benefit was observed among patients > 75 y or those with severe stroke.

7 other studies on the topic failed to confirm reduction in the risk of stroke at a range of aspirin doses (25mg bid-1,300mg qd) 2. These studies reported that aspirin is associated with a 19% reduction in stroke incidence (similar to patients with vascular disease), with a 95% CI that crosses zero (-1% to 35%), raising doubts about its actual benefit in AF3. For secondary prevention, aspirin was associated with a 2.5% reduction in the annual risk of stroke. However, these results were influenced by the only trial with a favorable outcome, SPAF-14.

In short, even at higher doses, aspirin may not be the answer for stroke prevention in patients with AF.

 References

  1. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84, 527–39.
  2. January CT, Wann LS, Alpert  JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation  2014;130, e199–e267.
  3. European Heart Rhythm Association et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace  2010; 12, 1360–420.
  4. Sabir IN, Matthews GDK,  Huang, CL-H. Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice. Postgrad Med J 2013; 89, 346–51.

 

Contributed by Jacqueline Boehme, M.D., Medical Resident, Mass General Hospital

My patient with atrial fibrillation (AF) with a CHA2DS2-VASc score ≥2 is not a candidate for anticoagulation due to excessive bleeding risk. Does high-dose aspirin provide an effective alternative for stroke prevention in this setting?

Is aspirin effective in reducing the risk of cancer?

Yes, at least for certain types of cancer! A recent report based on 2 ongoing prospective studies (Nurses’ Health Study and Health Professionals Follow-up Study) assessed the risk of cancer in non-regular and regular users of aspirin at a dose of at least 0.5-1.5 standard tablets (325 mg) per week or a low daily dose of 81 mg.  It involved nearly 136,000 subjects while taking into account many potential confounders, including age and cancer screening1.

Compared to non-regular use, aspirin use for at least 6 years was associated with a 3% lower risk of overall cancer, and 15% lower incidence of gastrointestinal cancers, especially colorectal cancers (19% risk reduction); the incidence of breast, advanced prostate or lung cancer was not affected. The irreversible inhibition of cyclooxygenase-2 (COX-2), the principle enzyme that produces pro-inflammatory prostaglandins such as prostaglandin E2 (PGE2) found in human colorectal adenomas and carcinomas2, may explain aspirin’s protective effect1.

 

References

  1. Cao Y, Nishihara R, Wu K, et al. The population impact of long-term use of aspirin and risk of cancer. JAMA Oncol 2016;2:762-769
  2. Greenhough A, Smartt HJM, Moore, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009;30:377-386.

 

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny

Is aspirin effective in reducing the risk of cancer?