Anticoagulation for secondary prevention of stroke

As an internal medicine resident, I often let my neurology colleagues make decisions about patients’ anticoagulation after a stroke. However, in clinic, I recently had a 70-year old man who had immigrated from Taiwan who had a history of vertebrobasiliar infarcts, Parkinsonism, and coronary artery disease who presented to establish care. He was on clopidogrel. His wife reported that his gait was poor and that he fell at least 5-6 times a week, sometimes hitting his head on the stairs or a table. His medication compliance was poor.

This led me to wonder: what agent should be given for anticoagulation for secondary prevention of stroke?

Options include:

  • aspirin
  • clopidogrel
  • dipyridamole
  • DOACs
  • ticlodipine (don’t use ticlodipine)
  • cilostazol (only studied in Asian populations, more expensive in the US)

Should you choose aspirin or clopidogrel? 

It depends greatly on the kind of stroke (was there major stenosis? Lacunar infarct? A minor ischemic stroke or TIA?) as well as the patient (are they elderly? Have diabetes? Atrial fibrillation?). The combination of aspirin + clopidogrel can be used for the first 90 days for ischemic stroke/TIA, but beyond that, this combination is not superior to aspirin or clopidogrel monotherapy, and causes higher rates of bleeding, as you might expect. CAPRIE showed that clopidogrel was more efficacious than aspirin; however, this was only significant for patients with PAD.

If you choose aspirin, 81 mg or 325 mg? 

This review nicely shows that doses of aspirin used in trials vary widely (from 30 mg to 1300 mg) and that for most patients, using 75-81 mg aspirin is probably the sweet spot to provide adequate protection while minimizing risk of bleeding.

I’ve heard about an aspirin-dipyridamole combination…? 

ESPS-1 and ESPRIT showed that the combination of aspirin + dipyridamole resulted in better outcomes than aspirin alone for large vessel disease. The recent PROFESS trial showed this combo is comparable to clopidogrel monotherapy. The caveat is that patients often have side effects from dipyridamole like nausea and fatigue and are not able to tolerate it.

Are there special considerations for patients with atrial fibrillation? 

There is now evidence suggesting warfarin, apixaban, and dabigatran are also ok in patients with AF who previously had strokes. (Class I, grade B recommendation) . Two birds with one stone!

I ended up switching my patient above to 81 mg aspirin. With his CAD, I felt that it was important for him to be on aspirin, and he didn’t have stents or other disease that would necessitate clopidogrel. Furthermore, with his falls and poor medication compliance, I didn’t feel that an irreversible agent or adding on dipyridamole would provide much benefit.


What do I do if my patient on an antiarrhythmic goes back into atrial fibrillation?!

I had a patient recently who flipped from normal sinus rhythm into asymptomatic afib with RVR with heart rates into the 150s on post-op day 2. Classic. The twist is that she had been in sinus rhythm for years on flecainide prior to the surgery, and was still taking flecainide post-op. I was stymied: did her being on flecainide change management?  Answer at the end of the post!

The urgent question: do you need to cardiovert? The indications for cardioversion are still the same when a patient is on an antiarrhythmic: (1) unacceptable symptoms like syncope, CHF; (2) hemodynamic instability; (3) first episode of new afib within 48 hours (this did NOT apply to my patient because she had a history of afib). Cardioverting whether mechanically or pharmacologically with something like amiodarone carries the same risk of thromboembolism, so the next question should be…

Is the patient anticoagulated? Patients who flip from sinus into afib are at the highest risk of thromboembolism in the first 48 hours. Sometimes patients’ anticoagulation may be held, like in the perioperative period like for my patient. Try to make sure that if there are no contraindications to anticoagulation, it’s restarted.

Is there an underlying trigger? Lots of things can trigger afib: infection, PE, MI, fluid shifts, hyperthyroidism, postoperative stress, etc…If there is a trigger, treating it will make the afib better. Try to make sure there is nothing else going on that could be fixed.

If you are looking for specific discussions on different antiarrhythmics, check out this comprehensive review.

To return to my patient, the goal was still rate control. We decided that it was fine to continue her flecainide, and more than likely her rates would come down and she would convert back to sinus on her own. The biggest concern for her was that she was off anticoagulation. Two days later, she was still in afib, but her rates were in the 90s and she was back on apixaban.

Side note: many cardiologists advocate an antiarrhythmic “pill in pocket” for patients with infrequent afib. If they develop symptomatic afib, they can take the pill right then and there, which increases their chance of going back to sinus. However, if they are also on beta blockers, they should take the beta blocker first, as a medication like flecainide can have greater toxicity if it binds to receptors before the beta blocker does. Flecainide should always be combined with a beta blocker or other rate control agent, as one adverse effect is organization of the atrial rhythm so that the AV node can conduct 1:1 –> conversion of afib into atrial flutter with RVR (rates as high as 200s) which is obviously not sustainable.

What’s the deal with contrast-induced nephropathy?

How is contrast-induced nephropathy (CIN) diagnosed? 

Generally speaking, CIN is thought of as a more quickly reversible form of ATN: muddy brown casts and tubular epithelial cells can be seen in the urine. You should not see features of glomerulonephritis or AIN (RBC casts or WBC casts) or large urine output a la post-ATN diuresis. The surprise twist is that CIN is associated with a FeNa of <1%, which is more consistent with prerenal physiology.  Core IM podcast did a great episode on CIN that discusses that what we know about CIN is largely based on animal models, and so there is much about this condition that remains poorly understood. Importantly, they note that biopsy is not helpful because lesions in CIN are non-specific.

Should I give pre- and post-contrast hydration? 

Wyatt et al, in this commentary on the 2017 AMACING trial, a Dutch study looking at about 400 patients with CKD stage III getting contrast and risk of CIN, makes clear that the patient’s pretest probability for CIN, as well as the pretest probability for complications from fluid overload, matter a lot. Patients who have diabetes, hypertension, and obviously, CKD that borders on ESRD, are at higher risk. In addition, patients with ESRD who still make urine could be at risk, and giving contrast could worsen their renal function even more. Age (>60 years) may be associated but it’s not clear.if you’re working in an inpatient setting and have a patient with borderline renal function who is at risk of intra-op hypotension and low risk of flashing/pulmonary edema, it’s probably safer to give fluids. A 500 mL NS/LR bolus 30-60 minutes before/after is adequate.

On the other hand, there is very limited evidence to support yes fluids/no fluids. Previous studies that showed reduced risk of AKI with fluids might have shown this benefit because fluids prevented hypotension and ATN, rather than CIN itself. The PRESERVE trial, published in 2018, did not show differences in mortality, dialysis requirement, or persistent worsened kidney function, or CIN in patients receiving preventive IV sodium bicarbonate, oral acetylcysteine, normal saline, or placebo. But, there is always debate in the renal world…if you have a patient with CHF and an EF of 20%…giving fluids or sodium bicarbonate might not be a great idea.

Does the kind of contrast and procedure matter? 

Yes.Interventional studies, like coronary angiography, are higher-risk than diagnostic studies. In addition, according to the Core IM podcast, arterial contrast carries a higher risk of inducing CIN compared to venous contrast, although there are issues with differentiating CIN from atheroembolic showers, selection bias, and lack of control groups in these studies.



What are donor-specific antibodies and why do we test for them?

A quick refresher on HLA antibodies: Class I molecules are found on almost all nucleated cells. Class II molecules are found on antigen-presenting cells, B cells, and activated T cells. HLA matching is most important in bone marrow transplant and kidney transplant. In liver transplant, HLA matching may be beneficial but not so much that it is routinely performed; ditto for heart and lung transplant.

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Choo, 2007

Donor-specific antibodies (DSA) are HLA antibodies that are thought to contribute to rejection of the graft (allograft loss). They can be either class I or class II, although class II are more common.

DSA can be found pre-transplant (present in the recipient before transplantation occurs) or de novo (antibodies form in the recipient at any time after the transplant). Pre-transplant DSA are identified through panel reactive antibody (PRA). PRA is important because according to the OPTN, “Nearly a third of the OPTN renal transplant wait list is sensitized patients with a PRA of 10% or more. These candidates wait significantly longer than non-sensitized patients do and once transplanted suffer a greater risk of graft loss from rejection,” so these patients get additional “points” on the transplant list.

DSA can form at any time, although they are most commonly found <1 year after transplant. One study of kidney transplants found that after 4 years, 20% of patients with undetectable pre-transplant DSA will be found to have DSA, and that within 3 years, 25% of those patients will have graft failure. However, it must be noted that the mere presence of DSA does not equal rejection. Rejection is a diagnosis that must be made through pathology.

DSA in and of themselves do not need to be “treated,” although they are a risk factor for rejection. When and how to treat DSA is way above my paygrade, but suffice to say that if “DSA” are invoked, start thinking about the treatment of antibody-mediated rejection. There are a variety of strategies including ATG, upping doses of MMF or tacro, IVIG, and new monoclonal antibodies like bortezomib and eculizumab.



Who should be tested for influenza?

The worst of flu season is November through February (at least in Boston) although it can be shorter or longer; flu should be considered in anyone presenting with a fever and cough or other viral symptoms during this time of year.


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image copyright: Working Nurse

Flu is a clinical diagnosis (see below) which means patients do NOT need a positive test result to get treated! If you think someone meets criteria for treatment, you can empirically give them antiviral medication. Plus, getting tested for flu is no fun: it’s a nasal swab, which has to go all the way back into the throat. However, as described below, certain kinds of patients should be tested.

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How do I select an agent for afterload reduction in a patient with heart failure?

Afterload reduction has been recommended in the management of systolic heart failure since the 1980s. Afterload= arterial resistance as blood is pumped out of the left ventricle. The thought is that by reducing afterload, cardiac filling pressures are decreased, which is beneficial.

What agents reduce afterload? Anything that is an arterial vasodilator. (Venodilators decrease preload, which are thought to have a similar beneficial effect.)

  • Nitrates (venous>arterial vasodilators)
  • Hydralazine (most selective arterial vasodilator, in my experience this has been used the most)
  • Minoxidil (arterial vasodilator)
  • Lisinopril, captopril (about equal veno- and arterial vasodilators)
  • Diuretics (long-term arterial vasodilator)
  • In the ICU: nitroprusside, phentolamine, dopamine
  • Inotropes like milrinone (patients with advanced heart failure may be put on this palliatively)
  • Technically, the intra-aortic balloon pump (IABP) does, too!

Pheresis for acute leukemia: the basics

Leukocytapheresis is a technique used to treat acute leukemia. NB: there is a contraindication to treating patients with APL (AML FAB M3) because of the risk of DIC. You should be able to check this with a blood smear. Pheresis (also referred to as apheresis) can be used for a huge number of conditions, which are outlined in exhaustive detail here.

How does it work? The concept is similar to dialysis or ECMO, except in pheresis, the plasma is siphoned off (and replacement fluid is given) and RBCs are returned to the body. There shouldn’t be any major fluid shifts like in dialysis.

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Do you need a special catheter for pheresis? Ideally, pheresis is done through a peripheral IV because a lot of times these patients are thrombocytopenic, and you don’t want to delay pheresis for line placement or risk additional bleeding. However, there is such a thing as a pheresis catheter, which is a large-bore tunneled central line. Pheresis lines should be placed when multiple rounds of pheresis are expected, but to give emergent pheresis, anything from a peripheral IV to a regular central line is okay.

How much can someone improve with pheresis? Lots! Pheresis can be done when the WBC is 50-100K, but is only absolutely indicated when WBC >300K, as patients are at risk of leukostasis (if they don’t already have it). According to this review, the WBC can be expected to drop by 10-70% with the first session alone. However, it’s a game of diminishing returns. The WBC is most viscous and concentrated at the first session, so as sessions go on and the WBC improves, pheresis will become less and less effective.