When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Optimal timing of resumption of therapeutic anticoagulation (AC) in patients with hemorrhagic stroke or intracranial hemorrhage (ICH) is unclear because of lack of randomized controlled trials, but existing evidence suggests that 4-8 weeks may be reasonable in our patient (1). 

 
The American Heart Association/American Stroke Association 2015 guidelines recommend avoiding AC for at least 4 weeks in patients without mechanical heart valves (class IIB-very weak), while 1 study reported that prediction models of ICH in atrial fibrillation at high risk of thromboembolic event suggest that resumption of AC at 7-8 weeks may be the “sweet spot” when weighing safety against efficacy of AC in this patient population (1-3).

 
Two meta-analyses (1 involving patients with non-lobar ICH, another ICH in patients with nonvalvular atrial fibrillation) found that resumption of AC ranging from 10 to 44 days following ICH may be associated with decrease rates of thromboembolic events without significant change in the rate of repeat ICH (4,5).

 
There are many limitations to the published literature including their retrospective nature, unreported location and size of ICH in many studies, and use of warfarin (not DOACs) as an AC agent (1).

 
Clearly we need randomized controlled trials to answer this important question. In the meantime, a heavy dose of clinical judgement on a case-by-case basis seems appropriate.

Bonus Pearl: Did you know that lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) usually due to hypertensive vessel disease (1)? 

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References
1. Gibson D et al. When is it safe to resume anticoagulation in my patient with hemorrhagic stroke. The Hospitalist, February 5, 2019. https://www.the-hospitalist.org/hospitalist/article/193924/neurology/when-it-safe-resume-anticoagulation-my-patient-hemorrhagic/page/0/1
2. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60. https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000069
3. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20 https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.116.014643
4. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600. https://www.ahajournals.org/doi/full/10.1161/strokeaha.116.016327
5. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730065/

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Is there a connection between my patient’s blood type and risk of thromboembolic events?

There seems to be, given the weight of the evidence to date suggesting that non-blood group O may be associated with non-valvular atrial fibrillation (NVAF)-related peripheral cardioembolic complications, myocardial infarction (MI) and ischemic stroke. 1-4

A 2015 retrospective Mayo Clinic study involving patients with NVAF adjusted for CHADS2 score found significantly lower rate of peripheral embolization in those with blood group O compared to those with other blood groups combined (3% vs 2%, O.R. 0.66, 95% CI, 0.5-0.8); rates of cerebral thromboembolic events were not significantly different between the 2 groups, however. 1

A 2008 systematic review and meta-analysis of studies spanning over 45 years reported a significant association between non-O blood group and MI, peripheral vascular disease, cerebral ischemia of arterial origin, and venous thromboembolism.2 Interestingly, the association was not significant for angina pectoris or for MI when only prospective studies were included.  Some studies have reported that the association between VWF and the risk of cardiovascular mortality may be independent of blood group. 5,6

Although the apparent lower risk of thromboembolic conditions in O blood group patients may be due to lower levels of von Willebrand factor (VWF) and factor VIII in this population 1,4, other pathways likely  play a role.7  

As for why the rate of peripheral (but not cerebral) thromboembolic events in NVAP is affected by blood group, it is suggested that, because of their size, larger clots (facilitated by lower VWF levels) may bypass the carotid and vertebral orifices in favor of their continuation downstream to the “peripheral bed”.1

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References

  1. Blustin JM, McBane RD, Mazur M, et al. The association between thromboembolic complications and blood group in patients with atrial fibrillation. Mayo Clin Proc 2015;90;216-23. https://www.sciencedirect.com/science/article/abs/pii/S002561961401043X
  2. Wu O, Bayoumi N, Vickers MA, et al. ABO (H) groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemostasis 2008;6:62-9. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2007.02818.x
  3. Medalie JH, Levene C, Papier C, et al. Blood groups, myocardial infarction, and angina pectoris among 10,000 adult males. N Engl J Med 1971;285:1348-53. https://www.nejm.org/doi/pdf/10.1056/NEJM197112092852404
  4. Franchini M, Capra F, Targher G, et al. Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications. Thrombosis Journal 2007, 5:14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042969/
  5. Meade TW, Cooper JA, Stirling Y, et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994;88:601-7. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2141.1994.tb05079.x
  6. Jager A, van Hinsbergh VW, Kostense PJ, et al. von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscl Thromb Vasc Biol 1999;19:3071-78. https://www.researchgate.net/publication/12709043_von_Willebrand_Factor_C-Reactive_Protein_and_5-Year_Mortality_in_Diabetic_and_Nondiabetic_Subjects_The_Hoorn_Study
  7. Sode BF, Allin KH, Dahl M, et al. Risk of venous thromboembolism and myocardial infarction associated with factor V Leiden and prothrombin mutations and blood type. CMAJ 2013.DOI:10.1503/cmaj.121636. https://www.ncbi.nlm.nih.gov/pubmed/23382263
Is there a connection between my patient’s blood type and risk of thromboembolic events?

Should my patient with non-valvular atrial fibrillation on hemodialysis be anticoagulated?

Whether patients with end-stage kidney disease (ESKD) and non-valvular atrial fibrillation (AF) benefit from anticoagulation is a matter of controversy. 1,3 Although there may be some suggestion of benefit of warfarin for stroke prevention in this patient population, 2 there is also a higher concern for bleeding. 4-6 An increased risk of stroke among patients with ESKD and AF on warfarin has also been reported. 7

A 2018 Kidney Disease:Improving Global Outcomes (KDIGO) Controversies Conference concluded that there is “insufficient high-quality evidence” to recommend anticoagulation for prevention of stroke in patients with ESKD and atrial fibrillation. 8

However, the 2014 American College of Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm (HRS) guideline states that it is reasonable to consider warfarin therapy in patients with ESKD and non-valvular AF with CHA2DS2 -VASc score of 2 or greater (Class IIa recommendation, level of evidence B).8 Of interest, the FDA recently approved the use of a direct oral anticoagulant (DOAC), apixaban, in ESKD potentially providing an alternative to the use of warfarin when anticoagulation is considered.10

Perhaps the decision to anticoagulate patients with ESKD for atrial fibrillation is best made on a case-by-case basis taking into account a variety of factors, including the risk of thromboembolic event, the risk of bleeding complications as well as patient preference.

References

1. Genovesi S, Vincenti A, Rossi E, et al. Atrial fibrillation and morbidity and mortality in a cohort of long-term hemodialysis patients. Am J Kidney Dis 2008;51:255-62. https://www.ncbi.nlm.nih.gov/pubmed/18215703

2. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-35. https://www.ncbi.nlm.nih.gov/pubmed/22894575

3. Shah M, Avgil TM, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation2014;129:1196-203. https://www.ncbi.nlm.nih.gov/pubmed/24452752

4. Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding rates. Am J Kidney Dis 2007;50:433-40. https://www.ncbi.nlm.nih.gov/pubmed/17720522

5. Holden RM, Harman GJ, Wang M, Holland D, Day AG. Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:105-10. https://www.ncbi.nlm.nih.gov/pubmed/18003768

6. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010;77:1098-106. https://www.ncbi.nlm.nih.gov/pubmed/20054291

7. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol2009;20:2223-33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754104/

8. Turakhia MP, Blankestijn PJ, Carrero J, et al. Chronic kidney disease and arrythias: conclusions from a Kidney Disease:Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J, ehy060. Published 07 March 2018. https://www.ncbi.nlm.nih.gov/pubmed/29522134

9. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2014;130:2071-104. http://circ.ahajournals.org/content/130/23/2071 

10. Moll S. Use of direct oral anticoagulants in patients on hemodialysis. Diffusion, October 11, 2017. http://www.hematology.org/Thehematologist/Diffusion/7794.aspx 

Contributed by Brad Lander, MD, Mass General Hospital, Boston, MA.

Should my patient with non-valvular atrial fibrillation on hemodialysis be anticoagulated?

My patient is asking about the benefits of smoking cessation. How soon should she realize the health benefits of quitting her habit?

She should realize the health benefits of smoking cessation (SC) almost immediately! As the effect of nicotine wears off, just 15-20 minutes after her last cigarette, her heart rate and blood pressure should begin to fall.1,2Other health benefits, some within a year others longer, soon follow. 3,4 Between 2-12 weeks after SC, your patient may notice an improvement in her breathing and pulmonary function tests.

Between 1-9 months, the cilia in the lungs should begin to regenerate and regain normal function, allowing her to adequately clear mucus and bacteria with a decrease in cough and shortness of breath.

At 1 year, the risk of cardiovascular disease (eg, myocardial infarction, stroke) falls by one-half.

At 5 years, the risk of mouth, throat, esophagus, and bladder cancer also drops by one-half.

It takes 10 years for the risk of lung cancer to drop by one-half, and 15 years for it to approach that of non-smokers asymptotically. 4

 

Fun fact: Did you know that in hypertensive patients who smoke, the blood pressure lowering effect of beta-blockers may be partly abolished by tobacco smoking,  whereas alpha-blockers may maintain their antihypertensive effects? 5

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References

  1. Omvik P. How smoking affects blood pressure. Blood Press. 1996;5:71–77. https://www.ncbi.nlm.nih.gov/pubmed/9162447
  2. Mahmud A, Feely J. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension. 2003;41(1):183-187. https://www.ncbi.nlm.nih.gov/pubmed/12511550
  3. US Surgeon General’s Report, 1990, pp. 193, 194, 196, 285, 323
  4. US Surgeon General’s Report, 2010 and World Health Organization. Tobacco Control: Reversal of Risk After Quitting Smoking. IARC Handbooks of Cancer Prevention, Vol. 11. 2007, p. 341.
  5. Trap-Jensen. Effects of smoking on the heart and peripheral circulation. Am Heart J 1988;115:263-7.   https://www.ncbi.nlm.nih.gov/pubmed/3276115

Contributed by Felicia Hsu, Medical Student, Harvard Medical School

My patient is asking about the benefits of smoking cessation. How soon should she realize the health benefits of quitting her habit?

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

The weight of the evidence suggests that methotrexate reduces the overall risk of cardiovascular events (CVEs)—including myocardial infarction, congestive heart failure, stroke, and or major adverse cardiac events—in RA patients (RR 0.72, 95% CI 0.57-0.91)1.

Aside from its effect on controlling systemic inflammation, methotrexate has also been shown to increase HDL and reduce total cholesterol/HDL ratio in patients with RA compared with treated non-RA controls2. In vitro, methotrexate appears to activate mechanisms involved in reverse transport of cholesterol out of the cell to the circulation for eventual excretion3. Not surprisingly then, methotrexate has also been reported to decrease atherosclerotic plaque burden measured by carotid artery intima-media thickness2.

We tend to think of RA as a disease that primarily causes arthritis but its effects may extend far beyond the joints. Patients with RA have an increased risk of cardiovascular deaths compared to the general population4, likely due to a variety of factors, including accelerated atherosclerosis secondary to chronic inflammation. At baseline, RA patients also have an unfavorable lipid profile with decreased HDL and higher total cholesterol/HDL ratio.

Fun Final Fact: Did you know that methotrexate is on the WHO Model List of Essential Medicines (April 2015) not only as a cancer drug but for treatment of RA as well5?

References:

  1. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480-9. https://www.ncbi.nlm.nih.gov/pubmed/25561362
  2. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008;38:13-9. https://www.ncbi.nlm.nih.gov/pubmed/18191989
  3. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008;58:3675-83. https://www.ncbi.nlm.nih.gov/pubmed/19035488
  4. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7. https://www.ncbi.nlm.nih.gov/pubmed/19035419
  5. WHO Model List of Essential Medicines (April 2015). http://www.who.int/medicines/publications/essentialmedicines/en/

 

Contributed by Brian Li, Medical Student, Harvard Medical School

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

Should I use a hemoglobin level of 7 or 8 g/dL as a threshold for blood transfusion in my hospitalized patient?

Unlike its previous 2012 guidelines that recommended overlapping hemoglobin level triggers of 7 g/dL to 8 g/dL for most inpatients, the 2016 guidelines from AABB (formerly known as the American Association of Blood Banks) assigns 2 distinct tiers of hemoglobin transfusion triggers: 7 g/DL for hemodynamically stable adults, including those in intensive care units, and 8 g/dL for patients undergoing cardiac or orthopedic surgery or with preexisting cardiovascular disease1 , often defined as history of coronary artery disease, angina, myocardial infarction, stroke, congestive heart failure, or peripheral vascular disease2,3.  

These recommendations are based on an analysis of over 30 randomized trials, taking into account the potential risks of withholding transfusions, including 30-day mortality, and myocardial infarction. The new 2-tier recommendation specifically excludes those with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia.

The guidelines also emphasize that good clinical practice dictates considering not only the hemoglobin level but the overall clinical context when considering blood transfusion in patients. These factors include alternative therapies to transfusion, rate of decline in hemoglobin level, intravascular volume status, dyspnea, exercise tolerance, light-headedness, chest pain considered of cardiac origin, hypotension, tachycardia unresponsive to fluid challenge, and patient preferences.

References

  1. Carson JL, Guyatt G, Heddle NW. Clinical practice guidelines from the AABB red blood cell transfusion thresholds and storage. JAMA. Doi:10.1001/jama.2016.9185. Published online October 12, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27732721
  2. Carson JL, Duff A, Poses RM, et al. Effect of anemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055-60. https://www.ncbi.nlm.nih.gov/pubmed/8874456
  3. Carson JL, Siever F, Cook DR, et al. Liberal versus restrictive blood transfusion strategy: 3-year survial and cause of death results from the FOCUS randomized controlled trial. Lancet 2015;385:1183-1189. https://www.ncbi.nlm.nih.gov/pubmed/25499165
Should I use a hemoglobin level of 7 or 8 g/dL as a threshold for blood transfusion in my hospitalized patient?

Does electroconvulsive therapy (ECT) pose a risk of embolic stroke in patients with atrial fibrillation (AF)?

Acute embolic stroke in the setting of AF without anticoagulation after ECT has been reported in a single case report in the absence of conversion to normal sinus rhythm (1). Several cases of episodic or persistent conversion to normal sinus rhythm (NSR) in patients with AF undergoing ECT have also been reported (in the absence of embolic stroke), leading some to recommend anticoagulation therapy in such patients (2), though no firm data exist.

The mechanism by which ECT promotes cardioversion from AF to NSR is unclear as direct electrical influence of ECT on the heart is thought to be negligible (1). Arrhythmias such as atrial flutter and AF have also been reported after ECT (1). Curiously, ECT is associated with increased 5- hydroxytryptamine (5- HT2)-receptor densities of platelets in patients with depression which may enhance platelet reactivity and increase the risk of embolic stroke (3) even in the absence of cardioversion.

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References

  1. Suzuki H, Takano T, Tominaga M, et al. Acute embolic stroke in a patient with atrial fibrillation after electroconvulsive therapy. J Cardiol Cases 2010; e12-e14. https://www.sciencedirect.com/science/article/pii/S1878540910000113
  2. Petrides G, Fink M. Atrial fibrillation, anticoagulation, electroconvulsive therapy. Convulsive Therapy 1996;12:91-98. https://journals.lww.com/ectjournal/Abstract/1996/06000/Atrial_Fibrillation,_Anticoagulation,_and.4.aspx
  3. Stain-Malmgren R, Tham A, Ǻberg-Wistedt A. Increased platelet 5-HT2 receptor binding after electroconvulsive therapy in depression. J ECT 1998;14:15-24. https://europepmc.org/abstract/med/9661089
Does electroconvulsive therapy (ECT) pose a risk of embolic stroke in patients with atrial fibrillation (AF)?

Which motor test may be the most useful maneuver when examining a patient suspected of having a stroke?

When limited by the number of motor tests that can be performed on a patient suspected of having a stroke, the pronator drift may be your best bet! This test may be positive in as many as 94% of patients within a week of having a stroke (1).  An advantage of this maneuver is that it can point to subtle lesions in the corticospinal tract (CST) often missed by formal strength testing.

To perform the test, ask the patient to hold his or her arms straight out in front with palms facing upwards and eyes closed for 20-30 seconds. Slight pronation of one hand and flexion of the elbow suggests mild drift. Additional downward drift of the entire arm may also be present with more severe deficits (2). Interestingly, if one arm drifts upward this suggests a lesions outside the CST, possibly a cerebellar or parietal lesion, which may be equally concerning.

 

References

  1. Louis ED, King D, Sacco R, et al. Upper motor neuron signs in acute stroke: prevalence, interobserver reliability, and timing of initial examination. J Stroke Cerebrovasc Dis 1995;5:49-55. https://www.ncbi.nlm.nih.gov/pubmed/26486559 
  2. Campbell, WW. In DeJong’s The Neurologic Examination-6th Ed, p389-392, 2005. Lippincott Williams&Wilkins, Philadelphia.

 

 

 

Contributed by Alexis Roy, Harvard Medical Student, Boston, MA.

Which motor test may be the most useful maneuver when examining a patient suspected of having a stroke?

How do I interpret an elevated serum C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) or vice-versa?

 

Discordance between serum CRP and ESR is not uncommon (1,2). This phenomenon may be due to a variety of factors including the fact that the kinetics of these two tests is quite different, as discussed under “Should I order C-reactive protein (CRP) or erythrocyte sedimentation (ESR) on patients suspected of having a new infection?” in this blog.

In a study of CRP/ESR discordance (defined as results differing by 2 or 3 quartiles) in adults, a high CRP/low ESR profile was more likely to be associated with  urinary, GI, blood stream, and pulmonary infections, myocardial infarction, and venous thromboembolism and less likely to be associated with bone and joint infections (1).

In the same study, a high ESR/low CRP was associated with connective tissue diseases, such as systemic lupus erythematosus and strokes (1).

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References

1. Feldman M, Aziz B, Kang GN, et al. C-reactive protein and erythrocyte sedimentation rate discordance: frequency and causes in adults. Translational Research 2013;161:37-43. https://www.ncbi.nlm.nih.gov/pubmed/22921838

2. Colombet I, Pouchot J, Kronz V. Agreement between erythrocyte sedimentation rate and C-reactive protein in hospital practice. Am J Med 2010;123:864.e7-863.e13.https://www.ncbi.nlm.nih.gov/pubmed/20800157

How do I interpret an elevated serum C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) or vice-versa?